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The transcription factor MYC is deregulated in over 70% of all human tumors and, in its oncogenic form, plays a major role in the cancer metabolic reprogramming, promoting the uptake of nutrients in order to sustain the biosynthetic needs of cancer cells.
The research presented in this work aimed to understand if MYC itself is regulated by nutrient availability, focusing on the two major fuels of cancer cells: glucose and glutamine.
Initial observations showed that endogenous MYC protein levels strongly depend on the availability of glutamine, but not of glucose. Subsequent analysis highlighted that the mechanism which accounts for the glutamine-mediated regulation of MYC is dependent on the 3´-untranslated region (3´-UTR) of MYC. Enhanced glutamine utilization by tumors has been shown to be directly linked to MYC oncogenic activity and MYC-dependent apoptosis has been observed under glutamine starvation. Such effect has been described in experimental systems which are mainly based on the use of MYC transgenes that do not contain the 3´-UTR. It was observed in the present study that cells are able to survive under glutamine starvation, which leads to cell cycle arrest and not apoptosis, as previously reported. However, enforced expression of a MYC transgene, which lacks the 3´-UTR, strongly increases the percentage of apoptotic cells upon starvation. Evaluation of glutamine-derived metabolites allowed to identify adenosine nucleotides as the specific stimulus responsible for the glutamine-mediated regulation of MYC, in a 3´-UTR-dependent way. Finally, glutamine-dependent MYC-mediated effects on RNA Polymerase II (RNAPII) function were evaluated, since MYC is involved in different steps of global transcriptional regulation. A global loss of RNAPII recruitment at the transcriptional start site results upon glutamine withdrawal. Such effect is overcome by enforced MYC expression under the same condition.
This study shows that the 3´UTR of MYC acts as metabolic sensor and that MYC globally regulates the RNAPII function according to the availability of glutamine. The observations presented in this work underline the importance of considering stress-induced mechanisms impinging on the 3´UTR of MYC.
Involvement of neuronal nitric oxide synthase (NOS-I) PDZ interactions in neuropsychiatric disorders
(2018)
Neuronal nitric oxide (NO) synthase (NOS-I) and its adaptor protein (NOS1AP) have been repeatedly and consistently associated with neuropsychiatric disorders in several genetic association and linkage studies, as well as functional studies. NOS-I has an extended PDZ domain which enables it to interact with postsynaptic density protein 95 (PSD-95) bringing NOS-I in close proximity to NMDA receptors. This interaction allows NMDA receptor activity dependent calcium-influx to activate NOS-I, linking NO synthesis to regulation of glutamatergic signaling pathways. NOS1AP is a PDZ-domain ligand of NOS-I and has been proposed to compete with PSD-95 for NOS-I interaction. Studies performed on post-mortem brain tissues have shown increased expression of NOS1AP in patients with schizophrenia and bipolar disorder, suggesting that increased NOS-I/NOS1AP interactions might be involved in neuropsychiatric disorders possibly through disruption of NOS-I PDZ interactions. Therefore, I have investigated the involvement of NOS-I in different endophenotypes of neuropsychiatric disorders by targeting its specific PDZ interactions in vitro and in vivo. To this end, I used recombinant adeno-associated virus (rAAV) vectors expressing NOS1AP isoforms/domains (NOS1AP-L: full length NOS1AP; NOS1AP-LC20: the last 20 amino acids of NOS1AP-L, containing the PDZ interaction motif suggested to stabilize interaction with NOS-I; NOS1AP-LΔC20: NOS1AP-L lacking the last 20 amino acids; NOS1AP-S: the short isoform of NOS1AP), residues 396-503 of NOS1AP-L (NOS1AP396-503) encoding the full NOS-I interaction domain, and N-terminal 133 amino acids of NOS-I (NOS-I1-133) encoding for the extended PDZ-domain.
Neuropsychiatric disorders involve morphological brain changes including altered dendritic
development and spine plasticity. Hence, I have examined dendritic morphology in primary cultured hippocampal and cortical neurons upon overexpression of constructed rAAV vectors. Sholl analysis revealed that overexpression of NOS1AP-L and NOS1AP-LΔC20 mildly reduced dendritic length/branching. Moreover, overexpression of all NOS1AP isoforms/domains resulted in highly altered spine plasticity including significant reduction in the number of mature spines and increased growth of filopodia. These findings suggest that NOS1AP affects dendritic growth
and development of dendritic spines, which may involve both, increased NOS-I/NOS1AP interaction as well as interaction of NOS1AP with proteins other than NOS-I. Interestingly, the observed alterations in dendritic morphology were reminiscent of those observed in post-mortem brains of patients with neuropsychiatric disorders.
Given the dendritic alterations in vitro, I have examined, whether disruption of NOS-I PDZ interaction would also result in behavioral deficits associated with neuropsychiatric disorders. To this end, rAAV vectors expressing NOS1AP-L, NOS1AP396-503, NOS-I1-133, and mCherry were stereotaxically delivered to the dorsal hippocampus of 6-week-old male C57Bl/6J mice. One week after surgery, mice were randomly separated into two groups. One of those groups underwent three weeks of chronic mild stress (CMS). Afterwards all mice were subjected to a comprehensive behavioral analysis. The findings revealed that overexpression of the constructs did not result in phenotypes related to anxiety or depression, though CMS had an anxiolytic effect independent of the injected construct. Mice overexpressing NOS-I1-133, previously shown to disrupt NOS-I/PSD-95 interaction, showed impaired spatial memory, sensorimotor gating, social interaction, and increased locomotor activity. NOS1AP overexpressing mice showed mild impairments in sensorimotor gating and spatial working memory and severely impaired social interaction. NOS1AP396-503 overexpressing mice also showed impaired social interaction but enhanced sensorimotor gating and reduced locomotor activity. Taken together, these behavioral findings indicate an involvement of NOS-I PDZ interactions in phenotypes associated with positive symptoms and cognitive deficits of psychotic disorders.
In summary, this study revealed an important contribution of NOS-I protein interactions in the development of endophenotypic traits of neuropsychiatric disorders, in particular schizophrenia,
at morphological and behavioral levels. These findings might eventually aid to a better
understanding of NOS-I-dependent psychopathogenesis, and to develop pharmacologically relevant treatment strategies.
The purpose of the present work was, in the first part, to investigate the potential of iron-based metal complexes in catalytic borylation reactions with alkyl halides as substrates and B2pin2 as the borylation reagent. Moreover, extended studies of the recently reported, copper mediated borylation reactions of aryl halides were performed, including the screening of substrates and alkoxy bases as well as ligand-screening. Investigations were undertaken on the role of Cu-nanoparticles, which might be involved in this catalytic reaction. Furthermore, Cu-phosphine complexes were synthesized as precursors, but attempts to isolate Cu-boryl species which are intermediates in the proposed catalytic cycle were unsuccessful, although 11B NMR evidence for a Cu-boryl complex was obtained.
In the second part of this work, the alternative, Lewis-acidic diboron(4) compound bis(ethylene glycolato)diboron (B2eg2) was synthesized to compare its reactivity with the reactivity of other diboron(4) compounds (e.g. B2neop2, B2cat2, B2pin2 and B2(NMe2)4). Therefore, reactions of B2eg2 with different Lewis-bases, such as NHCs and phosphines, were performed to investigate the possible formation of sp2-sp3 or sp3-sp3 adducts and ring-expansion reactions (RERs).
The aim was to obtain a better general insight into the reactivity of diboron(4) compounds with Lewis-bases because they are both used as reactants in transition metal-catalyzed and metal-free borylation reactions. Understanding the B–B bond activation process promoted by Lewis-bases provides a new perspective on the reaction pathways available for various borylation reactions.
Background:
Recurrent airway infections are common in patients with Down's syndrome (DS). Hence, ruling out Cystic Fibrosis (CF) in these patients is often required. In the past, the value of sweat testing the gold standard to diagnose CF -has been questioned in DS as false positive results have been reported. However, these reports are based on measurements of sweat osmolality or sodium concentrations, not chloride concentrations. This study analyses sweat secretion rate and chloride concentration in sweat samples of patients with DS in comparison to healthy controls.
Methods:
We assessed sweat samples in 16 patients with DS and 16 healthy controls regarding sweat secretion rate (SSR) and sweat chloride concentration.
Results:
All measured chloride concentrations were within the normal range. The chloride concentrations were slightly, but not significantly lower in patients with DS (15,54 mmol/l (±4,47)) compared to healthy controls (18,31 mmol/l (±10,12)). While no gender gap in chloride concentration could be found, chloride concentration increased with age in both groups.
Insufficient sweat was collected in 2 females with DS (12.5% of the study group) but not in an individual of the control group. A significant lower sweat secretion rate was found in the DS group (27,6 μl/30 min (± 12,18)) compared to the control group (42,7 μl/30 min (± 21,22)). In a sub-analysis, female patients produced significantly less sweat (20,8 ± 10,6 μl/30 min) than male patients with DS (36,4 ± 7,8 μl/30 min), which accounts for the difference between patients and controls. Furthermore, while the sweating secretion rate increased with age in the control group, it did not do so in the DS group. Once again this was due to female patients with DS, who did not show a significant increase of sweat secretion rate with age.
Conclusions:
Sweat chloride concentrations were within the normal range in patients with DS and therefore seem to be a reliable tool for testing for CF in these patients. Interestingly, we found a reduced sweat secretion rate in the DS group. Whether the last one has a functional and clinical counterpart, possibly due to a disturbed thermoregulation in DS patients, requires further investigation.
The rotation of the earth leads to a cyclic change of night and day. Numerous strategies evolved to cope with diurnal change, as it is generally advantageous to be synchronous to the cyclic change in abiotic conditions. Diurnal rhythms are regulated by the circadian clock, a molecular feedback loop of RNA and protein levels with a period of circa 24 hours. Despite its importance for individuals as well as for species interactions, our knowledge of circadian clocks is mostly confined to few model organisms.
While the structuring of activity is generally adaptive, a rigid temporal organization also has its drawbacks. For example, the specialization to a diurnal pattern limits the breadth of the temporal niche. Organisms that are adapted to a diurnal life style are often poor predators or foragers during night time, constraining the time budget to only diurnal parts of the day/night cycle.
Climate change causes shifts in phenology (seasonal timing) and northward range expansions, and changes in season or in latitude are associated with novel day length – temperature correlations. Thus, seasonal organisms will have some life history stages exposed to novel day lengths, and I hypothesized that the diurnal niche determines whether the day length changes are beneficial or harmful for the organism. I thus studied the effects of day length on life-history traits in a multi-trophic system consisting of the pea aphid Acyrthosiphon pisum and predatory larvae of Chrysoperla carnea (common green lacewing) and Episyrphus balteatus (marmalade hoverfly). In order to identify the mechanisms for phenological constraints I then focused on diurnal rhythms and the circadian clock of the pea aphid.
Aphids reacted to shorter days with a reduced fecundity and shorter reproductive period. Short days did however not impact population growth, because the fitness constraints only became apparent late in the individual’s life. In contrast, E. balteatus grew 13% faster in the shorter day treatment and preyed on significantly more aphids, whereas C. carnea grew 13% faster under longer days and the elevation of predation rates was marginally significant. These results show that day length affects vital life-history traits, but that the direction and effect size depends on species.
I hypothesized that the constraints or fitness benefits are caused by a constricted or expanded time budget, and hence depend on the temporal niche. E. balteatus is indeed night-active and C. carnea appears to be crepuscular, but very little data exists for A. pisum. Hence, I reared the pea aphid on an artificial diet and recorded survival, moulting and honeydew excretion. The activity patterns were clearly rhythmic and molting and honeydew excretion were elevated during day-time. Thus, the diurnal niche could explain the observed, but weak, day length constraints of aphids.
The diurnal niche of some organisms is remarkably flexible, and a flexible diurnal niche may explain why the day length constrains were relatively low in A. pisum. I thus studied its circadian clock, the mechanism that regulates diurnal rhythms. First, I improved an artificial diet for A. pisum, and added the food colorant Brilliant Blue FCF. This food colorant stained gut and honeydew in low concentration without causing mortalities, and thus made honeydew excretion visible under dim red light. I then used the blue diet to raise individual aphids in 16:08 LD and constant darkness (DD), and recorded honeydew excretion and molting under red light every three hours. In addition, we used a novel monitoring setup to track locomotor activity continuously in LD and DD. Both the locomotor rhythm and honeydew excretion of A. pisum appeared to be bimodal, peaking in early morning and in the afternoon in LD. Both metabolic and locomotor rhythm persisted also for some time under constant darkness, indicating that the rhythms are driven by a functional circadian clock. However, the metabolic rhythm damped within three to four days, whereas locomotor rhythmicity persisted with a complex distribution of several free-running periods. These results fit to a damped circadian clock that is driven by multiple oscillator populations, a model that has been proposed to link circadian clocks and photoperiodism, but never empirically tested.
Overall, my studies integrate constraints in phenological adaptation with a mechanistic explanation. I showed that a shorter day length can constrain some species of a trophic network while being beneficial for others, and linked the differences to the diurnal niche of the species. I further demonstrated that a flexible circadian clock may alleviate the constraints, potentially by increasing the plasticity of the diurnal niche.
Molecules containing multiple bonds between atoms—most often in the form of olefins—are ubiquitous in nature, commerce, and science, and as such have a huge impact on everyday life. Given their prominence, over the last few decades, frequent attempts have been made to perturb the structure and reactivity of multiply-bound species through bending and twisting. However, only modest success has been achieved in the quest to completely twist double bonds in order to homolytically cleave the associated π bond. Here, we present the isolation of double-bond-containing species based on boron, as well as their fully twisted diradical congeners, by the incorporation of attached groups with different electronic properties. The compounds comprise a structurally authenticated set of diamagnetic multiply-bound and diradical singly-bound congeners of the same class of compound.
Molecules containing multiple bonds between atoms—most often in the form of olefins—are ubiquitous in nature, commerce, and science, and as such have a huge impact on everyday life. Given their prominence, over the last few decades, frequent attempts have been made to perturb the structure and reactivity of multiply-bound species through bending and twisting. However, only modest success has been achieved in the quest to completely twist double bonds in order to homolytically cleave the associated π bond. Here, we present the isolation of double-bond-containing species based on boron, as well as their fully twisted diradical congeners, by the incorporation of attached groups with different electronic properties. The compounds comprise a structurally authenticated set of diamagnetic multiply-bound and diradical singly-bound congeners of the same class of compound.
It’s a matter of design - how pitfall trap design affects trap samples and possible predictions
(2018)
Background:
Pitfall traps are commonly used to assess ground dwelling arthropod communities. The effects of different pitfall trap designs on the trapping outcome are poorly investigated however they might affect conclusions drawn from pitfall trap data greatly.
Methods:
We tested four pitfall trap types which have been used in previous studies for their effectiveness: a simple type, a faster exchangeable type with an extended plastic rim plate and two types with guidance barriers (V- and X-shaped). About 20 traps were active for 10 weeks and emptied biweekly resulting in 100 trap samples.
Results:
Pitfall traps with guidance barriers were up to five times more effective than simple pitfall traps and trap samples resulted in more similar assemblage approximations. Pitfall traps with extended plastic rim plates did not only perform poorly but also resulted in distinct carabid assemblages with less individuals of small species and a larger variation.
Discussion:
Due to the obvious trait filtering and resulting altered assemblages, we suggest not to use pitfall traps with extended plastic rim plates. In comprehensive biodiversity inventories, a smaller number of pitfall traps with guidance barriers and a larger number of spatial replicates is of advantage, while due to comparability reasons, the use of simple pitfall traps will be recommended in most other cases.
Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.
Rapid immune reconstitution (IR) following stem cell transplantation (SCT) is essential for a favorable outcome. The optimization of graft composition should not only enable a sufficient IR but also improve graft vs. leukemia/tumor effects, overcome infectious complications and, finally, improve patient survival. Especially in haploidentical SCT, the optimization of graft composition is controversial. Therefore, we analyzed the influence of graft manipulation on IR in 40 patients with acute leukemia in remission. We examined the cell recovery post haploidentical SCT in patients receiving a CD34(+)-selected or CD3/CD19-depleted graft, considering the applied conditioning regimen. We used joint model analysis for overall survival (OS) and analyzed the dynamics of age-adjusted leukocytes; lymphocytes; monocytes; CD3(+), CD3(+) CD4(+), and CD3(+) CD8(+) T cells; natural killer (NK) cells; and B cells over the course of time after SCT. Lymphocytes, NK cells, and B cells expanded more rapidly after SCT with CD34(+)-selected grafts (P = 0.036, P = 0.002, and P < 0.001, respectively). Contrarily, CD3(+) CD4(+) helper T cells recovered delayer in the CD34 selected group (P = 0.026). Furthermore, reduced intensity conditioning facilitated faster immune recovery of lymphocytes and T cells and their subsets (P < 0.001). However, the immune recovery for NK cells and B cells was comparable for patients who received reduced-intensity or full preparative regimens. Dynamics of all cell types had a significant influence on OS, which did not differ between patients receiving CD34(+)-selected and those receiving CD3/CD19-depleted grafts. In conclusion, cell reconstitution dynamics showed complex diversity with regard to the graft manufacturing procedure and conditioning regimen.
The present thesis considers the modelling of gas mixtures via a kinetic description. Fundamentals about the Boltzmann equation for gas mixtures and the BGK approximation are presented. Especially, issues in extending these models to gas mixtures are discussed. A non-reactive two component gas mixture is considered. The two species mixture is modelled by a system of kinetic BGK equations featuring two interaction terms to account for momentum and energy transfer between the two species. The model presented here contains several models from physicists and engineers as special cases. Consistency of this model is proven: conservation properties, positivity of all temperatures and the H-theorem. The form in global equilibrium as Maxwell distributions is specified. Moreover, the usual macroscopic conservation laws can be derived.
In the literature, there is another type of BGK model for gas mixtures developed by Andries, Aoki and Perthame, which contains only one interaction term. In this thesis, the advantages of these two types of models are discussed and the usefulness of the model presented here is shown by using this model to determine an unknown function in the energy exchange of the macroscopic equations for gas mixtures described in the literature by Dellacherie. In addition, for each of the two models existence and uniqueness of mild solutions is shown. Moreover, positivity of classical solutions is proven.
Then, the model presented here is applied to three physical applications: a plasma consisting of ions and electrons, a gas mixture which deviates from equilibrium and a gas mixture consisting of polyatomic molecules.
First, the model is extended to a model for charged particles. Then, the equations of magnetohydrodynamics are derived from this model. Next, we want to apply this extended model to a mixture of ions and electrons in a special physical constellation which can be found for example in a Tokamak. The mixture is partly in equilibrium in some regions, in some regions it deviates from equilibrium. The model presented in this thesis is taken for this purpose, since it has the advantage to separate the intra and interspecies interactions. Then, a new model based on a micro-macro decomposition is proposed in order to capture the physical regime of being partly in equilibrium, partly not. Theoretical results are presented, convergence rates to equilibrium in the space-homogeneous case and the Landau damping for mixtures, in order to compare it with numerical results.
Second, the model presented here is applied to a gas mixture which deviates from equilibrium such that it is described by Navier-Stokes equations on the macroscopic level. In this macroscopic description it is expected that four physical coefficients will show up, characterizing the physical behaviour of the gases, namely the diffusion coefficient, the viscosity coefficient, the heat conductivity and the thermal diffusion parameter. A Chapman-Enskog expansion of the model presented here is performed in order to capture three of these four physical coefficients. In addition, several possible extensions to an ellipsoidal statistical model for gas mixtures are proposed in order to capture the fourth coefficient. Three extensions are proposed: An extension which is as simple as possible, an intuitive extension copying the one species case and an extension which takes into account the physical motivation of the physicist Holway who invented the ellipsoidal statistical model for one species. Consistency of the extended models like conservation properties, positivity of all temperatures and the H-theorem are proven. The shape of global Maxwell distributions in equilibrium are specified.
Third, the model presented here is applied to polyatomic molecules. A multi component gas mixture with translational and internal energy degrees of freedom is considered. The two species are allowed to have different degrees of freedom in internal energy and are modelled by a system of kinetic ellipsoidal statistical equations. Consistency of this model is shown: conservation properties, positivity of the temperature, H-theorem and the form of Maxwell distributions in equilibrium. For numerical purposes the Chu reduction is applied to the developed model for polyatomic gases to reduce the complexity of the model and an application for a gas consisting of a mono-atomic and a diatomic gas is given.
Last, the limit from the model presented here to the dissipative Euler equations for gas mixtures is proven.
In 3 Maccabees, kingship as a form of rule is addressed on two levels: On the political level the question about a good king is addressed against the background of Hellenistic understandings of kingship, using the example of Ptolemy IV Philopator. This king is portrayed at the beginning of 3 Maccabees as a successful, positive, Hellenistic ruler, but one whose good rule goes off the rails. This analysis of the ideal of Hellenistic rule (cf. 3 Macc. 3:12-29; 6:24-28; 7:1-9) is then taken to a theological level: the God of Israel is portrayed as the true good king, the Soter who saves his people in their time of greatest trial (6:29, 32; 7:16). By these means the many divine epithets that are a striking feature of 3 Maccabees are incorporated into the narrative (cf. 2:2-3). Thereby 3 Maccabees not only thematises the conflict with a Hellenistic king who exploits his power in diverse ways but also focuses in a concentrated way the notion of a good (Hellenistic) king into the notion of God as king and ruler.
Epichloë endophytes associated with cool-season grass species can protect their hosts from herbivory and can suppress mycorrhizal colonization of the hosts’ roots. However, little is known about whether or not Epichloë endophyte infection can also change the foliar fungal assemblages of the host. We tested 52 grassland study sites along a land-use intensity gradient in three study regions over two seasons (spring vs. summer) to determine whether Epichloë infection of the host grass Lolium perenne changes the fungal community structure in leaves. Foliar fungal communities were assessed by Next Generation Sequencing of the ITS rRNA gene region. Fungal community structure was strongly affected by study region and season in our study, while land-use intensity and infection with Epichloë endophytes had no significant effects. We conclude that effects on non-systemic endophytes resulting from land use practices and Epichloë infection reported in other studies were masked by local and seasonal variability in this study’s grassland sites.
Progranulin (PGRN) is a secreted anti-inflammatory protein which can be processed by neutrophil proteases to various granulins. It has been reported that at least a significant portion of the anti-inflammatory effects of PGRN is due to direct high affinity binding to tumor necrosis factor receptor-1 (TNFR1) and TNFR2 and inhibition of tumor necrosis factor (TNF)-induced TNFR1/2 signaling. Two studies failed to reproduce the interaction of TNFR1 and TNFR2 with PGRN, but follow up reports speculated that this was due to varying experimental circumstances and/or the use of PGRN from different sources. However, even under consideration of these speculations, there is still a striking discrepancy in the literature between the concentrations of PGRN needed to inhibit TNF signaling and the concentrations required to block TNF binding to TNFR1 and TNFR2. While signaling events induced by 0.2–2 nM of TNF have been efficiently inhibited by low, near to equimolar concentrations (0.5–2.5 nM) of PGRN in various studies, the reported inhibitory effects of PGRN on TNF-binding to TNFR1/2 required a huge excess of PGRN (100–1,000-fold). Therefore, we investigated the effect of PGRN on TNF binding to TNFR1 and TNFR2 in highly sensitive cellular binding studies. Unlabeled TNF inhibited >95% of the specific binding of a Gaussia princeps luciferase (GpL) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to >95%, too. Purified PGRN, however, showed in both assays no effect on TNF–TNFR1/2 interaction even when applied in huge excess. To rule out that tags and purification- or storage-related effects compromise the potential ability of PGRN to bind TNF receptors, we directly co-expressed PGRN, and as control TNF, in TNFR1- and TNFR2-expressing cells and looked for binding of GpL-TNF. While expression of TNF strongly inhibited binding of GpL-TNF to TNFR1/2, co-expression of PGRN had not effect on the ability of the TNFR1/2-expressing cells to bind TNF.
Lagrange Multiplier Methods for Constrained Optimization and Variational Problems in Banach Spaces
(2018)
This thesis is concerned with a class of general-purpose algorithms for constrained minimization problems, variational inequalities, and quasi-variational inequalities in Banach spaces.
A substantial amount of background material from Banach space theory, convex analysis, variational analysis, and optimization theory is presented, including some results which are refinements of those existing in the literature. This basis is used to formulate an augmented Lagrangian algorithm with multiplier safeguarding for the solution of constrained optimization problems in Banach spaces. The method is analyzed in terms of local and global convergence, and many popular problem classes such as nonlinear programming, semidefinite programming, and function space optimization are shown to be included as special cases of the general setting.
The algorithmic framework is then extended to variational and quasi-variational inequalities, which include, by extension, Nash and generalized Nash equilibrium problems. For these problem classes, the convergence is analyzed in detail. The thesis then presents a rich collection of application examples for all problem classes, including implementation details and numerical results.
Crop diversification has been proposed as farm management tool that could mitigate the externalities of conventional farming while reducing productivity-biodiversity trade-offs. Yet evidence for the acclaimed biodiversity benefits of landscape-level crop diversity is ambiguous. Effects may strongly depend on spatial scale and the level of landscape heterogeneity (e.g. overall habitat diversity). At the same time, contrasting within-taxon responses obscure benefits to specific functional groups (i.e. species with shared characteristics or requirements) if studied at the community level. The objectives of this study were to 1) disentangle the relative effects of crop diversity and landscape heterogeneity on avian species richness across five spatial scales ranging from 250 to 3000 m radii around focal winter wheat fields; and 2) assess whether functional groups (feeding guild, conservation status, habitat preference, nesting behaviour) determine the strength and direction of responses to crop diversity and landscape heterogeneity. In central Germany, 14 landscapes were selected along independent gradients of crop diversity (annual arable crops) and landscape heterogeneity. Bird species richness in each landscape was estimated using four point counts throughout the breeding season. We found no effects of landscape-level crop diversity on bird richness and functional groups. Instead, landscape heterogeneity was strongly associated with increased total bird richness across all spatial scales. In particular, insect-feeding and non-farmland birds were favoured in heterogeneous landscapes, as were species not classified as endangered or vulnerable on the regional Red List. Crop-nesting farmland birds, however, were less species-rich in these landscapes. Accordingly, crop diversification may be less suitable for conserving avian diversity and associated ecosystem services (e.g. biological pest control), although confounding interactions with management intensity need yet to be confirmed. In contrast, enhancement of landscape heterogeneity by increasing perennial habitat diversity, reducing field sizes and the amount of cropland has the potential to benefit overall bird richness. Specialist farmland birds, however, may require more targeted management approaches.
Background:
The treatment strategies for colorectal cancer located in the right side of the colon have changed dramatically during the last decade. Due to the introduction of complete mesocolic excision (CME) with central ligation of the vessels and systematic lymph node dissection, the long-term survival of affected patients has increased significantly. It has also been proposed that right-sided colon resection can be performed laparoscopically with the same extent of resection and equal long-term results.
Methods:
A retrospective evaluation of a prospectively expanded database on right-sided colorectal cancer or adenoma treated at the University Hospital of Wuerzburg between 2009 and 2016 was performed. All patients underwent CME. This data was analyzed alone and in comparison to the published data describing laparoscopic right-sided colon resection for colon cancer.
Results:
The database contains 279 patients, who underwent right-sided colon resection due to colorectal cancer or colorectal adenoma (255 open; 24 laparoscopic). Operation data (time, length of stay, time on ICU) was equal or superior to laparoscopy, which is comparable to the published results. Surprisingly, the surrogate parameter for correct CME (the number of removed lymph nodes) was significantly higher in the open group. In a subgroup analysis only including patients who were feasible for laparoscopic resection and had been operated with an open procedure by an experienced surgeon, operation time was significantly shorter and the number of removed lymph nodes is significantly higher in the open group.
Conclusion:
So far, several studies demonstrate that laparoscopic right-sided colon resection is comparable to open resection. Our data suggests that a consequent CME during an open operation leads to significantly more removed lymph nodes than in laparoscopically resected patients and in several so far published data of open control groups from Europe. Further prospective randomized trials comparing the long-term outcome are urgently needed before laparoscopy for right-sided colon resection can be recommended ubiquitously.
In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.
Background:
Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction.
The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test.
Methods:
The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed.
Results:
With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values.
Conclusion:
A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).
Stories are a powerful means to change recipients’ views on themselves by being transported into the story world and by identifying with story characters. Previous studies showed that recipients temporarily change in line with a story and its characters (assimilation). Conversely, assimilation might be less likely when recipients are less identified with story protagonists or less transported into a story by comparing themselves with a story character. This may lead to changes, which are opposite to a story and its characters (contrast). In two experiments, we manipulated transportation and experience taking via two written reviews (Experiment 1; N = 164) and by varying the perspective of the story’s narrator (Experiment 2; N = 79) of a short story about a negligent student. Recipients’ self-ratings in comparison to others, motives, and problem-solving behavior served as dependent variables. However, neither the review nor the perspective manipulation affected transportation or experience taking while reading the story. Against our expectations, highly transported recipients (in Study 1) and recipients with high experience taking (in Study 2) showed more persistency working on an anagram-solving task, even when controlling for trait conscientiousness. Our findings are critically discussed in light of previous research.
The validity of Kirchhoff’s laws in plasmonic nanocircuitry is investigated by studying a junction of plasmonic two-wire transmission lines. We find that Kirchhoff’s laws are valid for sufficiently small values of a phenomenological parameter κ relating the geometrical parameters of the transmission line with the effective wavelength of the guided mode. Beyond such regime, for large values of the phenomenological parameter, increasing deviations occur and the equivalent impedance description (Kirchhoff’s laws) can only provide rough, but nevertheless useful, guidelines for the design of more complex plasmonic circuitry. As an example we investigate a system composed of a two-wire transmission line and a nanoantenna as the load. By addition of a parallel stub designed according to Kirchhoff’s laws we achieve maximum signal transfer to the nanoantenna.
The success of semantic systems has been proven over the last years.
Nowadays, Linked Data is the driver for the rapid development of ever new intelligent systems.
Especially in enterprise environments semantic systems successfully support more and more business processes.
This is especially true for after sales service in the mechanical engineering domain.
Here, service technicians need effective access to relevant technical documentation in order to diagnose and solve problems and defects.
Therefore, the usage of semantic information retrieval systems has become the new system metaphor.
Unlike classical retrieval software Linked Enterprise Data graphs are exploited to grant targeted and problem-oriented access to relevant documents.
However, huge parts of legacy technical documents have not yet been integrated into Linked Enterprise Data graphs.
Additionally, a plethora of information models for the semantic representation of technical information exists.
The semantic maturity of these information models can hardly be measured.
This thesis motivates that there is an inherent need for a self-contained semantification approach for technical documents.
This work introduces a maturity model that allows to quickly assess existing documentation.
Additionally, the approach comprises an abstracting semantic representation for technical documents that is aligned to all major standard information models.
The semantic representation combines structural and rhetorical aspects to provide access to so called Core Documentation Entities.
A novel and holistic semantification process describes how technical documents in different legacy formats can be transformed to a semantic and linked representation.
The practical significance of the semantification approach depends on tools supporting its application.
This work presents an accompanying tool chain of semantification applications, especially the semantification framework CAPLAN that is a highly integrated development and runtime environment for semantification processes.
The complete semantification approach is evaluated in four real-life projects: in a spare part augmentation project, semantification projects for earth moving technology and harvesting technology, as well as an ontology population project for special purpose vehicles.
Three additional case studies underline the broad applicability of the presented ideas.
Optical remote sensing is an important tool in the study of animal behavior providing ecologists with the means to understand species-environment interactions in combination with animal movement data. However, differences in spatial and temporal resolution between movement and remote sensing data limit their direct assimilation. In this context, we built a data-driven framework to map resource suitability that addresses these differences as well as the limitations of satellite imagery. It combines seasonal composites of multiyear surface reflectances and optimized presence and absence samples acquired with animal movement data within a cross-validation modeling scheme. Moreover, it responds to dynamic, site-specific environmental conditions making it applicable to contrasting landscapes. We tested this framework using five populations of White Storks (Ciconia ciconia) to model resource suitability related to foraging achieving accuracies from 0.40 to 0.94 for presences and 0.66 to 0.93 for absences. These results were influenced by the temporal composition of the seasonal reflectances indicated by the lower accuracies associated with higher day differences in relation to the target dates. Additionally, population differences in resource selection influenced our results marked by the negative relationship between the model accuracies and the variability of the surface reflectances associated with the presence samples. Our modeling approach spatially splits presences between training and validation. As a result, when these represent different and unique resources, we face a negative bias during validation. Despite these inaccuracies, our framework offers an important basis to analyze species-environment interactions. As it standardizes site-dependent behavioral and environmental characteristics, it can be used in the comparison of intra- and interspecies environmental requirements and improves the analysis of resource selection along migratory paths. Moreover, due to its sensitivity to differences in resource selection, our approach can contribute toward a better understanding of species requirements.
This Thesis investigates the interplay of a central degree of freedom with an environment. Thereby, the environment is prepared in a localized phase of matter.
The long-term aim of this setup is to store quantum information on the central degree of freedom while exploiting the advantages of localized systems.
These many-body localized systems fail to equilibrate under the description of thermodynamics, mostly due to disorder. Doing so, they form the most prominent phase of matter that violates the eigenstate thermalization hypothesis. Thus, many-body localized systems preserve information about an initial state until infinite times without the necessity to isolate the system.
This unique feature clearly suggests to store quantum information within localized environments, whenever isolation is impracticable.
After an introduction to the relevant concepts, this Thesis examines to which extent a localized phase of matter may exist at all if a central degree of freedom dismantles the notion of locality in the first place. To this end, a central spin is coupled to the disordered Heisenberg spin chain, which shows many-body localization. Furthermore, a noninteracting analog describing free fermions is discussed. Therein, an impurity is coupled to an Anderson localized environment.
It is found that in both cases, the presence of the central degree of freedom manifests in many properties of the localized environment. However, for a sufficiently weak coupling, quantum chaos, and thus, thermalization is absent. In fact, it is shown that the critical disorder, at which the metal-insulator transition of its environment occurs in the absence of the central degree of freedom, is modified by the coupling strength of the central degree of freedom. To demonstrate this, a phase diagram is derived.
Within the localized phase, logarithmic growth of entanglement entropy, a typical signature of many-body localized systems, is increased by the coupling to the central spin. This property is traced back to resonantly coupling spins within the localized Heisenberg chain and analytically derived in the absence of interactions. Thus, the studied model of free fermions is the first model without interactions that mimics the logarithmic spreading of entanglement entropy known from many-body localized systems.
Eventually, it is demonstrated that observables regarding the central spin significantly break the eigenstate thermalization hypothesis within the localized phase. Therefore, it is demonstrated how a central spin can be employed as a detector of many-body localization.
The remarkable diversity of sex determination mechanisms known in fish may be fuelled by exceptionally high rates of sex chromosome turnovers or transitions. However, the evolutionary causes and genomic mechanisms underlying this variation and instability are yet to be understood. Here we report on an over 30-year evolutionary experiment in which we tested the genomic consequences of hybridisation and selection between two Xiphophorus fish species with different sex chromosome systems. We find that introgression and imposing selection for pigmentation phenotypes results in the retention of an unexpectedly large maternally derived genomic region. During the hybridisation process, the sex-determining region of the X chromosome from one parental species was translocated to an autosome in the hybrids leading to the evolution of a new sex chromosome. Our results highlight the complexity of factors contributing to patterns observed in hybrid genomes, and we experimentally demonstrate that hybridisation can catalyze rapid evolution of a new sex chromosome.
Long-term monitoring of the ANTARES optical module efficiencies using \(^{40}\)K decays in sea water
(2018)
Cherenkov light induced by radioactive decay products is one of the major sources of background light for deep-sea neutrino telescopes such as ANTARES. These decays are at the same time a powerful calibration source. Using data collected by the ANTARES neutrino telescope from mid 2008 to 2017, the time evolution of the photon detection efficiency of optical modules is studied. A modest loss of only 20% in 9 years is observed. The relative time calibration between adjacent modules is derived as well.
Background
Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.
Methods
We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).
Findings
Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45).
Interpretation
Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.
Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis.
Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund’s adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease).
Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.
In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n = 93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n = 98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.
A negative mood-congruent attention bias has been consistently observed, for example, in clinical studies on major depression. This bias is assumed to be dysfunctional in that it supports maintaining a sad mood, whereas a potentially adaptive role has largely been neglected. Previous experiments involving sad mood induction techniques found a negative mood-congruent attention bias specifically for young individuals, explained by an adaptive need for information transfer in the service of mood regulation. In the present study we investigated the attentional bias in typically developing children (aged 6–12 years) when happy and sad moods were induced. Crucially, we manipulated the age (adult vs. child) of the displayed pairs of facial expressions depicting sadness, anger, fear and happiness. The results indicate that sad children indeed exhibited a mood specific attention bias toward sad facial expressions. Additionally, this bias was more pronounced for adult faces. Results are discussed in the context of an information gain which should be stronger when looking at adult faces due to their more expansive life experience. These findings bear implications for both research methods and future interventions.
Finite volume methods for compressible Euler equations suffer from an excessive diffusion in the limit of low Mach numbers. This PhD thesis explores new approaches to overcome this.
The analysis of a simpler set of equations that also possess a low Mach number limit is found to give valuable insights. These equations are the acoustic equations obtained as a linearization of the Euler equations. For both systems the limit is characterized by a divergencefree velocity. This constraint is nontrivial only in multiple spatial dimensions. As the Jacobians of the acoustic system do not commute, acoustics cannot be reduced to some kind of multi-dimensional advection. Therefore first an exact solution in multiple spatial dimensions is obtained. It is shown that the low Mach number limit can be interpreted as a limit of long times.
It is found that the origin of the inability of a scheme to resolve the low Mach number limit is the lack a discrete counterpart to the limit of long times. Numerical schemes whose discrete stationary states discretize all the analytic stationary states of the PDE are called stationarity preserving. It is shown that for the acoustic equations, stationarity preserving schemes are vorticity preserving and are those that are able to resolve the low Mach limit (low Mach compliant). This establishes a new link between these three concepts.
Stationarity preservation is studied in detail for both dimensionally split and multi-dimensional schemes for linear acoustics. In particular it is explained why the same multi-dimensional stencils appear in literature in very different contexts: These stencils are unique discretizations of the divergence that allow for stabilizing stationarity preserving diffusion.
Stationarity preservation can also be generalized to nonlinear systems such as the Euler equations. Several ways how such numerical schemes can be constructed for the Euler equations are presented. In particular a low Mach compliant numerical scheme is derived that uses a novel construction idea. Its diffusion is chosen such that it depends on the velocity divergence rather than just derivatives of the different velocity components. This is demonstrated to overcome the low Mach number problem. The scheme shows satisfactory results in numerical simulations and has been found to be stable under explicit time integration.
Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.
LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy
(2018)
The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.
Within three self-contained chapters, this dissertation provides new insights into the macroeconomic consequences of income inequality from a global perspective. Following an introduction, which summarizes the main findings and offers a brief overview of trends in income distribution, Chapter 2 evaluates the relationship between the labor share of income and the evolution of aggregate demand. Chapter 3 analyzes the link between income inequality and aggregate saving; and Chapter 4 directly estimates the effect of inequality and public redistribution on economic growth.
Background:
To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH).
Methods:
107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 – 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT.
Results:
In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05).
Conclusion:
DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.
Whereas the measurement of the quality of democracy focused on the rough differentiation of democracies and autocracies in the beginning (e.g. Vanhanen, Polity, Freedom House), the focal point of newer instruments is the assessment of the quality of established democracies. In this context, tensions resp. trade-offs between dimensions of democracy are discussed as well (e.g. Democracy Barometer, Varieties of Democracy). However, these approaches lack a systematic discussion of trade-offs and they are not able to show trade-offs empirically. We address this research desideratum in a three-step process: Firstly, we propose a new conceptual approach, which distinguishes between two different modes of relationships between dimensions: mutual reinforcing effects and a give-and-take relationship (trade-offs) between dimensions. By introducing our measurement tool, Democracy Matrix, we finally locate mutually reinforcing effects as well as trade-offs. Secondly, we provide a new methodological approach to measure trade-offs. While one measuring strategy captures the mutual reinforcing effects, the other strategy employs indicators, which serve to gauge trade-offs. Thirdly, we demonstrate empirical findings of our measurement drawing on the Varieties of Democracy dataset. Incorporating trade-offs into the measurement enables us to identify various profiles of democracy (libertarian, egalitarian and control-focused democracy) via the quality of its dimensions.
We argue that making accept/reject decisions on scientific hypotheses, including a recent call for changing the canonical alpha level from p = 0.05 to p = 0.005, is deleterious for the finding of new discoveries and the progress of science. Given that blanket and variable alpha levels both are problematic, it is sensible to dispense with significance testing altogether. There are alternatives that address study design and sample size much more directly than significance testing does; but none of the statistical tools should be taken as the new magic method giving clear-cut mechanical answers. Inference should not be based on single studies at all, but on cumulative evidence from multiple independent studies. When evaluating the strength of the evidence, we should consider, for example, auxiliary assumptions, the strength of the experimental design, and implications for applications. To boil all this down to a binary decision based on a p-value threshold of 0.05, 0.01, 0.005, or anything else, is not acceptable.
Previous studies have shown that weighted angular moments derived from jet constituents encode the colour connections between partons that seed the jets. This paper presents measurements of two such distributions, the jet-pull angle and jet-pull magnitude, both of which are derived from the jet-pull angular moment. The measurement is performed in delivered by the Large Hadron Collider. The observables are measured for two dijet systems, corresponding to the colour-connected daughters of the Wboson and the two b-jets from the top-quark decays, which are not expected to be colour connected. To allow the comparison of the measured distributions to colour model predictions, the measured distributions are unfolded to particle level, after correcting for experimental effects introduced by the detector. While good agreement can be found for some combinations of predictions and observables, none of the predictions describes the data well across all observables.
This paper presents a measurement of the W boson production cross section and the W+/W- cross-section ratio, both in association with jets, in proton-proton collisions at root s = 8 TeV with the ATLAS experiment at the Large Hadron Collider. The measurement is performed in final states containing one electron and missing transverse momentum using data corresponding to an integrated luminosity of 20.2 fb(-1). Differential cross sections for events with at least one or two jets are presented for a range of observables, including jet transverse momenta and rapidities, the scalar sum of transverse momenta of the visible particles and the missing transverse momentum in the event, and the transverse momentum of the W boson. For a subset of the observables, the differential cross sections of positively and negatively charged W bosons are measured separately. In the cross-section ratio of W+/W- the dominant systematic uncertainties cancel out, improving the measurement precision by up to a factor of nine. The observables and ratios selected for this paper provide valuable input for the up quark, down quark, and gluon parton distribution functions of the proton.
This Letter presents the measurement of differential cross sections of isolated prompt photons produced in association with a b-jet or a c-jet. These final states provide sensitivity to the heavy-flavour content of the proton and aspects related to the modelling of heavy-flavour quarks in perturbative QCD. The measurement uses proton–proton collision data at a centre-of-mass energy of 8 TeV recorded by the ATLAS detector at the LHC in 2012 corresponding to an integrated luminosity of up to 20.2 fb−1 . The differential cross sections are measured for each jet flavour with respect to the transverse energy of the leading photon in two photon pseudorapidity regions: |η γ | < 1.37 and 1.56 < |η γ | < 2.37. The measurement covers photon transverse energies 25 < Eγ T < 400 GeV and 25 < Eγ T < 350 GeV respectively for the two |η γ | regions. For each jet flavour, the ratio of the cross sections in the two |η γ | regions is also measured. The measurement is corrected for detector effects and compared to leading-order and next- to-leading-order perturbative QCD calculations, based on various treatments and assumptions about the heavy-flavour content of the proton. Overall, the predictions agree well with the measurement, but some deviations are observed at high photon transverse energies. The total uncertainty in the measurement ranges between 13% and 66%, while the central γ + b measurement exhibits the smallest uncertainty, ranging from 13% to 27%, which is comparable to the precision of the theoretical predictions.
The differential cross-section for the production of a W boson in association with a top quark is measured for several particle-level observables. The measurements are performed using 36.1 fb(-1) of pp collision data collected with the ATLAS detector at the LHC in 2015 and 2016. Differential cross-sections are measured in a fiducial phase space defined by the presence of two charged leptons and exactly one jet matched to a b-hadron, and are normalised with the fiducial cross-section. Results are found to be in good agreement with predictions from several Monte Carlo event generators.
measurement of the rapidity and transverse momentum dependence of dijet azimuthal decorrelations is presented, using the quantity R-Delta phi. The quantity R-Delta phi specifies the fraction of the inclusive dijet events in which the azimuthal opening angle of the two jets with the highest transverse momenta is less than a given value of the parameter Delta phi(max). The quantity R-Delta phi is measured in proton-proton collisions at root s = 8 TeV as a function of the dijet rapidity interval, the event total scalar transverse momentum, and Delta phi(max). The measurement uses an event sample corresponding to an integrated luminosity of 20.2 fb(-1) collected with the ATLAS detector at the CERN Large Hadron Collider. Predictions of a perturbative QCD calculation at next-to-leading order in the strong coupling with corrections for nonperturbative effects are compared to the data. The theoretical predictions describe the data in the whole kinematic region. The data are used to determine the strong coupling alpha(S) and to study its running for momentum transfers from 260 GeV to above 1.6 TeV. Analysis that combines data at all momentum transfers results in alpha(S) (m(Z)) = 0.1127(- 0.0027) (+0.0063).
Inclusive jet and dijet cross-sections are measured in proton-proton collisions at a centre-of-mass energy of 13 TeV. The measurement uses a dataset with an integrated luminosity of 3.2 fb(-1) recorded in 2015 with the ATLAS detector at the Large Hadron Collider. Jets are identified using the anti-lit algorithm with a radius parameter value of R = 0.4. The inclusive jet cross-sections are measured double-differentially as a function of the jet transverse momentum, covering the range from 100 GeV to 3.5 TeV, and the absolute jet rapidity up to vertical bar y vertical bar = 3. The double-differential dijet production cross-sections are presented as a function of the dijet mass, covering the range from 300 GeV to 9 TeV, and the half absolute rapidity separation between the two leading jets within vertical bar y vertical bar < 3, y*, up to y* = 3. Next-to-leading-order, and next-to-next-to-leading-order for the inclusive jet measurement, perturbative QCD calculations corrected for non-perturbative and electroweak effects are compared to the measured cross-sections.
A detailed study of multiparticle azimuthal correlations is presented using pp data at root s = 5.02 and 13 TeV, and p+Pb data at root s(NN) = 5.02 TeV, recorded with the ATLAS detector at the CERN Large Hadron Collider. The azimuthal correlations are probed using four-particle cumulants c(n){4} and flow coefficients v(n){4} = (-c(n){4})(1/4) for n = 2 and 3, with the goal of extracting long-range multiparticle azimuthal correlation signals and suppressing the short-range correlations. The values of c(n){4} are obtained as a function of the average number of charged particles per event, < N-ch >, using the recently proposed two-subevent and three-subevent cumulant methods, and compared with results obtained with the standard cumulant method. The standard method is found to be strongly biased by short-range correlations, which originate mostly from jetswith a positive contribution to c(n){4}. The threesubevent method, on the other hand, is found to be least sensitive to short-range correlations. The three-subevent method gives a negative c(2){4}, and therefore a well-defined v(2){4}, nearly independent of < N-ch >, which implies that the long-range multiparticle azimuthal correlations persist to events with low multiplicity. Furthermore, v(2){4} is found to be smaller than the v(2){2} measured using the two-particle correlation method, as expected for long-range collective behavior. Finally, the measured values of v(2){4} and v(2){2} are used to estimate the number of sources relevant for the initial eccentricity in the collision geometry. The results based on the subevent cumulant technique provide direct evidence, in small collision systems, for a long-range collectivity involving many particles distributed across a broad rapidity interval.
Measurements of longitudinal flow correlations are presented for charged particles in the pseudorapidity range vertical bar eta vertical bar < 2.4 using 7 mu b(-1) and 470 mu b(-1) of Pb+Pb collisions at root s(NN) = 2.76 and 5.02 TeV, respectively, recorded by the ATLAS detector at the LHC. It is found that the correlation between the harmonic flow coefficients v(n) measured in two separated eta intervals does not factorise into the product of single-particle coefficients, and this breaking of factorisation, or flow decorrelation, increases linearly with the eta separation between the intervals. The flow decorrelation is stronger at 2.76 TeVthan at 5.02 TeV. Higher-order moments of the correlations are also measured, and the corresponding linear coefficients for the kth-moment of the v(n) are found to be proportional to k for v(3), but not for v(2). The decorrelation effect is separated into contributions from the magnitude of v(n) and the event-plane orientation, each as a function of eta. These two contributions are found to be comparable. The longitudinal flow correlations are also measured between v(n) of different order in n. The decorrelations of v(2) and v(3) are found to be independent of each other, while the decorrelations of v(4) and v(5) are found to be driven by the nonlinear contribution from v(2)(2) and v(2)v(3), respectively.
The dynamics of isolated-photon production in association with a jet in proton-proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb(-1). Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti-k(t) algorithm with radius parameter R = 0.4 and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon-jet invariant mass and the scattering angle in the photon-jet centre-of-mass system. Tree-level plus parton-shower predictions from SHERPA and PYTHIA as well as next-to-leading-order QCD predictions from JETPHOX and SHERPA are compared to the measurements. (C) 2018 The Author. Published by Elsevier B.V.
The production of exclusive gamma gamma -> mu(+)mu(-) events in proton-proton collisions at a centre-of-mass energy of 13 TeV is measured with the ATLAS detector at the LHC, using data corresponding to an integrated luminosity of 3.2 fb(-1). The measurement is performed for a dimuon invariant mass of 12 GeV < m(mu+mu-) < 70 GeV. The integrated cross-section is determined within a fiducial acceptance region of the ATLAS detector and differential cross-sections are measured as a function of the dimuon invariant mass. The results are compared to theoretical predictions both with and without corrections for absorptive effects. (c) 2017 The Author(s). Published by Elsevier B.V.
The mass of the Higgs boson is measured in the H -> ZZ* -> 4l and in the H -> gamma gamma decay channels with 36.1 fb(-1) of proton-proton collision data from the Large Hadron Collider at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector in 2015 and 2016. The measured value in the H -> ZZ* -> 4l channel is m(H)(ZZ*) = 124.79 +/- 0.37 GeV, while the measured value in the H -> gamma gamma channel is m(H)(gamma gamma) = 124.93 +/- 0.40 GeV. Combining these results with the ATLAS measurement based on 7 and 8 TeV proton-proton collision data yields a Higgs boson mass of m(H) = 124.97 +/- 0.24 GeV. (c) 2018 The Author. Published by Elsevier B.V.
The inclusive and fiducial t (t) over bar production cross sections are measured in the lepton+jets channel using 20.2 fb(-1) of proton proton collision data at a centre-of mass energy of 8 TeV recorded with the ATLAS detector at the LHC. Major systematic uncertainties due to the modelling of the jet energy scale and b-tagging efficiency are constrained by separating selected events into three disjoint regions. In order to reduce systematic uncertainties in the most important background, the W+jets process is modelled using Z+jets events in a data-driven approach. The inclusive t (t) over bar cross-section is measured with a precision of 5.7% to be (sigma(inc) (t (t) over bar) = 248.3 +/- 0.7 (stat.) +/- 13.4 (syst.) +/- 4.7 (lumi.) pb, assuming a top-quark mass of 172.5 GeV. The result is in agreement with the Standard Model prediction. The cross-section is also measured in a phase space close to that of the selected data. The fiducial cross-section is sigma(fid) (t (t) over bar) = 48.8 +/- 0.1 (stat.) +/- 2.0 (syst.) +/- 0.9 (lumi.) pb with a precision of 4.5%.
A measurement of the production of three isolated photons in proton-proton collisions at a centre-of-mass energy root s = 8 TeV is reported. The results are based on an integrated luminosity of 20.2 fb(-1) collected with the ATLAS detector at the LHC. The differential cross sections are measured as functions of the transverse energy of each photon, the difference in azimuthal angle and in pseudorapidity between pairs of photons, the invariant mass of pairs of photons, and the invariant mass of the triphoton system. A measurement of the inclusive fiducial cross section is also reported. Next-to-leading-order perturbative QCD predictions are compared to the cross-section measurements. The predictions underestimate the measurement of the inclusive fiducial cross section and the differential measurements at low photon transverse energies and invariant masses. They provide adequate descriptions of the measurements at high values of the photon transverse energies, invariant mass of pairs of photons, and invariant mass of the triphoton system. (C) 2018 The Author. Published by Elsevier B.V.
The production of a top quark in association with a Z boson is investigated. The proton-proton collision data collected by the ATLAS experiment at the LHC in 2015 and 2016 at a centre-of-mass energy of root s = 13 TeV are used, corresponding to an integrated luminosity of 36.1 fb(-1). Events containing three identified leptons (electrons and/or muons) and two jets, one of which is identified as a b-quark jet are selected. The major backgrounds are diboson, tt($)over-bar and Z + jets production. A neural network is used to improve the background rejection and extract the signal. The resulting significance is 4.2 sigma in the data and the expected significance is 5.4 sigma. The measured cross-section for tZq production is 600 +/- 170(stat.)+/- 140(syst.)fb. (C) 2018 The Author(s). Published by Elsevier B.V.
Jet substructure observables have significantly extended the search program for physics beyond the standard model at the Large Hadron Collider. The state-of-the-art tools have been motivated by theoretical calculations, but there has never been a direct comparison between data and calculations of jet substructure observables that are accurate beyond leading-logarithm approximation. Such observables are significant not only for probing the collinear regime of QCD that is largely unexplored at a hadron collider, but also for improving the understanding of jet substructure properties that are used in many studies at the Large Hadron Collider. This Letter documents a measurement of the first jet substructure quantity at a hadron collider to be calculated at next-to-next-to-leading-logarithm accuracy. The normalized, differential cross section is measured as a function of log(10)rho(2), where rho is the ratio of the soft-drop mass to the ungroomed jet transverse momentum. This quantity is measured in dijet events from 32.9 fb(-1) of root s = 13 TeV proton-proton collisions recorded by the ATLAS detector. The data are unfolded to correct for detector effects and compared to precise QCD calculations and leading-logarithm particle-level Monte Carlo simulations.
This paper presents a measurement of the polarisation of tau leptons produced in Z/gamma* -> tau tau decays which is performed with a dataset of proton-proton collisions at root s = 8 TeV, corresponding to an integrated luminosity of 20.2 fb(-1) recorded with the ATLAS detector at the LHC in 2012. The Z/gamma* -> tau tau decays are reconstructed from a hadronically decaying tau lepton with a single charged particle in the final state, accompanied by a tau lepton that decays leptonically. The tau polarisation is inferred from the relative fraction of energy carried by charged and neutral hadrons in the hadronic tau decays. The polarisation is measured in a fiducial region that corresponds to the kinematic region accessible to this analysis. The tau polarisation extracted over the full phase space within the Z/gamma* mass range of 66 < mZ/gamma* < 116GeVis found to be P-tau = -0.14 +/- 0.02(stat)+/- 0.04(syst). It is in agreement with the Standard Model prediction of Pt = -0.1517 +/- 0.0019, which is obtained from the ALP-GEN event generator interfaced with the PYTHIA 6 parton shower modelling and the TAUOLA tau decay library.
Measurements of di ff erential cross sections of top quark pair production in association with jets by the ATLAS experiment at the LHC are presented. The measurements are performed as functions of the top quark transverse momentum, the transverse momentum of the top quark-antitop quark system and the out-of-plane transverse momentum using data from pp collisions at p s = 13TeV collected by the ATLAS detector at the LHC in 2015 and corresponding to an integrated luminosity of 3.2 fb. The top quark pair events are selected in the lepton (electron or muon) + jets channel. The measured cross sections, which are compared to several predictions, allow a detailed study of top quark production.
Properties of the Higgs boson are measured in the two-photon final state using 36.1 fb(-1) of proton-proton collision data recorded at root s = 13 TeV by the ATLAS experiment at the Large Hadron Collider. Cross-section measurements for the production of a Higgs boson through gluon-gluon fusion, vector-boson fusion, and in association with a vector boson or a top-quark pair are reported. The signal strength, defined as the ratio of the observed to the expected signal yield, is measured for each of these production processes as well as inclusively. The global signal strength measurement of 0.99 +/- 0.14 improves on the precision of the ATLAS measurement at root s = 7 and 8 TeV by a factor of two. Measurements of gluon-gluon fusion and vector-boson fusion productions yield signal strengths compatible with the Standard Model prediction. Measurements of simplified template cross sections, designed to quantify the different Higgs boson production processes in specific regions of phase space, are reported. The cross section for the production of the Higgs boson decaying to two isolated photons in a fiducial region closely matching the experimental selection of the photons is measured to be 55 +/- 10 fb, which is in good agreement with the Standard Model prediction of 64 +/- 2 fb. Furthermore, cross sections in fiducial regions enriched in Higgs boson production in vector-boson fusion or in association with large missing transverse momentum, leptons or top-quark pairs are reported. Differential and double-differential measurements are performed for several variables related to the diphoton kinematics as well as the kinematics and multiplicity of the jets produced in association with a Higgs boson. These differential cross sections are sensitive to higher order QCD corrections and properties of the Higgs boson, such as its spin and CP quantum numbers. No significant deviations from a wide array of Standard Model predictions are observed. Finally, the strength and tensor structure of the Higgs boson interactions are investigated using an effective Lagrangian, which introduces additional CP-even and CP-odd interactions. No significant new physics contributions are observed.
Measurements are made of differential cross-sections of highly boosted pair-produced top quarks as a function of top-quark and t (t) over bar system kinematic observables using proton-proton collisions at a center-of-mass energy of root s = 13 TeV. The data set corresponds to an integrated luminosity of 36.1 fb(-1), recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Events with two large-radius jets in the final state, one with transverse momentum p(T) > 500 GeV and a second with p(T) > 350 GeV, are used for the measurement. The top-quark candidates are separated from the multijet background using jet substructure information and association with a b-tagged jet. The measured spectra are corrected for detector effects to a particle-level fiducial phase space and a parton-level limited phase space, and are compared to several Monte Carlo simulations by means of calculated chi(2) values. The cross-section for t (t) over bar production in the fiducial phase-space region is 292 +/- 7(stat) +/- 71(syst) tb, to be compared to the theoretical prediction of 384 +/- 36 fb.
Reinforcing hydrogels with micro-fibre scaffolds obtained by a Melt-Electrospinning Writing (MEW) process has demonstrated great promise for developing tissue engineered (TE) constructs with mechanical properties compatible to native tissues. However, the mechanical performance and reinforcement mechanism of the micro-fibre reinforced hydrogels is not yet fully understood. In this study, FE models, implementing material properties measured experimentally, were used to explore the reinforcement mechanism of fibre-hydrogel composites. First, a continuum FE model based on idealized scaffold geometry was used to capture reinforcement effects related to the suppression of lateral gel expansion by the scaffold, while a second micro-FE model based on micro-CT images of the real construct geometry during compaction captured the effects of load transfer through the scaffold interconnections. Results demonstrate that the reinforcement mechanism at higher scaffold volume fractions was dominated by the load carrying-ability of the fibre scaffold interconnections, which was much higher than expected based on testing scaffolds alone because the hydrogel provides resistance against buckling of the scaffold. We propose that the theoretical understanding presented in this work will assist the design of more effective composite constructs with potential applications in a wide range of TE conditions.
The brain is the central organ of an animal controlling its behavior. It integrates internal information from the body and external stimuli from the surrounding environment to mediate an appropriate behavioral response. Since the environment is constantly changing, a flexible adjustment of the brain to new conditions is crucial for the animals’ fitness. The ability of the nervous system to adapt to new challenges is defined as plasticity. Over the last few decades great advances have been made in understanding the cellular and molecular mechanisms underlying neuronal plasticity. Plasticity may refer to structural changes physically remodeling the neuronal circuit, or to functional adaptations which are manifested in modified synaptic transmission, and in altered response and firing properties of single neurons. These structural and functional modifications are mediated by a complex interplay of environmental stimuli, intracellular signal transduction cascades, protein modifications, gene translation and transcription, and epigenetic gene regulatory mechanisms. However, especially the molecular mechanisms of environmentally-induced structural neuronal plasticity are still poorly understood.
In this thesis the honey bee was used as an innovative model organism to investigate this issue. The honey bee with its rich behavioral repertoire, highly sophisticated and plastic neuronal system, sequenced genome and full epigenetic machinery is well suited for studying the molecular underpinnings of environmentally-induced neuronal plasticity. Adult honey bees progress through a series of tasks within the dark hive until after about three weeks they start with foraging activities in the external world. The transition from in-hive to outside tasks is associated with remarkable structural neuronal plasticity. Subdivisions of the mushroom body, a brain region related to higher cognitive functions, are increased in volume. The volume expansion is mediated by a remarkable outgrowth of the dendritic network of mushroom body intrinsic neurons, so called Kenyon cells. In parallel, prominent synaptic structures, referred to as microglomeruli, are pruned. Most interestingly for this thesis, the pruning of microglomeruli and the dendritic expansion in Kenyon cells can be induced by a simple light exposure paradigm.
In the first chapter of the present thesis I used this paradigm to induce synaptic plasticity in the mushroom bodies under controlled lab conditions to search for correlating molecular changes which possibly mediate the observed plasticity. I compared the brain transcriptome of light-exposed and dark-kept control bees by whole transcriptome sequencing. This revealed a list of differentially expressed genes (DEGs). The list contains conserved genes which have reported functions in neuronal plasticity, thereby introducing them as candidate genes for plasticity in the honey bee brain. Furthermore, with this transcriptomic approach I discovered many candidate genes with unknown functions or functions so far unrelated to neuronal plasticity suggesting that these novel genes may have yet unrecognized roles in neuronal plasticity. A number of DEGs are known to be methylated or to exert epigenetic modifications on themselves speaking for a strong impact of epigenetic mechanisms in light-induced structural plasticity in the honey bee brain. This notion is supported by a differential methylation pattern of one examined DEG between light-exposed and dark-kept bees as shown in this thesis. Also a plasticity-related microRNA, which is predicted to target genes associated with cytoskeleton formation, was found to be upregulated in light-exposed bees. This speaks for a translation regulatory mechanism in structural plasticity in the honey bee.
Another interesting outcome of this study is the age-dependent expression of DEGs. For some plasticity-related DEGs, the amplitude of light-induced expression differs between one- and seven-day-old bees, and also the basal expression level of many DEGs in naive dark-kept control bees significantly varies between the two age groups. This suggests that the responsiveness of plasticity-related genes to environmental stimuli is also under developmental (age-dependent) control, which may be important for normal maturation and for the regulation of age-related changes in behavior. Indeed, I was able to demonstrate in phototaxis experiments that one- and seven-day-old bees show different behaviors in response to light exposure and thus the correlating age-dependent transcriptional differences may serve as mechanisms promoting age-related changes in behavior.
Together the results of the transcriptomic study demonstrate the successfulness of my approach to identify candidate molecular mechanisms for environmentally-induced structural plasticity in the honey bee brain. Furthermore, the thesis provides seminal evidence for the implication of DNA methylation in this process.
To better understand the role of DNA methylation for neuronal and behavioral plasticity in the honey bee, the second chapter of the thesis aims at characterizing this molecular process under more natural conditions. Therefore, I examined the expression of the DNA methyltransferase 3 (DNMT3) and of Ten-eleven translocation methylcytosine dioxygenase (TET) between in-hive bees and foragers. DNMT3 is responsible for DNA de novo methylation, whereas TET promotes DNA demethylation by converting methylcytosine (5mC) to hydroxymethylcytosine (5hmC). The data suggest that age and experience determine the expression of these two epigenetic key genes. Additionally, in this context, two examined DEGs are shown to be differentially methylated between nurses and foragers. One of these two DEGs, the plasticity related gene bubblegum (bgm), also exhibits an altered DNA methylation pattern in response to light exposure. Hence, these results of my thesis provide additional evidence for the importance of DNA methylation in behavioral and neuronal plasticity.
Results from the second chapter of this thesis also suggest additional functions of DNMT3 and TET to their traditional roles in DNA methylation/demethylation. I show that TET is far more expressed in the honey bee brain than DNMT3. This stands in contrast to the relative scarcity of 5hmC compared to 5mC and points at extra functions of this gene like RNA modifications as reported for Drosophila. Antibody staining against the DNMT3 gene product revealed an unexpected rare localization of the enzyme in the nucleus, but a surprisingly high abundance in the cytoplasm. The role of cytoplasmic DNMT3 is unknown. One possibility for the high abundance in the cytoplasm is a regulatory mechanism for DNA methylation by cytoplasmic-nuclear trafficking, or an additional function of DNMT3 in RNA modification, similar to TET.
Altogether, this thesis points at future research directions for neuronal plasticity by providing promising evidence for the involvement of epigenetic mechanisms and of a number of new candidate genes in environmentally induced structural plasticity in the honey bee brain. Furthermore, I present data suggesting so far unrecognized functions of DNMT3 which certainly need to be experimentally addressed in the future to fully understand the role of this enzyme.
This work summarizes the results of studies on several major aspects of platelet activation and platelet receptor regulation. Therefore, this thesis is divided into four parts.
Platelet activation and aggregation at sites of vascular injury is critical to prevent excessive blood loss, but may also lead to life-threatening ischemic disease states, such as myocardial infarction and stroke. Agonist-induced elevation in cytosolic Ca2+ concentrations is essential for platelet activation in hemostasis and thrombosis. The principal route of Ca2+ influx in platelets is store-operated calcium entry (SOCE). The calcium sensor molecule stromal interaction molecule 1 (STIM1) regulates SOCE by activating the membrane calcium channel protein Orai1, but the exact mechanisms of this interaction are not fully understood. Using affinity chromatography to screen for STIM1 interacting proteins in platelets, bridging integrator 2 (BIN2), an adapter protein belonging to the family of BAR proteins that is mainly expressed in the hematopoietic system, was identified. Newly generated BIN2 KO mice were viable and fertile but their platelets displayed markedly impaired SOCE in response to thapsigargin (TG) as well as agonists acting on immunoreceptor tyrosine-based activation motif (ITAM) or G protein-coupled receptors. This SOCE defect resulted in impaired (hem)ITAM induced platelet activation, aggregate formation under flow and procoagulant activity. As a consequence, mice lacking BIN2 in platelets were protected from occlusive arterial thrombus formation and thrombo-inflammatory cerebral infarct progression in a model of experimental stroke. These results identify BIN2 as a critical regulator of platelet SOCE in thrombosis and thrombo-inflammatory disease.
Integrin αIIbβ3 plays a central role in the adhesion and aggregation of platelets. Integrin activation requires the transmission of a signal from the small cytoplasmic tails of the α or β
subunit to the large extracellular domains resulting in conformational changes of the extracellular domains to enable ligand binding. It was hypothesized that Hic-5 is a novel regulator of integrin αIIbβ3 activation in mice. As demonstrated in the second part of this thesis, lack of Hic-5 had no detectable effect on platelet integrin activation and function in vitro and in vivo under all tested conditions. These results indicate that Hic-5 is dispensable for integrin αIIbβ3 activation and consequently for arterial thrombosis and hemostasis in mice.
The Rho GTPase family members RhoA and Rac1 play major roles in platelet activation at sites of vascular injury. Little is known about possible redundant functions of these Rho GTPases in regulating platelet function. To investigate functional redundancies of RhoA and Rac1 in platelet production and function, mice with MK- and platelet-specific double- deficiencies in RhoA and Rac1 were generated. RhoA/Rac1 double-deficiency phenocopied the respective single knockouts without any additional effects in the double-knockout animals, demonstrating for the first time a functional non-redundancy of RhoA and Rac1 in platelet function.
Antibodies against platelet glycoproteins (GP) trigger platelet destruction in immune thrombocytopenia (ITP) by binding to Fcγ receptors (FcγRs) on immune cells. However, antibodies against the platelet collagen receptor GPVI exert powerful anti-thrombotic action in vivo by inducing ectodomain shedding of the receptor associated with a transient thrombocytopenia. As shown in the final part of this thesis, blockade or deficiency of the inhibitory FcγRIIB abolished sequestration of anti-GPVI opsonized platelets in the hepatic vasculature and GPVI shedding. This process was mediated by liver sinusoidal endothelial cells (LSEC), the major FcγRIIB expressing cell type in the body. Furthermore, LSEC FcγRIIB mediated hepatic platelet sequestration and contributed to thrombocytopenia in mice treated with antibodies against αIIbβ3, the major target antigen in human ITP. These results reveal a novel and unexpected function of hepatic FcγRIIB in the processing of antibody-opsonized platelets.
Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound
(2018)
Influenza virus (IV) infections cause severe respiratory illnesses that can be complicated by bacterial super-infections. Previously, we identified the cellular Raf-MEK-ERK cascade as a promising antiviral target. Inhibitors of MEK, such as CI-1040, showed potent antiviral activity. However, it remained unclear if this inhibitor and its active form, ATR-002, might sensitize host cells to either IV or secondary bacterial infections. To address these questions, we studied the anti-pathogen activity of ATR-002 in comparison to CI-1040, particularly, its impact on Staphylococcus aureus (S. aureus), which is a major cause of IV super-infections. We analysed IV and S. aureus titres in vitro during super-infection in the presence and absence of the drugs and characterized the direct impact of ATR-002 on bacterial growth and phenotypic changes. Importantly, neither CI-1040 nor ATR-002 treatment led to increased bacterial titres during super-infection, indicating that the drug does not sensitize cells for bacterial infection. In contrast, we rather observed reduced bacterial titres in presence of ATR-002. Surprisingly, ATR-002 also led to reduced bacterial growth in suspension cultures, reduced stress- and antibiotic tolerance without resistance induction. Our data identified for the first time that a particular MEK-inhibitor metabolite exhibits direct antibacterial activity, which is likely due to interference with the bacterial PknB kinase/Stp phosphatase signalling system.
BACKGROUND:
Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay.
MATERIAL AND METHODS:
Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with \(^{18}\)F‑2‑fluoro‑2‑deoxy‑d‑glucose (\(^{18}\)F-FDG) and \(^{125}\)I‑β‑methyl‑iodophenyl‑pentadecanoic acid (\(^{125}\)I-BMIPP) as transport markers of glucose and fatty acids, respectively.
RESULTS:
After cardiac differentiation of hiPSCs, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM.
CONCLUSIONS:
During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications.
Background: Recent developments in cellular reprogramming technology enable the production of virtually unlimited numbers of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Although hiPSC-CM share various characteristic hallmarks with endogenous cardiomyocytes, it remains a question as to what extent metabolic characteristics are equivalent to mature mammalian cardiomyocytes. Here we set out to functionally characterize the metabolic status of hiPSC-CM in vitro by employing a radionuclide tracer uptake assay. Material and Methods: Cardiac differentiation of hiPSC was induced using a combination of well-orchestrated extrinsic stimuli such as WNT activation (by CHIR99021) and BMP signalling followed by WNT inhibition and lactate based cardiomyocyte enrichment. For characterization of metabolic substrates, dual tracer uptake studies were performed with \(^{18}\)F-2-fluoro-2-deoxy-D-glucose (\(^{18}\)F-FDG) and \(^{125}\)I-β-methyl-iodophenyl-pentadecanoic acid (\(^{125}\)I-BMIPP) as transport markers of glucose and fatty acids, respectively. Results: After cardiac differentiation of hiPSC, in vitro tracer uptake assays confirmed metabolic substrate shift from glucose to fatty acids that was comparable to those observed in native isolated human cardiomyocytes. Immunostaining further confirmed expression of fatty acid transport and binding proteins on hiPSC-CM. Conclusions: During in vitro cardiac maturation, we observed a metabolic shift to fatty acids, which are known as a main energy source of mammalian hearts, suggesting hi-PSC-CM as a potential functional phenotype to investigate alteration of cardiac metabolism in cardiac diseases. Results also highlight the use of available clinical nuclear medicine tracers as functional assays in stem cell research for improved generation of autologous differentiated cells for numerous biomedical applications.
BACKGROUND. Prostate cancer (PCa) remains a major health concern in men of the Western World. However, we still lack effective diagnostic tools a) for an effective screening with both high sensitivity and specificity, b) to guide biopsies and avoid histology sampling errors and c) to predict tumor aggressiveness in order to avoid overtreatment. Therefore, a more reliable, highly cancer-specific and ideally in vivo approach is needed. The present study has been designed in order to further develop and test the method of "metabolomic imaging" using magnetic resonance spectroscopy (MRS) at 7T to address those challenges.
METHODS. Thirty whole prostates with biopsy-proven PCa were in vitro analyzed with a 7T human MR scanner. A voxel grid containing the spectral information was overlaid with the MR image of the middle transverse cross-sectional plane of each case. Subsequent histopathological evaluation of the prostate specimen followed. After the spectral output was processed, all voxels were compared with a metabolomic PCa profile, which had been established within a preliminary study, in order to create a metabolomic map indicating MRS cancer-suspicious regions. Those regions were compared with the histologically identified tumor lesions regarding location.
RESULTS. Sixty-one percent of the histological cancer lesions were detected by metabolomic imaging. Among the cases with PCa on the examined slice, 75% were identified as cancerous. None of the tested features significantly differed between detected and undetected cancer lesions. A defined "Malignancy Index" (MI) significantly differentiated between MRS-suspicious lesions corresponding with a histological cancer lesion and benign lesions (p = 0.006) with an overall accuracy of 70%. The MI furthermore showed a positive correlation with the Gleason grade (p = 0.021).
CONCLUSION. A new approach within PCa diagnostics was developed with spectral analysis including the whole measureable metabolome - referred to as "metabolomics" - rather than focusing on single metabolites. The MI facilitates precise tumor detection and may additionally serve as a marker for tumor aggressiveness. Metabolomic imaging might contribute to a highly cancer-specific in vivo diagnostic protocol for PCa.
A key functionality of cloud systems are automated resource management mechanisms at the infrastructure level. As part of this, elastic scaling of allocated resources is realized by so-called auto-scalers that are supposed to match the current demand in a way that the performance remains stable while resources are efficiently used.
The process of rating cloud infrastructure offerings in terms of the quality of their achieved elastic scaling remains undefined. Clear guidance for the selection and configuration of an auto-scaler for a given context is not available. Thus, existing operating solutions are optimized in a highly application specific way and usually kept undisclosed.
The common state of practice is the use of simplistic threshold-based approaches. Due to their reactive nature they incur performance degradation during the minutes of provisioning delays. In the literature, a high-number of auto-scalers has been proposed trying to overcome the limitations of reactive mechanisms by employing proactive prediction methods.
In this thesis, we identify potentials in automated cloud system resource management and its evaluation methodology. Specifically, we make the following contributions:
We propose a descriptive load profile modeling framework together with automated model extraction from recorded traces to enable reproducible workload generation with realistic load intensity variations. The proposed Descartes Load Intensity Model (DLIM) with its Limbo framework provides key functionality to stress and benchmark resource management approaches in a representative and fair manner.
We propose a set of intuitive metrics for quantifying timing, stability and accuracy aspects of elasticity. Based on these metrics, we propose a novel approach for benchmarking the elasticity of Infrastructure-as-a-Service (IaaS) cloud platforms independent of the performance exhibited by the provisioned underlying resources.
We tackle the challenge of reducing the risk of relying on a single proactive auto-scaler by proposing a new self-aware auto-scaling mechanism, called Chameleon, combining multiple different proactive methods coupled with a reactive fallback mechanism.
Chameleon employs on-demand, automated time series-based forecasting methods to predict the arriving load intensity in combination with run-time service demand estimation techniques to calculate the required resource consumption per work unit without the need for a detailed application instrumentation. It can also leverage application knowledge by solving product-form queueing networks used to derive optimized scaling actions. The Chameleon approach is first in resolving conflicts between reactive and proactive scaling decisions in an intelligent way.
We are confident that the contributions of this thesis will have a long-term impact on the way cloud resource management approaches are assessed. While this could result in an improved quality of autonomic management algorithms, we see and discuss arising challenges for future research in cloud resource management and its assessment methods: The adoption of containerization on top of virtual machine instances introduces another level of indirection. As a result, the nesting of virtual resources increases resource fragmentation and causes unreliable provisioning delays. Furthermore, virtualized compute resources tend to become more and more inhomogeneous associated with various priorities and trade-offs. Due to DevOps practices, cloud hosted service updates are released with a higher frequency which impacts the dynamics in user behavior.
Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader’s confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.
Tropical peat swamp forests sequester globally significant stores of carbon in deep layers of waterlogged, anoxic, acidic and nutrient-depleted peat. The roles of microbes in supporting these forests through the formation of peat, carbon sequestration and nutrient cycling are virtually unknown. This study investigated physicochemical peat properties and microbial diversity between three dominant tree species: Shorea uliginosa (Dipterocarpaceae), Koompassia malaccensis (legumes associated with nitrogen-fixing bacteria), Eleiodoxa conferta (palm) and depths (surface, 45 and 90 cm) using microbial 16S rRNA gene amplicon sequencing. Water pH, oxygen, nitrogen, phosphorus, total phenolic contents and C/N ratio differed significantly between depths, but not tree species. Depth also strongly influenced microbial diversity and composition, while both depth and tree species exhibited significant impact on the archaeal communities. Microbial diversity was highest at the surface, where fresh leaf litter accumulates, and nutrient supply is guaranteed. Nitrogen was the core parameter correlating to microbial communities, but the interactive effects from various environmental variables displayed significant correlation to relative abundance of major microbial groups. Proteobacteria was the dominant phylum and the most abundant genus, Rhodoplanes, might be involved in nitrogen fixation. The most abundant methanogens and methanotrophs affiliated, respectively, to families Methanomassiliicoccaceae and Methylocystaceae. Our results demonstrated diverse microbial communities and provide valuable insights on microbial ecology in these extreme ecosystems.
Objective:
Halothane and caffeine are known to cause skeletal muscular contractions in vitro and have been proven to induce circumscribed metabolic reactions when injected into rat skeletal muscle. In this study 26 rats were investigated by either continuous application of calcium 160 mM or bolus injection of caffeine 160 mM or halothane 10% vol via a microdialysis probe in the tibialis anterior muscle. Tissue elasticity at the injection site was monitored by ultrasound strain elastography. Aim of this study was to detect (I) changes in local lactate concentrations and (II) whether these can be attributed to a muscular contraction detected by ultrasound elastography.
Results:
Localized metabolic reactions were verified by increasing intramuscular lactate concentrations following continuous application of calcium (0.6 [0.3;0.6] to 3.6 [3.0;4.3] mmol/l after 60 min) and bolus application of caffeine (0.2 [0.2;0.3] to 1.6 [0.9;1.9] mmol/l after 30 min) and halothane (0.3 [0.1;0.3] to 4.7 [4.3;6.3] mmol/l after 30 min). However, ultrasound elastography did not detect any differences in tissue elasticity compared to control animals. The authors identified potential limitations of the study conditions, which might be crucial to avoid for future investigations.
The aim of the book is to ground the logical origins of consciousness in what I have previously called the ‘minimal self’. The idea is that elementary forms of consciousness are logically dependent not, as is commonly assumed, on ownership of an anatomical brain or nervous system, but on the intrinsic reflexivity that defines minimal selfhood. The book seeks to trace the logical pathway by which minimal selfhood gives rise to the possible appearance of consciousness. It is argued that in specific circumstances it thus makes sense to ascribe elementary consciousness to certain predatory single-celled organisms such as amoebae and dinoflagellates as well as to some of the simpler animals. Such an argument involves establishing exactly what those specific circumstances are and determining how elementary consciousness differs in nature and scope from its more complex manifestations.
Background: Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure. Objective: To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL). Design: Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P<0.001), found to have larger tumors (P=0.003) and higher metanephrine and normetanephrine levels at diagnosis (P=0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P< 0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed. Precis: Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.
The host's defense against invasive mold infections relies on diverse antimicrobial activities of innate immune cells. However, studying these mechanisms in vitro is complicated by the filamentous nature of such pathogens that typically form long, branched, multinucleated and compartmentalized hyphae. Here we describe a novel method that allows for the visualization and quantification of the antifungal killing activity exerted by human granulocytes against hyphae of the opportunistic pathogen Aspergillus fumigatus. The approach relies on the distinct impact of fungal cell death on the morphology of mitochondria that were visualized with green fluorescent protein (GFP). We show that oxidative stress induces complete fragmentation of the tubular mitochondrial network which correlates with cell death of affected hyphae. Live cell microscopy revealed a similar and non-reversible disruption of the mitochondrial morphology followed by fading of fluorescence in Aspergillus hyphae that were killed by human granulocytes. Quantitative microscopic analysis of fixed samples was subsequently used to estimate the antifungal activity. By utilizing this assay, we demonstrate that lipopolysaccharides as well as human serum significantly increase the killing efficacy of the granulocytes. Our results demonstrate that evaluation of the mitochondrial morphology can be utilized to assess the fungicidal activity of granulocytes against A. fumigatus hyphae.
A mathematical optimal-control tumor therapy framework consisting of radio- and anti-angiogenesis control strategies that are included in a tumor growth model is investigated. The governing system, resulting from the combination of two well established models, represents the differential constraint of a non-smooth optimal control problem that aims at reducing the volume of the tumor while keeping the radio- and anti-angiogenesis chemical dosage to a minimum. Existence of optimal solutions is proved and necessary conditions are formulated in terms of the Pontryagin maximum principle. Based on this principle, a so-called sequential quadratic Hamiltonian (SQH) method is discussed and benchmarked with an “interior point optimizer―a mathematical programming language” (IPOPT-AMPL) algorithm. Results of numerical experiments are presented that successfully validate the SQH solution scheme. Further, it is shown how to choose the optimisation weights in order to obtain treatment functions that successfully reduce the tumor volume to zero.
Shiga toxin producing E. coli strains (STEC) are a great concern to human health. Upon an infection with as few as 100 bacteria, humans can develop disease symptoms ranging from watery to bloody diarrhea or even develop the hemolytic uremic syndrome (HUS). The major factor contributing to the disease symptoms is Shiga toxin (Stx) which can bind to the eukaryotic cells in the intestine of the human and induce cell death via apoptosis. Based, among other things, on the microbiota composition, the impact of STEC can vary. Some bacteria of the microbiota can interfere with the colonization of STEC strains in the first place. Others cannot impair the colonization but interfere with the toxin production and there are still others which are even infected by stx encoding phages, being released from STEC strains. Those previously harmless bacteria subsequently contribute to the toxin increase and worsen the disease progression. Since the genetic information of Stx is encoded on a prophage, antibiotic treatment of patients can lead to an increased toxin and stx-phage release and is therefore not recommended. Several STEC epidemics in different countries, which even resulted in the death of some patients, demonstrated that there is an urgent need for alternative treatment strategies.
The E. coli strain Nissle 1917 (EcN) has been used as a probiotic to treat gastrointestinal infections for more than 100 years. It harbors several fitness factors which contribute to the establishment of an intact intestinal barrier in the human gut. Moreover, studies with EcN unraveled that the probiotic E. coli can interfere with the colonization of STEC strains and their toxin production. This study aimed to investigate if EcN could be a possible alternative or supplementary treatment strategy for STEC infected patients, or a preventive treatment for the patient’s close contact persons.
Therefore, EcN was firstly investigated for a possible stx-prophage integration into its’s genome which would eliminate it from being a potential treatment due to the possibility of disease worsening. Despite the presence of the stx-phage surface receptor YaeT, EcN demonstrated a complete resistance towards the lysis and the lysogeny by stx-phages, which was proven by PCR, phage-plaque assays and phage enrichment approaches. Transcriptome data could unravel that a lambdoid prophage in the genome of EcN is involved in the resistance towards the phage infection. Other commensal E. coli tested presented a stx-phage resistance as well and in silico analysis revealed that all of them harbor a complete lambdoid prophage besides the stx-phage susceptible K-12 strain MG1655. We assume that the resistance of EcN towards a stx-phage infection is connected to the presence of an intact lambdoid prophage which interferes with superinfection.
Further experiments regarding the impact of the microcin negative EcN mutant SK22D towards STEC strains depicted that SK22D did not only interfere with the toxin production but also negatively regulated the transcription of the entire stx-prophage in coculture with all STEC strains tested (O157:H7, O26:H11, O145:H25, O103:H2, O111:H- and two O104:H4 isolates from the 2011 outbreak in Germany). This influence on the pathogenic factor production was evinced to be cell contact independent as SK22D could even interfere with the pathogenic factor production when being separated from the STEC strain EDL933 by a Transwell membrane with the pore size of 0.4 µm. From this data we concluded, that factor(s) released by SK22D interfere with the lysis of STEC strains by stabilizing the lysogenic state.
Another positive aspect of EcN towards the pathogenicity of STEC strains was encountered when EcN was incubated with isolated stx-phages. The probiotic strain could reduce the infectivity of the phages towards a MG1655 lysis from ~ 1e7 pfus/ml to 0 after 44 h of incubation. Various approaches to determine the characteristics of the factor(s) of EcN which are involved in the phage inactivation depicted it to be a heat resistant stationary phase protein on the surface of EcN, which could be a component of its biofilm.
Regarding the protective role of EcN we could further evince that SK22D was capable of interfering with the lysogenic K 12 mediated increase of Stx and stx phages. Lysogenic K-12 strains were characterized by a huge increase of Stx and stx-phage production. The presence of SK22D anyhow, could interfere with this K-12 mediated pathogenic factor increase. Transwell and stx phage infection kinetics led to the proposal that SK22D interfered with the stx-phage infection of K-12 strains in the first place rather than disturbing the lysis of lysogenic K 12. The protection from the phage infection could be due to the growth of K 12 strains within the SK22D culture, whereby the phage susceptible strains are masked from phage detection.
Summarizing, this work could underline the beneficial attributes of EcN towards the STEC pathogenicity in vitro. These results should be considered as pioneers for future in vivo studies to enable EcN medication as a supportive STEC infection treatment strategy.
Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization.
The heart failure (HF) epidemic continues to rise with coronary artery disease (CAD) as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 sec), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.
Imagine a technology that automatically creates a full 3D thermal model of an environment and detects temperature peaks in it. For better orientation in the model it is enhanced with color information. The current state of the art for analyzing temperature related issues is thermal imaging. It is relevant for energy efficiency but also for securing important infrastructure such as power supplies and temperature regulation systems. Monitoring and analysis of the data for a large building is tedious as stable conditions need to be guaranteed for several hours and detailed notes about the pose and the environment conditions for each image must be taken. For some applications repeated measurements are necessary to monitor changes over time. The analysis of the scene is only possible through expertise and experience.
This thesis proposes a robotic system that creates a full 3D model of the environment with color and thermal information by combining thermal imaging with the technology of terrestrial laser scanning. The addition of a color camera facilitates the interpretation of the data and allows for other application areas. The data from all sensors collected at different positions is joined in one common reference frame using calibration and scan matching. The first part of the thesis deals with 3D point cloud processing with the emphasis on accessing point cloud data efficiently, detecting planar structures in the data and registering multiple point clouds into one common coordinate system. The second part covers the autonomous exploration and data acquisition with a mobile robot with the objective to minimize the unseen area in 3D space. Furthermore, the combination of different modalities, color images, thermal images and point cloud data through calibration is elaborated. The last part presents applications for the the collected data. Among these are methods to detect the structure of building interiors for reconstruction purposes and subsequent detection and classification of windows. A system to project the gathered thermal information back into the scene is presented as well as methods to improve the color information and to join separately acquired point clouds and photo series.
A full multi-modal 3D model contains all the relevant geometric information about the recorded scene and enables an expert to fully analyze it off-site. The technology clears the path for automatically detecting points of interest thereby helping the expert to analyze the heat flow as well as localize and identify heat leaks. The concept is modular and neither limited to achieving energy efficiency nor restricted to the use in combination with a mobile platform. It also finds its application in fields such as archaeology and geology and can be extended by further sensors.
Improved treatment options for the degenerative joint disease osteoarthritis (OA) are of major interest, since OA is one of the main sources of disability, pain, and socioeconomic burden worldwide [202]. According to epidemiological data, already 27 million people suffer from OA in the US [23]. Moreover, the WHO expects OA to be the fourth most common cause of disability in 2020 [203], illustrating the need for effective and long-lasting therapy options of severe cartilage defects. Despite numerous clinically available products for the treatment of cartilage defects [62], the development of more cartilage-specific materials is still at the beginning.
Hyaluronic acid (HA) is a major component of the cartilaginous extracellular matrix (ECM) and inherently creates a cell-friendly niche by providing cell attachment and migration sites. Furthermore, it is known that the functional groups of HA are well suited for chemical modification. These characteristics render HA an attractive material for hydrogel-based tissue engineering approaches. Poly(glycidol) (PG) as chemical crosslinker basically features similar chemical characteristics as the widely used poly(ethylene glycol) (PEG), but provides additional side groups at each repeating unit that can be further chemically functionalized. With the introduction of PG as multifunctional crosslinker for HA gels, a higher cross-linking density and, accordingly, a greater potential for biomimetic functionalization may be achieved. However, despite the mentioned potential benefits, PG has not been used for cartilage regeneration approaches so far.
The initial aim of the study was to set up and optimize a HA-based hydrogel for the chondrogenic differentiation of mesenchymal stromal cells (MSCs), using different amounts and variations of cross-linkers. Therefore, the hydrogel composition was optimized by the utilization of different PEG diacrylate (PEGDA) concentrations to cross-link thiol-modified HA (Glycosil, HA-SH) via Michael addition. We aimed to generate volumestable scaffolds that simultaneously enable a maximum of ECM deposition. Histological and biochemical analysis showed 0.4% PEGDA as the most suitable concentration for these requirements (Section 5.1.2).
In order to evaluate the impact of a differently designed cross-linker on MSC chondrogenesis, HA-SH was cross-linked with PEGTA (0.6%) and compared to PEGDA (0.4%) in a next step. Following this, acrylated PG (PG-Acr) as multifunctional cross-linker alternative to acrylated PEG was evaluated. It provides around five times more functional groups when utilized in PG-Acr (0.6%) HA-SH hydrogels compared to PEGTA (0.6%) HA-SH hydrogels, thus enabling higher degrees of biomimetic functionalization. Determination of cartilage-specific ECM components showed no substantial differences between both cross-linkers while the deposition of cartilaginous matrix appeared more homogeneous in HA-SH PG-Acr gels. Taken together, we were able to successfully increase the possibilities for biomimetic functionalization in the developed HA-SH hydrogel system by the introduction of PG-Acr as cross-linker without negatively affecting MSC chondrogenesis (Section 5.1.3).
The next part of this thesis focused extensively on the biomimetic functionalization of PG-Acr (0.6%) cross-linked HA-SH hydrogels. Here, either biomimetic peptides or a chondrogenic growth factor were covalently bound into the hydrogels.
Interestingly, the incorporation of a N-cadherin mimetic (HAV), a collagen type II binding (KLER), or a cell adhesion-mediating peptide (RGD) yielded no improvement of MSC chondrogenesis. For instance, the covalent binding of 2.5mM HAV changed morphology of cell nuclei and reduced GAG production while the incorporation of 1.0mM RGD impaired collagen production. These findings may be attributed to the already supportive conditions of the employed HA-based hydrogels for chondrogenic differentiation. Most of the previous studies reporting positive peptide effects on chondrogenesis have been carried out in less supportive PEG hydrogels or in significantly stiffer MeHA-based hydrogels [99, 101, 160]. Thus, the incorporation of peptides may be more important under unfavorable conditions while inert gel systems may be useful for studying single peptide effects (Section 5.2.1).
The chondrogenic factor transforming growth factor beta 1 (TGF-b1) served as an example for growth factor binding to PG-Acr. The utilization of covalently bound TGF-b1 may thereby help overcome the need for repeated administration of TGF-b1 in in vivo applications, which may be an advantage for potential clinical application. Thus, the effect of covalently incorporated TGF-b1 was compared to the effect of the same amount of TGF-b1 without covalent binding (100nM TGF-b1) on MSC chondrogenesis. It was successfully demonstrated that covalent incorporation of TGF-b1 had a significant positive effect in a dose-dependent manner. Chondrogenesis of MSCs in hydrogels with covalently bound TGF-b1 showed enhanced levels of chondrogenesis compared to hydrogels into which TGF-b1 was merely mixed, as shown by stronger staining for GAGs, total collagen, aggrecan and collagen type II. Biochemical evaluation of GAG and collagen amounts, as well as Western blot analysis confirmed the histological results. Furthermore, the positive effect of covalently bound TGF-b1 was shown by increased expression of chondrogenic marker genes COL2A1, ACAN and SOX9. In summary, covalent growth factor incorporation utilizing PG-Acr as cross-linker demonstrated significant positive effects on chondrogenic differentiation of MSCs (Section 5.2.2).
In general, PG-Acr cross-linked HA hydrogels generated by Michael addition represent a versatile hydrogel platform due to their high degree of acrylate functionality. These hydrogels may further offer the opportunity to combine several biological modifications, such as the incorporation of biomimetic peptides together with growth factors, within one cell carrier.
A proof-of-principle experiment demonstrated the suitability of pure PG gels for studying single peptide effects. Here, the hydrogels were generated by the utilization of thiol-ene-click reaction. In this setting, without the supportive background of hyaluronic acid, MSCs showed enhanced chondrogenic differentiation in response to the incorporation of 1.0mM HAV. This was demonstrated by staining for GAGs, the cartilage-specific ECM molecules aggrecan and type II collagen, and by increased GAG and total collagen amounts shown by biochemical analysis. Thus, pure PG gels exhibit the potential to study the effects and interplay of peptides and growth factors in a highly modifiable, bioinert hydrogel environment.
The last section of the thesis was carried out as part of the EU project HydroZONES that aims to develop and generate zonal constructs. The importance of zonal organization has attracted increased attention in the last years [127, 128], however, it is still underrepresented in tissue engineering approaches so far. Thus, the feasibility of zonal distribution of cells in a scaffold combining two differently composed hydrogels was investigated. A HA-SH(FMZ) containing bottom layer was generated and a pure PG top layer was subsequently cast on top of it, utilizing both times thiol-ene-click reaction. Indeed, stable, hierarchical constructs were generated that allowed encapsulated MSCs to differentiate chondrogenically in both zones as shown by staining for GAGs and collagen type II, and by quantification of GAG amount. Thus, the feasibility of differently composed zonal hydrogels utilizing PG as a main component was successfully demonstrated (Section 5.4).
With the first-time utilization and evaluation of PG-Acr as versatile multifunctional cross-linker for the preparation of Michael addition-generated HA-SH hydrogels in the context of cartilage tissue engineering, a highly modifiable HA-based hydrogel system was introduced. It may be used in future studies as an easily applicable and versatile toolbox for the generation of biomimetically functionalized hydrogels for cell-based cartilage regeneration. The introduction of reinforcement structures to enhance mechanical resistance may thereby further increase the potential of this system for clinical applications.
Additionally, it was also demonstrated that thiol-ene clickable hydrogels can be used for the generation of cell-laden, pure PG gels or for the generation of more complex, coherent zonal constructs. Furthermore, thiol-ene clickable PG hydrogels have already been further modified and successfully been used in 3D bioprinting experiments [204]. 3D bioprinting, as part of the evolving biofabrication field [205], offers the possibilities to generate complex and hierarchical structures, and to exactly position defined layers, yet at the same time alters the requirements for the utilized hydrogels [159, 206–209]. Since a robust chondrogenesis of MSCs was demonstrated in the thiol-ene clickable hydrogel systems, they may serve as a basis for the development of hydrogels as so called bioinks which may be utilized in more sophisticated biofabrication processes.
Arbuscular Mycorrhiza and Root Nodule Symbiosis are symbiotic interactions with a high benefit for plant growth and crop production. Thus, it is of great interest to understand the developmental process of these symbioses in detail. We analysed very early symbiotic responses of Medicago truncatula root hair cells, by stimulation with lipochitinoligosaccharides specific for the induction of nodules (Nod-LCOs), or the interaction with mycorrhiza (Myc-LCOs). Intracellular micro electrodes were used, in combination with Ca\(^{2+}\) sensitive reporter dyes, to study the relations between cytosolic Ca\(^{2+}\) signals and membrane potential changes. We found that sulfated Myc- as well as Nod-LCOs initiate a membrane depolarization, which depends on the chemical composition of these signaling molecules, as well as the genotype of the plants that were studied. A successive application of sulfated Myc-LCOs and Nod-LCOs resulted only in a single transient depolarization, indicating that Myc-LCOs can repress plasma membrane responses to Nod-LCOs. In contrast to current models, the Nod-LCO-induced depolarization precedes changes in the cytosolic Ca\(^{2+}\) level of root hair cells. The Nod-LCO induced membrane depolarization thus is most likely independent of cytosolic Ca\(^{2+}\) signals and nuclear Ca\(^{2+}\) spiking.
Myocardial B-cell infiltration after LAD occlusion in mice is driven by CXCL13
After myocardial infarction, the immune system is activated and regulates wound healing and remodeling processes in the heart.
While the role of T cells has been elucidated already, the function of B cells in myocardial infarction remained relatively unclear until now. It is, however, already known that B cells are of importance in healing processes in other tissues, for example in the skin.
Our studies therefore addressed the role and function of B cells in healing and early remodeling processes in the myocardium after infarction.
Under physiological conditions, only few B cells can be found in the heart. After myocardial infarction, however, which we modelled with a permanent ligation of the left anterior descending artery (LAD) in C57BL/6J mice, we could demonstrate that B lymphocytes accumulate in the early phase after tissue injury (days one to seven) in the myocardium.
To detect B cells, we performed immunofluorescence stainings on cryosections of infarcted hearts using an anti-B220 antibody. Quantitative analysis of tissue infiltration revealed that B cells peaked at day seven. In flow cytometry, we further characterized the B cells infiltrating infarcted tissue. We found that most of them were mature B cells (IgM+, IgD+).
Next, we wanted to outline a potential mechanism responsible for B-cell infiltration to the site of tissue injury. We therefore performed ELISA experiments revealing that CXCL13 was upregulated in scar tissue.
Antibody-mediated neutralization of CXCL13 verifiably attenuated B-cell infiltration.
Treated mice also showed – in the tendency – smaller infarct sizes and an improved survival.
In conclusion, we could show that B lymphocytes infiltrate the myocardium after MI in mice following a local CXCL13 gradient and that it is, most likely, beneficial to inhibit this process.
Deoxyribozymes are synthetic enzymes made of DNA that can catalyze the cleavage or formation of phosphodiester bonds and are useful tools for RNA biochemistry. Here we report new RNA-cleaving deoxyribozymes to interrogate the methylation status of target RNAs, thereby providing an alternative method for the biochemical validation of RNA methylation sites containing N\(^6\)-methyladenosine, which is the most wide-spread and extensively investigated natural RNA modification. Using in vitro selection from random DNA, we developed deoxyribozymes that are sensitive to the presence of N\(^6\)-methyladenosine in RNA near the cleavage site. One class of these DNA enzymes shows faster cleavage of methylated RNA, while others are strongly inhibited by the modified nucleotide. The general applicability of the new deoxyribozymes is demonstrated for several examples of natural RNA sequences, including a lncRNA and a set of C/D box snoRNAs, which have been suggested to contain m\(^6\)A as a regulatory element that influences RNA folding and protein binding.
Given points in the plane, connect them using minimum ink. Though the task seems simple, it turns out to be very time consuming. In fact, scientists believe that computers cannot efficiently solve it. So, do we have to resign? This book examines such NP-hard network-design problems, from connectivity problems in graphs to polygonal drawing problems on the plane. First, we observe why it is so hard to optimally solve these problems. Then, we go over to attack them anyway. We develop fast algorithms that find approximate solutions that are very close to the optimal ones. Hence, connecting points with slightly more ink is not hard.
Neuroanatomy of the equine brain as revealed by high-field (3Tesla) magnetic-resonance-imaging
(2018)
In this study, the morphology of the horse brain (Equus caballus) is decribed in detail using high field MRI. The study includes sagittal, dorsal, and transverse T2-weighted images at 0.25 mm resolution at 3 Tesla and 3D models of the brain presenting the external morphology of the brain. Representative gallocyanin stained histological slides of the same brain are presented. The images represent a useful tool for MR image interpretation in horses and may serve as a starting point for further research aiming at in vivo analysis in this species.
The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.
The thesis describes the development of new synthetic strategies towards planar nanometer-sized and electron-deficient polycyclic aromatic dicarboximides, which are rather unexplored compared with the large variety of electron-rich polycyclic aromatic hydrocarbons and nanographenes. Thus, new polycyclic aromatic systems containing a different number of dicarboximide groups were designed since this class of compounds has revealed its significance in the past due to a range of desirable molecular properties and its high thermal and photochemical stability. The synthetic concept towards these systems includes different C–C coupling techniques that were combined within coupling cascade reactions. Therefore, this thesis provides new insights into the reactivity of aromatic substrates and elucidates mechanistic aspects of C–C coupling cascade reactions to facilitate the precise design of new and desirable materials based on polycyclic aromatic dicarboximides. Furthermore, structure-property relationships as well as the optical and electrochemical properties were investigated by UV/Vis absorption and fluorescence spectroscopy and cyclic or square wave voltammetry. Insights into the molecular structures in the solid state were obtained by single-crystal X-ray analysis. In subsequent studies, highly electron-deficient perylene bisimides and their reduced species have been investigated in detail. Thus, core-functionalized perylene bisimides were synthesized and UV/Vis absorption spectroscopy, spectroelectrochemistry and cyclic or square wave voltammetry were used to determine their optical properties and the stability of the individual reduced species.
In the recent two decades, LIM and SH3 protein 1 (LASP1) has been developed from a simple actin-binding structural protein to a tumor biomarker and subsequently to a complex, nuclear transcriptional regulator. Starting with a brief historical perspective, this review will mainly compare and contrast LASP1 and LASP2 from the angle of the newest data and importantly, examine their role in transcriptional regulation. We will summarize the current knowledge through pictorial models and tables including the roles of different microRNAs in the differential regulation of LASP1 levels and patient outcome rather than specify in detail all tumor entities. Finally, the novel functional roles of LASP1 in secretion of vesicles, expression of matrix metalloproteinases and transcriptional regulation as well as the activation of survival and proliferation pathways in different cancer types are described.
Background
Conjunctival melanoma is a potentially deadly eye tumour. Despite effective local therapies, tumour recurrence and metastasis remain frequent. The genetics of conjunctival melanomas remain incompletely understood.
Methods
A large cohort of 63 conjunctival melanomas was screened for gene mutations known to be important in other melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with patient prognosis.
Results
Frequent mutations in genes activating the MAP kinase pathway were identified. NF1 mutations were most frequent (n = 21, 33%). Recurrent activating mutations were also identified in BRAF (n = 16, 25%) and RAS genes (n = 12, 19%; 11 NRAS and 1 KRAS).
Conclusions
Similar to cutaneous melanomas, conjunctival melanomas can be grouped genetically into four groups: BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type melanomas. This genetic classification may be useful for assessment of therapeutic options for patients with metastatic conjunctival melanoma
The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy. In addition to altering the metabolic state in cancer cells, some multifunctional enzymes possess non-metabolic functions that also contribute to cell transformation. Some multifunctional enzymes that are highly expressed in cancer, such as pyruvate kinase M2 (PKM2), have non-canonical functions that are co-opted by oncogenic signaling to drive proliferation and inhibit apoptosis. Other multifunctional enzymes that are frequently downregulated in cancer, such as fructose-bisphosphatase 1 (FBP1), are tumor suppressors, directly opposing mitogenic signaling via their non-canonical functions. In some cases, the enzymatic and non-canonical roles of these enzymes are functionally linked, making the modulation of non-metabolic cellular processes dependent on the metabolic state of the cell.
The rise of automated driving will fundamentally change our mobility in the near future. This thesis specifically considers the stage of so called highly automated driving (Level 3, SAE International, 2014). At this level, a system carries out vehicle guidance in specific application areas, e.g. on highway roads. The driver can temporarily suspend from monitoring the driving task and might use the time by engaging in so called non-driving related tasks (NDR-tasks). However, the driver is still in charge to resume vehicle control when prompted by the system. This new role of the driver has to be critically examined from a human factors perspective.
The main aim of this thesis was to systematically investigate the impact of different NDR-tasks on driver behavior and take-over performance. Wickens’ (2008) architecture of multiple resource theory was chosen as theoretical framework, with the building blocks of multiplicity (task interference due to resource overlap), mental workload (task demands), and aspects of executive control or self-regulation. Specific adaptations and extensions of the theory were discussed to account for the context of NDR-task interactions in highly automated driving.
Overall four driving simulator studies were carried out to investigate the role of these theoretical components. Study 1 showed that drivers focused NDR-task engagement on sections of highly automated compared to manual driving. In addition, drivers avoided task engagement prior to predictable take-over situations. These results indicate that self-regulatory behavior, as reported for manual driving, also takes place in the context of highly automated driving. Study 2 specifically addressed the impact of NDR-tasks’ stimulus and response modalities on take-over performance. Results showed that particularly visual-manual tasks with high motoric load (including the need to get rid of a handheld object) had detrimental effects. However, drivers seemed to be aware of task specific distraction in take-over situations and strictly canceled visual-manual tasks compared to a low impairing auditory-vocal task. Study 3 revealed that also the mental demand of NDR-tasks should be considered for drivers’ take-over performance. Finally, different human-machine-interfaces were developed and evaluated in Simulator Study 4. Concepts including an explicit pre-alert (“notification”) clearly supported drivers’ self-regulation and achieved high usability and acceptance ratings.
Overall, this thesis indicates that the architecture of multiple resource theory provides a useful framework for research in this field. Practical implications arise regarding the potential legal regulation of NDR-tasks as well as the design of elaborated human-machine-interfaces.
Fremdschämen or Fremdscham, a negative emotion which arises while observing someone behave inappropriately, comes to fame after the turn of the millennium in german speaking countries. There, they name it literally „other‘s shame“ and it becomes obvious that this emotion happens most commonly while watching TV: reality shows, talent shows and bad comedies. The word even makes it to the dictionaries starting 2009, as its use increases unstoppably in everyday language, starting to get used in more and more situations, seemingly as a synonym of embarrassing or shameful. Still, a look in the emotional research on the subject returns exactly zero results as of 2011, leaving open the question as of what this emotion might be, and what it is not. The present wort aims at explaining not only the phenomenon of Fremdschämen, but also the Emotion behind it - Embarrassment -, at a process level.
Renin–angiotensin system (RAS) plays an important role in the regulation of blood pressure and hormonal balance. Using positron emission tomography (PET) technology, it is possible to monitor the physiological and pathological distribution of angiotensin II type 1 receptors (AT\(_1\)), which reflects the functionality of RAS. A new \(^{18}\)F-labeled PET tracer derived from the clinically used AT\(_1\) antagonist valsartan showing the least possible chemical alteration from the valsartan structure has been designed and synthesized with several strategies, which can be applied for the syntheses of further derivatives. Radioligand binding study showed that the cold reference FV45 (K\(_i\) 14.6 nM) has almost equivalent binding affinity as its lead valsartan (K\(_i\) 11.8 nM) and angiotensin II (K\(_i\) 1.7 nM). Successful radiolabeling of FV45 in a one-pot radiofluorination followed by the deprotection procedure with 21.8 ± 8.5% radiochemical yield and >99% radiochemical purity (n = 5) enabled a distribution study in rats and opened a path to straightforward large-scale production. A fast and clear kidney uptake could be observed, and this renal uptake could be selectively blocked by pretreatment with AT\(_1\)-selective antagonist valsartan. Overall, as the first \(^{18}\)F-labeled PET tracer based on a derivation from clinically used drug valsartan with almost identical chemical structure, [\(^{18}\)F]FV45 will be a new tool for assessing the RAS function by visualizing AT\(_i\) receptor distributions and providing further information regarding cardiovascular system malfunction as well as possible applications in inflammation research and cancer diagnosis.
Marine sponge-associated actinomycetes are reservoirs of diverse natural products with novel biological activities. Their antibiotic potential has been well explored against a range of Gram positive and negative bacteria. However, not much is known about their anti-infective or anti-virulence potential against human pathogens. This Ph.D. project aimed to investigate the anti-infective (anti-Shiga toxin and anti-biofilm) potential of sponge-derived actinobacteria through identification and isolation of their bioactive metabolites produced and characterizing their mechanism of action by transcriptomics. This thesis is divided into three studies with the overall objective of exploring the anti-infective efficacy of actinomycetes-derived extracts and compound(s) that could possibly be used as future therapeutics.
The first study deals with investigation on the anti-Shiga toxin effects of sponge-associated actinomycetes. Diarrheal infections pose a huge burden in several developing and developed countries. Diarrheal outbreaks caused by Enterohemorrhagic Escherichia coli (EHEC) could lead to life-threatening complications like gastroenteritis and haemolytic uremic syndrome (HUS) if left untreated. Shiga toxin (Stx) produced by EHEC is a major virulence factor that negatively affects the human cells, leading them to death via apoptosis. Antibiotics are not prescribed against EHEC infections since they may enhance the risk of development of HUS by inducing the production and release of Stx from disintegrating bacteria and thereby, worsening the complications. Therefore, an effective drug that blocks the Stx production without affecting the growth needs to be urgently developed. In this study, the inhibitory effects of 194 extracts and several compounds originating from a collection of marine sponge-derived actinomycetes were evaluated against the Stx production in EHEC strain EDL933 with the aid of Ridascreen® Verotoxin ELISA assay kit. It was found that treatment with the extracts did not lead to significant reduction in Stx production. However, strepthonium A isolated from the culture of Streptomyces sp. SBT345 (previously cultivated from the Mediterranean sponge Agelas oroides) reduced the Stx production (at 80 μM concentration) in EHEC strain EDL933 without affecting the bacterial growth. The structure of strepthonium A was resolved by spectroscopic analyses including 1D and 2D-NMR, as well as ESI-HRMS and ESI-HRMS2 experiments. This demonstrated the possible application of strepthonium A in restraining EHEC infections.
VI
In the second study, the effect of marine sponge-associated actinomycetes on biofilm formation of staphylococci was assessed. Medical devices such as contact lenses, metallic implants, catheters, pacemakers etc. are ideal ecological niches for formation of bacterial biofilms, which thereby lead to device-related infections. Bacteria in biofilms are multiple fold more tolerant to the host immune responses and conventional antibiotics, and hence are hard-to-treat. Here, the anti-biofilm potential of an organic extract derived from liquid fermentation of Streptomyces sp. SBT343 (previously cultivated from the Mediterranean sponge Petrosia ficiformis) was reported. Results obtained in vitro demonstrated its anti-biofilm (against staphylococci) and non-toxic nature (against mouse macrophage (J774.1), fibroblast (NIH/3T3) and human corneal epithelial cell lines). Interestingly, SBT343 extract could inhibit staphylococcal biofilm formation on polystyrene, glass and contact lens surfaces without affecting the bacterial growth. High Resolution Fourier Transform Mass Spectrometry (HR-MS) analysis indicated the complexity and the chemical diversity of components present in the extract. Preliminary physio-chemical characterization unmasked the heat stable and non-proteinaceous nature of the active component(s) in the extract. Finally, fractionation experiments revealed that the biological activity was due to synergistic effects of multiple components present in the extract.
In the third study, anti-biofilm screening of 50 organic extracts generated from solid and liquid fermentation of 25 different previously characterized sponge-derived actinomycetes was carried out. This led to identification of the anti-biofilm organic extract derived from the solid culture of Streptomyces sp. SBT348 (previously cultivated from the Mediterranean sponge Petrosia ficiformis). Bioassay-guided fractionation was employed to identify the active fraction Fr 7 in the SBT348 crude extract. Further purification with semi-preparative HPLC led to isolation of the bioactive SKC1, SKC2, SKC3, SKC4 and SKC5 sub-fractions. The most active sub-fraction SKC3 was found to be a pure compound having BIC90 and MIC values of 3.95 μg/ml and 31.25 μg/ml against S. epidermidis RP62A. SKC3 had no apparent toxicity in vitro on cell lines and in vivo on the greater wax moth Galleria melonella larvae. SKC3 was stable to heat and enzymatic treatments indicating its non-proteinaceous nature. HR-MS analysis revealed the mass of SKC3 to be 1258.3 Da. Structure elucidation of SKC3 with the aid of 1D and 2D-NMR data is currently under investigation. Further, to obtain insights into the mode of action of SKC3 on S. epidermidis RP62A, RNA sequencing was done. Transcriptome data revealed that SKC3 was recognized by RP62A at 20 min and SKC3 negatively interfered with the central metabolism of staphylococci at 3 h. Taken
VII
together, these findings suggest that SKC3 could be a lead structure for development of new anti-staphylococcal drugs.
Overall, the results obtained from this work underscore the anti-infective attributes of actinomycetes consortia associated with marine sponges, and their applications in natural product drug discovery programs.
This work summarizes the results of studies on three major aspects of platelet signaling and of the pathogenesis of immune thrombocytopenia. Therefore, this thesis is divided into three parts. i) Platelet activation and subsequent thrombus formation at sites of vascular injury is crucial for normal hemostasis, but it can also trigger myocardial infarction and stroke. The initial capture of flowing platelets to the injured vessel wall is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on the exposed subendothelial extracellular matrix (ECM). The central importance of GPIb for platelet adhesion is well established, whereas GPV is generally considered to be of minor relevance for platelet physiology and thrombus formation. This study intended to clarify the relevance of this receptor during thrombus formation using Gp5-/- mice and mice with different double-deficiencies in GPV and in other platelet receptors. It was found that GPV and the collagen receptor integrin a2b1 have partially redundant functions in collagentriggered platelet aggregation. Further, it was revealed that GPV limits thrombus formation and impairs hemostasis in vivo. The data presented here demonstrate that the protective effect of GPVI-deficiency (another platelet collagen receptor) in arterial thrombosis and ischemic stroke depends on the expression of GPV. Moreover, it was demonstrated that lack of GPV restores the hemostatic function of mice lacking both GPVI and a2b1 or mice lacking GPVI and the C-type lectin receptor 2 (CLEC-2). Conclusively, GPV-depletion or blockade might have the potential to treat hemorrhagic disease states. ii) Platelets contain the two phospholipase (PL) D isoforms, PLD1 and PLD2, both of which presumably become activated upon platelet stimulation. However, the function of PLD in the process of platelet activation and aggregation has not been definitively explored. Thus, PLD-deficient mice were analyzed. Mice lacking PLD1 or PLD2 were viable, fertile and had normal platelet counts. PLD1 was found to be responsible for the inducible PLD-activity in platelets and to contribute to efficient integrin activation under static conditions. Moreover, flow adhesion experiments revealed that PLD1 is essential for efficient GPIb-mediated integrin activation. Consequently, Pld1-/- mice were protected from arterial thrombosis and ischemic brain infarction without affecting tail bleeding times. Hence, inhibition of PLD1 might be a novel approach for antithrombotic therapy. iii) Cellular activation of platelets or immune cells results in increased cytosolic calcium (Ca2+) levels. Store-operated calcium entry (SOCE) via the STIM1-Orai1 axis is the main route of Ca2+ entry downstream of immunoreceptor tyrosine-based activating motif (ITAM) receptor stimulation in mast cells and T cells. However, the requirement of Ca2+-mobilization in Fcg receptor (FcgR)-signaling and the relevance of STIM2 for T cell SOCE have been unclear. To address these questions, genetically modified mice lacking central molecules of the SOCE machinery were analyzed. Ca2+-measurements revealed that both STIM isoforms contribute to Ca2+-mobilization downstream of T cell receptor activation. Additionally, it was found that FcgR stimulation results in SOCE and is mediated by STIM1 and probably Orai1. Animal models of immune thrombocytopenia (ITP) revealed that SOCE is essential for platelet clearance and that both STIM isoforms contribute to the pathology of ITP. Moreover, in this work it was also demonstrated that STIM1 and Orai1 are essential in IgG-mediated systemic anaphylaxis. STIM2 contributes to IgG-mediated, but not to IgE-mediated anaphylaxis. The data indicate that interference with SOCE might become a new strategy to prevent or treat IgG-dependent autoimmune diseases.
Since four decades, high-throughput screenings have been conducted in drug discovery, fuelling the identification of potential new drug candidates. This approach, however, often promotes the detection of compounds with undesired physico-chemical properties like poor aqueous solubility or low membrane permeability. Indeed, dissolution and absorption of a drug are prerequisites for systemic exposure and therapeutic effects. Therefore, innovative strategies to optimize unfavourable performance of new drug candidates are in great demand in order to increase drug concentrations at the site of action whilst simultaneously reducing drug variability.
In chapter I of this research work, hydrophobic ion pairing (HIP) is discussed as a promising strategy to improve the bioavailability of BCS class III compounds, which have high aqueous solubility and low permeability. The review points out the limitations of poorly absorbable drugs and details the approach of pairing these APIs with hydrophobic counterions. Apart from the motivation to tailor physico-chemical, biopharmaceutical and toxicological properties of BCS class III compounds, the hydrophobic ion pairing facilitates their formulation into drug delivery systems. Besides advantageous effects, disadvantages of the ion pair formation, such as the decreased aqueous solubility of the ions pair, are critically outlined. Finally, the review covers an overview of non-invasive administration routes permitted after ion pair formation, including oral/enteral, buccal, nasal, ocular and transdermal drug administration. Overall, the HIP approach offers substantial benefits regarding the bioavailability enhancement of BCS class III compounds.
Chapter II concerns GHQ168 developed by Holzgrabe et al., a BCS class II compound characterized by low aqueous solubility and high permeability. GHQ168 was developed for the treatment of human African trypanosomiasis (HAT), a tropical disease for which novel active compounds are urgently needed. This lead compound was found to be very active against trypanosoma brucei brucei and trypanosoma brucei rhodesiense in cell
culture assays, however, the low aqueous solubility prevented further preclinical development. To target this drawback, two different approaches were selected, including (I) the chemical modification and (II) the spray drying of GHQ168. The newly synthesized set of derivatives as well as the spray dried GHQ168 were subjected to a physico-chemical and microbiological characterization. It turned out that both approaches successfully improved aqueous solubility, however, for the derivatives of GHQ168 at the expense of activity. Furthermore, the pharmacokinetic parameters of GHQ168 and of the most active derivatives, GHQ242 and GHQ243, were evaluated. Elimination half-lives between 1.5 to 3.5 h after intraperitoneal administration and modest to strong serum albumin binding for GHQ243 (45%) and GHQ168 (80%) and very high binding (> 99%) for GHQ242 were detected. The spray dried formulation of GHQ168, as well as GHQ242 and GHQ243 were investigated in two in vivo studies in mice infected with t. b. rhodesiense (STIB900), referred to as (I) stringent model and (II) early-treatment model. In the stringent model (2 applications/day on day 3-6 after infection) the mean survival duration (MSD) of mice treated with spray dried GHQ168 exceeded the MSD of the untreated control group (17 days versus 9 days), a difference that was statistically significant. In contrast, no statistical difference was observed for GHQ242 (14 days) and GHQ243 (12 days). GHQ168 was further assessed in the early-treatment model (2 applications/day on day 1-4 after infection) and again a statistically significant improvement of MSD (32 days (end of observation period) versus 7 days) was observed. Finally, exciting antitrypanosomal efficacy for the spray dried formulation of GHQ168 was demonstrated.
NADPH oxidases (NOX) were found to be the main source of endothelial reactive oxygen species (ROS) formation. Chapter III reports on the formulation studies on triazolopyrimidine derivatives from the VAS library, a set of NADPH oxidase inhibitors. These were developed for the treatment of elevated ROS levels, which contribute to the development of cardiovascular diseases. Although in vitro results from numerous studies indicated promising efficacy and selectivity for the VAS-compounds, the low water solubility impeded the in vivo translation and further preclinical development. For this reason, three derivatives, VAS2870, VAS3947, and VAS4024 were physico-chemically characterized and VAS3947, the most soluble compound, was selected for further formulation studies. These approaches included (I) spray drying, (II) microemulsification and (III) complexation with cyclodextrins in order to develop formulations for oral and parenteral application. Solubility improvement of VAS3947 was successfully demonstrated for all preparations as expressed by supersaturation ratios in comparison to the solubility of the unformulated compound. For seven spray dried formulations, the ratio ranged from 3-9, and the ratio for four microemulsions was 8-19 after 120 min, respectively. The six cyclodextrin formulations achieved the highest supersaturation ratio between 3 and 174 after 20 hours. NMR measurements elucidated the inclusion of VAS3947 within the CD’s cavity as well as the interaction with its outer surface. Ultimately, NOX inhibitors were opened for oral and parenteral administration for the first time.
After successful solubility improvement of VAS3947, further investigations towards in vivo studies were conducted including stability studies with a focus on stability in solution and in plasma as presented in chapter IV. Furthermore, permeability and cytotoxicity assays were performed for the first time. It turned out that VAS3947 was instable in buffer and when exposed to light. Moreover, the compound showed decomposition in the presence of mouse microsomes and in human plasma. The VAS compounds contain an oxazol moiety linked to the triazolopyrimidine skeleton via a thioether. This structural element is responsible for the efficacy of the compound class, however it is susceptible to hydrolysis and to further degradation reactions. Moreover, VAS3947 harmed membrane integrity in the cell permeability assays and cytotoxicity investigations in HEK-293 and HEP-G2 cells revealed IC50 values in the same concentration range as reported for efficacy assays. Summarized, it was demonstrated that substances from the VAS library were no appropriate model compounds for ROS investigations nor suitable candidates for further preclinical development.
Background:
Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce.
Methods:
We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry.
Results:
LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands.
Conclusions:
We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.
Bosonic condensation belongs to the most intriguing phenomena in physics, and was mostly reserved for experiments with ultra-cold quantum gases. More recently, it became accessible in exciton-based solid-state systems at elevated temperatures. Here, we demonstrate bosonic condensation driven by excitons hosted in an atomically thin layer of MoSe2, strongly coupled to light in a solid-state resonator. The structure is operated in the regime of collective strong coupling between a Tamm-plasmon resonance, GaAs quantum well excitons, and two-dimensional excitons confined in the monolayer crystal. Polariton condensation in a monolayer crystal manifests by a superlinear increase of emission intensity from the hybrid polariton mode, its density-dependent blueshift, and a dramatic collapse of the emission linewidth, a hallmark of temporal coherence. Importantly, we observe a significant spin-polarization in the injected polariton condensate, a fingerprint for spin-valley locking in monolayer excitons. Our results pave the way towards highly nonlinear, coherent valleytronic devices and light sources.
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
Obese children and adolescents are at high risk of developing cardiovascular diseases later in life. We hypothesized that cardiovascular prophylaxis with omega-3 fatty acids could benefit them. In our study, 20 children and adolescents (mean body mass index percentile: 99.1; mean age: 11.0 years) underwent two ambulatory 24 h Holter electrocardiography (ECG) recordings (before and after at least 3 months of omega-3 fatty acid supplementation). Time domain heart rate variability (HRV) and heart rate (HR) were examined for these patients. As a control, we used 24 h Holter ECG recordings of 94 nonobese children and adolescents. Time domain HRV parameters, which are indicators of vagal stimulation, were significantly lower in obese patients than in healthy controls, but HR was higher (standard deviation of the normal-to-normal [SDNN] interbeat intervals: −34.02%; root mean square of successive differences [RMSSD] between normal heartbeats: −40.66%; percentage of consecutive RR intervals [pNN50]: −60.24%; HR: +13.37%). After omega-3 fatty acid supplementation, time domain HRV parameters and HR of obese patients were similar to the values of healthy controls (SDNN interbeat intervals: −21.73%; RMSSD: −19.56%; pNN50: −25.59%; HR: +3.94%). Therefore, omega-3 fatty acid supplementation may be used for cardiovascular prophylaxis in obese children and adolescents.
Beatty sets (also called Beatty sequences) have appeared as early as 1772 in the astronomical studies of Johann III Bernoulli as a tool for easing manual calculations and - as Elwin Bruno Christoffel pointed out in 1888 - lend themselves to exposing intricate properties of the real irrationals. Since then, numerous researchers have explored a multitude of arithmetic properties of Beatty sets; the interrelation between Beatty sets and modular inversion, as well as Beatty sets and the set of rational primes, being the central topic of this book. The inquiry into the relation to rational primes is complemented by considering a natural generalisation to imaginary quadratic number fields.
The aim of this work is to provide further insight into the qualitative behavior of mechanical systems that are well described by Lennard-Jones type interactions on an atomistic scale. By means of Gamma-convergence techniques, we study the continuum limit of one-dimensional chains of atoms with finite range interactions of Lennard-Jones type, including the classical Lennard-Jones potentials. So far, explicit formula for the continuum limit were only available for the case of nearest and next-to-nearest neighbour interactions. In this work, we provide an explicit expression for the continuum limit in the case of finite range interactions. The obtained homogenization formula is given by the convexification of a Cauchy-Born energy density. Furthermore, we study rescaled energies in which bulk and surface contributions scale in the same way. The related discrete-to-continuum limit yields a rigorous derivation of a one-dimensional version of Griffith' fracture energy and thus generalizes earlier derivations for nearest and next-to-nearest neighbors to the case of finite range interactions. A crucial ingredient to our proofs is a novel decomposition of the energy that allows for re fined estimates.
The main theme of this thesis is the development of multigrid and hierarchical matrix solution procedures with almost linear computational complexity for classes of partial integro-differential problems. An elliptic partial integro-differential equation, a convection-diffusion partial integro-differential equation and a convection-diffusion partial integro-differential optimality system are investigated. In the first part of this work, an efficient multigrid finite-differences scheme for solving an elliptic
Fredholm partial integro-differential equation (PIDE) is discussed. This scheme combines a second-order accurate finite difference discretization and a Simpson's quadrature rule to approximate the PIDE problem and a multigrid scheme and a fast
multilevel integration method of the Fredholm operator allowing the fast solution of the PIDE problem. Theoretical estimates of second-order accuracy and results of local Fourier analysis of convergence of the proposed multigrid scheme
are presented. Results of numerical experiments validate these estimates and demonstrate optimal computational complexity of the proposed framework that includes numerical experiments for elliptic PIDE problems with singular kernels. The experience gained in this part of the work is used for the investigation of convection diffusion partial-integro differential equations in the second part of this thesis.
Convection-diffusion PIDE problems are discretized using a finite volume scheme referred to as the Chang and Cooper (CC) scheme and a quadrature rule. Also for this class of PIDE problems and this numerical setting, a stability and accuracy analysis of the CC scheme combined with a Simpson's quadrature rule is presented proving second-order accuracy of the numerical solution. To extend and investigate the proposed approximation and solution strategy to the case of systems of convection-diffusion PIDE, an optimal control problem governed by this model is considered. In this case the research focus is the CC-Simpson's discretization of the optimality system and its solution by the proposed multigrid strategy. Second-order accuracy of the optimization solution is proved and results of local Fourier analysis are presented that provide sharp convergence estimates of the optimal computational complexity of the multigrid-fast integration technique.
While (geometric) multigrid techniques require ad-hoc implementation depending on the structure of the PIDE problem and on the dimensionality of the domain where the problem is considered, the hierarchical matrix framework allows a more general treatment that exploits the algebraic structure of the problem at hand. In this thesis, this framework is extended to the case of combined differential and integral problems considering the case of a convection-diffusion PIDE. In this case, the starting point is the CC discretization of the convection-diffusion operator combined with the trapezoidal quadrature rule. The hierarchical matrix approach exploits the algebraic nature of the hierarchical matrices for blockwise approximations by low-rank matrices of the sparse convection-diffusion approximation and enables data sparse representation of the fully populated matrix where all essential matrix operations are performed with at most logarithmic optimal complexity. The factorization of part of or the whole coefficient matrix is used as a preconditioner to the solution of the PIDE problem using a generalized minimum residual (GMRes) procedure as a solver.
Numerical analysis estimates of the accuracy of the
finite-volume and trapezoidal rule approximation are
presented and combined with estimates of the
hierarchical matrix approximation and with the
accuracy of the GMRes iterates. Results of numerical experiments are reported that
successfully validate the theoretical estimates and
the optimal computational complexity of the proposed hierarchical matrix
solution procedure. These results include an extension to higher dimensions and an application to the time evolution of the probability density function of a jump diffusion process.