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Modern software is often realized as a modular combination of subsystems for, e. g.,
knowledge management, visualization, verification, or the interaction with users. As
a result, software libraries from possibly different programming languages have to
work together. Even more complex the case is if different programming paradigms
have to be combined. This type of diversification of programming languages and
paradigms in just one software application can only be mastered by mechanisms
for a seamless integration of the involved programming languages. However, the
integration of the common logic programming language Prolog and the popular
object-oriented programming language Java is complicated by various interoperability
problems which stem on the one hand from the paradigmatic gap between the
programming languages, and on the other hand, from the diversity of the available
Prolog systems.
The subject of the thesis is the investigation of novel mechanisms for the integration
of logic programming in Prolog and object–oriented programming in Java. We are
particularly interested in an object–oriented, uniform approach which is not specific
to just one Prolog system. Therefore, we have first identified several important
criteria for the seamless integration of Prolog and Java from the object–oriented
perspective. The main contribution of the thesis is a novel integration framework
called the Connector Architecture for Prolog and Java (CAPJa). The framework is
completely implemented in Java and imposes no modifications to the Java Virtual
Machine or Prolog. CAPJa provides a semi–automated mechanism for the integration
of Prolog predicates into Java. For compact, readable, and object–oriented
queries to Prolog, CAPJa exploits lambda expressions with conditional and relational
operators in Java. The communication between Java and Prolog is based
on a fully automated mapping of Java objects to Prolog terms, and vice versa. In
Java, an extensible system of gateways provides connectivity with various Prolog
system and, moreover, makes any connected Prolog system easily interchangeable,
without major adaption in Java.
Regulation of actin cytoskeletal turnover is necessary to coordinate cell movement and cell adhesion. Proteins of the Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family are important mediators in cytoskeleton control, linking cyclic nucleotide signaling pathways to actin assembly. In mammals, the Ena/VASP family consists of mammalian Enabled (Mena), VASP, and Ena-VASP-like (EVL). The family members share a tripartite domain organization, consisting of an N-terminal Ena/VASP homology 1 (EVH1) domain, a central proline-rich region (PRR), and a C-terminal EVH2 domain. The EVH1 domain mediates binding to the focal adhesion proteins vinculin and zyxin, the PRR interacts with the actin-binding protein profilin and with Src homology 3 (SH3) domains, and the EVH2 domain mediates tetramerization and actin binding.
Endothelial cells line vessel walls and form a semipermeable barrier between blood and the underlying tissue. Endothelial barrier function depends on the integrity of cell-cell junctions and defective sealing of cell-cell contacts results in vascular leakage and edema formation. In a previous study, we could identify a novel interaction of the PRR of VASP with αII-spectrin. VASP-targeting to endothelial cell-cell contacts by interaction with the αII-spectrin SH3 domain is sufficient to initiate perijunctional actin filament assembly, which in turn stabilizes cell-cell contacts and decreases endothelial permeability. Conversely, barrier function of VASP-deficient endothelial cells and microvessels of VASP- null mice is defective, demonstrating that αII-spectrin/VASP complexes regulate endothelial barrier function in vivo.
The aim of the present study was to characterize the structural aspects of the binding of Ena/VASP proteins to αII-spectrin in more detail. These data are highly relevant to understand the cardiovascular function of VASP and its subcellular targeting. In the present study, the following points were experimentally addressed:
1. Comparison of the interaction between αII-spectrin and Mena, VASP, or EVL
In contrast to the highly conserved EVH1/EVH2 domains, the PRR is the most divergent part within the Ena/VASP proteins and may differ in binding modes and mechanisms of regulation. More specifically, VASP contains a triple GP5 motif, whereas EVL and Mena contain one or more GP6 motifs or even longer proline stretches. In the present study, we used peptide scans and competitive αII-spectrin SH3 pull-down assays with the recombinant Mena, VASP, and VASP mutants to investigate the relative binding efficiency. Our results indicate that binding of the αII-spectrin SH3 domain to GP6 motifs is superior to GP5 motifs, giving a rationale for a stronger interaction of αII-spectrin with EVL and Mena than with VASP.
2. Interaction of SH3i with Ena/VASP proteins
In the mammalian heart, an αII-spectrin splice variant exists (SH3i), which contains a 20 amino acid insertion C-terminal to the SH3 domain. We used GST-fusion proteins of αII-spectrin, comprising the SH3 domain with or without the alternatively spliced amino acids, to pull-down recombinant Mena, VASP or VASP mutants. The results demonstrate a substantially increased binding of the C-terminal extended SH3 domain as compared to the general αII-spectrin isoform without the 20 amino acid insertion. These findings were also confirmed in pull-down experiments with heart lysates and purified Mena from heart muscle. The increased binding was not due to an alternative, SH3-independent binding interface because a pointmutation of the SH3 domain (W1004R) in the alternatively spliced αII-spectrin isoform completely abrogated the interaction. To analyze the interaction of SH3i and Ena/VASP proteins in living cells, we expressed the extended SH3 domain as GFP fusion proteins in endothelial cells. Here, we observed an extensive co-localization with Mena and VASP at the leading edge of lamellipodia confirming the in vivo relevance of the interaction with potential impact on cell migration and angiogenesis.
3. Binding affinity and influence of the Ena/VASP tetramerization domain
We also determined the binding affinity of the general and the alternatively spliced αII-spectrin SH3 with Ena/VASP proteins by isothermal titration calorimetry (ITC) using a peptide from the PRR of Mena (collaboration with Dr. Stephan Feller, University of Oxford). Surprisingly, the binding affinity of the general SH3 domain was low (~900 μM) as compared to other SH3 domain- mediated interactions, which commonly display binding constants in the low micromolar range. Furthermore and in contrast to the pull-down assays, we could not detect an increased binding affinity of the C-terminally extended SH3 domain. This could be either explained by the existence of a third protein, which “bridges” the Mena/αII-spectrin complex in the pull-down assays, or, more likely, by the small size of the Mena peptide, which lacks major parts of the Mena protein, including the tetramerization domain. Indeed, it has been previously shown that the tetramerization of Ena is crucial for the interaction with the Abl- SH3 domain, although no SH3 binding sites are found in the tetramerization domain. To address this point experimentally, we used a VASP mutant that lacks the tetramerization domain in pull-down assays. Neither the general nor the alternatively spliced SH3 domain bound to the monomeric VASP, demonstrating the crucial (indirect) impact of Ena/VASP tetramerization on the interaction with αII-spectrin.
In summary, we conclude that the αII-spectrin SH3 domain binds to the proline- rich region of all Ena/VASP proteins. However, binding to EVL and Mena, which both possess one or more GP6 motifs, is substantially more efficient than VASP, which only contains GP5 motifs. The C-terminally extended SH3 domain, which is present in the αII-spectrin splice variant SH3i, binds stronger to the Ena/VASP proteins than the general isoform and expression of the isolated domain is sufficient for co-localization with Ena/VASP in living endothelial cells. Finally, the tetramerization of the Ena/VASP proteins is indispensable for the interaction with either isoform of αII-spectrin.
Background/Aims:
Acute kidney injury (AKI) is a postoperative complication after cardiac surgery with a high impact on mortality and morbidity. Nephrocheck® [TIMP-2*IGFBP7] determines markers of tubular stress, which occurs prior to tubular damage. It is unknown at which time-point [TIMP-2*IGFBP7] measurement should be performed to ideally predict AKI. We investigated the association of [TIMP-2*IGFBP7] at various time-points with the incidence of AKI in patients undergoing elective cardiac surgery including cardio-pulmonary bypass.
Methods: In a prospective cohort study, serial blood and urine samples were collected from 150 patients: pre-operative, at ICU-admission, 24h and 48h post-surgery. AKI was defined as Serum-Creatinine rise >0.3 mg/dl within 48hrs. Urinary [TIMP-2*IGFBP7] was measured at pre-operative, ICU-admission and 24h post-surgery; medical staff was kept blinded to these results.
Results: A total of 35 patients (23.5%) experienced AKI, with a higher incidence in those with high [TIMP-2*IGFBP7] values at ICU admission (57.1% vs. 10.1%, p<0.001). In logistic regression [TIMP-2*IGFBP7] at ICU admission was independently associated with the occurrence of AKI (Odds Ratio 11.83; p<0.001, C-statistic= 0.74) after adjustment for EuroSCORE II and CBP-time.
Conclusions: Early detection of elevated [TIMP-2*IGFBP7] at ICU admission was strongly predictive for postoperative AKI and appeared to be more precise as compared to subsequent measurements.
Preclinical development of an immunotherapy against antibiotic-resistant Staphylococcus aureus
(2017)
The Gram-positive bacterium Staphylococcus aureus is the leading cause of nosocomial infections. In particular, diseases caused by methicillin-resistant S. aureus (MRSA) are associated with higher morbidity, mortality and medical costs due to showing resistance to several classes of established antibiotics and their ability to develop resistance mechanisms against new antibiotics rapidly. Therefore, strategies based on immunotherapy approaches have the potential to close the gap for an efficient treatment of MRSA.
In this thesis, a humanized antibody specific for the immunodominant staphylococcal antigen A (IsaA) was generated and thoroughly characterized as potential candidate for an antibody based therapy. A murine monoclonal antibody was selected for humanization based on its binding characteristics and the ability of efficient staphylococcal killing in mouse infection models. The murine antibody was humanized by CDR grafting and mouse and humanized scFv as well as scFv-Fc fragments were constructed for comparative binding studies to analyse the successful humanization. After these studies, the full antibody with the complete Fc region was constructed as isotype IgG1, IgG2 and IgG4, respectively to assess effector functions, including antibody-dependent killing of S. aureus. The biological activity of the humanized antibody designated hUK-66 was analysed in vitro with purified human PMNs and whole blood samples taken from healthy donors and patients at high risk of S. aureus infections, such as those with diabetes, end-stage renal disease, or artery occlusive disease (AOD).
Results of the in vitro studies show, that hUK-66 was effective in antibody-dependent killing of S. aureus in blood from both healthy controls and patients vulnerable to S. aureus infections. Moreover, the biological activity of hUK-66 and hUK-66 combined with a humanized anti-alpha-toxin antibody (hUK-tox) was investigated in vivo using a mouse pneumonia model. The in vivo results revealed the therapeutic efficacy of hUK-66 and the antibody combination of hUK-66 and hUK-tox to prevent staphylococcal induced pneumonia in a prophylactic set up.
Based on the experimental data, hUK-66 represents a promising candidate for an antibody-based therapy against antibiotic resistant MRSA.
Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund’s adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.
Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.
The instructive component of waggle dance communication has been shown to increase resource uptake of Apis mellifera colonies in highly heterogeneous resource environments, but an assessment of its relevance in temperate landscapes with different levels of resource heterogeneity is currently lacking. We hypothesized that the advertisement of resource locations via dance communication would be most relevant in highly heterogeneous landscapes with large spatial variation of floral resources. To test our hypothesis, we placed 24 Apis mellifera colonies with either disrupted or unimpaired instructive component of dance communication in eight Central European agricultural landscapes that differed in heterogeneity and resource availability. We monitored colony weight change and pollen harvest as measure of foraging success. Dance disruption did not significantly alter colony weight change, but decreased pollen harvest compared to the communicating colonies by 40%. There was no general effect of resource availability on nectar or pollen foraging success, but the effect of landscape heterogeneity on nectar uptake was stronger when resource availability was high. In contrast to our hypothesis, the effects of disrupted bee communication on nectar and pollen foraging success were not stronger in landscapes with heterogeneous compared to homogenous resource environments. Our results indicate that in temperate regions intra-colonial communication of resource locations benefits pollen foraging more than nectar foraging, irrespective of landscape heterogeneity. We conclude that the so far largely unexplored role of dance communication in pollen foraging requires further consideration as pollen is a crucial resource for colony development and health.
The Kaapvaal Craton hosts a number of large gold deposits (e.g. Witwatersrand Supergroup) which mining companies have exploited at certain stratigraphic positions. It also hosts the largest platinum group element (PGE) deposits (e.g. Bushveld Igneous Complex) which mining companies have exploited in different mineralised layered magmatic zones. In spite of the extensive exploration history in the Kaapvaal Craton, the origin of the Witwatersrand gold deposits and Bushveld Igneous Complex PGE deposits has remained one of the most debated topics in economic geology. The goal of this study was to identify the geochemical characteristics of marine shales in the Barberton, Witwatersrand, and Transvaal supergroups in South Africa in order to make inferences on their sediment provenance and siderophile element endowments. Understanding why some of the Archaean and Proterozoic hinterlands are heavily mineralised, compared to others with similar geological characteristics, will aid in the development of more efficient exploration models. Fresh, unmineralised marine shales from the Barberton (Fig Tree and Moodies groups), Witwatersrand (West Rand and Central Rand groups), and Transvaal (Black Reef Formation and Pretoria Group) supergroups were sampled from drill core and underground mining exposures. Analytical methods, such as X-ray powder diffraction (XRD), optical microscopy, X-ray fluorescence (XRF), inductively coupled plasma optical emission spectroscopy (ICP-OES), inductively coupled plasma mass spectrometry (ICP-MS), and electron microprobe analysis (EMPA) were applied to comprehensively characterise the shales. All of the Au and PGE assays examined the newly collected shale samples.
The Barberton Supergroup shales consist mainly of quartz, illite, chlorite, and albite, with diverse heavy minerals, including sulfides and oxides, representing the minor constituents. The regionally persistent Witwatersrand Supergroup shales consist mainly of quartz, muscovite, and chlorite, and also contain minor constituents of sulfides and oxides. The Transvaal Supergroup shales comprise quartz, chlorite, and carbonaceous material. Major, trace (including rare-earth element) concentrations were determined for shales from the above supergroups to constrain their source and post-depositional evolution. Chemical variations were observed in all the studied marine shales. Results obtained from this study revealed that post-depositional modification of shale chemistry was significant only near contacts with over- and underlying coarser-grained siliciclastic rocks and along cross-cutting faults, veins, and dykes. Away from such zones, the shale composition remained largely unaltered and can be used to draw inferences concerning sediment provenance and palaeoweathering in the source region and/or on intrabasinal erosion surfaces. Evaluation of weathering profiles through sections of the studied supergroups revealed that the shales therein are characterised by high chemical index of alteration (CIA), chemical index of weathering (CIW), and index of compositional variability (ICV), suggesting that the source area was lithologically complex and subject to intense chemical weathering.
A progressive change in the chemical composition was identified, from a dominant ultramafic–mafic source for the Fig Tree Group to a progressively felsic–plutonic provenance for the Moodies Group. The West Rand Group of the Witwatersrand Supergroup shows a dominance of tonalite–trondhjemite–granodiorite and calcalkaline granite sources. Compositional profiles through the only major marine shale unit within the Central Rand Group indicate the progressive unroofing of a granitic source in an otherwise greenstone-dominated hinterland during the course of sedimentation. No plausible likely tectonic setting was obtained through geochemical modelling. However, the combination of the systematic shale chemistry, geochronology, and sedimentology in the Witwatersrand Supergroup supports the hypothesised passive margin setting for the >2.98 to 2.91 Ga West Rand Group, and an active continental margin source for the overlying >2.90 to 2.78 Ga Central Rand Group, along with a foreland basin setting for the latter.
Ultra-low detection limit analyses of gold and PGE concentrations revealed a variable degree of gold accumulation within pristine unmineralised shales. All the studied shales contain elevated gold and PGE contents relative to the upper continental crust, with marine shales from the Central Rand Group showing the highest Au (±9.85 ppb) enrichment. Based on this variation in the provenance of contemporaneous sediments in different parts of the Kaapvaal Craton, one can infer that the siderophile elements were sourced from a fertile hinterland, but concentrated into the marine shales by a combination of different processes. It is proposed that accumulation of siderophile elements in the studied marine shales was mainly controlled by mechanical coagulation and aggregation. These processes involved suspended sediments, fine gold particles, and other trace elements being trapped in marine environments. Mechanical coagulation and aggregation resulted in gold enrichments by 2–3 orders of magnitude, whereas some of the gold in these marine shales can be reconciled by seawater adsorption into sedimentary pyrite.
For the source of gold and PGEs in the studied marine shales in the Kaapvaal Craton, a genetic model is proposed that involves the following:
(1) A highly siderophile elements enriched upper mantle domain, herein referred to as “geochemically anomalous mantle domain”, from which the Kaapvaal crust was sourced. This mantle domain enriched in highly siderophile elements was formed either by inhomogeneous mixing with cosmic material that was added during intense meteorite bombardment of the Hadaean to Palaeoarchaean Earth or by plume-like ascent of relics from the core–mantle boundary. In both cases, elevated siderophile elements concentrations would be expected. The geochemically anomalous mantle domain is likely the ultimate source of the Witwatersrand modified palaeoplacer gold deposits and was tapped again ca. 2.054 Ga during the emplacement of the Bushveld Igneous Complex. Therefore, I propose that there is a genetic link (i.e. common geochemically anomalous mantle source) between the Witwatersrand gold deposits and the younger Bushveld Igneous Complex PGE deposits.
(2) Scavenging of crustal gold by various surface processes such as trapping of gold from Archaean/Palaeoproterozoic river water on the surface of local photosynthesizing cyanobacterial or microbial mats, and reworking of these mats into erosion channels during flooding events.
The above two models complement each other, with model (1) providing a common geological source for the Witwatersrand gold and Bushveld Igneous Complex PGE deposits, and model (2) explaining the processes responsible for Witwatersrand-type gold pre-concentration processes. In sequences such as the Transvaal Supergroup, a less fertile hinterland and/or less reworking of older sediments led to a correspondingly lower gold endowment. These findings indicate temporal distribution of siderophile elements in the upper crust (e.g. marine shales). The overall implications of these findings are that background concentrations of gold and PGEs can be used to target potential exploration areas in other cratons of similar age. This increases the likelihood of finding other Witwatersrand-type gold or Bushveld Igneous Complex-type PGE deposits in other cratons.
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.
The aim of the present study was to examine whether fostering positive activating affect during multimedia learning enhances learning outcome. University students were randomly assigned to either a multimedia learning environment designed to induce positive activating affect through the use of “warm” colours and rounded shapes () or an affectively neutral environment that used achromatic colours and sharp edges (). Participants learned about the topic of functional neuroanatomy for 20 minutes and had to answer several questions for comprehension and transfer afterwards. Affective states as well as achievement goal orientations were investigated before and after the learning phase using questionnaires. The results show that participants in the affectively positive environment were superior in comprehension as well as transfer when initial affect was strong. Preexperimental positive affect was therefore a predictor of comprehension and a moderator for transfer. Goal orientations did not influence these effects. The findings support the idea that positive affect, induced through the design of the particular multimedia learning environment, can facilitate performance if initial affective states are taken into account.
Epidermal growth factors (EGFs) e.g. EGF, heparin-binding EGF and transforming growth factor alpha and their receptors e.g. EGFR and ErbB2 control proinflammatory signaling and modulate proliferation in bone marrow stromal cells (BMSC). Interleukin-6 and interleukin-8 are EGF targets and participate in the inflammatory phase of bone regeneration via non-canonical wnt signaling. BMSC differentiation is also influenced by mechanical strain-related activation of ERK1/2 and AP-1, but the role of EGFR signaling in mechanotransduction is unclear. We investigated the effects of EGFR signaling in telomerase-immortalized BMSC, transfected with a luciferase reporter, comprising a mechanoresponsive AP1 element, using ligands, neutralizing antibodies and EGFR inhibitors on mechanotransduction and we found that EGF via EGFR increased the response to mechanical strain. Results were confirmed by qPCR analysis of mechanoresponsive genes. EGF-responsive interleukin-6 and interleukin-8 were synergistically enhanced by EGF stimulation and mechanical strain. We show here in immortalized and primary BMSC that EGFR signaling enhances mechanotransduction, indicating that the EGF system is a mechanosensitizer in BMSC. Alterations in mechanosensitivity and -adaptation are contributors to age-related diseases like osteoporosis and the identification of a suitable mechanosensitizer could be beneficial. The role of the synergism of these signaling cascades in physiology and disease remains to be unraveled.
Plants are exposed to high temperature, especially during hot summer days. Temperatures are typically lowest in the morning and reach a maximum in the afternoon. Plants can tolerate and survive short-term heat stress even on hot summer days. A. thaliana seedlings have been reported to tolerate higher temperatures for different time periods, a phenomenon that has been termed basal thermotolerance. In addition, plants have the inherent capacity to acclimate to otherwise lethal temperatures. Arabidopsis thaliana seedlings acclimate at moderately elevated temperatures between 32–38° C. During heat acclimation, a genetically programmed heat shock response (HSR) is triggered that is characterized by a rapid activation of heat shock transcription factors (HSFs), which trigger a massive accumulation of heat shock proteins that are chiefly involved in protein folding and protection.
Although the HSF-triggered heat-shock response is well characterized, little is known about the metabolic adjustments during heat stress. The aim of this work was to get more insight into heat-responsive metabolism and its importance for thermotolerance.
In order to identify the response of metabolites to elevated temperatures, global metabolite profiles of heat-acclimated and control seedlings were compared. Untargeted metabolite analyses revealed that levels of polyunsaturated triacylglycerols (TG) rapidly increase during heat acclimation. TG accumulation was found to be temperature-dependent in a temperature range from 32–50° C (optimum at 42° C). Heat-induced TG accumulation was localized in extra-chloroplastic compartments by chloroplast isolation as well as by fluorescence microscopy of A. thaliana cell cultures.
Analysis of mutants deficient in all four HSFA1 master regulator genes or the HSFA2 gene revealed that TG accumulation occurred independently to HSF. Moreover, the TG response was not limited to heat stress since drought and salt stress (but not short-term osmotic, cold and high light stress) also triggered an accumulation of TGs.
In order to reveal the origin of TG synthesis, lipid analysis was carried out. Heat-induced accumulation of TGs does not derive from massive de novo fatty acid (FA) synthesis. On the other hand, lipidomic analyses of A. thaliana seedlings indicated that polyunsaturated FA from thylakoid galactolipids are incorporated into cytosolic TGs during heat stress. This was verified by lipidomic analyses of A. thaliana fad7/8 transgenic seedlings, which displayed altered FA compositions of plastidic lipids. In addition, wild type A. thaliana seedlings displayed a rapid conversion of plastidic monogalactosyldiacylglycerols (MGDGs) into oligogalactolipids, acylated MGDGs and diacylglycerols (DGs). For TG synthesis, DG requires a FA from the acyl CoA pool or phosphatidylcholine (PC). Seedlings deficient in phospholipid:diacylglycerol acyltransferase1 (PDAT1) were unable to accumulate TGs following heat stress; thus PC appears to be the major FA donor for TGs during heat treatment. These results suggest that TG and oligogalactolipid accumulation during heat stress is driven by post-translationally regulated plastid lipid metabolism.
TG accumulation following heat stress was found to increase basal thermotolerance. Pdat1 mutant seedlings were more sensitive to severe heat stress without prior acclimatization, as revealed by a more dramatic decline of the maximum efficiency of PSII and lower survival rate compared to wild type seedlings. In contrast, tgd1 mutants over-accumulating TGs and oligogalactolipids displayed a higher basal thermotolerance compared to wild type seedlings. These results therefore suggest that accumulation of TGs increases thermotolerance in addition to the genetically encoded heat shock response.
In transparent orthographies, persistent reading fluency difficulties are a major cause of poor reading skills in primary school. The purpose of the present study was to investigate effects of a syllable-based reading intervention on word reading fluency and reading comprehension among German-speaking poor readers in Grade 4. The 16-session intervention was based on analyzing the syllabic structure of words to strengthen the mental representations of syllables and words that consist of these syllables. The training materials were designed using the 500 most frequent syllables typically read by fourth graders. The 75 poor readers were randomly allocated to the treatment or the control group. Results indicate a significant and strong effect on the fluency of recognizing single words, whereas text-level reading comprehension was not significantly improved by the training. The specific treatment effect provides evidence that a short syllable-based approach works even in older poor readers at the end of primary school.
The present randomized controlled study aimed to investigate the in vivo distribution of constituents or metabolites of the standardized maritime pine bark extract Pycnogenol\(^{®}\). Thirty-three patients with severe osteoarthritis scheduled for a knee arthroplasty were randomized to receive either 200 mg per day Pycnogenol\(^{®}\) (P+) or no treatment (Co) over three weeks before surgery. Serum, blood cells, and synovial fluid samples were analyzed using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization (LC-ESI/MS/MS). Considerable interindividual differences were observed indicating pronounced variability of the polyphenol pharmacokinetics. Notably, the highest polyphenol concentrations were not detected in serum. Catechin and taxifolin primarily resided within the blood cells while the microbial catechin metabolite δ-(3,4-dihydroxy-phenyl)-γ-valerolactone, ferulic, and caffeic acid were mainly present in synovial fluid samples. Taxifolin was detected in serum and synovial fluid exclusively in the P+ group. Likewise, no ferulic acid was found in serum samples of the Co group. Calculating ratios of analyte distribution in individual patients revealed a simultaneous presence of some polyphenols in serum, blood cells, and/or synovial fluid only in the P+ group. This is the first evidence that polyphenols distribute into the synovial fluid of patients with osteoarthritis which supports rationalizing the results of clinical efficacy studies.
A successful therapy for colorectal cancer (CRC), one of the most common malignancies worldwide, requires the greatest possible research effort. Of critical importance is an understanding of the relevant intracellular networks of signaling cascades, their activation, and the resulting cellular changes that are a prerequisite for a more successful CRC therapy. Vascular endothelial growth factor (VEGF) and the appropriate VEGF receptors represent molecular targets that have already been successfully implemented in the clinic (i.e. using monoclonal antibodies, tyrosine kinase inhibitors). However, for platelet derived growth factor (PDGF) and the relevant PDGF receptors, there are currently no clinically approved molecular therapeutics available. However, there are preliminary data to show that PDGF and its associated signaling pathways play an important role in CRC progression. In particular, the PI3K/Akt/mTOR pathway is emerging as an important intracellular partner of PDGF with which to control proliferation, migration, and angiogenesis in tumor cells.
Therefore it was the objective of this work to investigate the multifactorial influence of PDGF on proliferation and metabolism, depending on CRC mutation status. The intention was to identify new therapeutic targets for future cancer therapy through analyses of PDGF-induced intracellular changes.
For this purpose two human colorectal cancer cell lines were analyzed at gene and/or protein level for components of the PI3K/Akt/mTOR and MAPK signaling pathway, c-Myc, p53, and HIF1α (hypoxia-inducible-factor 1α). Changes in proliferation and metabolism, either during stimulation with PDGF and/or PI3K/Akt/mTOR inhibition, were also investigated. Experiments conducted at protein level during PDGF stimulation and/or PI3K/Akt/mTOR inhibition revealed changes in signaling pathways and crosstalk. The influence of the tumor suppressors (retinoblastoma, Rb), oncogenes (c-Myc, p53mut), and HIF1α during stimulation with PDGF, and their interactions in the tumor cell with respect to proliferation and glycolysis warrant further examination in terms of clinical treatment options. Investigations at the gene level of ex vivo samples (UICC I-IV) complete the study with regards to the clinical relevance of PDGF.
PDGF stimulation increases tumor cell proliferation in HT29 cells via the PI3K/Akt/mTOR pathway rather than the MAPK pathway. However, if the PI3K/Akt/mTOR pathway is pharmacologically blocked, PDGF stimulation is mediated by inhibitory crosstalk through the MAPK pathway. Further analyses revealed that specific Akt inhibition impedes tumor cell growth, while PI3K inhibition had little effect on proliferation. Inhibitory crosstalk was found to be responsible for these different effects. Careful intervention strategies are therefore required if future therapies intend to make use of these specific signaling pathways. One aim of future research should be to gain a better understanding of the crosstalk between these signaling pathways. In this fashion, “over-inhibition” of the signal pathways, which would result in additional clinical side effects for patients, could be prevented.
In late stage UICC, more mutation events occur, with tumorigenicity promoted by an increased mutation rate. Given that PDGF is increasingly expressed in the late UICC stages, our data would indicate that PDGF's effects are amplified with increasing malignancy. The activating effect of PDGF on the PI3K/Akt/mTOR pathway and subsequent changes in the activity of p53mut, Rb, c-Myc, and HIF1α, lead to an unfavorable prognosis for colon cancer patients. PDGF acts on colon cancer cells in an Akt-activating, glycolysis-dependent manner. PDGF increases glycolysis and the ability of CRC cells to adjust their energy metabolism. These activities should be taken as possible starting points with which to design therapeutic interventions for CRC therapy.
PDGF, as another representative of the growth factor family, seems to play a similar role to VEGF in CRC. The data from this study underline the importance of the PDGF - PI3K/Akt/mTOR pathway-axis and its potential as a possible target in colorectal cancer. Thus PDGF represents an attractive therapeutic target, besides the VEGF/EGFR-based therapies already used in CRC.
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.
Background:
Heart failure (HF) patient education aims to foster patients’ self-management skills. These are assumed to bring about, in turn, improvements in distal outcomes such as quality of life. The purpose of this study was to test the hypothesis that change in self-reported self-management skills observed after participation in self-management education predicts changes in physical and mental quality of life and depressive symptoms up to one year thereafter.
Methods:
The sample comprised 342 patients with chronic heart failure, treated in inpatient rehabilitation clinics, who received a heart failure self-management education program. Latent change modelling was used to analyze relationships between both short-term (during inpatient rehabilitation) and intermediate-term (after six months) changes in self-reported self-management skills and both intermediate-term and long-term (after twelve months) changes in physical and mental quality of life and depressive symptoms.
Results:
Short-term changes in self-reported self-management skills predicted intermediate-term changes in mental quality of life and long-term changes in physical quality of life. Intermediate-term changes in self-reported self-management skills predicted long-term changes in all outcomes.
Background:
The foamy viral genome encodes four central purine-rich elements localized in the integrase-coding region of pol. Previously, we have shown that the first two of these RNA elements (A and B) are required for protease dimerization and activation. The D element functions as internal polypurine tract during reverse transcription. Peters et al., described the third element (C) as essential for gag expression suggesting that it might serve as an RNA export element for the unspliced genomic transcript.
Results:
Here, we analysed env splicing and demonstrate that the described C element composed of three GAA repeats known to bind SR proteins regulates env splicing, thus balancing the amount of gag/pol mRNAs. Deletion of the C element effectively promotes a splice site switch from a newly identified env splice acceptor to the intrinsically strong downstream localised env 3′ splice acceptor permitting complete splicing of almost all LTR derived transcripts. We provide evidence that repression of this env splice acceptor is a prerequisite for gag expression. This repression is achieved by the C element, resulting in impaired branch point recognition and SF1/mBBP binding. Separating the branch point from the overlapping purine-rich C element, by insertion of only 20 nucleotides, liberated repression and fully restored splicing to the intrinsically strong env 3′ splice site. This indicated that the cis-acting element might repress splicing by blocking the recognition of essential splice site signals.
Conclusions:
The foamy viral purine-rich C element regulates splicing by suppressing the branch point recognition of the strongest env splice acceptor. It is essential for the formation of unspliced gag and singly spliced pol transcripts.
Background
Data on ESBL carriage of healthy people including children are scarce especially in developing countries. We analyzed the prevalence and genotypes of ESBL-producing Enterobacteriaceae (EPE) in Tanzanian street children with rare contact to healthcare facilities but significant interactions with the environment, animals and other people.
Methodology/ Principle findings
Between April and July 2015, stool samples of 107 street children, who live in urban Mwanza were analyzed for EPE. Intestinal carriage of EPE was found in 34 (31.8%, 95% CI; 22.7–40.3) children. Of the 36 isolates from 34 children, 30 (83.3%) were Escherichia coli (E. coli) and six Klebsiella pneumoniae (K. pneumoniae). Out of 36 isolates, 36 (100%), 35 (97%), 25 (69%) and 16 (44%) were resistant to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin and gentamicin, respectively. Beta-lactamase genes and the multilocus sequence types of E. coli and K. pneumoniae were characterized. ESBL gene bla\(_{CTX-M-15}\) was detected in 75% (27/36) of ESBL isolates. Sequence types (STs) 131, 10, 448 and 617 were the most prevalent in E. coli. Use of local herbs (OR: 3.5, 95% CI: 1.51–8.08, P = 0.003) and spending day and night on streets (OR: 3.6, 95% CI: 1.44–8.97, P = 0.005) were independent predictors of ESBL carriage.
Conclusions/ Significance
We observed a high prevalence of bla\(_{CTX-M-15}\) in EPE collected from street children in Tanzania. Detection of E. coli STs 131, 10, 38 and 648, which have been observed worldwide in animals and people, highlights the need for multidisciplinary approaches to understand the epidemiology and drivers of antimicrobial resistance in low-income countries.