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We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
We report on new localities for Anolis gruuo Köhler, Ponce, Sunyer and Batista, 2007 along the Serranía de Tabasará in the Comarca Ngöbe-Buglé and Veraguas province of western Panama. These records extend the known geographic distribution of this lizard about 80 km eastward, and the known vertical distribution approximately 40 m lower and 630 m higher. We provide photos of specimens from different localities and comment on their morphology. Only the easternmost populations of this Panamanian endemic live inside a protected area.
Folding of RNA molecules into their functional three-dimensional structures is often supported by RNA chaperones, some of which can catalyse the two elementary reactions helix disruption and helix formation. Hfq is one such RNA chaperone, but its strand displacement activity is controversial. Whereas some groups found Hfq to destabilize secondary structures, others did not observe such an activity with their RNA substrates. We studied Hfq’s activities using a set of short RNAs of different thermodynamic stabilities (GC-contents from 4.8% to 61.9%), but constant length. We show that Hfq’s strand displacement as well as its annealing activity are strongly dependent on the substrate’s GC-content. However, this is due to Hfq’s preferred binding of AU-rich sequences and not to the substrate’s thermodynamic stability. Importantly, Hfq catalyses both annealing and strand displacement with comparable rates for different substrates, hinting at RNA strand diffusion and annealing nucleation being rate-limiting for both reactions. Hfq’s strand displacement activity is a result of the thermodynamic destabilization of the RNA through preferred single-strand binding whereas annealing acceleration is independent from Hfq’s thermodynamic influence. Therefore, the two apparently disparate activities annealing acceleration and duplex destabilization are not in energetic conflict with each other.
Collection methods and/or habitats sampled influence how many and which species are captured during entomological surveys. Here we compare Coleoptera catches among three survey activities, each using a single collection method, at the same study sites in Great Smoky Mountains National Park, USA. Activities included: short-term flight intercept trapping (FITs); sifting/Berlese funneling of leaf litter and extremely decayed downed coarse woody debris; and using emergence chambers containing coarse woody debris of various decay classes. In total, 2472 adult beetle specimens, representing 217 lowest identifiable taxa within 164 genera and 42 families, were collected during the FIT survey. Each survey activity yielded more than 2000 specimens, and a combined total of 413 species was collected. A combination of all surveys yielded the highest species richness when normalized for number of specimens indicating that variation of habitat and/or collection method significantly increases species richness. Of single surveys the FIT survey had the highest absolute species richness (217) and the highest richness when normalized for number of specimens. Species overlap among survey activities was low (Sorensen’s quotient of similarity was 0.20–0.27), which showed that each was about equally dissimilar from all others. Overlap of catch between FITs and emergence chambers was too low to justify substitution of emergence surveys with the FIT survey protocol used when attempting to collect saproxylic Coleoptera.
BACKGROUND: There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV) is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV) or the modified vaccinia Ankara strain (MVA).
METHODS: Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining.
RESULTS: The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min.
CONCLUSIONS: Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.
Chemical contamination of the environment and thus of aquatic ecosystems is steadily increasing. Whenever environmental pollutants enter a water body, they affect not only the water, but also the sediment. Substances that bind to sediment particles can be stored for a long time, whereby sediments act as sinks for some contaminants. Therefore, sediment
assessments often more accurately describe the contamination of a water body than investigations of the water itself. Among environmental chemicals, endocrine disrupting compounds (EDCs) have gained more and more attention in recent years. Since they interfere with endocrine systems and may disturb reproduction, they endanger the survival of populations or even species. Hazardous substances enter the aquatic environment by different pathways, with sewage treatment plants (STPs) belonging to the most important contamination sources.The main objective of this work is a comprehensive sediment assessment of predominantly small surface waters in the German federal state of Hesse. The 50 study sites, located in 44 different creeks and small rivers, are situated in the densely populated and economically important Frankfurt/Rhine-Main area, as well as in rural and less urbanized regions.
Chemical analytical data, provided by the Hessian Agency for the Environment and Geology (HLUG), indicated different contamination levels of the study sites. In order to investigate the general toxicity of the sediment samples, the oligochaete Lumbriculus variegatus and the midge Chironomus riparius were exposed to whole sediments and apical endpoints regarding biomass, survival, and reproduction were determined. In further experiments, special attention was paid to the contamination with endocrine active compounds. For this purpose, the reproductive success of the New Zealand mudsnail Potamopyrgus antipodarum was analyzed after exposure to whole sediments. Additionally, a yeast-based reporter gene assay was applied with sediment eluates to assess the estrogenic and androgenic activity of the samples. Biotest results were compared with chemical analysis data to investigate whether the test organisms reflect the measured pollution of the study sites and if the observed effects can be explained by chemical contamination.
Five study sites, all located less than 1 km downstream of a STP discharger, were selected for further investigations based on the results of the sediment monitoring. The sediments from these sites were conspicuous due to their general toxic and/or estrogenic activity. In order to investigate whether the observed effects can be ascribed to the effluents, an active biomonitoring study was conducted with the mudsnail P. antipodarum and the zebra mussel Dreissena polymorpha, exposed at study sites located up- and downstream of the discharger.
In addition to endocrine activity, genotoxic effects were investigated using the comet assay and the micronucleus assay. Endocrine activity was examined based on the reproductive output of P. antipodarum and the content of vitellogenin-like proteins in D. polymorpha. Yeast-based reporter gene assays were used to estimate the endocrine potential (estrogen, anti-estrogen, anti-androgen, dioxin-like) of sediment and water samples.
22% of the 50 sediments showed ecologically relevant effects in the biotests with L. variegatus and C. riparius. Only one sediment caused a relevant effect on both test organisms, while the other ten positively tested sediments affected either L. variegatus or C. riparius, probably due to differences in inter-species sensitivities. This suggests that a combination of different biotests is necessary for a comprehensive evaluation of sediment toxicity. 78% of the sediments caused a significantly increased number of embryos in P. antipodarum, which could be ascribed to estrogenic contamination of the sediment samples. An increase in the number of embryos by 60%, as observed in this study, and an associated increase in population size may result in the displacement of other, less competitive species.
In the in vitro tests, 66% of the sediments showed estrogenic activity and 68% showed androgenic activity. Maximum observed values were 40.9 ng EEQ/kg sediment (EEQ = estradiol equivalent) for estrogenic and 93.4 ng TEQ/kg sediment (TEQ = testosterone equivalent) for androgenic activity. Natural and synthetic hormones as well as alkylphenols were the major contributors to the total estrogenicity of environmental samples in several other studies, and are likely responsible for a large part of the estrogenic activity in this case as well. Similarly, androgenic activity is mainly due to natural steroids and their metabolites.
Bioassay results reflect the analytically measured contamination levels at the study sites only very infrequently. This can be ascribed to the occurrence of integrated effects of chemical mixtures present in the sediments. Additionally, effects of substances not included in the analytical program or of substances present in concentrations below the detection limit of the chemical analytical investigations as well as varying bioavailabilities might be relevant. The fact that a large part of the observed effects cannot be explained by the chemical contamination demonstrates the need for effect studies in ecotoxicological sediment assessments.
In order to identify possible causes for the effects observed in the sediment monitoring, e.g. contamination sources, the area types (urban fabrics, arable lands, pasturages, etc.) of the catchment areas belonging to the study sites were analyzed. No significant differences were found between the area profiles of the sampling sites with and without effects in the biotests.
The results indicate that the contamination responsible for the observed effects can be ascribed to different sources. Furthermore, study sites whose sediments exerted significant effects in biotests were located in anthropogenic as well as in predominantly natural areas. The active biomonitoring study at STPs revealed genotoxic and endocrine effects only sporadically.
However, in the in vitro tests considerable endocrine activities of sediment and water samples were determined. No conclusive picture emerges as to whether the observed effects occur more frequently downstream of the dischargers, and thus could be attributed to a contamination by sewage. This indicates that contamination sources other than STP dischargers, for example agricultural runoff, may contribute to the observed effects. Weaker effects and biological activities downstream of a discharger compared to an upstream site might be ascribed to a dilution effect by the effluents. A comparison of the measured in vitro estrogenicity with exposure studies described in the literature shows that adverse effects in aquatic organisms can be expected at the EEQ concentrations determined in the present study.
The results of the sediment monitoring and the STP study revealed a widespread endocrine pollution of small surface waters in Hesse. The fact that the bioassay results only rarely reflect study site contamination as determined by chemical analysis demonstrates the need for effect studies in comprehensive sediment assessments. In some cases STP dischargers increased, in other cases they decreased the observed in vivo effects and in vitro activity of environmental samples. Transferring the results obtained in laboratory studies to the field, adverse effects on aquatic ecosystems can be expected. The study illustrates the need for restrictive measures that contribute to the removal or reduction of environmental pollutants.
For the identification of substances that have so far not been linked to adverse effects on the environment, methods such as effect-directed analyses (EDA) or toxicity identification evaluation (TIE) should be increasingly applied in future studies. Furthermore, bioassays for the assessment of endocrine activity should be implemented in standardized monitoring programs.
This paper studies constrained portfolio problems that may involve constraints on the probability or the expected size of a shortfall of wealth or consumption. Our first contribution is that we solve the problems by dynamic programming, which is in contrast to the existing literature that applies the martingale method. More precisely, we construct the non-separable value function by formalizing the optimal constrained terminal wealth to be a (conjectured) contingent claim on the optimal non-constrained terminal wealth. This is relevant by itself, but also opens up the opportunity to derive new solutions to constrained problems. As a second contribution, we thus derive new results for non-strict constraints on the shortfall of inter¬mediate wealth and/or consumption.
The Strongest Meaning Hypothesis (SMH henceforth), a pragmatic principle motivated in Dalrymple et al.'s (1998) study of reciprocals, has recently been applied to problems in implicatures (Chierchia et al. to appear) and Vagueness (Cobreros et al. 2011). In this snippet, I argue that the SMH can apply to embedded sentences, which is perhaps unusual for a pragmatic principle.
Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-20
Peri-urban Land Transactions : Everyday Practices and Relations in Peri-urban Blantyre, Malawi
(2012)
This book explores the changing land relations in the peri-urban villages of Blantyre in Malawi. It questions and debates how and why the peri-urban villages have become the locus of the selling and buying of customary land, the practices and also the relations involved. The book provides rich ethnographic insights on the commodification of land relations, custom, practices, disputes and social relations between land sellers, land buyers, traditional leaders, and intermediaries. The transactions draw strength from the growing peri-urbanization and monetization of social relations, both of which push towards land decisions at family and individual levels. Bigger groups like the village, clan or extended family have minimal, if not symbolic role only. Village headmen benefit materially by taking gifts (signing fee) rationalized by custom on reciprocity, while estate agents claim commission. Numerous constraints are negotiated about the ownership, rights to sale, multiple selling and the use and sharing of land money. Peri-urban land transactions offer scope for examining a wider range of social and economic relations, and the subtle ways in which the state infiltrates the everyday lives of actors. Overtime, the practices reproduce but also transform land relations in significant but less appreciated ways.
ABSTRACT: BACKGROUND: Particulate matter (PM) is assumed to exert a major burden on public health. Most studies that address levels of PM use stationary measure systems. By contrast, only few studies measure PM concentrations under mobile conditions to analyze individual exposure situations.
METHODS: By combining spatial-temporal analysis with a novel vehicle-mounted sensor system, the present Mobile Air Quality Study (MAQS) aimed to analyse effects of different driving conditions in a convertible vehicle. PM10 was continuously monitored in a convertible car, driven with roof open, roof closed, but windows open, or windows closed.
RESULTS: PM10 values inside the car were nearly always higher with open roof than with roof and windows closed, whereas no difference was seen with open or closed windows. During the day PM10 values varied with high values before noon, and occasional high median values or standard deviation values due to individual factors. Vehicle speed in itself did not influence the mean value of PM10; however, at traffic speed (10 -- 50 km/h) the standard deviation was large. No systematic difference was seen between PM10 values in stationary and mobile cars, nor was any PM10 difference observed between driving within or outside an environmental (low emission) zone.
CONCLUSIONS: he present study has shown the feasibility of mobile PM analysis in vehicles. Individual exposure of the occupants varies depending on factors like time of day as well as ventilation of the car; other specific factors are clearly identifiably and may relate to specific PM10 sources. This system may be used to monitor individual exposure ranges and provide recommendations for preventive measurements. Although differences in PM10 levels were found under certain ventilation conditions, these differences likely are not of concern for the safety and health of passengers.
Urban health is potentially affected by particle emissions. The potential toxicity of nanoparticles is heavily debated and there is an enormous global increase in research activity in this field. In this respect, it is commonly accepted that nanoparticles may also be generated in processes occurring while driving vehicles. So far, a variety of studies addressed traffic-related particulate matter emissions, but only few studies focused on potential nanoparticles. Therefore, the present study analyzed the literature with regard to nanoparticles and cars. It can be stated that, to date, only a limited amount of research has been conducted in this area and more studies are needed to 1) address kind and sources of nanoparticles within automobiles and to 2) analyse whether there are health effects caused by these nanoparticles.
The complexity resulting from intertwined uncertainties regarding model misspecification and mismeasurement of the state of the economy defines the monetary policy landscape. Using the euro area as laboratory this paper explores the design of robust policy guides aiming to maintain stability in the economy while recognizing this complexity. We document substantial output gap mismeasurement and make use of a new model data base to capture the evolution of model specification. A simple interest rate rule is employed to interpret ECB policy since 1999. An evaluation of alternative policy rules across 11 models of the euro area confirms the fragility of policy analysis optimized for any specific model and shows the merits of model averaging in policy design. Interestingly, a simple difference rule with the same coefficients on inflation and output growth as the one used to interpret ECB policy is quite robust as long as it responds to current outcomes of these variables.
The tumour suppressor p53 controls transcription of various genes involved in apoptosis, cell-cycle arrest, DNA repair and metabolism. However, its DNA-recognition specificity is not nearly sufficient to explain binding to specific locations in vivo. Here, we present evidence that KLF4 increases the DNA-binding affinity of p53 through the formation of a loosely arranged ternary complex on DNA. This effect depends on the distance between the response elements of KLF4 and p53. Using nuclear magnetic resonance and fluorescence techniques, we found that the amino-terminal domain of p53 interacts with the KLF4 zinc fingers and mapped the interaction site. The strength of this interaction was increased by phosphorylation of the p53 N-terminus, particularly on residues associated with regulation of cell-cycle arrest genes. Taken together, the cooperative binding of KLF4 and p53 to DNA exemplifies a regulatory mechanism that contributes to p53 target selectivity.
Xenorhabdus and Photorhabdus spp. are bacterial symbionts of entomopathogenic nematodes (EPNs). In this study, we isolated and characterized Xenorhabdus and Photorhabdus spp. from across Thailand together with their associated nematode symbionts, and characterized their phylogenetic diversity. EPNs were isolated from soil samples using a Galleria-baiting technique. Bacteria from EPNs were cultured and genotyped based on recA sequence. The nematodes were identified based on sequences of 28S rDNA and internal transcribed spacer regions. A total of 795 soil samples were collected from 159 sites in 13 provinces across Thailand. A total of 126 EPNs isolated from samples taken from 10 provinces were positive for Xenorhabdus (n = 69) or Photorhabdus spp. (n = 57). Phylogenetic analysis separated the 69 Xenorhabdus isolates into 4 groups. Groups 1, 2 and 3 consisting of 52, 13 and 1 isolates related to X. stockiae, and group 4 consisting of 3 isolates related to X. miraniensis. The EPN host for isolates related to X. stockiae was S. websteri, and for X. miraniensis was S. khoisanae. The Photorhabdus species were identified as P. luminescens (n = 56) and P. asymbiotica (n = 1). Phylogenenic analysis divided P. luminescens into five groups. Groups 1 and 2 consisted of 45 and 8 isolates defined as subspecies hainanensis and akhurstii, respectively. One isolate was related to hainanensis and akhurstii, two isolates were related to laumondii, and one isolate was the pathogenic species P. asymbiotica subsp. australis. H. indica was the major EPN host for Photorhabdus. This study reveals the genetic diversity of Xenorhabdus and Photorhabdus spp. and describes new associations between EPNs and their bacterial symbionts in Thailand.
We study the implications on compact star properties of a soft nuclear equation of state determined from kaon production at subthreshold energies in heavy-ion collisions. On one hand, we apply these results to study radii and moments of inertia of light neutron stars. Heavy-ion data provides constraints on nuclear matter at densities relevant for those stars and, in particular, to the density dependence of the symmetry energy of nuclear matter. On the other hand, we derive a limit for the highest allowed neutron star mass of three solar masses. For that purpouse, we use the information on the nucleon potential obtained from the analysis of the heavy-ion data combined with causality on the nuclear equation of state.
In this paper we investigate the comparative properties of empirically-estimated monetary models of the U.S. economy using a new database of models designed for such investigations. We focus on three representative models due to Christiano, Eichenbaum, Evans (2005), Smets and Wouters (2007) and Taylor (1993a). Although these models differ in terms of structure, estimation method, sample period, and data vintage, we find surprisingly similar economic impacts of unanticipated changes in the federal funds rate. However, optimized monetary policy rules differ across models and lack robustness. Model averaging offers an effective strategy for improving the robustness of policy rules.
Assessing the uncertainties of simulation results of ecological models is becoming increasingly important, specifically if these models are used to estimate greenhouse gas emissions on site to regional/national levels. Four general sources of uncertainty effect the outcome of process-based models: (i) uncertainty of information used to initialise and drive the model, (ii) uncertainty of model parameters describing specific ecosystem processes, (iii) uncertainty of the model structure, and (iv) accurateness of measurements (e.g., soil-atmosphere greenhouse gas exchange) which are used for model testing and development.
The aim of our study was to assess the simulation uncertainty of the process-based biogeochemical model LandscapeDNDC. For this we set up a Bayesian framework using a Markov Chain Monte Carlo (MCMC) method, to estimate the joint model parameter distribution. Data for model testing, parameter estimation and uncertainty assessment were taken from observations of soil fluxes of nitrous oxide (N2O), nitric oxide (NO) and carbon dioxide (CO2) as observed over a 10 yr period at the spruce site of the Höglwald Forest, Germany. By running four independent Markov Chains in parallel with identical properties (except for the parameter start values), an objective criteria for chain convergence developed by Gelman et al. (2003) could be used.
Our approach shows that by means of the joint parameter distribution, we were able not only to limit the parameter space and specify the probability of parameter values, but also to assess the complex dependencies among model parameters used for simulating soil C and N trace gas emissions. This helped to improve the understanding of the behaviour of the complex LandscapeDNDC model while simulating soil C and N turnover processes and associated C and N soil-atmosphere exchange. In a final step the parameter distribution of the most sensitive parameters determining soil-atmosphere C and N exchange were used to obtain the parameter-induced uncertainty of simulated N2O, NO and CO2 emissions. These were compared to observational data of an calibration set (6 yr) and an independent validation set of 4 yr. The comparison showed that most of the annual observed trace gas emissions were in the range of simulated values and were predicted with a high certainty (Root-mean-squared error (RMSE) NO: 2.4 to 18.95 g N ha−1 d−1, N2O: 0.14 to 21.12 g N ha−1 d−1, CO2: 5.4 to 11.9 kg C ha−1 d−1). However, LandscapeDNDC simulations were sometimes still limited to accurately predict observed seasonal variations in fluxes.
We show how Sestoft’s abstract machine for lazy evaluation of purely functional programs can be extended to evaluate expressions of the calculus CHF – a process calculus that models Concurrent Haskell extended by imperative and implicit futures. The abstract machine is modularly constructed by first adding monadic IO-actions to the machine and then in a second step we add concurrency. Our main result is that the abstract machine coincides with the original operational semantics of CHF, w.r.t. may- and should-convergence.
In the title molecule, C18H17N5O2, the dihedral angle between the benzene plane and the benzimidazole plane is 19.8 (1)° and the angle between the benzene plane and the triazole plane is 16.7 (1)°. In the crystal, molecules are connected by O—H[cdots, three dots, centered]N hydrogen bonds, forming zigzag chains along the c-axis direction. The chains are connected by bifurcated N—H[cdots, three dots, centered](N,N) hydrogen bonds into layers parallel to (100). These layers are connected along the a-axis direction by weak C—H[cdots, three dots, centered]O contacts, forming a three-dimensional network.
Hepatitis C virus (HCV) assembly and production is closely linked to lipid metabolism. Indeed, lipid droplets (LD) have been shown to serve as a platform for HCV assembly. To investigate the effect of HCV on the host cell proteome, 2D-gelelectrophoresis with subsequent MALDI-TOF mass spectrometry of HCV replicating and the corresponding control cells were done. Based on this analysis, it was found out that HCV-replicating Huh7.5 cells revealed lower amounts of TIP47 (tail interacting protein of 47kD) compared to HCV-negative cells. TIP47, a cytoplasmic sorting factor, has been shown to be associated with lipid droplets. As it is known that HCV-replication and assembly takes place at the so called ”membranous web” that is composed of LDs and rearranged ER-derived membranes, it was tempting to investigate the role of TIP47 in HCV life-cycle. Western blot analysis did reveal that overexpression of TIP47 in HCV replicating Huh7.5 cells leads to decreased amounts of the HCV core protein while the levels of non-structural protein (NS)5A and intracellular HCVgenomes are increased. Moreover, in TIP47 overproducing cells higher amounts of infectious HCV particles are secreted. Vice versa, inhibition of TIP47 expression by siRNA results in a decreased level of intracellular NS5A, increased amounts of intracellular core and less infectious viral particles in the supernatant. In addition, complete silencing of TIP47 by lentiviral transduction abolishes HCV replication that can be restored by transfection of these cells with a TIP47 expression construct. It has been shown recently that apoE binds to NS5A and that this interaction plays an important role for the HCV life cycle (Benga et al., 2010). The C-terminal part of TIP47 harbours a 4 helix bundle motif and displays high homology to the N-terminus of apoE. Therefore, we investigated the interaction of NS5A and TIP47. Confocal double immunofluorescence microscopy revealed that a fraction of NS5A colocalizes with TIP47. Coimmunoprecipitation experiments and a yeast-two-hybrid screening confirmed the interaction between NS5A and TIP47 and deletion of the N-terminal-TIP47-PAT domain abolishes this interaction. From this we conclude that the TIP47-NS5A interaction is required for virus morphogenesis. Moreover, TIP47 can bind to Rab9 and this is relevant for targeting the viral particle out of the cell. In accordance to this, TIP47 was identified to be associated to the viral particle. Mutants of TIP47 that fail to bind Rab9 reveal lower amounts and a changed distribution of the HCV core protein. Furthermore, we could see that the core staining colocalizes with subcellular structures that were identified as autophagosomes using a p62-specific antibody which is a specific autophagosome-marker. Based on this, we hypothized that destruction of the Rab9 binding domain misdirects the viral particle towards the lysosomal compartment.
For the first time it could be shown that TIP47 interacts with NS5A and is associated to the viral particle, therefore plays a crucial role for the virus morphogenesis and secretion of the viral article.
Taken together, these results indicate that TIP47 is an essential cellular factor for the life cycle of HCV Abstract and might be used as target for antiviral treatment, e.g. by targeting the NS5A-TIP47 interaction, based on small molecules that mimic the NS5A-specific sequence that binds to TIP47 which might result in a competition of the TIP47/NS5A interaction.
Modelling protein structure seems a challenging enterprise because the number of structure parameters required ordinarily exceeds the amount of independent data points available from experimental observations. Expressing the predominant conformation of a protein in terms of a geometry model, a polypeptide chain consisting of N atoms would command 3N – 6 Cartesian coordinates be fixed. Even for small proteins, this becomes a daunting number. Fortunately, so-called holonomic constraints limit the number of variables, leaving substantially fewer, truly relevant parameters for folding the polypeptide chain into its native tertiary structure. For example, adjusting bond lengths and the many angles between the covalent bonds connecting the atoms is of little concern and appropriate standard values can be inserted from tableworks (Pople & Gordon, 1967; Engh & Huber, 1991, 2006). Table 1 exemplifies for the 147-residue protein Desulfovibrio vulgaris flavodoxin how the number of truly independent internal rotational degrees of freedom amounts to less than one-tenth of the Cartesian coordinate set size...
Visual perception is highly variable and can be influenced by the surrounding world. Previous research has revealed that body perception can be biased due to adaptation to thin or fat body shapes. The aim of the present study was to show that adaptation to certain body shapes and the resulting perceptual biases transfer across different identities of adaptation and test stimuli. We designed two similar adaptation experiments in which healthy female participants adapted to pictures of either thin or fat bodies and subsequently compared more or less distorted pictures of their own body to their actual body shape. In the first experiment (n = 16) the same identity was used as adaptation and test stimuli (i.e. pictures of the participant’s own body) while in the second experiment (n = 16) we used pictures of unfamiliar thin or fat bodies as adaptation stimuli. We found comparable adaptation effects in both experiments: After adaptation to a thin body, participants rated a thinner than actual body picture to be the most realistic and vice versa. We therefore assume that adaptation to certain body shapes transfers across different identities. These results raise the questions of whether some type of natural adaptation occurs in everyday life. Natural and predominant exposure to certain bodily features like body shape – especially the thin ideal in Western societies – could bias perception for these features. In this regard, further research might shed light on aspects of body dissatisfaction and the development of body image disturbances in terms of eating disorders.
In Germany, as in almost all industrial countries, active pharmaceutical substances can now be found in virtually all water bodies and occasionally also in drinking water. Even though the concentrations in question tend to be very low, there are initial signs of their impact on aquatic life. There is no evidence as yet of any acute consequences for human health. It is, however, impossible to rule out long-term consequences from these minimal concentrations or unexpected effects from the interaction between various active ingredients (cocktail effect). At special risk here are sensitive segments of the population such as children and the chronically ill. There is thus a need for action on precautionary grounds.
The main actors in the health system are largely unaware of the problem posed by drug residues in water. Although knowledge cannot be equated with awareness – given the existence of the ‘not wanting to know' phenomenon – the first step is to generate a consolidated knowledge base. Only by creating awareness of the problem can further strategies be implemented to ultimately enlighten and bring about behavioural change. At stake here is the overall everyday handling of medications, including prescription, compliance, and drug-free disease prevention down to the doctor-patient relationship. The latter, namely, is often characterised by misunderstandings and a lack of communication about the – supposed – need to prescribe drugs.
The first part of the strategy for the general public involves using various channels and media to address three different target groups. These were identified by ISOE in an empirical survey as reacting differently to the problem under review:
· ‘The Deniers/Relativists'
· ‘The Truth-Seekers'
· ‘The Hypersensitives'
The intention is to address each target group in the right tone and using the most suitable line of reasoning via specific media and with the proper degree of differentiation. The ‘Truth-Seekers' play an opinion-leading role here. They can be provided with highly differentiated information through sophisticated media which they then pass on to their dialogue partners in an appropriate form.
The second part of the strategy for the general public relates to the communication of proper disposal routes for expired drugs. The goal is to confine disposal to pharmacies so that on no account are they flushed down the sink or toilet. Based on an analysis of typical errors in existing communications media on this topic, ISOE prepared recommendations for drafting proper information materials.
In addressing pharmacists, the first priority is to convey hard facts: to this end we propose a PR campaign to place articles in the main specialist media. At the same time, the subject should feature in training and continuing education programmes. Another aim is to strengthen the advisory function of the pharmacies. The environmentally sensitive target group would indeed react positively to having their attention drawn to the issue of drug residues in water. For all other customers, the pharmacists can and should act as consultants: they emphasise how important it is to take medication as instructed (compliance) and use suitable pack sizes, and warn older customers in particular about the potential hazards of improper drug intake.
The first stage of the communications strategy for doctors likewise revolves around knowledge. Here, however, it is important to take into account their self-image as scientists while in fact having little grasp of this specific area. The line to take is that of ‘discursive selfenlightenment'. This means that the issue of drug residues in water cannot be conveyed to doctors by laymen but must be taken up and imparted via the major media of the medical profession and by medical association officials (top-down).
The second stage, namely that of raising doctors’ awareness of the problem, is likely to encounter strong resistance from some of the medical profession. They may fear a threat of interference in treatment plans from an environmental perspective and feel the need to emphasise that doctors are not responsible for environmental issues. As shown in empirical surveys by ISOE, such a defensive reaction is ultimately down to an underlying taboo: people are loath to discuss the over-prescription taking place in countless doctors' surgeries. And it is a fact that this problem cannot be tackled from the environmental perspective, although the goals of water protection are indeed consistent with the economic objectives of restraint in the deployment of drugs. Any communications measure for this target group has to bear in mind that doctors feel restricted by what they see as a ‘perpetual health reform' no matter which government is in power. On no account are they prepared to tolerate any new form of regulation, in this case for environmental reasons.
An entirely different view of the problem is taken by ‘critical doctors' such as specialists in environmental health and those with a naturopathic focus. They are interested in the problem because they see a connection between the quality of our environment and our health. What is more, they have patients keen to be prescribed as few drugs as possible and who are instead interested in ‘talking medicine'. So, any communication strategy intent on tackling the difficult problem of oversubscribing drugs needs to look carefully at the experiences of these medical professionals and also at a ‘bottom-up strategy'.
Implementation of strategic communications should be entrusted to an agency with experience in ‘issue management'. Knowledge of social marketing and the influencing of behaviour are further prerequisites. All important decisions should be taken by a consensus committee (‘MeriWa'1 round table), in which the medical profession, pharmacists and consumers are represented.
This paper examines data on financial sophistication among the U.S. older population, using a special-purpose module implemented in the Health and Retirement Study. We show that financial sophistication is deficient for older respondents (aged 55+). Specifically, many in this group lack a basic grasp of asset pricing, risk diversification, portfolio choice, and investment fees. Subpopulations with particular deficits include women, the least educated, persons over the age of 75, and non-Whites. In view of the fact that people are increasingly being asked to take on responsibility for their own retirement security, such lack of knowledge can have serious implications.
We develop a dynamic network model with heterogenous banks which undertake optimizing portfolio decisions subject to liquidity and capital constraints and trade in the interbank market whose equilibrium is governed by a tatonnement process. Due to the micro-funded structure of the decisional process as well as the iterative dynamic adjustment taking place in the market, the links in the network structures are endogenous and evolve dynamically. We use the model to assess the diffusion of systemic risk (measured as default probability), the contribution of each bank to it as well as the evolution of the network in response to financial shocks and across different prudential policy regimes.
Background: After focal neuronal injury the endocannabinioid system becomes activated and protects or harms neurons depending on cannabinoid derivates and receptor subtypes. Endocannabinoids (eCBs) play a central role in controlling local responses and influencing neural plasticity and survival. However, little is known about the functional relevance of eCBs in long-range projection damage as observed in stroke or spinal cord injury (SCI).
Methods: In rat organotypic entorhino-hippocampal slice cultures (OHSC) as a relevant and suitable model for investigating projection fibers in the CNS we performed perforant pathway transection (PPT) and subsequently analyzed the spatial and temporal dynamics of eCB levels. This approach allows proper distinction of responses in originating neurons (entorhinal cortex), areas of deafferentiation/anterograde axonal degeneration (dentate gyrus) and putative changes in more distant but synaptically connected subfields (cornu ammonis (CA) 1 region).
Results: Using LC-MS/MS, we measured a strong increase in arachidonoylethanolamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels in the denervation zone (dentate gyrus) 24 hours post lesion (hpl), whereas entorhinal cortex and CA1 region exhibited little if any changes. NAPE-PLD, responsible for biosynthesis of eCBs, was increased early, whereas FAAH, a catabolizing enzyme, was up-regulated 48hpl.
Conclusion: Neuronal damage as assessed by transection of long-range projections apparently provides a strong time-dependent and area-confined signal for de novo synthesis of eCB, presumably to restrict neuronal damage. The present data underlines the importance of activation of the eCB system in CNS pathologies and identifies a novel site-specific intrinsic regulation of eCBs after long-range projection damage.
Molecules of the title compound, C20H14O2, show approximate C s symmetry with the approximate mirror plane perpendicular to the central ring. The torsion angles about the acyclic bonds are 30.05 (15) and 30.77 (15)° in one half compared to −36.62 (14) and −18.60 (15)° in the other half of the molecule. The central aromatic ring makes dihedral angles of 47.78 (4) and 51.68 (3)° with the two terminal rings.
In the title compound, [Ag(BF4)(C14H12N2O4)]n, the coordination of the Ag+ ion is trigonal–bipyramidal with the N atoms of two ethane-1,2-diyl bis(pyridine-3-carboxylate) ligands in the apical positions and three F atoms belonging to different tetrafluoridoborate anions in the equatorial plane. The material consists of infinite chains of [Ag(C14H12N2O4)] units running along [001], held together by BF4 − bridging anions.
We argue that the U.S. personal saving rate’s long stability (1960s–1980s), subsequent steady decline (1980s–2007), and recent substantial rise (2008–2011) can be interpreted using a parsimonious ‘buffer stock’ model of consumption in the presence of labor income uncertainty and credit constraints. Saving in the model is affected by the gap between ‘target’ and actual wealth, with the target determined by credit conditions and uncertainty. An estimated structural version of the model suggests that increased credit availability accounts for most of the long-term saving decline, while fluctuations in wealth and uncertainty capture the bulk of the business-cycle variation.
The ongoing debate on deforestation in the tropics usually points out agriculture and logging as the main causes. The two activities are often linked and the trails created by logging com-panies with their heavy machines are afterwards used by farmers to penetrate deep into the forest and cultivate. Shifting cultivation is a widespread agricultural practice in the tropics and its sustainability is often a matter of controversy. It is necessary to investigate forest recovery after shifting cultivation, analyze its succession stages for comparison with regeneration after natural disturbance, and evaluate its role for discussing the hazards of deforestation.
Savanna regions in West Africa are valuable cultural landscapes and provide a wide range of ecosystem services for human well-being and are frequently affected by human-induced disturbances. Aside from agricultural activities (crop production and animal husbandry), the harvesting of timber and non-timber forest products is crucial for household income, alimentation and medicinal purposes. Most indigenous woody species have undergone increasing anthropogenic pressure as social and economic conditions have changed dramatically during recent decades, resulting in further habitat fragmentation and increased disturbance severity. Human land use activities influence growth conditions for plants by altering various abiotic factors, such as light, nutrient availability and water supply. They are found to alter demographic parameters (e.g., germination, seedling and sapling growth, survival and mortality rates) of woody plant individuals and alter the structure and stability of populations. The degree of anthropogenic disturbance varies between land-cover types, distance to settlements, and protection status. In the context of land-use change, there is an urgent need to better understand and evaluate the impact of land-use on savanna vegetation, particularly on the population biology of common savanna woody species. A major conclusion to be drawn from this thesis is that land use influences savanna vegetation in a complex way and does not necessarily lead to a decline or loss of tree populations and species. It is rather that in a constantly changing landscape, as a result of human-induced disturbances, populations of ubiquitous and some common species can be stable over time. The abundance of some species tends to decline consistently, whereas others benefit from human disturbance. Moreover, the study provides an insight into the structure and dynamics of common, dominant and less dominant savanna woody plants in a communal and a protected area. There is a need for further basic studies to assess the impact of land use and ecological preferences of all species, including repeated density studies that look at survivorship and transition probabilities over a number of seasons as well as longterm in-situ experiments in settlement areas in order to better understand woody plant populations in settlement areas as the few remaining semi-natural sites are likely to decrease in the future. A challenge will be the development of strategies to protect species within a landscape under cultivation.
Global climate change and land use change will not only alter entire ecosystems and biodiversity patterns, but also the supply of ecosystem services. A better understanding of the consequences is particularly needed in under-investigated regions, such as West Africa. The projected environmental changes suggest negative impacts on nature, thus representing a threat to the human well-being. However, many effects caused by climate and land use change are poorly understood so far. Thus, the main objective of this thesis was to investigate the impact of climate and land use change on vegetation patterns, plant diversity and important provisioning ecosystem services in West Africa. The three different aspects are separately explored and build the chapters of this thesis. The findings help to improve our understanding of the effects of environmental change on ecosystems and human well-being. In the first study, the main objectives were to model trends and the extent of future biome shifts in West Africa that may occur by 2050. Also, I modelled a trend in West African tree cover change, while accounting for human impact. Additionally, uncertainty in future climate projections was evaluated to identify regions with reliable trends and regions where the impacts remain uncertain. The potential future spatial distributions of desert, grassland, savanna, deciduous and evergreen forest were modelled in West Africa, using six bioclimatic models. Future tree cover change was analysed with generalized additive models (GAMs). I used climate data from 17 general circulation models (GCMs) and included human population density and fire intensity to model tree cover. Consensus projections were derived via weighted averages to: 1) reduce inter-model variability, and 2) describe trends extracted from different GCM projections. The strongest predicted effect of climate change was on desert and grasslands, where the bioclimatic envelope of grassland is projected to expand into the Sahara desert by an area of 2 million km2. While savannas are predicted to contract in the south (by 54 ± 22 × 104 km2), deciduous and evergreen forest biomes are expected to expand (64 ± 13 × 104 km2 and 77 ± 26 × 104 km2). However, uncertainty due to different GCMs was particularly high for the grassland and the evergreen forest biome shift. Increasing tree cover (1–10%) was projected for large parts of Benin, Burkina Faso, Côte d’Ivoire, Ghana and Togo, but a decrease was projected for coastal areas (1–20%). Furthermore, human impact negatively affected tree cover and partly changed the direction of the projected climate-driven tendency from increase to decrease. Considering climate change alone, the model results of potential vegetation (biomes) showed a ‘greening’ trend by 2050. However, the modelled effects of human impact suggest future forest degradation. Thus, it is essential to consider both climate change and human impact in order to generate realistic future projections on woody cover. The second study focused on the impact and the interplay of future (2050) climate and land use change on the plant diversity of the West African country Burkina Faso. Synergistic forecasts for this country are lacking to date. Burkina Faso covers a broad bioclimatic gradient which causes a similar gradient in plant diversity. Thus, the impact of climate and land use change can be investigated in regions with different levels of species richness. The LandSHIFT model from the Centre of Environmental System research CESR (Kassel, Germany) was adapted for this study to derive novel regional, spatially explicit future (2050) land use simulations for Burkina Faso. Additionally, the simulations include different assumptions on the technological developments in the agricultural sector. Oneclass support vector machines (SVMs), a machine learning method, were performed with these land use simulations together with current and future (2050) climate projections at a 0.1° resolution (cell: ~ 10 × 10 km). The modelling results showed that the flora of Burkina Faso will be primarily negatively impacted by future climate and land use changes. The species richness will be significantly reduced by 2050 (P < 0.001, paired Wilcoxon signed-rank test). However, contrasting latitudinal patterns were found. Although climate change is predicted to cause species loss in the more humid regions in Southern Burkina Faso (~ 200 species per cell), the model projects an increase of species richness in the Sahel. However, land use change is expected to suppress this increase to the current species diversity level, depending on the technological developments. Climate change is a more important threat to the plant diversity than land use change under the assumption of technological stagnation in the agricultural sector. Overall, the study highlights the impact and interplay of future climate and land use change on plant diversity along a broad bioclimatic gradient in West Africa.Furthermore, the results suggest that plant diversity in dry and humid regions of the tropics might generally respond differently to climate and land use change. This pattern has not been detected by global studies so far. Several of the plant species in West Africa significantly contribute to the livelihoods of the population. The plants provide so-called non-timber forest products (NTFPs), which are important provisioning ecosystem services. However, these services are also threatened by environmental change. Thus, the third study aimed at developing a novel approach to assess the impacts of climate and land use change on the economic benefits derived from NTFPs. This project was carried out in cooperation with Katja Heubach (BiK-F) who provided data on household economics. These data include 60 interviews that were conducted in Northern Benin on annual quantities and revenues of collected NTFPs from the three most important savanna tree species: Adansonia digitata, Parkia biglobosa and Vitellaria paradoxa. The current market prices of the NTFPs were derived from respective local markets. To assess current and future (2050) occurrence probabilities of the three species, I calibrated niche-based models with climate data (from Miroc3.2medres) and land use data (LandSHIFT) at a 0.1° resolution (cell: ~ 10 × 10 km). Land use simulations were taken from the previous study on plant diversity. Three different niche-based models were used: 1) generalized additive models (regression method), 2) generalized boosting models (machine learning method), and 3) flexible discriminant analysis (classification method). The three model simulations were averaged (ensemble forecasting) to increase the robustness of the predictions. To assess future economic gains and losses, respectively, the modelled species’ occurrence probabilities were linked with the spatially assigned monetary values. Highest current annual benefits are obtained from V. paradoxa (54,111 ± 28,126 US$/cell), followed by P. biglobosa (32,246 ± 16,526 US$/cell) and A. digitata (9,514 ± 6,243 US$/cell). However, in the prediction large areas will lose up to 50% of their current economic value by 2050. Vitellaria paradoxa and Parkia biglobosa, which currently reveal the highest economic benefits, are heavily affected. Adansonia digitata is negatively affected less strongly by environmental change and might regionally even supply increasing economic benefits, in particular in the west and east of the investigation area. We conclude that adaptive strategies are needed to create alternative income opportunities, in particular for women that are responsible for collecting the NTFPs. The findings provide a benchmark for local policy-makers to economically compare different land use options and adjust existing management strategies for the near future. Overall, this thesis improves our understanding of the impacts of climate and land use changes on West African vegetation patterns, plant diversity and provisioning ecosystem services. Climate change had spatially varying impacts (positive and negative effects) on the vegetation cover and plant diversity, while predominantly negative effects resulted from human pressure. Regional contrasting impacts of environmental change were also found considering the provisioning ecosystem services.
The impacts of human activities, notably the conversion of tropical forests into farmland habitat, has profound impacts on biological diversity and ecosystem functions (Millennium Ecosystem Assessment 2005). It is widely debated to what extent human modified landscapes can maintain tropical biodiversity and their ecosystem functionality (e.g. Waltert et al. 2004, Sekercioglu et al. 2007). In this thesis, I have used a huge and temporarily replicated dataset to assess the value of different habitat types differing in land-use intensities for bird communities in tropical East Africa. I investigated bird abundance and species richness along a forest-farmland habitat gradient and assessed spatial and temporal fluctuations of bird assemblages and their food resources.
I could show that forest and farmland habitats harbor distinct bird communities. Moreover, the protection of natural forests merits the highest priority for conserving the high diversity of forest-dependent bird species. My study, however, also shows that farmland habitats in the proximity of natural forest can support a high bird diversity. High bird diversity in tropical farmlands depends on a high structural complexity, such as in small-scale subsistence farmlands. From my findings, I conclude that the conversion of forest to farmland leads to substantial losses in bird diversity, in particular in specialized feeding guilds such as insectivores, while the conversion of structurally heterogeneous subsistence farmlands to sugarcane plantation causes erosion of bird diversity in agricultural ecosystems. Both findings are important for conservation planning in times when tropical forests and agroecosystems are under constantly high pressure due to increasing human population numbers and global demands for biofuel crops (Gibbs et al. 2008). From an ecosystem function perspective, my study demonstrates the potential of agroecosystems in supporting important ecosystem functions, such as seed dispersal by frugivorous birds and pest control by insectivorous birds. I could show that bird abundances in both frugivorous and insectivorous guilds were strongly predicted by their respective food resources, implying that seasonal shifts in fruit and invertebrate abundance at Kakamega forest and surrounding farmlands affect community dynamics and appear to influence local movement patterns of birds. The most interesting finding of this study was that feeding guilds responded idiosyncratically to resource fluctuations. Frugivore richness fluctuated asynchronously in forest and farmland habitats, suggesting foraging movements and fruit tracking across habitat borders. In contrast, I found that insectivores fluctuated synchronously in the two habitat types, suggesting a lack of inter-habitat movements. I therefore predict that insectivorous bird communities in this forest-farmland landscape may be more susceptible to the combined effects of land-use and climate change, due to their narrow habitat niche and limited capacity to track their resources.
The fact that a number of bird species regularly moved across the landscape mosaic in my study system implies that birds are able to provide long-distance seed dispersal across habitat borders. Thus, birds may enhance forest regeneration in human-modified landscapes, such as those in most parts of tropical Africa, given that forest remnants are protected within an agricultural habitat matrix. In order to effectively conserve tropical biodiversity within forest-farmland mosaics, this study advocates for conservation strategies that go beyond forest protection and explicitly integrate farmlands into forest management plans and policies. This should emphasize the retention of keystone habitat elements within tropical farmland landscapes, such as indigenous trees, forest galleries and hedgerows, whose presence enhance species diversity. Such grassroot-level approaches can be operationalized for instance through providing incentives to farmers to maintain their traditional subsistence land-use practices and through community-based livelihood projects aiming at enhancing local habitat heterogeneity and inter-habitat connectivity.
Making use of United Nations (U.N.) materials and documents, Anja Matwijkiw and Bronik Matwijkiw argue that the organization – in 2004 – converted to a stakeholder jurisprudence for human rights. However, references to “stakeholders” may both be made in the context of narrow stakeholder theory and broad stakeholder theory. Since the U.N. does not specify its commitment by naming the theory it credits for its conversion, the authors of the article embark on a comparative analysis, so as to be able to try the two frameworks for fit. The hypothesis is that it is the philosophy and methodology of broad stakeholder theory that best matches the norms and strategies of the U.N. While this is the case, certain challenges nevertheless present themselves. As a consequence of these, the U.N. has to – as a minimum – take things under renewed consideration.
Human rights and the law: the unbreachable gap between the ethics of justice and the efficacy of law
(2012)
This paper explores the structure of justice as the condition of ethical, inter-subjective responsibility. Taking a Levinasian perspective, this is a responsibility borne by the individual subject in a pre-foundational, proto-social proximity with the other human subject, which takes precedence over the interests of the self. From this specific post-humanist perspective, human rights are not the restrictive rights of individual self-will, as expressed in our contemporary legal human rights discourse. Rights do not amount to the prioritisation of the so-called politico-legal equality of the individual citizen-subject animated by the universality of the dignity of autonomous, reasoned intentionality. Rather, rights enlivened by proximity invert this discourse and signify, first and foremost, rights for the other, with the ethical burden of responsibility towards the other.
In this article I advance an account of human rights as individual claims that can be justified within the conceptual framework of social contract theories. The contractarian approach at issue here aims, initially, at a justification of morality at large, and then at the specific domain of morality which contains human rights concepts. The contractarian approach to human rights has to deal with the problem of universality, i.e. how can human rights be ‘universal’? I deal with this problem by examining the relationship between moral dispositions and what I call ‘diffuse legal structure’.
This paper intends to discuss some contemporary issues on human rights and democracy related to the concept of justice. Is the set of individual rights that is assumed by western democracies really universal? If so, how are they supposed to be interpreted? On the other side if I take into account the “other” and pluralism in a serious way how to conciliate different concepts of justice? Taking Jacques Derrida’s approach of justice as its standpoint this paper aims to stress the difficulty to achieve a unique concept of justice as well as to think justice in the sphere of international law and the problem of ensuring human rights in the international order. Western democracies has becoming more and more multiethnic and multicultural and the set of rights that is at the center of the legal order has to be interpreted in a dialogical sense, one that assumes difference and plurality as its starting point. The plurality of conceptions of the good and the impossibility of establishing a unique concept of justice demands the re-creation of a democratic sphere where the dissent and the conflict could be experienced and, at the same time, the legal order needs to ensure individual and group rights against majority’s dictatorship. The main goal of this paper is to re-think the interpretation of law in a multicultural scenario in which it is not possible to have only one criteria of justice and difference and pluralism are envisaged are values themselves.
The tumor suppressor programmed cell death 4 (Pdcd4) exerts its function by inhibiting protein translation initiation. Specifically, it displaces the scaffold protein eukaryotic initiation factor 4G (eIF4G) from its binding to the eukaryotic initiation factor 4A (eIF4A). Thereby, Pdcd4 inhibits the helicase activity of eIF4A, which is necessary for the unwinding of highly structured 5’ untranslated regions (UTRs) of messenger RNAs (mRNAs) often found in oncogenes like c-myc to make them accessible for the translation machinery and subsequent protein production. Overexpression of Pdcd4 inhibits tumorigenesis in vitro and in vivo and inversely, Pdcd4 knockout mice show enhanced tumor formation. In line, Pdcd4 is lost in various tumor types and proposed as prognostic factor in colon carcinomas. Unlike most other tumor suppressors that are rendered nonfunctional by mutations (e.g., p53), Pdcd4 loss is not attributable to mutational inactivation. It is regulated via translational repression by microRNAs and increased degradation of the protein under tumor promoting, inflammatory conditions and mitogens. Specifically, proteasomal degradation of Pdcd4 is controlled by p70 S6 Kinase (p70S6K)-mediated phosphorylation in its degron sequence (serines 67, 71 and 76). Stimulation of the PI3K-AKT-mTOR pathway by growth factors, hormones and cytokines initiates p70S6K activity. Phosphorylated Pdcd4 is subsequently recognized by the E3 ubiquitin ligase beta-transducin repeats-containing protein (β-TrCP) and marked with a polyubiquitin tail to be detected by the 26S proteasome for degradation. β-TrCP represents the substrate specific recognition subunit of the ubiquitin ligase complex responsible for protein-protein interaction with Pdcd4 as substrate for ubiquitin transfer and subsequent proteasomal disassembly.
The first part of the present work aimed at identifying novel stabilizers of the tumor suppressor Pdcd4 in a high throughput screen (HTS). As assay design, a fragment of Pdcd4 from amino acid 39 to 91, containing the phosphorylation sensitive degron sequence, was fused to a luciferase reporter gene construct. Stable expression of this Pdcd4(39-91)luciferase (Pdcd4(39-91)luc) fusion protein in HEK 293 cells served as read-out for the Pdcd4 protein amount to be detected in a high throughput compatible cell-based assay. Loss of Pdcd4(39-91)luc was induced by treatment with 12-O-
tetradecanoylphorbol-13-acetate (TPA), a phorbolester, which activates the PI3K signaling cascade leading to degradation of Pdcd4. The cut-off for hit definition was set at >50% activity in rescuing the Pdcd4(39-91)luc signal from TPA-induced degradation. Activity was calculated relative to the difference of DMSO- and TPA-treated cells (ΔDMSO-TPA = RLUDMSO-RLUTPA). Initial screening of a protein kinase inhibitor library (PKI) revealed hit substances expected to show Pdcd4 stabilizing activity by inhibition of kinases involved in Pdcd4 downregulation, e.g., the mTOR inhibitor rapamycin, the PI3K inhibitors wortmannin and LY294002 and the PKC inhibitors GF 109203X and Ro 31-8220.
The Molecular Targets Laboratory (MTL) of the National Cancer Institute (NCI) in Frederick, USA, hosts one of the largest collections of crude natural product extracts as well as a big substance libraries from pure synthetic sources. Screening of over 15 000 pure compounds and over 135 000 natural product extracts identified 46 pure and 42 extract hits as Pdcd4 stabilizers. For nine synthetic and six natural product derived compounds (after bioassay-guided fractionation), dose-dependent activities for recovering the TPA-induced Pdcd4(39-91)luc loss defined IC50s in the low micromolar range. Most importantly, these compounds were confirmed to stabilize endogenous Pdcd4 protein levels from forced degradation as well. This result proved the assay design to be highly representative for endogenous cellular mechanisms regulating Pdcd4 protein stability. The next step was to stratify the hit substances according to their likely mechanism of action to be located either up- or downstream of the p70S6K-mediated phosphorylation of Pdcd4. Therefore, phosphorylation of S6, as proto-typical p70S6K target, was analyzed and uncovered two natural derived compounds to influence p70S6K activity. Four substances did not affect p70S6K phosphorylation activity and were therefore considered to stabilize Pdcd4 by acting downstream, i.e. on the β-TrCP-mediated proteasomal degradation.
In the second part of this work, one of these compounds, namely the sesquiterpene lactone erioflorin, isolated by bioassay-guided fraction from the active extract of Eriophyllum lanatum, Asteraceae, was further characterized in detail with respect to its molecular mechanism of action. Erioflorin dose-dependently protected both Pdcd4(39-91)luc and endogenous Pdcd4 protein from TPA-induced degradation with IC50s of 1.28 and 2.64 μM, respectively. Pdcd4 stabilizing activity was maximal at 5 μM erioflorin. Up to this concentration, erioflorin was verified not to inhibit p70S6K activity. In addition, it was observed that erioflorin rescued Pdcd4(39-91)luc from both, wild type and constitutively active p70S6K-mediated downregulation. Only wild type p70S6K was inhibitable by the mTOR inhibitor rapamycin which served as an upstream acting control. To study the next section of Pdcd4 regulation, i.e. recognition by the E3 ubiquitin ligase β-TrCP, Pdcd4(39-91)luc and endogenous Pdcd4 were immunoprecipitated from whole cell extracts with the corresponding antibodies. In this key experiment, treatment with TPA increased overexpressed β-TrCP binding to both and this coimmunoprecipitation could be strongly reduced by erioflorin treatment. This result strongly pointed to an inhibitory mechanism of the β-TrCP specific binding to Pdcd4 by erioflorin. In addition, erioflorin disrupted the binding of in vitro transcribed/translated β-TrCP to Pdcd4 in an in vitro interaction assay to exclude nonspecific intracellular signals. Furthermore, polyubiquitination of Pdcd4 was decreased by erioflorin treatment as well. To clarify questions regarding specificity of erioflorin for the E3 ubiquitin ligase β-TrCP, stability of another important β-TrCP target was explored, i.e. the tumor suppressor inhibitor of kappa B alpha (IκBα). Indeed, the tumor necrosis factor alpha (TNFα)-mediated loss of IκBα could be prevented by erioflorin cotreatment. On the other hand, the E3 ubiquitin ligase von Hippel Lindau protein (pVHL) was left unaffected as its target hypoxia inducible factor 1 alpha (HIF-1α) could not be stabilized from oxygen-dependent degradation by erioflorin treatment. These results argued strongly for erioflorin being a specific inhibitor of β-TrCP-mediated protein degradation. Functional consequences of erioflorin treatment were investigated by observing its influence on the transcriptional activities of the transformation marker activator protein 1 (AP-1, an indirect downstream target of Pdcd4) and nuclear factor κB (NF-κB which is directly inhibited by IκBα). Indeed, erioflorin showed significant inhibition of AP-1 and NF-κB reporter constructs at 5 μM, a concentration for which an impact on cell viability was excluded. Finally to characterize the significance of erioflorin in a cell-based tumorigenesis assay, the highly invasive colon carcinoma cell line RKO was tested in a two dimensional migration assay. Erioflorin was discovered to significantly lower cell migration in a wound closure assay.
In conclusion, development of a high throughput compatible cell-based reporter assay successfully identified novel substances from pure synthetic and natural product derived background as potent stabilizers of the tumor suppressor Pdcd4. In addition, this work aimed at elucidating the detailed mechanism of action of the sesquiterpene lactone erioflorin from Eriophyllum lanatum, Asteraceae. Erioflorin was discovered to inhibit the E3 ubiquitin ligase β-TrCP, thereby preventing protein degradation of tumor suppressors like Pdcd4 and IκBα. This may offer the possibility to more specifically target protein degradation and generate less adverse side effects by blocking a particular E3 ubiquitin ligase compared to general proteasome inhibition.
Recent fieldwork on North Andros Island by the authors resulted in the collection of six species of Pterophoridae
(Lepidoptera), five of which were previously unrecorded for the Bahamas in published accounts. Three
additional species are noted for the Bahamian fauna based on specimens collected in the 1980s on other islands.
Representative specimens are illustrated from North Andros along with genitalic images for species where these
are not readily available in other publications. In addition, images of the larva and pupa are provided for a reared
species for which the life history was previously unknown.
Snoqualmia, new genus, is described for two species of polydesmid millipeds from the northwestern
United States: Snoqualmia snoqualmie, new species, from Washington State, and S. idaho, new species,
from Idaho. Males of S. idaho possess unusually complex gonopods, perhaps the most complex to be found in the Order
Polydesmida. Snoqualmia is placed in context with other polydesmid genera known from North America. The
polydesmid fauna of North America is discussed, as well as characters of the gonopods of the family.
The first measurement of the fluctuation of the kaon-to-proton ratio in relativistic heavy-ion collisions is presented. This thesis details the analysis procedure for identifying kaons and protons using the NA49 experiment at CERN-SPS and discusses the results in the context of the current state of the field.
1 Editorial ; 2 Increased Disclosure Requirements for the Supervisory Boards of Stock Corporations ; 3 Can Facebook Predict Stock Market Activity? ; 4 Combining Structured and Unstructured Data :Sources for Support in Financial Decision Making ; 5 Liikanen Commission makes proposals for an efficient and sustainable financial system ; 6 INTERVIEW: What Economists Can Learn from Neuroscientists ; 7 News ; 8 Selected Research and Policy Publications
Parallel Banking – Frankfurt Can Bring some Light into the Darkness_3
THOMAS SCHÄFER
Inflation and Growth: New Evidence from a Dynamic Panel Threshold Analysis_4
ALEXANDER BICK | STEPHANIE KREMER | DIETER NAUTZ
Who Benefits from Building Insurance Groups?_6
SEBASTIAN SCHLÜTTER | HELMUT GRÜNDL
IT Innovation: Mindfully Resisting the Bandwagon_8
ROMAN BECK | WOLFGANG KÖNIG | IMMANUEL PAHLKE | MARTIN WOLF
“The Part-Time Master in Finance is GBS' Answer to the Bologna Process”_10
UWE WALZ
House of Finance Wins New LOEWE Center_12