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- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (4)
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ResearcherID
- M-1240-2017 (1)
Work is seen by many thinkers as the fundamental dimension of man`s existence on earth. Through work, he provides his basic necessities on earth and co-operate with God in the work of creation.
He received this mandate to work from the very beginning of creation by God. In carrying out this mandate, man every human being reflects the very action of the creator of the Universe.
God worked and intended that man who is created in His image and likeness continues the work of creation by working.
Even though Man suffers and sweats through work and yet, in spite of all this toil-perhaps in a sense because of it – work is a good thing for man. It is not only good in the sense that it is useful or something to enjoy; it is also good as being something worthy, that is to say something that corresponds to man's dignity that expresses this dignity and increases it.
This project examines man as a creature called to work and born into work. It is true that through work, man provides himself and his family with the basic necessities of life and everyday needs for the reason he charges wages for his sweat. Work goes beyond and should exceed the boundaries of the material benefit that comes out of it to the satisfaction and fulfilment for the very purpose we should work. The modern society has attached so much importance to money and material possession, the question then is how do we go along working in the spirit of improvement and renewal of the earth? The modern man understands work only as a means of making his daily bread. For this reason, he engages himself in an occupation that he has little or no interest in. He ends up quarrelling everyday with the people that he or she is supposed to serve through work. The result is low work output and waste of talents and the society loses an opportunity for improvement as every creature is supposed to contribute uniquely.
A good example is Nigeria, Africa’s most populous nation with a population estimate of about over 170,000,000 people and the sixth Oil producing Nation.
Adult human skeletal stem cells are considered to give rise to the bone marrow stromal
compartment, including bone-forming osteoblasts and marrow adipocytes. Reduced osteogenesis
and enhanced adipogenesis of these skeletal progenitors may contribute to the bone loss and
marrow fat accumulation observed during aging and osteoporosis, the main disorder of bone
remodeling. Concordantly, in vitro evidence indicates that adipogenic and osteogenic
differentiation of human bone marrow stromal cells (hBMSCs) display an inverse relationship
under numerous conditions. Hence, the identification of factors modulating inversely both
differentiation pathways is of great therapeutic interest.
Based on mRNA expression analysis of inversely regulated genes after switching differentiation
conditions, our group had previously proposed that fibroblast growth factor 1 (FGF1) might play
such a modulator role in hBMSC differentiation. The main aim of this work was, therefore, to
investigate the role of FGF1 signaling in the adipogenic and osteogenic differentiation of hBMSCs
using a three-dimensional (3D) culture system based on collagen type I hydrogels in order to
better mimic the natural microenvironment.
Adipogenic and osteogenic differentiation of hBMSCs embedded in collagen gels was successfully
established. Treatment with recombinant human FGF1 (rhFGF1), as well as rhFGF2, throughout
differentiation induction was found to exert a dose-dependent inhibitory effect on adipogenesis
in hBMSCs. This inhibitory effect was found to be reversible and dependent on FGF receptors
(FGFR) signaling, given that simultaneous pharmacological blockage of FGFRs rescued adipogenic
differentiation. Additionally, matrix mineralization under osteogenic induction was also inhibited
by rhFGF1 and rhFGF2 in a dose-dependent manner. A transient treatment with rhFGF1 and
rhFGF2 during an expansion phase, however, enhanced proliferation of hBMSCs without affecting
the differentiation capacity, although matrix mineralization under osteogenic conditions was
hindered.
Additionally, rhFGF1 and rhFGF2 treatments affected the matrix remodeling ability of hBMSCs,
which displayed alterations in the cytoskeletal phenotype and the expression patterns of matrix
metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).
On the other hand, inhibition of FGFR signaling throughout differentiation induction elicited a
strong enhancement of matrix mineralization under osteogenic conditions but had no significant
effect on adipocyte formation under adipogenic induction.
IX
In conclusion, FGF1 and FGF2 signaling was found to support the expansion of bone marrow
stromal precursors with adipogenic and osteogenic capacities, to hinder adipogenic and
osteogenic differentiation if continuously present during differentiation induction and to alter the
matrix remodeling ability of hBMSCs within a 3D collagenous microenvironment.
In highly polarized cells like neurons, cytoskeleton dynamics play a crucial role in establishing neuronal connections during development and are required for adult plasticity. Actin turnover is particularly important for neurite growth, axon path finding, branching and synaptogenesis. Motoneurons establish several thousand branches that innervate neuromuscular synapses (NMJs). Axonal branching and terminal arborization are fundamental events during the establishment of synapses in motor endplates. Branching process is triggered by the assembly of actin filaments along the axon shaft giving rise to filopodia formation. The unique contribution of the three actin isoforms, α-, β- and γ-actin, in filopodia stability and dynamics during this process is not well characterized. Here, we performed high resolution in situ hybridization and qRT-PCR and showed that in primary mouse motoneurons α-, β- and γ-actin isoforms are expressed and their transcripts are translocated into axons. Using FRAP experiments, we showed that transcripts for α-, β- and γ-actin become locally translated in axonal growth cones and translation hot spots of the axonal branch points. Using live cell imaging, we showed that shRNA depletion of α-actin reduces dynamics of axonal filopodia which correlates with reduced number of collateral branches and impairs axon elongation. Depletion of β-actin correlates with reduced dynamics of growth cone filopoida, disturbs axon elongation and impairs presynaptic differentiation. Also, depletion of γ-actin impairs axonal growth and decreases axonal filopodia dynamics. These findings implicate that actin isoforms accomplish unique functions during development of motor axons. Depletions of β- and γ-actin lead to compensatory upregulation of other two isoforms. Consistent with this, total actin levels remain unaltered and F-actin polymerization capacity is preserved. After the knockdown of either α- or γ-actin, the levels of β-actin increase in the G-actin pool indicating that polymerization and stability of β-actin filaments depend on α- or γ-actin. This study provides evidence both for unique and overlapping function of actin isoforms in motoneuron growth and differentiation. In the soma of developing motoneurons, actin isoforms act redundantly and thus could compensate for each other’s loss. In the axon, α-, β- and γ-actin accomplish specific functions, i.e. β-actin regulates axon elongation and plasticity and α- and γ-actin regulate axonal branching.
Furthermore, we show that both axonal transport and local translation of α-, β- and γ-actin isoforms are impaired in Smn knockout motoneurons, indicating a role for Smn protein in RNA granule assembly and local translation of these actin isoforms in primary mouse motoneurons.
Describing the light-to-energy conversion in OSCs requires a multiscale understanding of the involved optoelectronic processes, i.e., an understanding from the molecular, intermolecular, and aggregate perspective. This thesis presents such a multiscale description to provide insight into the processes in the vicinity of the organic::organic interface, which are crucial for the overall performance of OSCs. Light absorption, exciton diffusion, photoinduced charge transfer at the donor-acceptor interface, and charge separation are included. In order to establish structure-property relationships, a variety of different molecular p-type semiconductors are combined at the organic donor-acceptor heterojunction with fullerene C60, one of the most common acceptors in OSCs. Starting with a comprehensive analysis of the accuracy of diverse ab initio, DFT, and semiempiric methods for the properties of the individual molecules, the intermolecular, and aggregate/device stage are subsequently addressed. At all stages, both methodological concepts and physical aspects in OSCs are discussed to extend the microscopic understanding of the charge generation processes.
The dissertation deals with the market and welfare effects of different business practices and the firm's incentives to use them: resale price maintenance, revenue sharing of a platform operator, membership fees to buyers using a platform and patent licensing.
In the second chapter we investigate the incentives of two manufacturers with common retailers to use resale price maintenance (RPM). Retailers provide product specific services that increase demand and manufacturers use minimum RPM to compete for favorable services for their products. Minimum RPM increases consumer pricesby voiding retailer price competition and can create a prisoner’s dilemma for manufacturers without increasing, and possibly even decreasing the overall service level. If manufacturer market power is asymmetric, minimum RPM tends to distort the allocation of sales services towards the high-priced products of the manufacturer with more market power. These results challenge the service argument as an efficiency defense for minimum RPM.
The third chapter deals with trade platforms whose operators not only allow third party sellers to offer their products to consumers, but also offer products themselves. In this context, the platform operator faces a hold-up problem if he uses classical two-part tariffs only (which previous literature on two-sided markets has focused on) as potential competition between the platform operator and sellers reduces platform attractiveness. Since some sellers refuse to join the platform, some products that are not known to the platform operator will not be offered at all. We discuss the effects of different platform tariffs on this hold-up problem. We find that revenue-based fees lower the platform operator's incentives to compete with sellers, increasing platform attractiveness. Therefore, charging such proportional fees can be profitable, what may explain why several trade platforms indeed charge proportional fees.
The fourth chapter investigates the optimal tariff system in a model in which buyers are heterogeneous. A platform model is presented in which transactions are modeled explicitly and buyers can differ in their expected valuations when they decide to join the platform. The main effect that the model identifies is that the participation decision sorts buyers according to their expected valuations. This affects the pricing of sellers. Furthermore diffing form the usual approach, in which buyers are ex-ante homogeneous, the platform does not internalize the full transaction surplus. Hence it does not implement the socially efficient price on the platform, also it has control of the price with the transaction fee.
The fifth chapter investigates the effects of licensing on the market outcome after the patent has expired. In a setting with endogenous entry, a licensee has a head start over the competition which translated into a first mover advantage if strategies are strategic substitutes. As competitive strategies quantities and informative advertising are considered explicitly. We find that although licensing increases the joint profit of the patentee and licensee, this does not necessarily come from a reduction in consumer surplus or other firms profits. For the case of quantity competition we show that licensing is welfare improving. For the case of informative advertising, however, we show that licensing increases prices and is thus detrimental to consumer surplus.
The contact of hot melt with liquid water - called Molten Fuel Coolant Interaction (MFCI) - can result in vivid explosions. Such explosions can occur in different scenarios: in steel or powerplants but also in volcanoes. Because of the possible dramatic consequences of such explosions an investigation of the explosion process is necessary.
Fundamental basics of this process are already discovered and explained, such as the frame conditions for these explosions. It has been shown that energy transfer during an MFCI-process can be very high because of the transfer of thermal energy caused by positive feedback mechanisms.
Up to now the influence of several varying parameters on the energy transfer and the explosions is not yet investigated sufficiently. An important parameter is the melt temperature, because the amount of possibly transferable energy depends on it. The investigation of this influence is the main aim of this work. Therefor metallic tin melt was used, because of its nearly constant thermal material properties in a wide temperature range. With tin melt research in the temperature range from 400 °C up to 1000 °C are
possible.
One important result is the lower temperature limit for vapor film stability in the experiments. For low melt temperatures up to about 600 °C the vapor film is so unstable that it already can collapse before the mechanical trigger. As expected the transferred thermal energy all in all increases with higher temperatures. Although this effect sometimes is superposed by other influences such as the premix of melt and water, the result is confirmed after a consequent filtering of the remaining influences. This trend is not only recognizable in the amount of transferred energy, but also in the fragmentation of melt or the vaporizing water. But also the other influences on MFCI-explosions showed interesting results in the frame of this work. To perform the experiments the installation and preparation of the experimental Setup in the laboratory were necessary.
In order to compare the results to volcanism and to get a better investigation of the brittle fragmentation
of melt additional runs with magmatic melt were made. In the results the thermal power during energy transfer could be estimated. Furthermore the model of “cooling fragments “ could be usefully applied.
The genetic information encoded with in the genes are transcribed and translated to give rise to
the functional proteins, which are building block of a cell. At first, it was thought that the
regulation of gene expression particularly occurs at the level of transcription by various
transcription factors. Recent discoveries have shown the vital role of gene regulation at the level
of RNA also known as post-transcriptional gene regulation (PTGR). Apart from non-coding RNAs
e.g. micro RNAs, various RNA binding proteins (RBPs) play essential role in PTGR. RBPs have
been implicated in different stages of mRNA life cycle ranging from splicing, processing,
transport, localization and decay. In last 20 years studies have shown the presence of hundreds
of RBPs across eukaryotic systems many of which are widely conserved. Given the rising number
of RBPs and their link to human diseases it is quite evident that RBPs have major role in cellular
processes and their regulation. The current study is aimed to describe the so far unknown
molecular mechanism of CCHC-type Zinc Finger Nucleic Acid Binding Protein (CNBP/ZNF9)
function in vivo.
CNBP is ubiquitously expressed across various human tissues and is a highly conserved RBP in
eukaryotes. It is required for embryonic development in mammals and has been implicated in
transcriptional as well as post-transcriptional gene regulation; however, its molecular function
and direct target genes remain elusive. Here, we use multiple systems-wide approaches to
identify CNBP targets and document the consequences of CNBP binding. We established CNBP as
a cytoplasmic RNA-binding-protein and used Photoactivatable Ribonucleoside Enhanced
Crosslinking and Immunoprecipitation (PAR-CLIP) to identify direct interactions of CNBP with
4178 mRNAs. CNBP preferentially bound a G-rich motif in the target mRNA coding sequences.
Functional analyses, including ribosome profiling, RNA sequencing, and luciferase assays
revealed the CNBP mode of action on target transcripts. CNBP binding was found to increase the
translational efficiency of its target genes. We hypothesize that this is consistent with an RNA
chaperone function of CNBP helping to resolve secondary structures, thus promoting
translation. Altogether this study provides a novel mechanism of CNBP function in vivo and acts
as a step-stone to study the individual CNBP targets that will bring us closer to understand the
disease onset.
In contrast to normal vessels, tumor vasculature is structurally and functionally abnormal. Tumor vessels are highly disorganized, tortuous and dilated, with uneven diameter and excessive branching. Consequently, tumor blood flow is chaotic, which leads to hypoxic and acidic regions in tumors. These conditions lower the therapeutic effectiveness and select for cancer cells that are more malignant and metastatic. The therapeutic outcome could be improved by increasing the functionality and density of the tumor vasculature. Tumor angiogenesis also shows parallels to epithelial to mesenchymal transition (EMT), a process enabling metastasis. Metastasis is a multi-step process, during which tumor cells have to invade the surrounding host tissue to reach the circulation and to be transported to distant sites.
We hypothesize that the variability in the phenotype of the tumor vasculature is controlled by the differential expression of key transcription factors. Inhibiting these transcription factors might be a promising way for angiogenic intervention and vascular re-engineering. Therefore, we investigated the interdependence of tumor-, stroma- and immune cell-derived angiogenic factors, transcription factors and resulting vessel phenotypes. Additionally, we evaluated whether transcription factors that regulate EMT are promising targets for vascular remodeling.
We used formalin fixed paraffin embedded samples from breast cancer patients, classified according to estrogen-, progesterone- and human epidermal growth factor receptor (HER) 2 status. Establishing various techniques (CD34 staining, laser microdissection, RNA isolation and expression profiling) we systematically analyzed tumor and stroma-derived growths factors. In addition, vascular parameters such as microvessel size, area, circularity and density were assessed. Finally the established expression profiles were correlated with the observed vessel phenotype. As the SNAI1 transcriptional repressor is a key regulator of EMT, we examined the effect of vascular knockdown of Snai1 in murine cancer models (E0771, B16-F10 and lewis lung carcinoma).
Among individual mammary carcinomas, but not among subtypes, strong differences of vascular parameters were observed. Also, little difference between lobular carcinomas and ductal carcinomas was found. Vessel phenotype of Her2 enriched carcinomas was similar to that of lobular carcinomas. Vessel morphology of luminal A and B and basal-like tumors resembled each other. Expression of angiogenic factors was variable across subtypes. We discovered an inverse correlation of PDGF-B and VEGF-A with vessel area in luminal A tumors. In these tumors expression of IL12A, an inhibitor of angiogenesis, was also correlated with vessel size. Treatment of endothelial cells with growth factors revealed an increased expression of transcription factors involved in the regulation of EMT. Knockdown of Snai1 in endothelial cells of mice increased tumor growth and decreased hypoxia in the E0771 and the B16-F10 models. In the lewis lung carcinomas, tumor vascularity and biodistribution of doxorubicin were improved. Here, doxorubicin treatment in combination with the endothelial cell-specific knockdown did slow tumor growth. This shows that SNAI1 is important for a tumor's vascularization, with the significance of its role depending on the tumor model.
The methods established in this work open the way for the analysis of the expression of key transcription factors in vessels of formalin fixed paraffin embedded tumors. This research enables us to find novel targets for vascular intervention and to eventually design novel targeted drugs to inhibit these targets.
The obligate human pathogen Neisseria gonorrhoeae is responsible for the widespread sexually transmitted disease gonorrhoea, which in rare cases also leads to the development of disseminated gonococcal infection (DGI). DGI is mediated by PorBIA-expressing bacteria that invade host cells under low phosphate condition by interaction with the scavenger receptor-1 (SREC-I) expressed on the surface of endothelial cells. The interaction of PorBIA and SREC-I was analysed using different in vitro approaches, including surface plasmon resonance experiments that revealed a direct phosphate-independent high affinity interaction of SREC-I to PorBIA. However, the same binding affinity was also found for the other allele PorBIB, which indicates unspecific binding and suggests that the applied methods were unsuitable for this interaction analysis.
Since N. gonorrhoeae was recently classified as a “super-bug” due to a rising number of antibiotic-resistant strains, this study aimed to discover inhibitors against the PorBIA-mediated invasion of N. gonorrhoeae. Additionally, inhibitors were searched against the human pathogen Chlamydia trachomatis, which causes sexually transmitted infections as well as infections of the upper inner eyelid. 68 compounds, including plant-derived small molecules, extracts or pure compounds of marine sponges or sponge-associated bacteria and pipecolic acid derivatives, were screened using an automated microscopy based approach. No active substances against N. gonorrhoeae could be identified, while seven highly antichlamydial compounds were detected.
The pipecolic acid derivatives were synthesized as potential inhibitors of the virulence-associated “macrophage infectivity potentiator” (MIP), which exhibits a peptidyl prolyl cis-trans isomerase (PPIase) enzyme activity. This study investigated the role of C. trachomatis and N. gonorrhoeae MIP during infection. The two inhibitors PipN3 and PipN4 decreased the PPIase activity of recombinant chlamydial and neisserial MIP in a dose-dependent manner. Both compounds affected the chlamydial growth and development in epithelial cells. Furthermore, this work demonstrated the contribution of MIP to a prolonged survival of N. gonorrhoeae in the presence of neutrophils, which was significantly reduced in the presence of PipN3 and PipN4.
SF2446A2 was one of the compounds that had a severe effect on the growth and development of C. trachomatis. The analysis of the mode of action of SF2446A2 revealed an inhibitory effect of the compound on the mitochondrial respiration and mitochondrial ATP
production of the host cell. However, the chlamydial development was independent of proper functional mitochondria, which excluded the connection of the antichlamydial properties of SF2446A2 with its inhibition of the respiratory chain. Only the depletion of cellular ATP by blocking glycolysis and mitochondrial respiratory chain inhibited the chlamydial growth. A direct effect of SF2446A2 on C. trachomatis was assumed, since the growth of the bacteria N. gonorrhoeae and Staphylococcus aureus was also affected by the compound.
In summary, this study identified the severe antichlamydial activity of plant-derived naphthoquinones and the compounds derived from marine sponges or sponge-associated bacteria SF2446A2, ageloline A and gelliusterol E. Furthermore, the work points out the importance of the MIP proteins during infection and presents pipecolic acid derivatives as novel antimicrobials against N. gonorrhoeae and C. trachomatis.
Spliceosomal U-rich small ribonucleoprotein particles (U snRNPs) are the major building
blocks of the nuclear pre-mRNA splicing machinery. The core composition of U snRNPs
includes the name giving U snRNA and a set of seven common (Sm) proteins termed Sm
B/B’, D1, D2, D3, E, F and G. These Sm proteins are arranged in the form of a toroidal ring on
the single stranded conserved sequence element in the snRNA to form the Sm core domain.
Even though U snRNPs assemble spontaneously in vitro, their assembly in vivo requires an
amazingly large number of trans-acting assembly factors united in the Protein Arginine
Methyltransferase 5 (PRMT5) and the Survival Motor Neuron (SMN) complexes. The
cytoplasmic assembly pathway of U snRNPs can be divided into the early and the late phase.
The early phase is dominated by the assembly chaperone, pICln, a subunit of the PRMT5
complex. This factor binds to Sm proteins and delivers them in a pICln-bound form to the
PRMT5 complex. The early assembly phase then segregates into two lines. In one assembly
line, a stable hexameric ring intermediate (6S complex) composed of pICln and the five Sm
proteins D1, D2, F, E and G, is formed. This intermediate forms at the PRMT5 complex but
dissociates from the latter upon completion of its assembly. Within the 6S complex, these Sm
proteins are pre-organized into respective spatial positions adopted in the assembled U
snRNP. The other assembly line forms a protein trimer composed of pICln, Sm B/B’ and D3,
which unlike the 6S complex is not released from the PRMT5 complex. As a consequence of
their association with pICln, Sm proteins are kinetically trapped and fail to proceed in the
assembly pathway. The late phase of the U snRNP formation is dominated by the SMN
complex, which resolves this kinetic trap by dissociating pICln from the pre-organized Sm
proteins and, subsequently catalyzes the loading of the Sm proteins on the U snRNA.
Even though basic principles of U snRNP assembly have been understood in some detail, the
question arises as to why cells employ sophisticated assembly machinery for the assembly
despite the reaction occurring spontaneously in vitro. A few studies have shown that the
system works towards rendering specificity to the assembly reaction. However, Sm proteins
in their free form expose hydrophobic surfaces to the cytosolic solvent. Hence, I reasoned that
the assembly machinery of snRNPs might also prevent Sm protein aggregation.
In this thesis, I describe the work that leads to the discovery of a multi-layered regulatory
network for Sm proteins involving post-transcriptional and post-translational surveillance
mechanisms. Here, I show that the reduced level of SMN (a key assembly factor of the late
phase) leads to the initial tailback of Sm proteins over pICln followed by the transcriptional
down regulation of Sm protein encoding mRNAs. In contrast, depletion of pICln, a key factor
of the early phase, results in the retention of Sm proteins on the ribosomes followed by their
degradation via autophagy. Furthermore, I show that exceeding levels of Sm proteins over
pICln caused by overexpression results in aggregation and mis-localization of Sm proteins.
Thus, my findings uncover a complex regulatory network that helps to maintain the cellular
U snRNP homeostasis by either preventing or clearing the unassembled Sm protein
aggregates when they are not faithfully incorporated into the U snRNPs.
Objective: To examine the effects of two different treatment approaches on the course of anorexia nervosa (AN) over time.
Methods: The subjects were 27 hospitalized AN patients (mean age: 14.91 years; mean BMI: 14.58; mean height: 163.56) . In our retrospective analysis we compared weight gain in two groups. While one group was treated with a standard oral refeeding protocol (historical control) through January 2013 (N=16), the second group (highly standardized refeeding protocol) received a high energy liquid nutrition and nutritional supplements including omega-3 fatty acids (N=11).
Results: On admission, the two groups were comparable in terms of height, weight, age and heart rate. At the end of our monitoring time frame of 25 days, weight gain was 121.4% higher in the highly standardized refeeding protocol group than in the historical control group (66.5 ±52.4 vs 147.3 ±55.7 grams/day; t-Test p=0.004; CI95%: 29.3-132.2). About 45% of our patients stated they were vegetarians at admission. However, we could not identify a vegetarian diet as a statistically significant negative prognostic factor for weight gain.
Discussion: The highly standardized refeeding protocol seems to be helpful in malnourished AN patients to improve weight gain without enhancing the risk of a refeeding syndrome. Because of an increasing energy turnover, caloric intake should be adjusted during refeeding.
Recent advances in the field of cancer immunotherapy have enabled this therapeutic approach to enter the mainstream of modern cancer treatment. In particular, adoptive T cell therapy (ACT) is a potentially powerful immunotherapy approach that relies on the administration of tumor-specific T cells into the patient. There are several strategies to obtain tumor-reactive cytotoxic T lymphocytes (CTLs), which have already been shown to induce remarkable responses in the clinical setting. However, there are concerns and limitations regarding the conventional approaches to obtain tumor-reactive T cells, such as accuracy of the procedure and reproducibility. Therefore, we aimed to develop two approaches to improve the precision and efficacy of tumor-reactive T cells therapy. These two techniques could constitute effective, safe and broadly applicable alternatives to the conventional methods for obtaining tumor-specific CTLs.
The first approach of this study is the so called “Doublet Technology”. Here, we demonstrate that peptide-human leukocyte antigen-T cell receptor (pHLA-TCR) interactions that involve immune reactive peptides are stable and strong. Therefore, the CTLs that are bound by their TCR to tumor cells can be selected and isolated through FACS-based cell sorting taking advantage of this stable interaction between the CTLs and the target cells. The CTLs from acute myeloid leukemia (AML) patients obtained with this technique show cytolytic activity against blast cells suggesting a potential clinical use of these CTLs. “Doublet Technology” offers a personalized therapy in which there is no need for a priori knowledge of the exact tumor antigen.
The second approach of this study is the Chimeric Antigen Receptor (CAR) Technology. We design several CARs targeting the B-Cell Maturation Antigen (BCMA). BCMA CAR T cells show antigen-specific cytolytic activity, production of cytokines including IFN-γ and IL-2, as well as productive proliferation. Although we confirm the presence of soluble BCMA in serum of multiple myeloma (MM) patients, we demonstrate that the presence of soluble protein does not abrogate the efficacy of BCMA CAR T cells suggesting that BCMA CAR T cells can be used in the clinical setting to treat MM patients. The high antigen specificity of CAR T cells allows efficient tumor cell eradication and makes CAR Technology attractive for broadly applicable therapies.
This thesis contributes to several issues in the context of SDN and NFV, with an emphasis on performance and management.
The main contributions are guide lines for operators migrating to software-based networks, as well as an analytical model for the packet processing in a Linux system using the Kernel NAPI.
The progress which has been made in semiconductor chip production in recent years enables a multitude of cores on a single die. However, due to further decreasing structure sizes, fault tolerance and energy consumption will represent key challenges. Furthermore, an efficient communication infrastructure is indispensable due to the high parallelism at those systems. The predominant communication system at such highly parallel systems is a Network on Chip (NoC). The focus of this thesis is on NoCs which are based on deflection routing. In this context, contributions are made to two domains, fault tolerance and dimensioning of the optimal link width. Both aspects are essential for the application of reliable, energy efficient, and deflection routing based NoCs.
It is expected that future semiconductor systems have to cope with high fault probabilities. The inherently given high connectivity of most NoC topologies can be exploited to tolerate the breakdown of links and other components. In this thesis, a fault-tolerant router architecture has been developed, which stands out for the deployed interconnection architecture and the method to overcome complex fault situations. The presented simulation results show, all data packets arrive at their destination, even at high fault probabilities. In contrast to routing table based architectures, the hardware costs of the herein presented architecture are lower and, in particular, independent of the number of components in the network.
Besides fault tolerance, hardware costs and energy efficiency are of great importance. The utilized link width has a decisive influence on these aspects. In particular, at deflection routing based NoCs, over- and under-sizing of the link width leads to unnecessary high hardware costs and bad performance, respectively. In the second part of this thesis, the optimal link width at deflection routing based NoCs is investigated. Additionally, a method to reduce the link width is introduced. Simulation and synthesis results show, the herein presented method allows a significant reduction of hardware costs at comparable performance.
Driving simulators are powerful research tools. Countless simulator studies have contributed to traffic safety over the last decades. Constant improvements in simulator technology call for a measureable scale to assess driving simulators with regard to their utility in human factors research. A promising psychological construct to do so is presence. It is commonly defined as the feeling of being located in a remote or virtual environment that seems to be real. Another aspect of presence describes the ability to act there successfully.
The main aim of this thesis is to develop a presence model dedicated to the application in driving simulators. Established models have been combined and extended in order to gain a comprehensive model of presence that allows understanding its emergence and deriving recommendations on how to design or improve driving simulators. The five studies presented in this thesis investigate specific postulated model components and their interactions. All studies deal with motorcycling or a motorcycle riding simulator as exemplary field of application.
The first study used a speed estimation task to investigate the contribution of different sensory cues to presence. While visualization plays a particularly important role, further improvements could be achieved by adding more consistent sensory stimuli to the virtual environment. Auditory, proprioceptive and vestibular cues have been subject to investigation. In the second study, the speed production method was applied. It confirmed the positive contribution of action to presence as predicted by psychocybernetic models. The third study dealt with the effect of training on presence. Hence, no positive effect was observed. The fourth study aimed at replicating previous findings on sensory fidelity and diversity in a more complex riding situation than only longitudinal vehicle control. The riders had to cross an unexpectedly appearing deep pit with the virtual motorcycle. The contribution of more consistent sensory stimulation on presence was successfully shown in this scenario, too. The final study was a real riding experiment that delivered reference values for the speed estimation capabilities of motorcycle riders. Besides higher variations in the simulator data, the general speed estimation performance was on a comparable level. Different measures, such as subjective ratings, behavioral responses, performance, and physiological reactions, have been applied as presence indicators.
These studies’ findings deliver evidence for the meaningful application of the proposed presence model in driving simulator settings. The results suggest that presence can be interpreted as a quality measure for perception in virtual environments. In line with psychocybernetic models, taking action, which is seen as controlling perception, enhances this quality even further. Describing the psychological construct of presence in a theoretical framework that takes the diversity of perception and action in driving simulator settings into account closes a gap in traffic psychological research.
The diborene 1 was synthesized by reduction of a mixture of 1,2-di-9-anthryl-1,2-dibromodiborane(4) (6) and trimethylphosphine with potassium graphite. The X-ray structure of 1 shows the two anthryl rings to be parallel and their π(C\(_{14}\)) systems perpendicular to the diborene π(B=B) system. This twisted conformation allows for intercalation of the relatively high-lying π(B=B) orbital and the low-lying π* orbital of the anthryl moiety with no significant conjugation, resulting in a small HOMO-LUMO gap (HLG) and ultimately an unprecedented anthryl B–B bond hydroarylation. The HLG of 1 was estimated to be 1.57 eV from the onset of the long wavelength band in its UV–vis absorption spectrum (THF, λ\(_{onset}\) = 788 nm). The oxidation of 1 with elemental selenium afforded diboraselenirane 8 in quantitative yield. By oxidative abstraction of one phosphine ligand by another equivalent of elemental selenium, the B–B and C\(^1\)–H bonds of 8 were cleaved to give the cyclic 1,9-diboraanthracene 9.
Effects of timing and herbivory on a grass-endophyte association and its trophic interactions
(2017)
I.) Plant associated microorganisms can affect the plant`s interaction with herbivores and higher trophic levels. For instance, endophytic fungi infecting aerial plant parts of grass species produce bioactive alkaloids that can negatively affect species from higher trophic levels, indicating a defensive mutualism between the grass and the endophyte. However, beneficial insects can also be negatively affected by the endophyte, which might question the mutualistic effect of endophytic fungi. On the other hand, grass-endophytes are affected by environmental conditions and species interactions. Grazing can increase endophyte frequencies in natural habitats. Furthermore, endophyte mediated effects on herbivores are most pronounced during warm summers following rainy springs. In this study, we investigated whether endophyte derived alkaloids cascade up a food chain (chapter II) and whether their concentrations depend on plant age and season (chapter III). Further we analysed, whether altered herbivore phenology affects the endophytic fungus (chapter IV) and whether endophyte derived alkaloid production is induced by different herbivore species (chapter V).
II.) In our first experimental study we analysed whether grass-endophyte derived alkaloids decreased the performance of two ladybird species feeding on aphids exclusively reared on endophyte infected grass (6 weeks young grass). Further, we screened species from three trophic levels (grass, herbivores and aphid predators) for their alkaloid content using two year old infected grass as diet for herbivores. We established an UPLC-MS method to detect and quantify the amount of the endophyte derived alkaloids peramine and lolitrem B extracted from the organic plant and insect material. Performance parameters of ladybirds revealed little differences between ladybirds fed on aphids reared on endophyte infected and non-infected grass, which probably resulted from low alkaloid concentrations in the young (6-weeks old) endophyte infected grass used in this part of the study. Alkaloid quantification of the two year old endophyte infected grass, herbivores and aphid predators revealed similar concentrations between grass and aphids, while aphid predators contained approximately half of that amount which still exceeded the bioactive threshold. We conclude that alkaloids produced by grass-endophytes cascade up the food chain and are responsible for fitness disadvantages of higher trophic levels.
III.) In the second study we investigated the impact of plant age and seasonal timing on grass-endophyte growth and alkaloid production. Plants were sown in April of 2013 and sampled monthly over 30 consecutive months. Endophyte growth was quantified with real-time PCR (qPCR) and alkaloid concentrations with UPLC-MS. We showed that alkaloid concentrations and fungal growth followed a seasonal rhythmicity and that alkaloid concentrations increased with plant age. Alkaloid concentrations peak during summer, when also herbivore abundances are high. Consequently, we conclude that plant age and season contribute to the toxicity of endophytes on grass herbivores
IV.) In the third study we simulated earlier spring arrival of aphids by enhancing aphid abundance on endophyte infected and endophyte-free grass in spring and analysed responses across three trophic levels. Enhanced aphid abundance in spring caused higher aphid abundances during the study period. Predators stayed unaffected by increased herbivore abundances; however they did level aphid numbers within two weeks after arrival on the plants, independent of aphid abundance. Grass-endophyte showed a time delayed growth, two weeks after aphid abundance peak and after predators already controlled aphid infestations on the plants. We conclude that phenology shifts of herbivorous insects can affect multi-trophic interactions leading to desynchronizations between phenologies of interacting species and mismatches in food-webs.
V.) In the fourth study we analysed whether herbivores induce endophyte growth and alkaloid production and whether different types of herbivores induce specific alkaloid production. We applied three different herbivore treatments on endophyte infected grass over 18 weeks. Locust herbivory increased the insect deterring alkaloid peramine and clipping of plants (simulation of grazing livestock) increased the vertebrate toxic alkaloid lolitrem B. Aphid herbivory did not affect endophyte derived alkaloid concentrations. Endophyte responses to herbivory were species specific which indicates a primarily plant protecting role of alkaloid synthesis in endophyte infected plants and a close chemical crosstalk between interacting species.
VI.) In summary, we showed that endophyte derived alkaloids affect higher trophic levels and that alkaloid concentrations in the plant depend on prevalent herbivore species, plant age and seasonal timing. Our results indicate a close chemical crosstalk between the host plant and the endophytic fungus which is susceptible to environmental changes altering the endophyte`s alkaloid production in plants. We gained insights into the grass-endophyte symbiosis in ecological contexts and conclude that several factors determine the herbivore toxic potential of endophytic fungi and thereby their plant mutualistic or parasitic character. Future studies should investigate the mechanisms behind the herbivore induced alkaloid concentration increase, shown in this thesis, especially whether plant signals mediate the endophyte response. Furthermore it would be interesting to study the induction of indirect endophyte mediated defence and how it affects multi-trophic level interactions.
Drug delivery of therapeutic gases – strategies for controlled and local delivery of carbon monoxide
(2017)
The isoenzyme heme oxygenase 1 (HO-1) is a key element for maintaining cellular homeostasis. Upregulated in response to cellular stress, the HO-1 degrades heme into carbon monoxide (CO), biliverdin, and Fe2+. By means of a local cell-protective feedback loop the enzyme triggers numerous effects including anti-oxidative, anti-apoptotic, and anti-inflammatory events associated with complex signalling patterns which are largely orchestrated by CO. Various approaches to mimic this physiological HO-1 / CO system aiming for a treatment of medical conditions have been described [1]. These preclinical studies commonly applied CO systemically via (i) inhalation or (ii) using CO-Releasing Molecules (CORMs) [2]. The clinical use of these approaches, however, is challenged by a lack of practicability and substantial safety issues associated with the toxicity of high systemic doses of CO that are required for triggering therapeutic effects. Therefore, one rational of this thesis is to describe and evaluate strategies for the local delivery of CO aiming for safe and effective CO therapeutics of tomorrow.
Desert ants of the genus Cataglyphis (Formicinae) are widely distributed in arid
areas of the palearctic ecozone. Their habitats range from relatively cluttered environments in the Mediterranean area to almost landmark free deserts. Due to their
sophisticated navigational toolkit, mainly based on the sky-compass, they were
studied extensively for the last 4 decades and are an exceptional model organism
for navigation. Cataglyphis ants exhibit a temporal polyethism: interior workers
stay inside the dark nest and serve as repletes for the first ∼2 weeks of their adult
life (interior I). They then switch to nursing and nest maintenance (interior II)
until they transition to become day-active outdoor foragers after ∼4 weeks. The
latter switch in tasks involves a transition phase of ∼2-3 days during which the
ants perform learning and orientation walks. Only after this last phase do the ants
start to scavenge for food as foragers.
In this present thesis I address two main questions using Cataglyphis desert ants
as a model organism:
1. What are the underlying mechanisms of temporal polyethism?
2. What is the neuronal basis of sky-compass based navigation in Cataglyphis
ants?
Neuropeptides are important regulators of insect physiology and behavior and as
such are promising candidates regarding the regulation of temporal polyethism in
Cataglyphis ants. Neuropeptides are processed from large precursor proteins and undergo substantial post-translational modifications. Therefore, it is crucial to biochemically identify annotated peptides. As hardly any peptide data are available
for ants and no relevant genomic data has been recorded for Cataglyphis, I started
out to identify the neuropeptidome of adult Camponotus floridanus (Formicinae)
workers (manuscript 1). This resulted in the first neuropeptidome described in an
ant species – 39 neuropeptides out of 18 peptide families. Employing a targeted
approach, I identified allatostatin A (AstA), allatotropin (AT), short neuropeptide
F (sNPF) and tachykinin (TK) using mass spectrometry and immunohistology to
investigate the distribution of AstA, AT and TK in the brain (manuscript 2). All
three peptides are localized in the central complex, a brain center for sensory integration and high-order control of locomotion behavior. In addition, AstA and
TK were also found in visual and olfactory input regions and in the mushroom
bodies, the centers for learning and memory formation. Comparing the TK immunostaining in the brain of 1, 7 and 14 days old dark kept animals revealed that
the distribution in the central complex changes, most prominently in the 14 day
old group. In the Drosophila central complex TK modulates locomotor activity
levels. I therefore hypothesize that TK is involved in the internal regulation of the
interior I–interior II transition which occurs after ∼2 weeks of age.
I designed a behavioral setup to test the effect of neuropeptides on the two traits:
’locomotor activity level’ and ’phototaxis’ (manuscript 3). The test showed that
interior I ants are less active than interior II ants, which again are less active
than foragers. Furthermore, interior ants are negatively phototactic compared to
a higher frequency of positive phototaxis in foragers. Testing the influence of AstA
and AT on the ants’ behavior revealed a stage-specific effect: while interior I behavior is not obviously influenced, foragers become positively phototactic and more
active after AT injection and less active after AstA injection. I further tested the
effect of light exposure on the two behavioral traits of interior workers and show that it rises locomotor activity and results in decreased negative phototaxis in
interior ants. However, both interior stages are still more negatively phototactic
than foragers and only the activity level of interior II ants is raised to the forager
level. These results support the hypothesis that neuropeptides and light influence
behavior in a stage-specific manner.
The second objective of this thesis was to investigate the neuronal basis of skycompass navigation in Cataglyphis (manuscript 4). Anatomical localization of the
sky-compass pathway revealed that its general organization is highly similar to
other insect species. I further focused on giant synapses in the lateral complex,
the last relay station before sky-compass information enters the central complex.
A comparison of their numbers between newly eclosed ants and foragers discloses
a rise in synapse numbers from indoor worker to forager, suggesting task-related
synaptic plasticity in the sky-compass pathway. Subsequently I compared synapse
numbers in light preexposed ants and in dark-kept, aged ants. This experiment
showed that light as opposed to age is necessary and sufficient to trigger this rise
in synapse number. The number of newly formed synapses further depends on the
spectral properties of the light to which the ants were exposed to.
Taken together, I described neuropeptides in C. floridanus and C. fortis, and provided first evidence that they influence temporal polyethism in Cataglyphis ants.
I further showed that the extent to which neuropeptides and light can influence
behavior depends on the animals’ state, suggesting that the system is only responsive under certain circumstances. These results provided first insight into the
neuronal regulation of temporal polyethism in Cataglyphis. Furthermore, I characterized the neuronal substrate for sky-compass navigation for the first time in
Cataglyphis. The high level of structural synaptic plasticity in this pathway linked
to the interior–forager transition might be particularly relevant for the initial calibration of the ants’ compass system.
The inhibitory glycine receptors are one of the major mediators of rapid synaptic inhibition in the mammalian brainstem, spinal cord and higher brain centres. They are ligand-gated ion channels that are mainly involved in the regulation of motor functions. Dysfunction of the receptor is associated with motor disorders such as hypereklepxia or some forms of spasticity. GlyR is composed of two glycosylated integral membrane proteins α and β and a peripheral membrane protein of gephyrin. Moreover, there are four known isoforms of the α-subunit (α1-4) of GlyR while there is a single β-subunit. Glycine receptors can be homomeric including α subunits only or heteromeric containing both α and β subunits. To date, strychnine is the ligand that has the highest affinity as glycine receptor ligand. It acts as a competitive antagonist of glycine that results in the inhibition of Cl- ions permeation and consequently reducing GlyR-mediated inhibition.
For a long time, the details of the molecular mechanism of GlyRs inactivation by strychnine were insufficient due to the lack of high-resolution structures of the receptor. Only homology models based on structures of other cys-loop receptors have been available. Recently, 3.0 Å X-ray structure of the human glycine receptor- α3 homopentamer in complex with strychnine, as well as electro cryo-microscopy structures of the zebra fish α1 GlyR in complex with strychnine and glycine were published. Such information provided detailed insight into the molecular recognition of agonists and antagonists and mechanisms of GlyR activation and inactivation.
Very recently, a series of dimeric strychnine analogs obtained by diamide formation of two molecules of 2-aminostrychnine with diacids of different chain length was pharmacologically evaluated at human α1 and α1β glycine receptors. None of the dimeric analogs was superior to strychnine.
The present work focused on the extension of the structure-activity relationships of strychnine derivatives at glycine receptors
All the synthesized compounds were pharmacologically evaluated at human α1 and α1β glycine receptors in a functional FLIPRTM assay and the most potent analogs were pharmacologically evaluated in a whole cell patch-clamp assay and in [3H]strychnine binding studies.
It was reported that 11-(E)-isonitrosostrychnine displayed a 2-times increased binding to both α1 and α1β glycine receptors which prompted us to choose the hydroxyl group as a suitable attachment point to connect two 11-(E)-isonitrosostrychnine molecules using a spacer. In order to explore the GlyR pocket tolerance for oxime extension, a series of oxime ethers with different spacer lengths and sterical/lipophilic properties were synthesized biologically evaluated. Among all the oxime ethers, methyl, allyl and propagyl oxime ethers were the most potent antagonists displaying IC50 values similar to that of strychnine. These findings indicated that strychnine binding site at GlyRs comprises an additional small lipophilic pocket located in close proximity to C11 of strychnine and the groups best accommodated in this pocket are (E)-allyl and (E)-propagyl oxime ethers.
Moreover, 11-aminostrychnine, and the corresponding propionamide were prepared and pharmacologically evaluated to examine the amide function at C11 as potential linker.
A series of dimeric strychnine analogs designed by linking two strychnine molecules through amino groups in position 11 with diacids were synthesized and tested in binding studies and functional assays at human α1 and α1β glycine receptors. The synthesized bivalent ligands were designed to bind simultaneously to two α-subunits of the pentameric glycine receptors causing a possibly stronger inhibition than the monomeric strychnine. However, all the bivalent derivatives showed no significant difference in potency compared to strychnine. When comparing the reference monomeric propionamide containing ethylene spacer to the dimeric ligand containing butylene spacer, a 3-fold increase in potency was observed. Since the dimer containing (CH2)10 spacer length was found to be equipotent to strychnine, it is assumed that one molecule of strychnine binds to the receptor and the ‘additional’ strychnine molecule in the dimer probably protrudes from the orthosteric binding sites of the receptor.
Multiple sclerosis (MS) is the most prevalent neurological disease of the central nervous system (CNS) in young adults and is characterized by inflammation, demyelination and axonal pathology that result in multiple neurological and cognitive deficits. The focus of MS research remains on modulating the immune response, but common therapeutic strategies are only effective in slowing down disease progression and attenuating the symptoms; they cannot cure the disease. Developing an option to prevent neurodegeneration early on would be a valuable addition to the current standard of care for MS. Based on our results we suggest that application of nimodipine could be an effective way to target both neuroinflammation and neurodegeneration. We performed detailed analyses of neurodegeneration in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and in in vitro experiments regarding the effect of the clinically well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated the course of EAE and spinal cord histopathology. Furthermore, it promoted remyelination. The latter could be due to the protective effect on oligodendrocytes and oligodendrocyte precursor cells (OPCs) we observed in response to nimodipine treatment. To our surprise, we detected calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell type-specific and independent of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS expression and reactive oxygen species (ROS) activity in EAE. Overall, application of nimodipine seems to generate a favorable environment for regenerative processes and could therefore be a novel treatment option for MS, combining immunomodulatory effects while promoting neuroregeneration.
Synthesis of Dualsteric Ligands for Muscarinic Acetylcholine Receptors and Cholinesterase Inhibitors
(2017)
The study is dealing with the synthesis and pharmacological investigation of newly designed dualsteric ligands of muscarinic acetylcholine receptors belonging to the superfamily of G protein-coupled receptors. Such bipharmacophoric ligands combine the advantages of the orthosteric binding site (high-affinity) and of the topographically distinct allosteric binding site (subtype-selectivity) resulting in compounds with reduced side effects. This opens the way to a new therapeutic approach in the treatment of e.g. chronic pain, drug withdrawal, Parkinson`s and Alzheimer`s disease. Furthermore, the newly synthesized dualsteric compounds were pharmacologically investigated in order to get a better understanding of the activation and signaling processes in muscarinic acetylcholine receptors, especially with regard to partial agonism.
The development of the “dynamic ligand binding” concept offers new perspectives for ligand binding and signaling at G protein-coupled receptors. GPCRs are no longer considered as simple on/off switches. Dualsteric ligands can bind in a dualsteric pose, reflecting an active receptor state as well as in a purely allosteric binding pose, characterized by an inactive receptor state resulting in partial agonism. The degree of partial agonism depends on the ratio of active versus inactive receptor populations. On this basis, orthosteric/orthosteric hybrid ligands consisting of the antagonist atropine and scopolamine, respectively, as well as of the agonist iperoxo and isoxazole, respectively, linked via different alkyl chain length were synthesized in order to investigate partial agonism (Figure 1).
Figure 1: Structures of the synthesized iperoxo/isoxazole-atropine/scopolamine-hybrids.
Furthermore, different sets of quaternary and tertiary homodimers consisting either of two iperoxo or two acetylcholine units were synthesized in order to study their extent on partial agonism (Figure 2). The two agonists were connected by varying alkyl chain length. Binding studies on CHO-hM2 cells of the quaternary compounds revealed that dimerization of the agonist results in a loss of potency. The iperoxo-dimers reached higher maximum effects on the Gi- as well as on the Gs pathway in comparison to the acetylcholine-dimers. Besides the choice of the orthosteric building block (potency of the agonist), the alkyl chain length is also crucial for the degree of partial agonism.
Figure 2: Structures of the synthesized quat./tert. iperoxo/acetylcholine-homodimers.
Quinolone-based hybrids connected to the superagonist iperoxo and to the endogenous ligand acetylcholine, respectively, linked through an alkyl chain of different length were synthesized in order to develop further partial agonists (Figure 3). FRET studies confirmed M1 subtype-selectivity as well as linker dependent receptor response. The greatest positive FRET signal was observed with quinolone-C6-iper resulting from a positive cooperativity between the two separated moieties, alloster and orthoster. However, the corresponding hybrids with a longer linker led to an inverse FRET signal indicating a different binding mode, e.g. purely allosteric, in contrast to the shorter linked hybrids. Furthermore, the flexible alkyl spacer was replaced by a rigidified linker resulting in the hybrid quinolone-rigid-iperoxo (Figure 3). FRET studies on the M1 receptor showed reduced FRET kinetics, resulting from interactions between the bulky linker and the aromatic lid, located between the orthosteric and allosteric binding site. A bitopic binding mode of the rigidified hybrid is presumed. For further clarity, mutational studies are necessary.
Figure 3: M1-selective hybrid compounds.
Another aim of this work was the design and synthesis of new hybrid compounds, acting as agonists at the M1 and M2 receptor and as inhibitors for AChE and BChE in the context of M. Alzheimer. Several sets of hybrid compounds consisting of different pharmacophoric units (catalytic active site: phthalimide, naphthalimide, tacrine; peripheric anionic site: iperoxo, isoxazole) linked through a polymethylene chain of varying length were synthesized. Tac-C10-iper (Figure 4), consisting of tacrine and the superagonist iperoxo linked by a C10 polymethylene spacer, was found to have excellent anticholinesterase activity for both AChE (pIC50 = 9.81) and BChE (pIC50 = 8.75). Docking experiments provided a structural model to rationalize the inhibitory power towards AChE. Additionally, the tacrine related hybrids showed affinity to the M1 and M2 receptor. Such compounds, addressing more than one molecular target are favorable for multifactorial diseases such as Alzheimer.
Figure 4: Structure of the most active compound regarding anticholinesterase activity.
In summary, the choice of the pharmacophoric units, their connecting point as well as the nature, length, and flexibility of the linker play an important role for the activity of designed bivalent ligands. A shorter linker length cannot bridge both binding sites simultaneously in contrast to longer linker chains. On the other hand, too long linker chains can result in unwanted steric interactions. Further investigations with respect to structural variations of hybrid compounds, with or without quaternary ammonium groups, are necessary in the light of drug development.
Simple Solution-Phase Syntheses of Tetrahalodiboranes(4) and their Labile Dimethylsulfide Adducts
(2017)
Convenient, solution-phase syntheses of tetrahalodiboranes(4) B\(_2\)F\(_4\), B\(_2\)Cl\(_4\) and B\(_2\)I\(_4\) are presented herein from common precursor B\(_2\)Br\(_4\). In addition, the dimethylsulfide adducts B\(_2\)Cl\(_4\)(SMe\(_2\))\(_2\) and B\(_2\)Br\(_4\)(SMe\(_2\))\(_2\) are conveniently prepared in one-step syntheses from the commercially-available starting material B\(_2\)(NMe\(_2\))\(_4\). The results provide simple access to the full range of tetrahalodiboranes(4) for the exploration of their untapped synthetic potential.
An explicit Runge-Kutta discontinuous Galerkin (RKDG) method is used to device numerical schemes for both the compressible Euler equations of gas dynamics and the ideal magneto- hydrodynamical (MHD) model. These systems of conservation laws are known to have discontinuous solutions. Discontinuities are the source of spurious oscillations in the solution profile of the numerical approximation, when a high order accurate numerical method is used. Different techniques are reviewed in order to control spurious oscillations. A shock detection technique is shown to be useful in order to determine the regions where the spurious oscillations appear such that a Limiter can be used to eliminate these numeric artifacts. To guarantee the positivity of specific variables like the density and the pressure, a positivity preserving limiter is used. Furthermore, a numerical flux, proven to preserve the entropy stability of the semi-discrete DG scheme for the MHD system is used. Finally, the numerical schemes are implemented using the deal.II C++ libraries in the dflo code. The solution of common test cases show the capability of the method.
Tourism in Würzburg: Suggestions on how to enhance the travel experience for Chinese tourists
(2017)
This report provides suggestions on how to enhance the travel experience for Chinese tourists in the German city of Würzburg. Based on a user experience survey and a market research, this work includes a quantitative and competitive analysis. It further provides concrete and hands-on measurements for the city council to improve the experience of Chinese visitors coming to Würzburg.
Chapter 2 concerns the audit market for German credit institutions (excluding savings banks and cooperative banks), and the presented study allows conclusions to be drawn regarding recent concentration levels of this particular audit market. The last reliable (statistical) studies concerning the audit market for German credit institutions were published several years ago (Grothe 2005; Lenz 1996b; Lenz 1997; Lenz 1998). This is surprising because parts of the new regulations concerning the audit market for public-interest entities—which should also apply to credit institutions (European Commission 2006c)—in Europe would require analyses of the audit market concentration to be performed on a regular basis. Therefore, this study begins to fill this research gap, and it reveals that the audit market for German credit institutions was highly concentrated (market leadership: KPMG AG WPG and PricewaterhouseCoopers AG WPG) in 2006 and 2010. Moreover, the findings also highlight that between these years, neither a notable trend toward higher levels of concentration nor a deconcentration process was evident. Finally, it is illustrated that the regulatory requirements for publishing audit fees and the corresponding right to claim exemption (§§ 285 Sentence 1 No. 17, 314 (1) No. 9 Commercial Code) do not allow the calculation of concentration figures that cover the entire audit market for credit institutions. Thus, it will continue to be necessary to use surrogates for audit fees, and analyses reveal that the arithmetic mean of the total business volume (or total assets) of a credit institution and its square root is a very good surrogate for calculating concentration measures based on audit fees.
Chapter 3 seeks to determine whether public oversight of public-interest entities (PIEs) increases audit fees specifically in the financial industry, which is already a highly regulated industry characterized by intense supervision. To answer this question, a sample of 573 German credit institutions is examined over the 2009–2011 period, as not all credit institutions were considered PIEs in Germany (until very recently). First, the results show that a credit institution’s business risk is related to audit fees. In addition, the findings reveal not only that PIE credit institutions pay statistically significantly higher audit fees but also that this effect is economically substantial (representing an audit fee increase of 31.38%). Finally, there are several indications that the relationship between (other) credit institutions’ business risks and audit fees is greater for PIE credit institutions.
Chapter 4 examines the association between the results of auditor ratification votes and perceived external financial reporting quality. As has been recently remarked by Wei et al. (2015), far too little is known about shareholders’ interests in and perceptions of the election, approval or ratification of auditors. Although auditor ratification by shareholders is normally a routine, non-binding action and the voting ratios are in the range of 95% or higher, the SEC emphasized the importance of this process by amending the disclosure requirements for such voting results in 2010 (SEC 2009; SEC 2010). This study demonstrates that the results of auditor ratification votes are associated with market reactions to earnings surprises (SEC registrants; 2010 to 2013). Moreover, there are moderate indications that this effect may be positively related to higher levels of information asymmetry between managers and shareholders, that such voting results contain incremental informational content beyond that of other publicly available audit-related information, and that the time lag between the ratification of an auditor and the earnings announcement influences the vote’s importance. Finally, the study sheds additional light on an overlooked audit-related topic (e.g., Dao et al. 2012; Hermanson et al. 2009; Krishnan and Ye 2005; Sainty et al. 2002), and illustrates its relation to accounting. More importantly, the provided evidence indicates that disclosure of the results of auditor ratification votes might benefit (prospective) shareholders.
Chapter 5 addresses the question of whether and when shareholders may have a negative perception of an auditor’s economic dependence on the client. The results for a Big 4 client sample in the U.S. (2010 to 2014) show that the economic importance of the client—measured at the audit office-level—is negatively associated with shareholders’ perceptions of external financial reporting quality—measured in terms of the earnings response coefficient and the ex ante cost of equity capital—and, therefore, is perceived as a threat to auditor independence. Moreover, the study reveals that shareholders primarily regard independence due to client dependence as a problem for firms that are more likely to be in financially distressed conditions.
This essay argues that Orwell’s representation of animals as companion species offers a strikingly new, as-yet largely neglected view of animal agency and interiority in his work. In “Shooting an Elephant”, Burmese Days and “Marrakech”, the writer’s focus on the social reject is supplemented by a marked sense of community implying human tragedy yet framing it within precariously situated human-animal, colonial or urban-imperial transitions that visualise animals as agents of change and co-shaping species interdependent with the lives of the humans that utilize and domineer them. Animals are required whenever Orwell aspires to shift from isolation to communality, from the self-conscious outsider to the larger realm of ideas framing the world in which his characters strive to overstep the accepted lines of social performance and conformity. Read in and around disciplinary structures of rationalization, Orwell’s animals appear to secure themselves, quite paradoxically, a place within the normative anthropocentric framework excluding them. They extend beyond anthropomorphising or allegorical modes of description and open up bio-political perspectives within and across regimes of knowledge and empathy. Orwell’s writings thus present a challenge to the culturally accredited fantasy of human exceptionalism, collapsing any epistemic space between humans and animals and burying the idea of sustaining radical species distinction.
Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14–1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05–1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01–1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01–1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15–1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91–1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01–1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90–1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08–0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11–0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13–0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26–5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.
C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma.
Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up.
Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed.
In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.
Analysis of host microRNA function uncovers a role for miR-29b-2-5p in Shigella capture by filopodia
(2017)
MicroRNAs play an important role in the interplay between bacterial pathogens and host cells, participating as host defense mechanisms, as well as exploited by bacteria to subvert host cellular functions. Here, we show that microRNAs modulate infection by Shigella flexneri, a major causative agent of bacillary dysentery in humans. Specifically, we characterize the dual regulatory role of miR-29b-2-5p during infection, showing that this microRNA strongly favors Shigella infection by promoting both bacterial binding to host cells and intracellular replication. Using a combination of transcriptome analysis and targeted high-content RNAi screening, we identify UNC5C as a direct target of miR-29b-2-5p and show its pivotal role in the modulation of Shigella binding to host cells. MiR-29b-2-5p, through repression of UNC5C, strongly enhances filopodia formation thus increasing Shigella capture and promoting bacterial invasion. The increase of filopodia formation mediated by miR-29b-2-5p is dependent on RhoF and Cdc42 Rho-GTPases. Interestingly, the levels of miR-29b-2-5p, but not of other mature microRNAs from the same precursor, are decreased upon Shigella replication at late times post-infection, through degradation of the mature microRNA by the exonuclease PNPT1. While the relatively high basal levels of miR-29b-2-5p at the start of infection ensure efficient Shigella capture by host cell filopodia, dampening of miR-29b-2-5p levels later during infection may constitute a bacterial strategy to favor a balanced intracellular replication to avoid premature cell death and favor dissemination to neighboring cells, or alternatively, part of the host response to counteract Shigella infection. Overall, these findings reveal a previously unappreciated role of microRNAs, and in particular miR-29b-2-5p, in the interaction of Shigella with host cells.
Cross-modal Action Complexity: Action- and Rule-related Memory Retrieval in Dual-response Control
(2017)
Normally, we do not act within a single effector system only, but rather coordinate actions across several output modules (cross-modal action). Such cross-modal action demands can vary substantially with respect to their complexity in terms of the number of task-relevant response combinations and to-be-retrieved stimulus-response (S-R) mapping rules. In the present study, we study the impact of these two types of cross-modal action complexity on dual-response costs (i.e., performance differences between single- and dual-action demands). In Experiment 1, we combined a manual and an oculomotor task, each involving four response alternatives. Crucially, one (unconstrained) condition involved all 16 possible combinations of response alternatives, whereas a constrained condition involved only a subset of possible response combinations. The results revealed that preparing for a larger number of response combinations yielded a significant, but moderate increase in dual-response costs. In Experiment 2, we utilized one common lateralized auditory (e.g., left) stimulus to trigger incompatible response compounds (e.g., left saccade and right key press or vice versa). While one condition only involved one set of task-relevant S-R rules, another condition involved two sets of task-relevant rules (coded by stimulus type: noise/tone), while the number of task-relevant response combinations was the same in both conditions. Here, an increase in the number of to-be-retrieved S-R rules was associated with a substantial increase in dual-response costs that were also modulated on a trial-by-trial basis when switching between rules. Taken together, the results shed further light on the dependency of cross-modal action control on both action- and rule-related memory retrieval processes.
Background:
According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines.
Methods:
Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay.
Results:
O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract.
Conclusion:
The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients.
C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.
Interactions between different formative processes are reflected in the internal structure of rock glaciers. Therefore, the detection of subsurface conditions can help to enhance our understanding of landform development. For an assessment of subsurface conditions, we present an analysis of the spatial variability of active layer thickness, ground ice content and frost table topography for two different rock glaciers in the Eastern Swiss Alps by means of quasi-3-D electrical resistivity imaging (ERI). This approach enables an extensive mapping of subsurface structures and a spatial overlay between site-specific surface and subsurface characteristics. At Nair rock glacier, we discovered a gradual descent of the frost table in a downslope direction and a constant decrease of ice content which follows the observed surface topography. This is attributed to ice formation by refreezing meltwater from an embedded snow bank or from a subsurface ice patch which reshapes the permafrost layer. The heterogeneous ground ice distribution at Uertsch rock glacier indicates that multiple processes on different time domains were involved in the development. Resistivity values which represent frozen conditions vary within a wide range and indicate a successive formation which includes several advances, past glacial overrides and creep processes on the rock glacier surface. In combination with the observed topography, quasi-3-D ERI enables us to delimit areas of extensive and compressive flow in close proximity. Excellent data quality was provided by a good coupling of electrodes to the ground in the pebbly material of the investigated rock glaciers. Results show the value of the quasi-3-D ERI approach but advise the application of complementary geophysical methods for interpreting the results.
A measurement of the \(t\)-channel single-top-quark and single-top-antiquark production cross-sections in the lepton+jets channel is presented, using 3.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of 13 TeV, recorded with the ATLAS detector at the LHC in 2015. Events are selected by requiring one charged lepton (electron or muon), missing transverse momentum, and two jets with high transverse momentum, exactly one of which is required to be \(b\)-tagged. Using a binned maximum-likelihood fit to the discriminant distribution of a neural network, the cross-sections are determined to be \({σ(tq)}\) = 156 ± 5 (stat.) ± 27 (syst.) ± 3 (lumi.) pb for single top-quark production and \(σ(\overline{t}q)\) = 91 ± 4 (stat.) ± 18 (syst.) ± 2 (lumi.) pb for single top-antiquark production, assuming a top-quark mass of 172.5 GeV. The cross-section ratio is measured to be \(R_{t}\) = \(σ(tq)/σ(\overline{t}q)\) = 1.72 ± 0.09 (stat.) ± 0.18 (syst.). All results are in agreement with Standard Model predictions.
We present charged-particle distributions sensitive to the underlying event, measured by the ATLAS detector in proton-proton collisions at a centre-of-mass energy of 13 TeV, in low-luminosity Large Hadron Collider fills corresponding to an integrated luminosity of 1.6 nb\(^{−1}\). The distributions were constructed using charged particles with absolute pseudorapidity less than 2.5 and with transverse momentum greater than 500 MeV, in events with at least one such charged particle with transverse momentum above 1 GeV. These distributions characterise the angular distribution of energy and particle flows with respect to the charged particle with highest transverse momentum, as a function of both that momentum and of charged-particle multiplicity. The results have been corrected for detector effects and are compared to the predictions of various Monte Carlo event generators, experimentally establishing the level of underlying-event activity at LHC Run 2 energies and providing inputs for the development of event generator modelling. The current models in use for UE modelling typically describe this data to 5% accuracy, compared with data uncertainties of less than 1%.
Antimicrobial resistance is a growing global concern in human and veterinary medicine, with an ever-increasing void in the arsenal of clinicians. Novel classes of compounds including carbon monoxoide-releasing molecules (CORMs), for example the light-activated metal complex [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br, could be used as alternatives/to supplement traditional antibacterials. Avian pathogenic \(Escherichia\) \(coli\) (APEC) represent a large reservoir of antibiotic resistance and can cause serious clinical disease in poultry, with potential as zoonotic pathogens, due to shared serotypes and virulence factors with human pathogenic \(E.\) \(coli\). The \(in\) \(vitro\) activity of [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br against multidrug-resistant APECs was assessed via broth microtitre dilution assays and synergy testing with colistin performed using checkerboard and time-kill assays. \(In\) \(vivo\) antibacterial activity of [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br alone and in combination with colistin was determined using the \(Galleria\) \(mellonella\) wax moth larvae model. Animals were monitored for life/death, melanisation and bacterial numbers enumerated from larval haemolymph. \(In\) \(vitro\) testing produced relatively high [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br minimum inhibitory concentrations (MICs) of 1024 mg/L. However, its activity was significantly increased with the addition of colistin, bringing MICs down to \(\geq\)32 mg/L. This synergy was confirmed in time-kill assays. \(In\) \(vivo\) assays showed that the combination of [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br with colistin produced superior bacterial killing and significantly increased larval survival. In both \(in\) \(vitro\) and \(in\) \(vivo\) assays light activation was not required for antibacterial activity. This data supports further evaluation of [Mn(CO)\(_3\)(tpa-\(\kappa^{3}N\))]Br as a potential agent for treatment of systemic infections in humans and animals, when used with permeabilising agents such as colistin.
Within gauge/gravity duality, we consider the local quench-like time evolution obtained by joining two 1+1-dimensional heat baths at different temperatures at time \(t\) = 0. A steady state forms and expands in space. For the 2+1-dimensional gravity dual, we find that the “shockwaves” expanding the steady-state region are of spacelike nature in the bulk despite being null at the boundary. However, they do not transport information. Moreover, by adapting the time-dependent Hubeny-Rangamani-Takayanagi prescription, we holographically calculate the entanglement entropy and also the mutual information for different entangling regions. For general temperatures, we find that the entanglement entropy increase rate satisfies the same bound as in the ‘entanglement tsunami’ setups. For small temperatures of the two baths, we derive an analytical formula for the time dependence of the entanglement entropy. This replaces the entanglement tsunami-like behaviour seen for high temperatures. Finally, we check that strong subadditivity holds in this time-dependent system, as well as further more general entanglement inequalities for five or more regions recently derived for the static case.
The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells.
Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.
The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy.
Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R.
The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression.
Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability.
In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy.
The empty p\(_z\)-orbital of a three-coordinate organoboron compound leads to its electron-deficient properties, which make it an excellent π-acceptor in conjugated organic chromophores. The empty p-orbital in such Lewis acids can be attacked by nucleophiles, so bulky groups are often employed to provide air-stable materials. However, many of these can still bind fluoride and cyanide anions leading to applications as anion-selective sensors. One electron reduction generates radical anions. The π-acceptor strength can be easily tuned by varying the organic substituents. Many of these compounds show strong two-photon absorption (TPA) and two-photon excited fluorescence (TPEF) behaviour, which can be applied for e.g. biological imaging. Furthermore, these chromophores can be used as emitters and electron transporters in OLEDs, and examples have recently been found to exhibit efficient thermally activated delayed fluorescence (TADF). The three-coordinate organoboron unit can also be incorporated into polycyclic aromatic hydrocarbons. Such boron-doped compounds exhibit very interesting properties, distinct from their all-carbon analogues. Significant developments have been made in all of these areas in recent years and new applications are rapidly emerging for this class of boron compounds.
Self-organization is a promising method within the framework of bottom-up architectures to generate nanostructures in an efficient way. The present work demonstrates that self- organization on the length scale of a few to several tens of nanometers can be achieved by a proper combination of a large (organic) molecule and a vicinal metal surface if the local bonding of the molecule on steps is significantly stronger than that on low-index surfaces. In this case thermal annealing may lead to large mass transport of the subjacent substrate atoms such that nanometer-wide and micrometer-long molecular stripes or other patterns are being formed on high-index planes. The formation of these patterns can be controlled by the initial surface orientation and adsorbate coverage. The patterns arrange self-organized in regular arrays by repulsive mechanical interactions over long distances accompanied by a significant enhancement of surface stress. We demonstrate this effect using the planar organic molecule PTCDA as adsorbate and Ag(10 8 7) and Ag(775)surfaces as substrate. The patterns are directly observed by STM, the formation of vicinal surfaces is monitored by highresolution electron diffraction, the microscopic surface morphology changes are followed by spectromicroscopy, and the macroscopic changes of surface stress are measured by a cantilever bending method. The in situ combination of these complementary techniques provides compelling evidence for elastic interaction and a significant stress contribution to long-range order and nanopattern formation.
The orthorhombic rare-earth manganite compounds \(R\)MnO\(_3\) show a global magnetic order for \(T\) < \(T\)\(_N\), and several representatives are multiferroic with a cycloidal spin ground state order for \(T\) < \(T\)\(_c\)\(_y\)\(_c\)\(_l\) < \(T\)\(_N\) \(\approx\) 40 K. We deduce from the temperature dependence of spin–phonon coupling in Raman spectroscopy for a series of \(R\)MnO\(_3\) compounds that their spin order locally persists up to about twice \(T\)\(_N\). Along the same line, our observation of the persistence of the electromagnon in GdMnO\(_3\) up to \(T\) \(\approx\) 100 K is attributed to a local cycloidal spin order for \(T\) > \(T\)\(_c\)\(_y\)\(_c\)\(_l\), in contrast to the hitherto assumed incommensurate sinusoidal phase in the intermediate temperature range. The development of the magnetization pattern can be described in terms of an order–disorder transition at \(T\)\(_c\)\(_y\)\(_c\)\(_l\) within a pseudospin model of localized spin cycloids with opposite chirality.
[60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and thereby the spacing of the frameworks can be controlled and for the most elongated derivative, continuous channels are obtained within the structure. Stability, structural integrity and porosity of the material were investigated by powder X-ray diffraction, thermogravimetry and sorption measurements.
A striking feature of the metabolite profile of \(Ancistrocladus\) \(likoko\) (Ancistrocladaceae) is the exclusive production of 5,8\('\)-linked naphthylisoquinoline alkaloids varying in their OMe/OH substitution patterns and in the hydrogenation degree in their isoquinoline portions. Here we present nine new compounds of this coupling type isolated from the twigs of this remarkable Central African liana. Three of them, the ancistrolikokines E (9), E\(_2\) (10), and F (11), are the first 5,8\('\)-linked naphthyldihydroisoquinolines found in nature with \(R\)-configuration at C-3. The fourth new metabolite, ancistrolikokine G (12), is so far the only representative of the 5,8\('\)-coupling type that belongs to the very rare group of alkaloids with a fully dehydrogenated isoquinoline portion. Moreover, five new \(N\)-methylated naphthyltetrahydroisoquinolines, named ancistrolikokines A\(_2\) (13), A\(_3\) (14), C\(_2\) (5), H (15), and H\(_2\) (16) are presented, along with six known 5,8\('\)-linked alkaloids, previously identified in related African \(Ancistrocladus\) species, now found for the first time in \(A.\) \(likoko\). The structural elucidation was achieved by spectroscopic analysis (HRESIMS, 1D and 2D NMR) and by chemical (oxidative degradation) and chiroptical (electronic circular dichroism) methods. The new ancistrolikokines showed moderate to good preferential cytotoxic activities towards pancreatic PANC-1 cells in nutrient-deprived medium (NDM), without causing toxicity under normal, nutrient-rich conditions, with ancistrolikokine H\(_2\) (16) being the most potent compound.
West African summer monsoon precipitation is characterized by distinct decadal variability. Due to its welldocumented link to oceanic boundary conditions in various ocean basins it represents a paradigm for decadal predictability. In this study, we reappraise this hypothesis for several sub-regions of sub-Saharan West Africa using the new German contribution to the coupled model intercomparison project phase 5 (CMIP5) near-term prediction system.
In addition, we assume that dynamical downscaling of the global decadal predictions leads to an enhanced predictive skill because enhanced resolution improves the atmospheric response to oceanic forcing and landsurface feedbacks. Based on three regional climate models, a heterogeneous picture is drawn: none of the regional climate models outperforms the global decadal predictions or all other regional climate models in every region nor decade. However, for every test case at least one regional climate model was identified which outperforms the global predictions. The highest predictive skill is found in the western and central Sahel Zone with correlation coefficients and mean-square skill scores exceeding 0.9 and 0.8, respectively.
Objectives: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO).
Study design: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses.
Results: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses.
Conclusion: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.