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Challenging voluntary CSR-initiatives – a case study on the effectiveness of the Equator Principles
(2015)
The Equator Principles (EPs) are a voluntary and self-regulatory Corporate Social Responsibility (CSR) initiative in the field of project finance. The EPs provide a number of principles to businesses to reduce the negative impacts of lending practices linked to environment-damaging projects. The paper argues that the actual impact of the EPs even now as revised version is still limited. This is due to their voluntary nature and their lack of adequate governance mechanisms, that is, enforcement, monitoring and sanctioning. With the help of RepRisk, which provides a database capturing third-party criticism as well as a company’s or project’s exposure to controversial socio-environmental issues, the paper evaluates the on-the-ground performances of the two ‘Equator banks’ Barclays and JPMorgan Chase and compares their performance with the one of the two non-Equator banks Deutsche Bank and UBS. The paper shows that the EPs do not have a substantial influence on the broader CSR-performance of multinational banks due to the EPs’ limited scope – focusing mainly on project finance – and the (still) existing various loopholes, grey areas and discretionary leeway. The paper also gives an overview of the main institutional shortcomings of the EPs and their association and discusses some potential reform steps which should be taken to further strengthen and ‘harden’ this ‘soft law’ EP-framework. The paper thus argues in favor of (more) mandatory and legally binding rules and standards at the transnational level to overcome the EPs’ ‘voluntariness bias’.
In addition to the well-established quadrupole mixed-symmetry states, octupole and hexadecapole excitations with mixed-symmetry character have been recently proposed for the N = 52 isotones 92Zr and 94Mo. We performed two inelastic proton-scattering experiments to study this kind of excitations in the heaviest stable N = 52 isotone 96Ru. From the combined experimental data of both experiments absolute transition strengths were extracted.
Concepts of "Female Inversion" and the "New Woman" in Rhoda Broughton’s "Dear Faustina" (1897)
(2012)
Published in 1897, Rhoda Broughton’s fin de siècle novel "Dear Faustina" took an active part in the discursive production of two cultural figures: the New Woman and the Female Invert. Employing those identity constructs to negotiate conservative anxieties about social change, while at the same time commenting on a range of alternatives to Victorian middle-class lifestyle, the novel is clearly rooted in the discourses of transition that characterised the fin de siècle....
PERIOD proteins are central components of the Drosophila and mammalian circadian clocks. The crystal structure of a Drosophila PERIOD (dPER) fragment comprising two PER-ARNT-SIM (PAS) domains (PAS-A and PAS-B) and two additional C-terminal alpha-helices (alphaE and alphaF) has revealed a homodimer mediated by intermolecular interactions of PAS-A with tryptophane 482 in PAS-B and helix alphaF. Here we present the crystal structure of a monomeric PAS domain fragment of dPER lacking the alphaF helix. Moreover, we have solved the crystal structure of a PAS domain fragment of the mouse PERIOD homologue mPER2. The mPER2 structure shows a different dimer interface than dPER, which is stabilized by interactions of the PAS-B beta-sheet surface including tryptophane 419 (equivalent to Trp482dPER). We have validated and quantitatively analysed the homodimer interactions of dPER and mPER2 by site-directed mutagenesis using analytical gel filtration, analytical ultracentrifugation, and co-immunoprecipitation experiments. Furthermore we show, by yeast-two-hybrid experiments, that the PAS-B beta-sheet surface of dPER mediates interactions with TIMELESS (dTIM). Our study reveals quantitative and qualitative differences between the homodimeric PAS domain interactions of dPER and its mammalian homologue mPER2. In addition, we identify the PAS-B beta-sheet surface as a versatile interaction site mediating mPER2 homodimerization in the mammalian system and dPER-dTIM heterodimer formation in the Drosophila system.
Tapinesthis inermis Simon, 1882, the only species in the genus, is widely distributed in western Europe. This redescription provides the first information on the ultrastructure of the species using SEM. The morphology of the spinnerets, tarsal claws and tarsal organs, and the internal structure of the female genitalia and the male palp are described and illustrated in detail. The combination of these structures is very similar to those encountered in some dysderoid spiders and supports the basal placement of Tapinesthis among Oonopinae. The phylogenetic relationships of the species are discussed. The only female among the three syntypes is designated as the lectotype.
Purpose. To introduce additional methods to detect and to quantify single pathogens in the complex biofilm formation on an antibacterial dental material.
Materials and Methods. A conventional (ST) and an antibacterial dental composite (B) were manufactured. In vitro: specimens were incubated with a mixture of early colonizers. Bacterial adhesion was analyzed by TaqMan PCR after 8/24 h. In situ: TaqMan PCR and 16S rRNA Next Generation Sequencing (NGS) were performed.
Results. In vitro: after 8 h incubation, B was covered by 58.6% of the bacterial amount that was attached to ST. After 24 h, the amount of attached bacteria to ST remained constant on ST only slightly lower on B. In situ: after 8 h the amount of adhering A. viscosus and S. mitis was prominent on ST and reduced on B. NGS revealed that S. sanguinis, S. parasanguinis, and Gemella sanguinis were the mainly attached species with S. sanguinis dominant on ST and S. parasanguinis and G. sanguinis dominant on B.
Conclusions. Initial biofilm formation was altered by B. A shift between actinomycetes and streptococci was observed in situ. TaqMan PCR and 16S rRNA NGS revealed comparable results in situ and demonstrated the usefulness of NGS to characterize complex bacterial communities.
Bone marrow mononuclear cells (BMCs) are suitable for bone tissue engineering. Comparative data regarding the needs of BMC for the adhesion on biomaterials and biocompatibility to various biomaterials are lacking to a large extent. Therefore, we evaluated whether a surface coating would enhance BMC adhesion and analyze the biocompatibility of three different kinds of biomaterials. BMCs were purified from human bone marrow aspirate samples. Beta tricalcium phosphate (β-TCP, without coating or coated with fibronectin or human plasma), demineralized bone matrix (DBM), and bovine cancellous bone (BS) were assessed. Seeding efficacy on β-TCP was 95% regardless of the surface coating. BMC demonstrated a significantly increased initial adhesion on DBM and β-TCP compared to BS. On day 14, metabolic activity was significantly increased in BMC seeded on DBM in comparison to BMC seeded on BS. Likewise increased VEGF-synthesis was observed on day 2 in BMC seeded on DBM when compared to BMC seeded on BS. The seeding efficacy of BMC on uncoated biomaterials is generally high although there are differences between these biomaterials. Beta-TCP and DBM were similar and both superior to BS, suggesting either as suitable materials for spatial restriction of BMC used for regenerative medicine purposes in vivo.
Introduction. Cancellous bone is frequently used for filling bone defects in a clinical setting. It provides favourable conditions for regenerative cells such as MSC and early EPC. The combination of MSC and EPC results in superior bone healing in experimental bone healing models. Materials and Methods. We investigated the influence of osteogenic culture conditions on the endothelial properties of early EPC and the osteogenic properties of MSC when cocultured on cancellous bone. Additionally, cell adhesion, metabolic activity, and differentiation were assessed 2, 6, and 10 days after seeding.
Results. The number of adhering EPC and MSC decreased over time; however the cells remained metabolically active over the 10-day measurement period. In spite of a decline of lineage specific markers, cells maintained their differentiation to a reduced level. Osteogenic stimulation of EPC caused a decline but not abolishment of endothelial characteristics and did not induce osteogenic gene expression. Osteogenic stimulation of MSC significantly increased their metabolic activity whereas collagen-1α and alkaline phosphatase gene expressions declined. When cocultured with EPC, MSC’s collagen-1α gene expression increased significantly. Conclusion. EPC and MSC can be cocultured in vitro on cancellous bone under osteogenic conditions, and coculturing EPC with MSC stabilizes the latter’s collagen-1α gene expression.
Membrane proteins frequently assemble into higher order homo- or hetero-oligomers within their natural lipid environment. This complex formation can modulate their folding, activity as well as substrate selectivity. Non-disruptive methods avoiding critical steps, such as membrane disintegration, transfer into artificial environments or chemical modifications are therefore essential to analyze molecular mechanisms of native membrane protein assemblies. The combination of cell-free synthetic biology, nanodisc-technology and non-covalent mass spectrometry provides excellent synergies for the analysis of membrane protein oligomerization within defined membranes. We exemplify our strategy by oligomeric state characterization of various membrane proteins including ion channels, transporters and membrane-integrated enzymes assembling up to hexameric complexes. We further indicate a lipid-dependent dimer formation of MraY translocase correlating with the enzymatic activity. The detergent-free synthesis of membrane protein/nanodisc samples and the analysis by LILBID mass spectrometry provide a versatile platform for the analysis of membrane proteins in a native environment.
Paula Henrikson greift in ihrem Beitrag zum schwedischen Philhellenismus den Bouboulina-Stoff auf und zeichnet darüber hinaus Formen und Wege der Rezeption philhellenischer Gedanken u.a. zwischen Deutschland, Griechenland und Schweden nach.
Cross sections for neutron-induced reactions of short-lived nuclei are essential for nuclear astrophysics since these reactions in the stars are responsible for the production of most heavy elements in the universe. These reactions are also key in applied domains like energy production and medicine. Nevertheless, neutron-induced cross-section measurements can be extremely challenging or even impossible to perform due to the radioactivity of the targets involved. Indirect measurements through the surrogate-reaction method can help to overcome these difficulties.
The surrogate-reaction method relies on the use of an alternative reaction that will lead to the formation of the same excited nucleus as in the neutron-induced reaction of interest. The decay probabilities (for fission, neutron and gamma-ray emission) of the nucleus produced via the surrogate reaction allow one to constrain models and the prediction of the desired neutron cross sections.
We propose to perform surrogate reaction measurements in inverse kinematics at heavy-ion storage rings, in particular at the CRYRING@ESR of the GSI/FAIR facility. We present the conceptual idea of the most promising setup to measure for the first time simultaneously the fission, neutron and gamma-ray emission probabilities. The results of the first simulations considering the 238U(d,d') reaction are shown, as well as new technical developments that are being carried out towards this set-up.
Background: The ideal biofuel should not only be a regenerative fuel from renewable feedstocks, but should also be compatible with the existing fuel distribution infrastructure and with normal car engines. As the so-called drop-in biofuel, the fatty alcohol 1-octanol has been described as a valuable substitute for diesel and jet fuels and has already been produced fermentatively from sugars in small amounts with engineered bacteria via reduction of thioesterase-mediated premature release of octanoic acid from fatty acid synthase or via a reversal of the β-oxidation pathway.
Results: The previously engineered short-chain acyl-CoA producing yeast Fas1R1834K/Fas2 fatty acid synthase variant was expressed together with carboxylic acid reductase from Mycobacterium marinum and phosphopantetheinyl transferase Sfp from Bacillus subtilis in a Saccharomyces cerevisiae Δfas1 Δfas2 Δfaa2 mutant strain. With the involvement of endogenous thioesterases, alcohol dehydrogenases, and aldehyde reductases, the synthesized octanoyl-CoA was converted to 1-octanol up to a titer of 26.0 mg L−1 in a 72-h fermentation. The additional accumulation of 90 mg L−1 octanoic acid in the medium indicated a bottleneck in 1-octanol production. When octanoic acid was supplied externally to the yeast cells, it could be efficiently converted to 1-octanol indicating that re-uptake of octanoic acid across the plasma membrane is not limiting. Additional overexpression of aldehyde reductase Ahr from Escherichia coli nearly completely prevented accumulation of octanoic acid and increased 1-octanol titers up to 49.5 mg L−1. However, in growth tests concentrations even lower than 50.0 mg L−1 turned out to be inhibitory to yeast growth. In situ extraction in a two-phase fermentation with dodecane as second phase did not improve growth, indicating that 1-octanol acts inhibitive before secretion. Furthermore, 1-octanol production was even reduced, which results from extraction of the intermediate octanoic acid to the organic phase, preventing its re-uptake.
Conclusions: By providing chain length control via an engineered octanoyl-CoA producing fatty acid synthase, we were able to specifically produce 1-octanol with S. cerevisiae. Before metabolic engineering can be used to further increase product titers and yields, strategies must be developed that cope with the toxic effects of 1-octanol on the yeast cells.
Background: Hebb repetition learning is a form of long-term serial order learning that can occur when sequences of items in an immediate serial recall task are repeated. Repetition improves performance because of the gradual integration of serial order information from short-term memory into a more stable long-term memory trace.
Aims: The current study assessed whether adolescents with non-specific intellectual disabilities showed Hebb repetition effects, and if their magnitude was equivalent to those of children with typical development, matched for mental age.
Methods: Two immediate serial recall Hebb repetition learning tasks using verbal and visuospatial materials were presented to 47 adolescents with intellectual disabilities (11–15 years) and 47 individually mental age-matched children with typical development (4–10 years).
Results: Both groups showed Hebb repetition learning effects of similar magnitude, albeit with some reservations. Evidence for Hebb repetition learning was found for both verbal and visuospatial materials; for our measure of Hebb learning the effects were larger for verbal than visuospatial materials.
Conclusions: The findings suggested that adolescents with intellectual disabilities may show implicit long-term serial-order learning broadly commensurate with mental age level. The benefits of using repetition in educational contexts for adolescents with intellectual disabilities are considered.
The mirine plant bug Tropidosteptes forestierae, new species (Hemiptera: Miridae) is described from
Collier County, Florida, where it was found causing serious injury to an extensive ornamental hedge of Florida swampprivet, Forestiera segregata (Jacq.) Krug and Urb. (Oleaceae). Adult male and female, fifth instar, and egg are described. Color images of the adults, nymph, egg, and injury; scanning photomicrographs of selected adult structures; and illustrations of male genitalia are provided. A key to help distinguish the 16 species of Tropidosteptes known to occur in the southeastern United States is given.
Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.
Empirical credit demand analysis undertaken at the aggregate level obscures potential behavioral heterogeneity between various borrowing sectors. Looking at disaggregated data and analyzing bank loans to non-financial companies, to financial companies, to households for consumption and for house purchases separately with respect to a common set of macroeconomic determinants may facilitate more accurate empirical relationships and more reliable insights for economic policy. Using quarterly Euro area panel data between 2003 and 2013, empirical evidence for heterogeneity in borrowing behavior across sectors and the credit cycle with respect to interest rates, output and house prices is found. The results motivate sector-specific, counter-cyclical capital requirements.
Aims: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.
Subject and method: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.
Results: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.
Discussion: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.
Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance.
This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations.
KippCity
(2014)
On 28 April 2011, on the Rathausplatz of Neukölln, Christine Hentschel's puzzlement vis-à-vis Neukölln's liberation met the neighbourhood's flickering urbanity, which she seeks to capture in a project called KippCity. KippCity is an experiment in tracing urban change while it happens. If space is the 'event of place', as Doreen Massey holds, the space of KippCity is the transformation of Neukölln. This chapter explores the potentials of multistable figures (Kippbilder) for conceptualizing urban change. This potential, Hentschel argues, lies in the flip-moment itself, in the space-time of urban transformation. In Berlin-Neukölln, a neighbourhood long branded as poor and failing, multiple and partly conflicting flip-scenarios have begun to inspire and haunt the neighbourhood and its self-reflective talk. KippCity Neukölln is thus a flickering figure. But unlike an artefact Kippbild, which flickers between duck and rabbit, for example, KippCity Neukölln does not simply tip into a new pre-fabricated form, but rather wavers between different future scenarios. Neukölln's flickering urbanity is thus nervous, full of uncertainty, frustration and enthusiasm. The article shows how the neighbourhood seeks escape from the dystopia of two dominant flip scenarios of ghettoization and gentrification by digging its claws into its 'Now'.
Tumor hypoxia and nutrient starvation are common phenomena in cancerous tissue. Cells that resist this hostile environment are selected for a more aggressive phenotype, usually accompanied by therapy resistance. The hypoxia inducible factors HIF-1a and HIF-2a play a key role in the adaptive homeostatic responses to these challenging conditions inducing a number of target genes that are involved in the regulation of a variety of cellular processes such as angiogenesis, proliferation, metabolism, self-renewal and cell death/cycle arrest. Thus, the HIF pathway encompasses opposing adaptive responses on tumor growthgrowth promoting abilities on the one hand and growth inhibiting on the other. A recent study in our lab uncovered that this switch between cell death and cell survival critically depends on HIF-2a protein levels. Since PHDs (HIF prolyl hydroxylases) are the main regulators of HIF protein abundance and hypoxia drives the malignant phenotype of tumors, we wanted to characterize HIF regulatory functions of PHDs under hypoxic conditions. Our intention was to reveal the importance of PHD contribution to the opposing functions of HIFs under hypoxia. Characterization of PHD1-4 mRNA and protein expression levels under normoxic and hypoxic conditions in glioblastoma cell lines led to the identification of PHD2 and PHD3 as hypoxia inducible PHD isoforms and highlighted their predominant function under hypoxia. Mechanistically, we demonstrated that HIF mediates the hypoxic induction of PHD2 and 3 within a negative feedback loop, promoting its own degradation during prolonged hypoxia. The functional impact of PHD2 and 3 abundance on cell viability under hypoxic conditions was analyzed by disrupting PHD2 and PHD3 function either through a siRNA mediated approach or by application of the PHD inhibitor DMOG. These experiments uncovered that PHD2 and 3 are protective under hypoxic conditions and that PHD inhibition expedites cell death. Combined HIF and PHD suppression under hypoxic conditions abrogated this increased susceptibility to cell death, clearly showing that PHD2 and 3 act in a negative feedback regulatory loop to limit the HIF response under prolonged hypoxia. With respect to possible future therapeutical applications we co-treated cells with a PHD inhibitor and pro-apoptotic agents staurosporine or TRAIL. Co-challenging tumor cells even potentiated the cell death response, indicating a more widespread protective function of PHD. Taken together PHD2 and 3 protect tumor cells from cell death induction, functioning in a negative feedback regulatory loop to constrain the HIF dependent cell death responses under hypoxia. Interestingly, however, when assessing the role of PHD2 and PHD3 in in vivo tumor growth using an intracranial tumor model, we identified an exclusive tumor suppressor function for PHD3. Loss of PHD3 function enhanced tumor growth whereas increased PHD3 expression diminished the tumor burden. The accelerated tumor growth following PHD3 loss could be attributed to a decrease in the induction of apoptosis and an increase in proliferation. Tumor cells are frequently exposed to temporary and spatial depletion of nutrients. Interestingly, PHD3 loss conferred a growth advantage under growth factor deprivation. The growth regulatory function of PHD3 was isoform specific, HIF independent and importantly, did not require the hydroxylase function of PHD3. Previous reports have uncovered a regulatory function of the PHD system in NF-kB signaling. However, our results demonstrated that NF- kB signaling remained unaffected by alteration in the PHD3 status of the cell. Additionally, the PHD3 tumor suppressor function proved to be independent of two putative PHD3 downstream effectors, ATF4 and KIF1Bb. Mechanistically, PHD3 suppression reduced EGFR internalization, enhancing the amount of EGFR expressed on the cell surface. We further showed that the impaired EGFR internalization during PHD3 loss resulted in receptor hyperactivation under stimulated and growth factor deprived conditions. Importantly, PHD3 physcially associated with the EGFR complex as evidenced by co-immunoprecpitation. Consequently, this extended EGFR activation in PHD3 deficient cells resulted in enhanced downstream activation of EGFR signaling and increased proliferation. Consistent with the interpretation that PHD3 loss is beneficial for tumor growth, we found PHD3 promoter methylation in glioblastoma cell lines, hinting at a epigenetic mechanism to finetune PHD3 expression on top of the hypoxic driven gene regulation. Finally, we demonstrated that PHD3 tumor suppressor function is not restricted to glioblastomas since PHD3 suppression in lung adenocarcinoma accelerated subcutaneous tumor growth. With these findings, we expand the knowledge of PHD3 action from its oxygen sensing role to a regulatory function in growth factor signaling. This clearly discriminates PHD3 from the other isoforms and supports the exclusive tumor suppressor function in glioblastoma. Taken together our results identify a complex role of PHD signaling in cancer and delineate HIF dependent and HIF independent functions of the PHD system. We think that the HIF dependent protective effect of PHD2 and 3 and the HIF independent PHD3 tumor suppressor function are not mutually exclusive, but might be activated according to the heterogeneous intra-tumoral conditions. However, PHD3 hydroxylase activity is dispensable for its HIFindependent tumor suppressor function in glioma. This uncouples PHD3 function from co-factor and co-substrate requirements and allows it to act over a broader physiological range, since its influence on cellular processes is not constrained by the availability of rate limiting factors. It might explain, why the enzymatic independent functions of PHD3 predominate in vivo. Thus, therapeutic modulation of the PHD system to inhibit tumor growth has to be based on these contrasting functions of the PHD system. However, their differential dependence on the hydroxylase activity may facilitate a therapeutic strategy to specifically inhibit or promote the protective versus suppressive functions of the PHD system.
In the past decade, the optogenetic toolbox for the manipulation of ion currents and cNMP levels in Caenorhabditis elegans (C. elegans) expanded. However, the implemented tools for cAMP generation were soluble enzymes (euPAC, bPAC, IlaC22 k27 and PaaC) and thus they do not precisely mimic physiological cAMP signalling occurring in microdomains in close proximity to the plasma membrane. Here, cAMP is predominantly generated by membrane-bound adenylyl cyclases, that are located in microdomains together with G protein-coupled receptors (GPCRs), protein kinase A (PKA) and their targets, enabling spatially and temporal regulation of cAMP signalling. For this reason, one aim of this study was to develop and implement membrane bound photoactivatable adenylyl cyclases for the manipulation of cAMP mediated signalling in close proximity to the plasma membrane. For this purpose, the guanylyl cyclase domains of the Blastocladiella and Catenaria Cyclase Opsins (CyclOps) were mutated to adenylyl cyclases either by introducing the mutations E497K and C566D (abbreviated as (A-2x)) or by the mutations E497K, H564D, and C566T (abbreviated as (A-3x)).
To determine the nucleotide specificity switch from GTP to ATP and the extent of light-dependent cAMP generation, the engineered enzymes were expressed in body wall muscle cells of C. elegans and in vitro cNMP measurements using C. elegans extracts were performed. Here, the highest levels of light induced cAMP generation during sustained stimulation (0.5 mW/mm2; 470 nm, 15 min) were detected for the variants BeCyclOp(A-2x), YFP-BeCyclOp(A-2x), and YFP-CaCyclOp(A-2x) (39, 57, 40 nM, respectively), though they did not reach the extent produced by the soluble bPAC (142 nM). In contrast, low magnitudes of generated cAMP were measured for the versions BeCyclOp(A-3x) and CaCyclOp(A-2x) (8 and 7 nM, respectively). Importantly, no obvious residual cGMP and basal activity was ascertained for any of the engineered enzymes.
To assess their potential to trigger and modulate cAMP mediated cholinergic neurotransmission, and to evaluate the influence of cytosolic and membrane proximal optogenetic cAMP generation, the enzymes were expressed in cholinergic motor neurons and compared to the implemented soluble bPAC via locomotion behaviour analysis on solid and in liquid media. Photoactivation of BeCyclOp(A-2x), YFP-BeCyclOp(A-2x), and YFP-CaCyclOp(A-2x) caused similarly enhanced or even more potent behavioural changes (swimming and crawling) as bPAC, whereas a more rapidly decaying response was observed for the bPAC evoked effects. Moreover, an increased diversity of the behavioural output was detected for cytosolic cAMP production by bPAC, i.e. increased bending angles and a decreased body length.
Confocal fluorescence microscopy was performed to examine the expression levels of YFP-tagged enzymes in cholinergic neurons, whereas both YFP-CyclOp(A-2x)s were expressed at similar levels, but 1.4-fold lower relative to the soluble bPAC-YFP. To compare the amount of light-dependent cAMP generation bPAC and BeCyclOp(A-2x) at light conditions that match the conditions of the behavioural experiments (30 s), cAMP measurements using C. elegans extracts were performed, whereas BeCyclOp(A-2x) depicted a 4-fold lower amount of optogenetic cAMP production than the soluble bPAC.
In sum, local (membrane proximal) cAMP generation by the membrane-bound photoactivatable adenylyl cyclases may more specifically activate cAMP dependent neurotransmission of cholinergic motor neurons than cytosolic cAMP generation, i.e. an increased mobilization and priming/docking of synaptic vesicles and an increased filling of the synaptic vesicles with the neurotransmitter acetylcholine and thus an increase in locomotion behaviour.
The optogenetic toolbox for the manipulation of cGMP mediated signalling in C. elegans consisted of the natural membrane-bound BeCyclOp and the artificial soluble bPGC. The latter generates cGMP with low efficiency and slow kinetics (~0.2 cGMP s-1), whereas BeCyclOp enables the production of much larger amounts of cGMP (L/D = 5000) at a high turnover rate (~17 cGMP s-1). Thus, one aim of this thesis was to implement a tool with features in between those of BeCyclOp and bPGC. Several orthologous CyclOps were assessed by Gao et al., 2015 for light-regulated cGMP production by in vitro assays based on the measurement of the cNMP content from CyclOp containing oocyte membranes. Here, CaCyclOp showed the highest ratio of light versus dark activity (L/D = 230) after BeCyclOp, and thus was selected for characterization in C. elegans...
Background and Purpose: The cyclic nucleotides cAMP and cGMP are ubiquitous second messengers regulating numerous biological processes. Malfunctional cNMP signalling is linked to diseases and thus is an important target in pharmaceutical research. The existing optogenetic toolbox in Caenorhabditis elegans is restricted to soluble adenylyl cyclases, the membrane-bound Blastocladiella emersonii CyclOp and hyperpolarizing rhodopsins; yet missing are membrane-bound photoactivatable adenylyl cyclases and hyperpolarizers based on K+ currents.
Experimental Approach: For the characterization of photoactivatable nucleotidyl cyclases, we expressed the proteins alone or in combination with cyclic nucleotide-gated channels in muscle cells and cholinergic motor neurons. To investigate the extent of optogenetic cNMP production and the ability of the systems to depolarize or hyperpolarize cells, we performed behavioural analyses, measured cNMP content in vitro, and compared in vivo expression levels.
Key Results: We implemented Catenaria CyclOp as a new tool for cGMP production, allowing fine-control of cGMP levels. We established photoactivatable membrane-bound adenylyl cyclases, based on mutated versions (“A-2x”) of Blastocladiella and Catenaria (“Be,” “Ca”) CyclOp, as N-terminal YFP fusions, enabling more efficient and specific cAMP signalling compared to soluble bPAC, despite lower overall cAMP production. For hyperpolarization of excitable cells by two-component optogenetics, we introduced the cAMP-gated K+-channel SthK from Spirochaeta thermophila and combined it with bPAC, BeCyclOp(A-2x), or YFP-BeCyclOp(A-2x). As an alternative, we implemented the B. emersonii cGMP-gated K+-channel BeCNG1 together with BeCyclOp.
Conclusion and Implications: We established a comprehensive suite of optogenetic tools for cNMP manipulation, applicable in many cell types, including sensory neurons, and for potent hyperpolarization.
Adult females of the five Central European wolf spiders Trochosa hispanica Simon, 1870, T. robusta (Simon, 1876), T. ruricola (De Geer, 1778), T. spinipalpis (F. O. P.-Cambridge, 1895), and T. terricola Thorell, 1856 were morphologically analysed. We defined sets of continuous and binary (presence/absence) variables. Continuous data of various epigynal and carapace dimensions were subjected to Principal Components Analysis (PCA). Using the PC loadings each individual was plotted along the PC axis in order to find gaps/overlaps between the species. The binary data sets were subjected to Hierarchical Cluster Analysis (HCA) in order to find characters that clearly separate the five Trochosa species. Using PCA only individuals of T. robusta and T. ruricola and of T. robusta and T. hispanica could be separated from each other. Using HCA all five species could clearly be separated by epigynal and vulval characteristics.
A new feature for the separation of Trochosa spinipalpis and T. terricola males (Araneae, Lycosidae)
(2006)
A new feature on the tip of the palp, which enables the separation of male Trochosa spinipalpis (F. O. P.-Cambridge, 1895) from T. terricola Thorell, 1856, is described. T. terricola exhibits a hairless strip on the tip of the palp, while T. spinipalpis lacks this feature and has long hairs on the whole palp.
Inhibition is a central component of human behavior. It enables flexible and adaptive behavior by suppressing prepotent motor responses. In former studies, it has been shown that sport athletes acting in dynamic environments exhibit superior motor inhibitory control based on sensory stimuli. So far, existing studies have corroborated this in manual motor response settings only. Therefore, this study addresses the effector specificity of the inhibition benefit in elite athletes compared to physically active controls. A sport-unspecific stop-signal task has been adapted for hand as well as feet usage and 30 elite handball players as well as 30 controls were tested. A repeated-measures ANOVA with the two factors “effector” (hands, feet) and “group” (expert, recreational athletes) was conducted. Our results suggest no group differences in two-choice response times, but a convincing superiority of handball players in inhibitory control (i.e., shorter stop-signal reaction times), predominantly when responding with their hands, with weaker differential effects when responding with their feet. This suggests that motor inhibition might be a comprehensive performance characteristic of sport athletes acting in dynamic environments, detectable predominantly in eye-hand coordination tasks.
Being among the most habitat diverse countries in the world (and plant diversity is about 22,000 sp.), Mexico has a Lepidoptera fauna recorded at about 14,385 species but is estimated to be over 22,000 species, if not much higher (some estimates go to 35,000 sp.). High Lepidoptera numbers in Mexico are also due to the large influx of tropical species from the border with Guatemala, as well as Mexican endemics. In this report, the Lepidoptera families are summarized for Mexico, giving known species and what experts estimate to be the true total for each family when all have been described. Many regions of Mexico are still poorly known for smaller
moths.
Book Review: This is another volume in the extensive series planned on Palearctic Microlepidoptera (including Pyralidae). The expertise of Dr. Diakonoff, particularly in Tortricidae, provides a welcome coverage for the included species. This is especially true for the previously conglomerated assortment of species placed in Glyphipterigidae by E. Meyrick and the fact that until recently this classification was followed by most works on the Palearctic fauna. The previous concept of Glyphipterigidae has been considerably altered in the past decade; where Meyrick had over 1,200 species worldwide in one family, we now have four separate families and part of a fifth family for the bulk of these species, while about 200 other species have been assigned to about 20 other families from Meyrick's erroneous placements. This current MP volume revises and illustrates the Palearctic fauna of the five major groups of the previous Glyphipterigidae for the first time using modern taxonomic concepts and detailed analysis of characters such as genitalia, not used by Meyrick and many older workers.
Book review: This is a new directory of scientific organizations and related agencies from Gale Research, a publisher of several other directories of research facilities and other organizations. The present contribution covers both U.S. and foreign organizations, including virtually all nations. It complements the directories Gale Research has published on medical, technological, and earth sciences organizations.
We investigate the effectiveness of professional development (PD) aimed at promoting teachers' language-support skills in elementary school science instruction. In a 2-year quasi-experimental field trial study with 32 teachers in Germany, an intervention group (IG) and a control group (CG) received PD for teaching selected science topics; the IG additionally received PD for language support. Strong treatment effects emerged on teachers’ language-support skills and, to a lesser extent, on language support activities in classroom teaching. All teachers gained pedagogical content knowledge and self-efficacy for teaching elementary school science, thus pointing to the effectiveness of the PD.
Background: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.
Methods: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.
Results: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0–65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0–65.0). The median PFS was 3.0 months (95% CI 2.4–3.6). The median OS was estimated to 16.1 months (95% CI 12.9–19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).
Conclusions: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
Tropical geometry is the geometry of the tropical semiring \[\mathbb{T}:=(\mathbb{R}\cup\{\infty\},\min,+).\] Classical algebraic structures correspond to tropical structures. If $I\lhd K[x_1,\ldots,x_n]$ is an ideal in a polynomial ring over a field $K$ with valuation $v$, then the classical algebraic variety correspond to the tropical variety $T(I)$. It is the set of all points $w$, such that the minimum $\min\{v(c_\alpha)+w\cdot\alpha\}$ is achieved twice for all $f=\sum_\alpha c_\alpha x^\alpha\in I$. So tropical geometry relates algebraic geometric problems with discrete geometric problems. In this thesis we obtain a tropical version of the Eisenbud-Evans Theorem which states that every algebraic variety in $\mathbb{R}^n$ is the intersection of $n$ hypersurfaces. We find out that in the tropical setting every tropical variety $T(I)$ can be written as an intersection of only $(n+1)$ tropical hypersurfaces. So we get a finite generating system of $I$ such that the corresponding tropical hypersurfaces intersect to the tropical variety, a so-called tropical basis. Let $I \lhd K[x_1,\ldots,x_n]$ be a prime ideal generated by the polynomials $f_1, \ldots, f_r$. Then there exist $g_0,\ldots,g_{n} \in I$ such that \[ T(I) \ = \ \bigcap_{i=0}^{n}T(g_i)\] and thus $\mathcal{G} := \{f_1, \ldots, f_r, g_0, \ldots, g_{n}\}$ is a tropical basis for $I$ of cardinality $r+n+1$. Tropical bases are discussed by Bogart, Jensen, Speyer, Sturmfels and Thomas where it is shown that tropical bases of linear polynomials of a linear ideal have to be very large. We do not restrict the tropical basis to consist of linear polynomials and therefore we get a shorter tropical basis. But the degrees of our polynomials can be very large. The main ingredient to get a short tropical basis is the use of projections, in particular geometrically regular projections. Together with the fact that preimages of projections of tropical varieties are themselves tropical varieties of a certain elimination ideal we get the desired result. Let $I \lhd K[x_1, \ldots, x_n]$ be an $m$-dimensional prime ideal and $\pi : \mathbb{R}^n \to \mathbb{R}^{m+1}$ be a rational projection. Then $\pi^{-1}(\pi(T(I)))$ is a tropical variety, namely \[ \pi^{-1}(\pi(T(I))) \ = \ T(J \cap K[x_1, \ldots, x_n]) \,\] Here $J$ is an ideal in $K[x_1,\ldots,x_n,\lambda_1,\ldots,\lambda_{n-m-1}]$ derived from the ideal $I$. We show that this elimination ideal is a principal ideal which yields a polynomial in our tropical basis. The advantage of our method is that we find our polynomials by projections and therefore we can use the results of Gelfand, Kapranov and Zelevinsky , of Esterov and Khovanskii , and of Sturmfels, Tevelev and Yu. With mixed fiber polytopes we get the structure and combinatorics of the image of a tropical variety and therefore the structure of the polynomials in our tropical basis. Let $I=\lhd K[x_1,\ldots,x_n]$ an $m$-dimensional ideal, generated by generic polynomials $f_1,\ldots, f_{n-m}$, $\pi:\mathbb{R}^n\to\mathbb{R}^{m+1}$ a projection and $\psi$ a projection presented by a matrix with a rowspace equal to the kernel of $\pi$. Then up to affine isomorphisms, the cells of the dual subdivision of $\pi^{-1} \pi T(I)$ are of the form \[ \sum_{i=1}^p \Sigma_{\psi} (C_{i1}^{\vee}, \ldots, C_{i{k}}^{\vee}) \] for some $p\in\mathbb{N}$ and faces $F_1, \ldots, F_p$ of $T(f_1)\cap\ldots\cap T(f_k)$ and the dual cell of $F_i\subseteq U = T(f_1)\cup\ldots\cup T(f_k)$ is given by $F_i^\vee=C_{i1}^{\vee}+ \ldots+ C_{ik}^{\vee}$ with faces $C_{i1}, \ldots, C_{i k}$ of $T(f_1), \ldots, T(f_{k})$. In case that we project a tropical curve we want to find the number of $(n-1)$-cells of the above form with $p>1$, i.e. the cells which are dual to vertices of $\pi(T(I))$ which are the intersection of the images of two non-adjacent $1$-cells of $T(I)$. Vertices of this type are called selfintersection points. We show that there exist a tropcal line $L_n\subset\mathbb{R}^n$ and a projection $\pi:\mathbb{R}^n\to\mathbb{R}^2$, such that $L_n$ has $\sum_{i=1}^{n-2}i$ selfintersection points. Furthermore we find tropical curves $\mathcal{C}\subset\mathbb{R}^n$, which are transversal intersections of $n-1$ tropical hypersurfaces of degrees $d_1,\ldots,d_{n-1}$ and a projection $\pi:\mathbb{R}^n\to\mathbb{R}^2$, such that $\mathcal{C}$ has at least $(d_1\cdot\ldots\cdot d_{n-1})^2\cdot \sum_{i=1}^{n-2}i) $ selfintersection points. A caterpillar is a certain simple type of a tropical line and for this type we show that it can have at most $\sum_{i=1}^{n-2}i$ selfintersection points.
A preliminary list consisting of 159 bryophyte taxa (82 liverworts and 77 mosses) has been compiled from the bryological literature on the Republic of Equatorial Guinea (Central-Western Africa) until 1995. A general overview of the physical features and vegetation of the country, and an account of the history of its bryological exploration are also included.
Eight moss species corresponding to nomina nuda recorded in the literature from Annobon Island are listed with their recent determination and current names. Leucophanes unguiculatum, Philonotis uncinata var. glaucescens and Vesicularia strephomischos are new records for the Equatorial Guinean bryoflora.
The genus Afrodonta s. lat. is shown to comprise several lineages with distinctive shell characters primarily associated with the microsculpture of the protoconch and teleoconch, and the manner in which the apertural barriers are deposited. These lineages comprise Afrodonta s. str. and five new genera: Amatholedonta gen. nov., Biomphalodonta gen. nov., Costulodonta gen. nov., Iterodonta gen. nov. and Phialodonta gen. nov. Twelve new species are described, doubling the diversity of aperturally dentate charopid snails known from southern Africa. All new species are narrow-range endemics. A new subspecies of one of the more widely distributed species of Afrodonta s. str. is also described. Keys to genera and species are provided. New species and subspecies: Afrodonta geminodonta sp. nov., Af. inhluzaniensis leptolamellaris subsp. nov., Af. mystica sp. nov., Af. pentodon sp. nov., Amatholedonta fordycei gen. et sp. nov., Biomphalodonta forticostata gen. et sp. nov., Costulodonta bidens gen. et sp. nov., C. pluridens gen. et sp. nov., Iterodonta ammonita gen. et sp. nov., Phialodonta agulhasae gen. et sp. nov., P. atromontana gen. et sp. nov., P. aviana gen. et sp. nov. and P. rivalalea gen. et sp. nov. New synonyms: Afrodonta bilamellaris londonensis Solem, 1970 = Afrodonta bilamellaris Melvill & Ponsonby, 1908. New combinations: Afrodonta acinaces Connolly, 1933, Afrodonta burnupi Connolly, 1933 and Afrodonta trilamellaris Melvill & Ponsonby, 1908 are transferred to Costulodonta gen. nov.; Afrodonta bimunita Connolly, 1939 is transferred to Amatholedonta gen. nov.; Afrodonta introtuberculata Connolly, 1933 and Afrodonta perfida Burnup, 1912 are transferred to Phialodonta gen. nov.
A new genus and eight new species of urocyclid snails are described from eastern South Africa. The supra-specific taxa Kerkophorus Godwin-Austen, 1912 and Microkerkus Godwin-Austen, 1912 are considered distinct from Sheldonia Ancey, 1887 and are treated as separate genera. The diagnostic morphological features of all three genera are detailed and a fourth genus, for which there is no existing name, is described as new: Selatodryas gen. nov. A provisional key to genus-level taxa within Sheldonia s.l. is provided. Eight species are described as new: Kerkophorus piperatus sp. nov., K. vittarubra sp. nov., K. scrobicolus sp. nov., K. terrestris sp. nov., Microkerkus sibaya sp. nov., Selatodryas roseosoma gen. et sp. nov., S. luteosoma gen. et sp. nov. and Sheldonia fingolandensis sp. nov.
One new genus and five new species of land snails are described from high altitude, insular, Afrotemperate forest habitats in northern South Africa. The distribution of these species is discussed in relation to other narrowly endemic land snails occurring in this and neighbouring regions. The new genus is Ptilototheca gen. nov.; the five new species are: Gulella davisae sp. nov., G. hadroglossa sp. nov., Ptilototheca soutpansbergensis gen. et sp. nov., Sheldonia monsmaripi sp. nov. and S. wolkbergensis sp. nov.
The vetigastropod material collected on Walters Shoal during Cruise MD208 of the Tropical Deep-Sea Benthos programme is documented. In total, 50 species were obtained, 30 of which are new and apparently endemic to the seamount. Of the other 20 species, eight are regionally endemic to the south-western Indian Ocean, 11 are more widely distributed in the Indo-West Pacific and one is possibly of deep-water Atlantic origin. The primary affinities of the fauna are with warm temperate South Africa and the tropical western Indian Ocean, but one species is potentially a seamount endemic of southern affinity. A new pseudococculinid genus living on decomposing bird feathers is described, a biogenic substrate association previously unknown in the Mollusca. The following new genera are described: Imbricoscelis gen. nov. and Pterodacna gen. nov. The following new species are described: Akritogyra crenulata sp. nov., Bathymophila williamsae sp. nov., Benthobrookula araneum sp. nov., Be. galeneae sp. nov., Be. laticostata sp. nov., Be. scalaroides sp. nov., Be. semisculpta sp. nov., Bruceina areneformis sp. nov., Calliostoma pantopunctatum sp. nov., Cantrainea herosae sp. nov., Carinastele achrosta sp. nov., Cornisepta marshalli sp. nov., Emarginula lentiginosa sp. nov., E. nodulicostata sp. nov., E. retrogyra sp. nov., E. salebrosa sp. nov., Fluxinella dufresneae sp. nov., Gibbula roseosticta sp. nov., Hadroconus scobina sp. nov., Kaiparathina monticola sp. nov., Lissotesta wareni sp. nov., Microcollonia miniata sp. nov., Mikro crassus sp. nov., Parviturbo cicatricosus sp. nov., Phragmomphalina candida sp. nov., Pterodacna boucheti gen. et sp. nov., Solariella asaphea sp. nov., Spinicalliotropis lepidota sp. nov., Stomatella multilirata sp. nov. and Trenchia mcleani sp. nov. The following new combinations are proposed: Brookula coronis Barnard, 1963 is transferred to Imbricoscelis gen. nov., Cantharidus nolfi Poppe, Tagaro & H. Dekker, 2006 is transferred to Kaiparathina Laws, 1941 and Solariella incisura Melvill, 1909 is transferred to Phragmomphalina Herbert & Williams, 2020. The following new synonyms are proposed: Carinastele wareni Vilvens, 2014 is a synonym of Bruceina cognata (Marshall, 1988); Fluxinella stellaris Bozzetti, 2008 is a synonym of Agagus stellamaris Herbert, 1991.
Die vorliegende Arbeit beschäftigt sich mit der BFV-Reduktion von Hamiltonschen Systemen mit erstklassigen Zwangsbedingungen im Rahmen der klassischen Hamiltonschen Mechanik und im Rahmen der Deformationsquantisierung. Besondere Aufmerksamkeit wird dabei Zwangsbedingungen zuteil, die als Nullfaser singulärer äquivarianter Impulsabbildungen entstehen. Es ist schon länger bekannt, daß für Nullfasern regulärer äquivarianter Impulsabbildungen die in der theoretischen Physik gebräuchliche Methode der BFV-Reduktion zur Phasenraumreduktion nach Marsden/Weinstein äquivalent ist. In [24] konnte gezeigt werden, daß in dieser Situation die BFV-Reduktion sich auch im Rahmen der Deformationsquantisierung natürlich formulieren läßt und erfolgreich zur Konstruktion von Sternprodukten auf Marsden/Weinstein-Quotienten verwendet werden kann. Ein Hauptergebnis der vorliegenden Arbeit besteht in der Verallgemeinerung der Ergebnisse aus [24] auf den Fall singulärer Impulsabbildungen, deren Komponenten 1.) das Verschwindungsideal der Zwangsfläche erzeugen und 2.) einen vollständigen Durchschnitt bilden. Die Argumentation von [24] wird durch Gebrauch der Störungslemmata aus dem Anhang A.1 systematisiert und vereinfacht. Zum Existenzbeweis von stetigen Homotopien und stetiger Fortsetzungsabbildung für die Koszulauflösung werden der Zerfällungssatz und der Fortsetzungssatz von Bierstone und Schwarz [20] benutzt. Außerdem wird ein ’Jacobisches Kriterium’ für die Überprüfung von Bedingung 2.) angegeben. Basierend auf diesem Kriterium und Techniken aus [3] werden die Bedingungen 1.) und 2.) an einer Reihe von Beispielen getestet. Als Korollar erhält man den Beweis dafür, daß es symplektisch stratifizierte Räume gibt, die keine Orbifaltigkeiten sind und dennoch eine stetige Deformationsquantisierung zulassen. Ferner wird (ähnlich zu [92]) eine konzeptionielle Erklärung dafür gegeben, warum im Fall vollständiger Durchschnitte das Problem der Quantisierung der BRST-Ladung eine so einfache Lösung hat. Bildet die Impulsabbildung eine erstklassige Zwangsbedingung, ist aber kein vollständiger Durchschnitt, dann ist es im allgemeinen nicht bekannt, wie entsprechende Quantenreduktionsresultate zu erzielen sind. Ein Hauptaugenmerk der Untersuchung wird es deshalb sein, in dieser Situation die klassische BFV-Reduktion besser zu verstehen – natürlich in der Hoffnung, Grundlagen für eine etwaige (Deformations-)Quantisierung zu liefern. Wir werden feststellen, daß es zwei Gründe gibt, die Tate-Erzeuger (alias: Antigeister höheren Niveaus) notwendig machen: die Topologie der Zwangsfläche und die Singularitätentheorie der Impulsabbildung. Die Zahl der Tate-Erzeuger kann durch Übergang zu projektiven Tate-Erzeugern, also Vektorbündeln, verringert werden. Allerdings sorgt Halperins Starrheitssatz [57] dafür, daß im wesentlichen alle Fälle, für die die Zwangsfläche kein lokal vollständiger Durchschnitt ist, zu unendlich vielen Tate-Erzeugern führen. Erzeugen die Komponenten einer Impulsabbildung einer linearen symplektischen Gruppenwirkung das Verschwindungsideal der Zwangsfläche, so kann man eine lokal endliche Tate-Auflösung finden. Diese besitzt nach dem Fortsetzungssatz und dem Zerfällungssatz von Bierstone und Schwarz stetige, kontrahierende Homotopien. Ausgehend von einer solchen Tate-Auflösung konstruieren wir, die klassische BFV-Konstruktion für vollständige Durchschnitte verallgemeinernd, eine graduierte superkommutative Algebra. Wir können zeigen, daß diese graduierte Algebra auch im Vektorbündelfall eine graduierte Poissonklammer besitzt, die sogenannte Rothstein-Poissonklammer. Die Existenz einer solchen Poissonklammer war bereits von Rothstein [87] für die einfachere Situation einer symplektischen Supermannigfaltigkeit bewiesen worden. Darüberhinaus werden wir sehen, daß es auch im Vektorbündelfall eine BRST-Ladung gibt. Diese sieht im Fall von Impulsabbildungen etwas einfacher aus als für allgemeine erstklassige Zwangsbedingungen. Insgesamt wird also die klassische BFV-Konstruktion [95] auf den Fall projektiver Tate-Erzeuger verallgemeinert, und als eine Homotopieäquivalenz in der additiven Kategorie der Fréchet-Räume interpretiert.
This paper analyzes how on-the-job search (OJS) by an agent impacts the moral hazard problem in a repeated principal-agent relationship. OJS is found to constitute a source of agency costs because efficient search incentives require that the agent receives all gains from trade. Further, the optimal incentive contract with OJS matches the design of empirically observed compensation contracts more accurately than models that ignore OJS. In particular, the optimal contract entails excessive performance pay plus efficiency wages. Efficiency wages reduce the opportunity costs of work effort and hence serve as a complement to bonuses. Thus, the model offers a novel explanation for the use of efficiency wages. When allowing for renegotiation, the model generates wage and turnover dynamics that are consistent with empirical evidence. I argue that the model contributes to explaining the concomitant rise in the use of performance pay and in competition for high-skill workers during the last three decades.
Cancer is one of the leading causes of death across all countries and its diagnosis still yields fear for the affected patient. Although treatment of cancer has made marvelous progress compared to the agents available thirty years ago, a cure for cancer, however, is still a distant prospect. Modern therapy still is a burden for many patients due to heavy side effects. With the development of agents targeting specific molecular targets on cancer cells, a new field of cancer therapy was opened and a small success story in the history of cancer began.
Aurora kinases represent a relatively new target in cancer therapy. The kinase is a essential part of mitosis and cell cycle progression and its overexpression has been shown to be related to many kinds of malignancies. Allosteric inhibition of a kinase is an increasing pre-clinical approach not yet established in the treatment of patients. In this thesis, we combine allostery with another innovative approach that is drug repurposing. If repurposed, a drug can be permitted to fast track drug admission to clinical trials.
I set up a screening of 1280 FDA approved drugs to identify small molecule compounds that affect the binding of Aurora kinase A and its main physiologic binding partner, TPX2. Further, I characterized the positive hits in vitro for their capabilities to displace TPX2 from Aurora A, to inhibit Aurora kinase activity, to thermally stabilize the protein and performed assays to determine their dissociation constant. Last but not least, I tested the compounds in cells for their effect on the cell viability and cell cycle via flow cytometry. Comparing the hit-compounds with controls I found that ATP-competitive AurA inhibitor MLN 8237 strongly displaces the interaction of Aurora A with TPX2.
Summarized, we identified eight hit compounds allosterically affecting Aurora A, but no compound proved to be active in all assays. Just one compound, PS 731, identified in another screening performed by our group and further characterized in this thesis remains interesting, especially when put in context with recent publications released in the time between the start of experiments for this thesis and its finalization.
As central component of the peptide loading complex, the ABC transporter TAP is a key player in the adaptive immune response. By recognizing and translocating antigenic peptides derived from proteasomal degradation into the ER lumen it connects the processing of harmful intruders and the marking of an infected cell for elimination. This work focused mainly on the interaction between TAP and one of its viral inhibitors. Of the five known TAP inhibitors, ICP47 is the only one that is not anchored in the ER membrane and has a nonomolar affinity to TAP. These properties and its specific architecture make it an interesting protein engineering tool that can be used in a variety of ways to generate functionally arrested TAP complexes. Different lengths of ICP47 were chosen to map the optimal distance between the binding pocket and the N-terminal elbow helix of either TAP1 or TAP2. I demonstrated that the interaction of fused ICP47 with coreTAP inhibits antigen presentation via MHC I. Interestingly, the loss of MHC I surface expression only depended on the presence of the active domain and not on the length of the fused ICP47 fragments. Summarizing it can be said that TAP complexes containing an intact active domain of ICP47 successfully suppressed MHC I surface expression. Considering the MHC I surface expression in the use of free ICP47 fragments it was revealed that the active domain may not be sufficient. All free constructs, except the one that contains exclusively the active domain (1-35), were able to fully arrest peptide translocation, while the fragment 1-35 partially restored MHC I surface expression. This was the first evidence suggesting that more residues might be present in the ICP47 sequence that contribute to the interaction with TAP.
Further characterization of the ICP47-coreTAP fusion complexes comprised the determination of their thermostability and melting temperatures. The ICP47-coreTAP fusion complexes revealed a preferred orientation for ICP47. The ICP47(1-65) fragment led to a stable complex only if fused to TAP2, highlighting an interesting asymmetry at the TAP1/TAP2 interface, which suggests a shorter distance of the C-terminus of the stabilizing region to the elbow helix of TAP2 than of TAP1. The shorter fragments 1-35 and 1-50, and the ICP47 linker fragments, which inhibited, but did not trigger any thermostabilizing effects on TAP, revealed a second hint for the presence of other residues important for the ICP47/TAP interaction. To define the thermostability in more detail, the melting temperature of complexes with fused or freely bound ICP47 fragments was determined. Short fused fragments of ICP47 (residues 1-35 or 1-50) did not fully stabilize the TAP complex. Only ICP47 fragments longer than residues 1-50 raised the melting temperature to the full extent and led to a completely stabilized complex, suggesting that the critical melting temperature, which determines whether a complex is fully stabilized or not, is about 44-45°C. By comparing different ICP47 proteins from the herpesviral clade, I further noticed that the 21 residues following the active domain are highly conserved. The residues in this region were exchanged by glycines and alanines to study their impact on the thermostabilization of TAP. I demonstrated that several charged residues, an alanine rich, and a proline rich sequence were mainly responsible for the preservation of high melting temperatures. In summary, these findings reveal a dual inhibition mechanism of ICP47. While the active domain of ICP47 is wedged at the TAP1/2 interface and arrests the complex in an open-inward facing conformation, the highly conserved C-terminal region stabilizes the ICP47/TAP interaction and generates a thermostabilized TAP complex.
The second part of this thesis deals with two alternative expression and stabilization strategies for coreTAP, designed to provide a 1:1 ratio of TAP subunits during protein biosynthesis. Different glycine-serine (GS) linkers and a self cleaving 2A site were im- plemented into the TAP sequence and used for comparison with the classical coreTAP. Despite their functionality in antigen translocation, the utilization of GS linkers proved to be unsuitable due to low expression and scarce purification efficiency caused by the unfeasible orthogonal purification. In contrast, the use of a 2A site allowed orthogonal His10- and SBP-tag purification and yielded comparable amounts to the classical coreTAP. However, the ICP47/coreTAP interaction appeared to be hampered by the modified N-terminus of ICP47, due to the cleavage process.
The third and last part of this work deals with the Thermus thermophilus ABC trans- porter TmrAB, which was identified to be part of the same ABC subfamily as TAP. The structure of TmrAB is similar to that of coreTAP and includes a TMD and an NBD for each subunit. In comparison to TAP, TmrAB has a broader substrate range, but it can transport peptides, which are also transported by TAP. Since the natural substrate, and thus the actual function, of TmrAB has not yet been identified, it is counted among the multidrug resistance ABC transporters, from where it also takes its name. In this work, the question was investigated whether TmrAB can be utilized as a TAP substitute. To compare the function of TmrAB and TAP in a natural cell environment, the N-terminal domains of the TAP subunits called TMD0s were fused to the TmrAB subunits and subsequently expressed as different combinations. I found that especially the hybrid complexes containing a TMD0 of TAP2 were functional in terms of MHC I surface expression. Furthermore, TmrAB with TMD0 co-localized prevalently with the ER marker PDI while complexes without TMD0 did not co-localize. Interestingly, the analysis of the interaction with components of the PLC revealed that interaction with tapasin could only occur when a TMD0 was present. In turn, calreticulin, MHC I, and ERp57 were bound, regardless of the presence of a TMD0. It is remarkable that a bacterial protein, sharing only 27-30% sequence identity with human TAP is able to take over a key function of our adaptive immune system. Yet, TmrAB originates from a hyperthermophilic bacterium and may have assembly and folding difficulties that the human cell seeks to overcome by recruiting chaperones like calreticulin and ERp57. Although further experiments will be necessary to analyze the interaction of TmrAB with the PLC components in more detail, TmrAB appears to be homologous to coreTAP, not only in terms of sequence and structure, but also in terms of function.
As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion. The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. Here, we report on a thermostable ICP47-TAP complex, generated by fusion of different ICP47 fragments. These fusion complexes allowed us to determine the direction and positioning in the central cavity of TAP. ICP47-TAP fusion complexes are arrested in a stable conformation, as demonstrated by MHC I surface expression, melting temperature, and the mutual exclusion of herpesviral TAP inhibitors. We unveiled a conserved region next to the active domain of ICP47 as essential for the complete stabilization of the TAP complex. Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. Based on our findings, we propose a dual interaction mechanism for ICP47. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. These new insights into the ICP47 inhibition mechanism can be applied for future structural analyses of the TAP complex.
Suppliers play a major role in innovation processes. We analyze ownership allocations and the choice of R&D technology in vertical R&D cooperations. Given incomplete contracts on the R&D outcome, there is a tradeoff between R&D specifically designed towards a manufacturer (increasing investment productivity) and a general technology (hold-up reduction). We find that the market solution yields the specific technology in too few cases. More intense product market competition shifts optimal ownership towards the supplier. The use of exit clauses increases the gains from the collaboration. JEL Classification: L22, L24, O31, O32
We compute the phase and the modulus of an energy- and pressure-free, composite, adjoint, and
inert field φ in an SU(2) Yang-Mills theory at large temperatures. This field is physically relevant in describing part of the ground-state structure and the quasiparticle masses of excitations. The field φ possesses nontrivial S1-winding on the group manifold S3. Even at asymptotically high temperatures, where the theory reaches its Stefan-Boltzmann limit, the field φ, though strongly power suppressed, is conceptually relevant: its presence resolves the infrared problem of thermal perturbation theory.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
We present a lattice QCD calculation of the heavy-light decay constants fB and fBs performed with Nf = 2 maximally twisted Wilson fermions, at four values of the lattice spacing. The decay constants have been also computed in the static limit and the results are used to interpolate the observables between the charmand the infinite-mass sectors, thus obtaining the value of the decay constants at the physical b quark mass. Our preliminary results are fB = 191(14)MeV, fBs = 243(14)MeV, fBs/ fB = 1.27(5). They are in good agreement with those obtained with a novel approach, recently proposed by our Collaboration (ETMC), based on the use of suitable ratios having an exactly known static limit.