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The record-breaking prices observed in the art market over the last three years raise the question of whether we are experiencing a speculative bubble. Given the difficulty to determine the fundamental value of artworks, we apply a right-tailed unit root test with forward recursive regressions (SADF test) to detect explosive behaviors directly in the time series of four different art market segments (“Impressionist and Modern”, “Post-war and Contemporary”, “American”, and “Latin American”) for the period from 1970 to 2013. We identify two historical speculative bubbles and find an explosive movement in today’s “Post-war and Contemporary” and “American” fine art market segments.
The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation.
Iredi War : A Folkscript
(2014)
Iredi War was the winner of The Nigeria Prize for Literature 2014. The playwright introduces the notion of 'folk script' with its special stamp. The use of the oral literature genre allows for the full exploitation of the creative licence which allows for the swings from the historical to the oral, the natural to the supernatural, the real to the fantastic.
Natural products (NPs) have been a rich source for pharmaceutically used anti-infectives and other drugs. However, the application of anti-infectives inevitably causes the development of resistant and multiresistant pathogens, which have to be treated with novel anti-infectives. The industrial research for novel anti-infectives has been concentrating on members of the bacterial Actinomycetales for a long time. Due to several reasons, e.g. the rediscovery of already known NPs, pharmaceutical companies abandoned their NP-research and focused on drug development based on combinatorial chemistry. However, the limited structural diversity of merely synthetic compound libraries has not been a fruitful source for bioactive compounds. Hence the discovery of novel bioactive NPs as a source for anti-infectives is still of economical and humanitarian interest and will remain to be an important branch of research in the future. One strategy to circumvent the rediscovery of bioactive NPs is the analysis of yet unexplored bacterial taxa. Based on this assumption, this work aimed at the discovery of novel NPs from the entomopathogenic bacterial genera Xenorhabdus and Photorhabdus and other promising taxa, as well as the investigation of their biosynthesis. ...
Understanding the role of structure and social aspects regarding heat stress of people in urban areas requires an interdisciplinary scientific approach that connects methods from both natural sciences and social sciences. In this study, we combine three approaches to provide an interdisciplinary analysis of the structure and social components of heat stress in the city of Aachen, Germany. First, we assess the overall spatial structure of the urban heat island using spatially distributed measurements from mobile air temperature recordings on public transport units combined with spatially distributed geo-statistical data. The results indicate that the time of day matters: During the afternoon, areas with a relative low building density, like the industrial area northeast of the inner city, are the warmest, while surfaces in high-building-density areas like the inner city heat up faster during the evening. Second, we combine these measurements with place-based survey data collected in 2010 from residents aged 50 to 92 regarding their individual housing conditions, medical history and social integration to examine the match among heat-based stress of older residents, social conditions and elevated temperatures in their residential quarter. We identify disadvantaged areas for specific already-disadvantaged demographic groups in the city, pointing to a cumulation of inequalities, including heat stress among the most vulnerable. Third, we compare data of biometeorological measurements on urban public squares during the afternoon with results of the micrometeorological model ENVI-met to examine the spatial variability of the inner-city heat load. We complement the modelling results with on-site interviews to evaluate people’s heat perception at the same public places. A simulation shows that additional vegetation would increase thermal comfort at these public places, whereby the heat load assessed using the predicted mean vote (PMV) value would decrease by approximately 60 %. Furthermore, we demonstrate the strengths and weaknesses of heat stress simulation. ENVI-met allows for an overall reasonable representation of heat load during stable atmospheric conditions. However, due to the setup and structure of ENVI-met, large-scale atmospheric changes that occur during the day cannot readily be integrated into ENVI-met simulations.
Batten disease refers to neuronal ceroid lipofuscinoses (NCLs), which are inherited lysosomal storage diseases with diverse ages of onset and cause progressive neurodegeneration. The most common NCL is Juvenile NCL (JNCL), which begins in early childhood and is characterized by lysosomal accumulation of subunit c of the mitochondrial ATP synthase (subunit c). JNCL is caused by mutations in the gene CLN3. This gene encodes the CLN3 protein, a transmembrane protein of unknown structure. Localization of CLN3 is ambiguous, and its exact cellular function is not known. Thereby, it is unclear what mechanisms lead to neurodegeneration in JNCL. Models of JNCL present disturbed membrane bound organelles and cytoskeleton as well as impaired autophagy and lysosomal function. The JNCL gene defect that most patients harbor is deletion of the exons 7 and 8 of CLN3. In the Cln3Δex7/8/Δex7/8 mouse model of JNCL, this deletion has been introduced to the mouse Cln3 gene.
The actin cytoskeleton consists of filaments formed through polymerization of actin and provides a framework which defines cellular morphology and also facilitates cell motility, cytokinesis, and cell surface remodeling. Rho GTPases are signaling proteins which regulate the assembly and dynamics of the actin cytoskeleton and play an important role in neuronal morphology. Rho GTPases need to be membrane-anchored in order to become active and initiate a signaling cascade. Their membrane anchorage is achieved through their geranylgeranyl tails, which they acquire through prenylation. Protein prenylation refers to the attachment of a geranylgeranyl or farnesyl group to the C-terminus of a protein. The enzyme geranylgeranyl transferase (GGTase) catalyzes geranylgeranylation, whereas geranylgeranyl pyrophosphate (GGPP) is the donor of the geranylgeranyl group. Cells produce GGPP as well as cholesterol and other lipids through the mevalonate pathway (MVA pathway).
The aim of this study was to analyze how the JNCL gene defect affects cellular morphology, especially the actin cytoskeleton and Rho GTPases, and the MVA pathway which is connected with Rho GTPase activation. These important cellular components play crucial roles in neurons and are implicated in other neurodegenerative diseases, but have received little attention in JNCL. The immortalized CbCln3Δex7/8/Δex7/8 cerebellar precursor cell line from Cln3Δex7/8/Δex7/8 mice was used for the experiments and provides a genetically accurate, neuronal cell model of JNCL. CbCln3Δex7/8/Δex7/8 cells present subunit c accumulation only when aged at confluency, but sub-confluent cells display other phenotypes. The experiments of this study were performed both with confluency-aged and sub-confluent cells. Filamentous actin was visualized, and protein levels as well as membrane localization of several small Rho GTPases was analyzed biochemically. Also the protein levels of GGTase and the key enzymes of the mevalonate pathway were determined.
Staining pattern of filamentous actin was disturbed in confluency-aged CbCln3Δex7/8/Δex7/8 cells. Additionally it was found out that these cells did not grow to wild-type size and exhibited an elongated peroxisomal morphology. Rho GTPases had reduced total levels and showed a tendency of decreased membrane localization. Levels of GGTase and the MVA pathway enzymes were altered. Results of sub-confluent CbCln3Δex7/8/Δex7/8 cells were similar with the exception of HMG-CoA reductase, which is the rate-limiting enzyme of the MVA pathway: while its level in confluency-aged CbCln3Δex7/8/Δex7/8 cells was increased, at sub-confluency it showed a reduced level. Also, in contrast with the confluency-aged cells, Rho GTPases presented a tendency of increased membrane localization.
The results of this study reveal that the accurate JNCL gene defect alters cellular morphology and the activity of the MVA pathway in neuronal cells. Small cell size and disrupted architecture of the actin cytoskeleton are confirmed as neuronal JNCL phenotypes, and the peroxisome is introduced as a novel cellular component affected in JNCL. Through defects in endocytosis, autophagy, lysosomal and mitochondrial function, and cytoskeleton, the JNCL gene defect may prevent cells from growing to wild-type size. The JNCL gene defect may attenuate the MVA pathway via mitochondrial dysfunction and/or upregulation of degradative processes. Attenuation of the MVA pathway may contribute to impaired membrane rafts, which are an established phenotype of JNCL cells. As indicated by reduced GGTase level and supported by downregulation of lipid production through the MVA pathway, the JNCL gene defect might also decrease prenylation of proteins.
The mature palm forest of the Vallée de Mai, a UNESCO World Heritage Site, on the Seychelles island of Praslin, is a unique ecosystem containing many endemic species, including the iconic coco de mer palm Lodoicea maldivica. In 2009, the invasive yellow crazy ant Anoplolepis gracilipes was recorded for the first time within the palm forest, raising concern about its potential impacts on the endemic fauna. This research aimed to: (1) assess the current distribution and spread of A. gracilipes within the palm forest; (2) identify environmental variables that are linked to A. gracilipes distribution; and (3) compare endemic species richness and abundance in A. gracilipes invaded and uninvaded areas. Anoplolepis gracilipes was confined to the north-east of the site and remained almost stationary between April 2010 and December 2012, with isolated outbreaks into the forest. Infested areas had significantly higher temperature and humidity and lower canopy cover. Abundance and species richness of the endemic arboreal fauna were lower in the A. gracilipes invaded area. Molluscs were absent from the invaded area. The current restricted distribution of A. gracilipes in this ecosystem, combined with lower abundance of endemic fauna in the invaded area, highlight the need for further research to assess control measures and the possible role of biotic resistance to the invasion of the palm forest by A. gracilipes.
D2.1. provides further elaboration of the original research design and informs about ideas for the final Volume II of bEUcitizen. It is closely connected to task 1 of work package 2: specifying various concrete tasks for the different work packages and formulating overarching questions suitable to provide substantive cohesion and integration of the overall project. The elaboration of 10 crosscutting topics (to become chapters in the “horizontal” book, D2.3.) is a first step towards this goal. Discussing these cross-cutting topics is supposed to feed, infuse and inspire the work done in the different work packages and to build cross-cutting connections between them. Themes 1-10 merge into a valuable overview of the multi-faceted research on (EU) citizenship. They access the main issues of EU-citizenship and citizenship in general from different angles and different disciplines. Taken together these contributions help to identify barriers towards EU citizenship and ways to overcome them. Each Theme formulates questions how it might feed and be fed by further information and findings in the other work packages.
D2.1. is mainly meant for internal use. Its functions are firstly to inform about preliminary ideas, eventual contributions to planned final results and secondly to make out some more of less specific guiding questions that connect the work done by the single researchers in every different work package to the project as a whole. This task implies a normative yardstick, a clear picture of what would be a "good" EU citizenship practice. Elaborating on such a normative yardstick is a meta-topic that cuts across the range of cross-cutting topics presented in this working paper.
Introduction - Issue 7
(2014)
Introduction
(2014)
Bantu languages have been at the heart of the research on the interaction between syntax, prosody and information structure. In these predominantly SVO languages, considerable attention has been devoted to postverbal phenomena. By addressing issues related to Subjects, Topics and Object-Verb word orders, the goal of the present papers is to deepen our understanding of the interaction of different grammatical components (syntax, phonology, semantics/pragmatics) both in individual languages and across the Bantu family. Each paper makes a valuable contribution to ongoing discussions on the preverbal domain.
Introduction
(2014)
Introduction
(2014)
The experience of multistable figures or so-called Kippbilder - the sudden and repeated 'kippen' of perception as the same object is seen under different aspects - is fascinating in its own right. However, what animated the year-long discussion leading to this volume was a critical exploration of the proposition that such figures may offer a helpful model for thinking through the intercultural and interdisciplinary effort of productively negotiating between conflicting positions.
In my paper I take issue with proponents of ‘intersectionality’ which believe that a theoretical concept cannot/should not be detached from its original context of invention. Instead, I argue that the traveling of theory in a global context automatically involves appropriations, amendment and changes in response to the original meaning. However, I reject the idea that ‘intersectionality’ can be used as a freefloating signifier; on the contrary, it has to be embedded in the respective (historical, social, cultural) context in which it is used. I will start by mapping some of the current debates engaging with the pros and cons of the global implementation of the concept (the controversy about master categories, the dispute about the centrality of ‘race’, and the argument about the amendment of categories). I will then turn to my own use of ‘intersectionality’ as a methodological tool (elaborated in Lutz and Davis 2005). Here, we shifted attention from how structures of racism, class discrimination and sexism determine individuals’ identities and practices to how individuals ongoingly and flexibly negotiate their multiple and converging identities in the context of everyday life. Introducing the term doing intersectionality we explored how individuals creatively and often in surprising ways draw upon various aspects of their multiple identities as a resource to gain control over their lives.
In my paper I will show how ‘gender’ or ‘ethnicity’ are invariably linked to structures of domination, but can also mobilize or deconstruct disempowering discourses, even undermine and transform oppressive practices.
We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48–72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.
We propose an effective theory of SU(3) gluonic matter where interactions between color-electric and color-magnetic gluons are constrained by the center and scale symmetries. Through matching to the dimensionally-reduced magnetic theories, the magnetic gluon condensate qualitatively changes its thermal behavior above the critical temperature. We argue its phenomenological consequences for the thermodynamics, in particular the dynamical breaking of scale invariance.
The impact of international migration, both South-South as well as South-North, on the economic, social and political life of the people in Eastern and Southern Africa [was] not well documented and studied,- and 'the evidence-base for policy on migration and development [was] very weak.' With this in mind, OSSREA's invitation to conduct a study on international migration in Africa had the following objectives: To analyze the nature and type of South-South migration, focusing on issues, such as brain gain and/or brain drain, remittance flows, technical know-how transfers, violations of the right of African migrants and gender dimensions of migration; To investigate the dynamics of migration from Eastern and Southern Africa to the Arab Gulf States as well as to developed countries, focusing on the skills of migrants, brain gain and/or drain, remittance flows, technical know-how transfers, violations of the rights of African migrants and gender dimension of migrants; and to assess the successes, impediments and challenges of African international migrants from Eastern and Southern Africa and to formulate policy recommendations to maximize the gains and minimize the costs associated with international migration in Africa.
The article aims to investigate, under the aspect of translation, the process of legal appropriation and reproduction of international law during the course of the 19th century. An occidental understanding of translation played an important role in the so-called process of universalization in the 19th century, as it made the complexity of global circulation of ideas invisible. Approaches proposed by scholars of Postcolonial, Cultural and Translation Studies are useful for re-reading histories of the circulation of European ideas, particularly the international law doctrines, from a different perspective. The great strides made in Translation and Cultural Studies in the last decades, as well as the discernment practiced in the scholarship of Postcolonial Studies, are important for a broader and more differentiated understanding of the processes of appropriation and reproduction of the doctrines of international law during the 19th century. The present article begins by tracing the connection between translation and universalization of concepts in 19th century international law; after a short excursus on the Western idea of translation, the attention is focused on the translation of international law textbooks. The conclusive section is dedicated to a comparison between Emer de Vattel’s Droit des gens and Andrés Bello’s Principios de Derecho de Jentes.
While distribution conflicts over natural resources were central to the debates on a New International Economic Order, during the last decades the specific distribution conflicts surrounding natural resource exploitation no longer have been at the core of international law. In this paper I trace the developments in the relationship between international law and resource distribution conflicts. I first argue that the New International Economic Order favored the political resolution of distribution conflicts over natural resources and envisaged international distribution conflicts to be addressed by the political organs of international institutions within legal procedures Second, I show how the NIEO was surpassed by a different order that relied largely on the market as a distribution mechanism for raw materials and how international institutions and international law played a crucial role in the establishment of this order by promoting the privatization of natural resource exploitation and protecting foreign direct investment and trade. With reference to the copper industry in Zambia I thirdly illustrate how international investment law, and more broadly international economic law, is shaping (and affecting the resolution of) not only distribution conflicts between, but also within States. I conclude with a call for a renewed focus on an international law of resource conflicts to allow for their political resolution given the countermoves we can observe with respect to international investment law and the persistence of (violent) conflicts over natural resource exploitation within States.
The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.
Seven different instruments and measurement methods were used to examine the immersion freezing of bacterial ice nuclei from Snomax® (hereafter Snomax), a product containing ice active protein complexes from non-viable Pseudomonas syringae bacteria. The experimental conditions were kept as similar as possible for the different measurements. Of the participating instruments, some examined droplets which had been made from suspensions directly, and the others examined droplets activated on previously generated Snomax particles, with particle diameters of mostly a few hundred nanometers and up to a few micrometers in some cases. Data were obtained in the temperature range from −2 to −38 °C, and it was found that all ice active protein complexes were already activated above −12 °C. Droplets with different Snomax mass concentrations covering 10 orders of magnitude were examined. Some instruments had very short ice nucleation times down to below 1 s, while others had comparably slow cooling rates around 1 K min−1. Displaying data from the different instruments in terms of numbers of ice active protein complexes per dry mass of Snomax, nm, showed that within their uncertainty the data agree well with each other as well as to previously reported literature results. Two parameterizations were taken from literature for a direct comparison to our results, and these were a time dependent approach based on a contact angle distribution Niedermeier et al. (2014) and a modification of the parameterization presented in Hartmann et~al.~(2013) representing a time independent approach. The agreement between these and the measured data were good, i.e. they agreed within a temperature range of 0.6 K or equivalently a range in nm of a factor of 2. From the results presented herein, we propose that Snomax, at least when carefully shared and prepared, is a suitable material to test and compare different instruments for their accuracy of measuring immersion freezing.
Thought to be monotypic for decades, the only species in the goosefish genus Lophiomus Gill, Lm. setigerus (Vahl), shows a wide range of morphological variation and is distributed widely in the Indo-West Pacific (IWP). In this study, datasets for two mitochondrial and two nuclear genes sequences obtained from samples of Lophiomus collected in different localities across the IWP were constructed and analyzed to explore the phylogeny and species diversity within the genus. Our integrated approach with multiline evidence unveiled an unanticipated richness of at least six delimited species of Lophiomus. Herein, based on materials already available from museums and new specimens obtained primarily through the Tropical Deep-Sea Benthos program surveying IWP benthic fauna, we formally describe three new species: Lm. immaculioralis sp. nov., Lm. nigriventris sp. nov., and Lm. carusoi sp. nov. Also, we resurrect Lm. laticeps stat. rev. from synonyms of Lm. setigerus. These species can be diagnosed by genetics, body coloration, patterns on the floor of the mouth, peritoneum pigmentation, morphometric measurements, and meristic counts of cranial spines, dorsal-fin spines, and pectoral-fin and pelvic-fin rays from each other and from Lm. setigerus. The species Lm. setigerus, as well as the genus Lophiomus, are re-described accordingly based on the new results. Amended identification keys to the four extant lophiid genera and to species of Lophiomus are also provided.
Autophagy plays an essential role in maintaining an intricate balance between nutrient demands and energetic requirements during normal homeostasis. Autophagy recycles metabolic substrates from nonspecific bulk degradation of proteins and excess or damaged organelles. Recent work posits an active and dynamic signaling role for extracellular matrix-evoked autophagic regulation, that is, allosteric and independent of prevailing nutrient conditions. Several candidates, representing a diverse repertoire of matrix constituents (decorin, collagen VI, laminin α2, endostatin, endorepellin, and kringle V), can modulate autophagic signaling pathways. Importantly, a novel principle indicates that matrix constituents can differentially modulate autophagic induction and repression via interaction with specific receptors. Most of the matrix-derived factors described here appear to control autophagy in a canonical manner but independent of nutrient deprivation. Because the molecular composition and structure of the extracellular matrix are dynamically remodeled during various physiological and pathological conditions, we propose that matrix-regulated autophagy is key for maintaining proper tissue homeostasis and disease prevention, such as cancer progression and muscular dystrophies.
A recent trend in international development circles is "New Institutionalism". In a slogan, the idea is just that good institutions matter. The slogan itself is so innocuous as to be hardly worth comment. But the push to improve institutional quality has the potential to have a much less innocuous impact on aid efforts and other aspects of international development. This paper provides a critical introduction to some of the literature on institutional quality. It looks, in particular, at an argument for the conclusion that making aid conditional on good institutional quality will promote development by reducing poverty. This paper suggests that there is little theoretical or empirical evidence that this kind of conditionality is good for the poor.
Like in many parts of the world, water resources in sub-Saharan Africa (SSA) have been pivotal for human survival, economic growth, social development, and practicing certain religion and cultural ethos. However, in spite of the intrinsic values of water, its use and management in sub-Saharan Africa has not been without limitations. The demand for water resources is increasing mainly due to rapid population growth, industrialization and urbanization and dealing with water-related issues has been complex and challenging for sustainable growth. Whilst there are various efforts by national governments, non-government organizations and communities to effectively and efficiently utilize and manage water resources, there are few comprehensive studies in sub- Saharan Africa that show the impact of the efforts on poverty reduction. Although certain reports indicate that many SSA countries lack clear vision on how water use can be harnessed with pro-poor growth and how poor communities can be capacitated to use water for poverty reduction, there are little exhaustive studies that clearly show familiar and innovative water use and management interventions followed by communities, national governments and other stakeholders, and demonstrate the challenges and successes of the same. Cognizant of the knowledge gap, in 2012 OSSREA launched a research project on ordinary and innovative water use and management patterns and practices in SSA, with a view to generate new knowledge on unexploited opportunities that could enhance the contribution of water resources to poverty reduction. This anthology documents various issues including water use and management in agriculture especially in irrigation projects in Ethiopia, Kenya, Uganda and Zimbabwe; water harvesting in Kenya and Uganda; the role of local water use institutions in Ethiopia; and water source maintenance and protection in Uganda.
Background: Right heart failure is a fatal consequence of chronic pulmonary hypertension (PH). The development of PH is characterized by increased proliferation of vascular cells, in particular pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells. In the course of PH, an escalated right ventricular (RV) afterload occurs, which leads to increased perioperative morbidity and mortality. BKCa channels are ubiquitously expressed in vascular smooth muscle cells and their opening induces cell membrane hyperpolarization followed by vasodilation. Moreover, BK activation induces anti-proliferative effects in a multitude of cell types. On this basis, we hypothesized that treatment with the nebulized BK channel opener NS1619 might be a therapy option for pulmonary hypertension and tested this in rats.
Methods: (1) Rats received monocrotaline injection for PH induction. Twenty-four days later, rats were anesthetized and NS1619 or the solvent was administered by inhalation. Systemic hemodynamic parameters, RV hemodynamic parameters, and blood gas analyses were measured before as well as 30 and 120 minutes after inhalation. (2) Rat PASMCs were stimulated with PDGF-BB in the presence and absence of NS1619. AKT, ERK1 and ERK2 activation were investigated by western blot analyses, and relative cell number was determined 48 hours after stimulation.
Results: Inhalation of a 12 µM and 100 µM NS1619 solution significantly reduced RV pressure without affecting systemic arterial pressure. Blood gas analyses demonstrated significantly reduced carbon dioxide and improved oxygenation in NS1619-treated animals pointing towards a considerable pulmonary shunt-reducing effect. In PASMC’s, NS1619 (100 µM) significantly attenuated PASMC proliferation by a pathway independent of AKT and ERK1/2 activation.
Conclusion: NS1619 inhalation reduces RV pressure and improves oxygen supply and its application inhibits PASMC proliferation in vitro. Hence, BK opening might be a novel option for the treatment of pulmonary hypertension.
Introduction: Over the last years, electronic cigarettes (ECs) have become more popular, particularly in individuals who want to give up smoking tobacco. The aim of the present study was to assess the influence of the different e-smoking liquids on the viability and proliferation of human periodontal ligament fibroblasts.
Method and materials: For this study six test solutions with components from ECs were selected: lime-, hazelnut- and menthol-flavored liquids, nicotine, propylene glycol, and PBS as control group. The fibroblasts were incubated up to 96 h with the different liquids, and cell viability was measured by using the PrestoBlue® reagent, the ATP detection and the migration assay. Fluorescence staining was carried out to visualize cell growth and morphology. Data were statistically analyzed by two-tailed one-way ANOVA.
Results: The cell viability assay showed that the proliferation rates of the cells incubated with nicotine or the various flavored liquids of the e-cigarettes were reduced in comparison to the controls, though not all reductions were statistically significant. After an incubation of 96 h with the menthol-flavored liquid the fibroblasts were statistically significant reduced (p < 0.001). Similar results were found for the detection of ATP in fibroblasts; the incubation with menthol-flavored liquids (p < 0.001) led to a statistically significant reduction. The cell visualization tests confirmed these findings.
Conclusion: Within its limits, the present in vitro study demonstrated that menthol additives of e-smoking have a harmful effect on human periodontal ligament fibroblasts. This might indicate that menthol additives should be avoided for e-cigarettes.
Rapid alterations in protein expression are commonly regulated by adjusting translation. In addition to cap-dependent translation, which is e.g. induced by pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, alternative modes of translation, such as internal ribosome entry site (IRES)-dependent translation, are often enhanced under stress conditions, even if cap-dependent translation is attenuated. Common stress stimuli comprise nutrient deprivation, hypoxia, but also inflammatory signals supplied by infiltrating immune cells. Yet, the impact of inflammatory microenvironments on translation in tumor cells still remains largely elusive. In the present study, we aimed at identifying translationally deregulated targets in tumor cells under inflammatory conditions. Using polysome profiling and microarray analysis, we identified cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally upregulated in breast tumor cells co-cultured with conditioned medium of activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, we identified and validated an IRES within the 5′ untranslated region (5′UTR) of cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, IRES-dependent translation of cyp24a1 by CM was sensitive to phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation of Akt sufficed to induce its IRES activity. Our data provide evidence that cyp24a1 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment. Considering the negative feedback impact of cyp24a1 on the vitamin D responses, the identification of a novel, translational mechanism of cyp24a1 regulation might open new possibilities to overcome the current limitations of vitamin D as tumor therapeutic option.
This volume is an attempt to provide this intersectional and reflexive space. The thinking behind the book began in Lamu in mid-2010. It was a time when growing community resistance emerged towards the Kenyan government's plan to build a second seaport under a trans-frontier infrastructural project known as the Lamu Port- South Sudan-Ethiopia Transport Corridor (LAPSSET). The editors agreed that a book that draws community activists, academics, researchers and policy makers into a discussion of the predicament of indigenous rights and development against the backdrop of the Endorois case was timely and needed. Assembled here are the original contributions of some of the leading contemporary thinkers in the area of indigenous and human rights in Africa. The book is an interdisciplinary effort with the single purpose of thinking through indigenous rights after the Endorois case but it is not a singular laudatory remark on indigenous life in Africa. The discussion begins by framing indigenous rights and claims to indigeneity as found in the Endorois decision and its related socio-political history. Subsequent chapters provide deeper contextual analysis by evaluating the tense relationship between indigenous peoples and the post-colonial nation-state. Overall, the book makes a peering and provocative contribution to the relational interests between state policies and the developmental intersections of indigeneity, indigenous rights, gender advocacy, environmental conservation, chronic trauma and transitional justice.
It has long been observed that subjects cross-linguistically have topic properties: they are typically definite, referential and/or generic (Givón 1976). Bantu languages are said to illustrate this generalization: preverbal position for NPs is equated with both subject and topic status and postverbal position with focus (and non-subject). However, there is a growing body of work showing that preverbal subjects are not necessarily syntactically or semantically equivalent to topics. For example, Zerbian’s (2006) careful study of preverbal position in Northern Sotho shows that preverbal subjects meet few of the semantic tests for aboutness topics. The study of restrictions on preverbal subjects in Durban Zulu presented in this paper builds on Zerbian (2006) and Halpert (2012). In particular, we investigate the interpretational properties of preverbal indefinite subjects. These subjects show us that preverbal subjects carry a presupposition of existence. We explore an analysis connecting the "strong reading" of preverbal subjects with how high the verb moves in Zulu (following Tsai’s 2001 work on Mandarin).
The Eurozone fiscal crisis has created pressure for institutional harmonization, but skeptics argue that cultural predispositions can prevent convergence in behavior. Our paper derives a robust cultural classification of European countries and utilizes unique data on natives and immigrants to Sweden. Classification based on genetic distance or on Hofstede’s cultural dimensions fails to identify a single ‘southern’ culture but points to a ‘northern’ culture. Significant differences in financial behavior are found across cultural groups, controlling for household characteristics. Financial behavior tends to converge with longer exposure to common institutions, but is slowed down by longer exposure to original institutions.
The history of people with disabilities has been dominated by their isolation and exclusion. The long fight towards inclusion - and inclusive education in particular - started not many years ago. Most were powerless to control their own destiny. Their participation in society has been the object of other's actions. In many countries their disability policies have a substantial element of protection and charity but not the right to equalisation of opportunities. This book highlights the process of change that is underway internationally. The equalisation of opportunities requires new processes through which the various systems of society such as health services and education are delivered. It means the right for people with disabilities to remain in their communities and to receive the schooling and social supports they need within the ordinary structures available in local communities. Strong advocacy is needed for this to happen. In particular parents need to be empowered, communities mobilised and professionals trained in new ways of working: hence this book. Drawing on experiences in Africa, the book describes the issues to be considered when it comes to implementing inclusive strategies: the processes to be followed and the roles of different sectors, such as people with disabilities, parents, policy makers, educationalists, health and community development professionals and crucially, society at large.
This paper examines the effect of imperfect labor market competition on the efficiency of compensation schemes in a setting with moral hazard, private information and risk-averse agents. Two vertically differentiated firrms compete for agents by offering contracts with fixed and variable payments. Vertical differentiation between firms leads to endogenous, type-dependent exit options for agents. In contrast to screening models with perfect competition, we find that existence of equilibria does not depend on whether the least-cost separating allocation is interim efficient. Rather, vertical differentiation allows the inferior firm to offer (cross-)subsidizing fixed payments even above the interim efficient level. We further show that the efficiency of variable pay depends on the degree of competition for agents: For small degrees of competition, low-ability agents are under-incentivized and exert too little effort. For large degrees of competition, high-ability agents are over-incentivized and bear too much risk. For intermediate degrees of competition, however, contracts are second-best despite private information.
Many QCD based and phenomenological models predict changes of hadron properties in a strongly interacting environment. The results of these models differ significantly and the experimental determination of hadron properties in nuclear matter is essential. In this paper we present a review of selected physics results obtained at GSI Helmholtzzentrum für Schwerionenforschung GmbH by HADES (High-Acceptance Di-Electron Spectrometer). The e+e− pair emission measured for proton and heavy-ion induced collisions is reported together with results on strangeness production. The future HADES activities at the planned FAIR facility are also discussed.
In vitro investigation of genes identified by genome-wide association studies of Parkinson's disease
(2014)
Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.
South African poetry today is charged with restlessness, burstng with diversity. Gone is the intense inward focus required to deal with a situation of systematic oppression, the enclosing effort of concentration on a single predicament. While politics and identity continue to be central themes, the poetry since the late 1990s reveals a richer investigation of ancestors and history, alongside more experimentation with language and translation; and enduring concern with the touchstones of love, loss, memory, and acts of witnessing. In the Heat of Shadows: South African Poetry 1996-2013 presents work by 33 poets and includes some translations from Afrikaans, isiXhosa, isiZulu, Sesotho and Xitsonga. This collection follows on from Denis Hirson's 1997 anthology The Lava of this Land: South African Poetry 1960-1996.
Non-coding RNAs (ncRNAs) play various roles during central nervous system development. MicroRNAs (miRNAs) are a class of ncRNAs that exert their function together with argonaute proteins by post-transcriptional gene silencing of messenger RNAs (mRNAs). Several studies provide evidence for alterations in miRNA expression in patients with neurodegenerative diseases. Among these is huntington‘s disease (HD), a dominantly inherited fatal disorder characterized by deregulation of neuronal-specific mRNAs as well as miRNAs. Recently, next-generation sequencing (NGS) miRNA profiles from human HD and neurologically normal control brain tissues were reported. Five consistently upregulated miRNAs affect the expression of genes involved in neuronal differentiation, neurite outgrowth, cell death and survival. We re-analyzed the NGS data publicly available in array express and detected nineteen additional differentially expressed miRNAs. Subsequently, we connected these miRNAs to genes implicated in HD development and network analysis pointed to miRNA-mediated downregulation of twenty-two genes with roles in the pathogenesis as well as treatment of the disease. In silico prediction and reporter systems prove that levels of BDNF, a central node in the miRNA-mRNA regulatory network, can be post-transcriptionally controlled by upregulated miR-10b-5p and miR-30a-5p. Reduced BDNF expression is associated with neuronal dysfunction and death in HD. Moreover, the 3’UTR of CREB1 harbors a predicted binding site for these two miRNAs. CREB1 is similarly downregulated in HD and overexpression decreased susceptibility to 3-nitropropionic-induced toxicity in a cell model. In contradiction to these observations, it is presumed that miR-10b-5p upregulation in HD exerts a neuroprotective role in response to the mutation in the huntingtin gene. Therefore, the function of miR-10b-5p and especially its effect on BDNF expression in HD requires further academic research.
In Search of Happiness
(2014)
Nana is fifteen when she travels from her village in the Eastern Cape to the city. She is overjoyed to be reunited with her family, even if they are living in a tiny shack. But she struggles to fit in at her new school, and she is shocked at the violence shown to Chino and Agnes, her Zimbabwean neighbours. When she and Agnes become close friends, and find love in unexpected places, Nana learns firsthand just how brutal ignorance can be and how hard it is to hold on to happiness.
We analyze the differential impact of domestic and foreign monetary policy on the local supply of bank credit in domestic and foreign currencies. We analyze a novel, supervisory dataset from Hungary that records all bank lending to firms including its currency denomination. Accounting for time-varying firm-specific heterogeneity in loan demand, we find that a lower domestic interest rate expands the supply of credit in the domestic but not in the foreign currency. A lower foreign interest rate on the other hand expands lending by lowly versus highly capitalized banks relatively more in the foreign than in the domestic currency.
The approximate number system (ANS) has been consistently found to be associated with math achievement. However, little is known about the interactions between the different instantiations of the ANS and in how many ways they are related to exact calculation. In a cross-sectional design, we investigated the relationship between three measures of ANS acuity (non-symbolic comparison, non-symbolic estimation and non-symbolic addition), their cross-sectional trajectories and specific contributions to exact calculation. Children with mathematical difficulties (MD) and typically achieving (TA) controls attending the first six years of formal schooling participated in the study. The MD group exhibited impairments in multiple instantiations of the ANS compared to their TA peers. The ANS acuity measured by all three tasks positively correlated with age in TA children, while no correlation was found between non-symbolic comparison and age in the MD group. The measures of ANS acuity significantly correlated with each other, reflecting at least in part a common numerosity code. Crucially, we found that non-symbolic estimation partially and non-symbolic addition fully mediated the effects of non-symbolic comparison in exact calculation.
In Chains for My Country is an account of the struggle of the Southern Cameroons National Council (SCNC), a nonviolent liberation movement, to wrestle British Southern Cameroons from the colonial claws of la République du Cameroun. It is an epic and thrilling account of the life of British Southern Cameroons, which passed from colonial rule to foreign domination through annexation and attempted assimilation into neighbouring la République du Cameroun. Under British trusteeship, British Southern Cameroons graduated to self-government in 1954 with all hopes of independence. Instead, the Trust Territory was doomed to subservience in a contested union with la République du Cameroun. Failure to implement United Nations Resolution 1608 of April 1961 to establish the envisioned federation of two states equal in status facilitated la République du Cameroun's annexation and colonial occupation of a defenseless United Nations Trust as Britain withdrew all its personnel and forces. The territory has been reduced to two provinces of la République du Cameroun under the rule of proconsuls backed by an imperial occupation force with an agenda of nipping in the bud any resistance.
One of the leading methods of estimating the structural parameters of DSGE models is the VAR-based impulse response matching estimator. The existing asympotic theory for this estimator does not cover situations in which the number of impulse response parameters exceeds the number of VAR model parameters. Situations in which this order condition is violated arise routinely in applied work. We establish the consistency of the impulse response matching estimator in this situation, we derive its asymptotic distribution, and we show how this distribution can be approximated by bootstrap methods. Our methods of inference remain asymptotically valid when the order condition is satisfied, regardless of whether the usual rank condition for the application of the delta method holds. Our analysis sheds new light on the choice of the weighting matrix and covers both weakly and strongly identified DSGE model parameters. We also show that under our assumptions special care is needed to ensure the asymptotic validity of Bayesian methods of inference. A simulation study suggests that the frequentist and Bayesian point and interval estimators we propose are reasonably accurate in finite samples. We also show that using these methods may affect the substantive conclusions in empirical work.
ORGANIZATIONAL MINDFULNESS (OM) SUPPORTS THE MANAGEMENT AND EMPLOYEES WORKING IN THE INCREASINGLY DYNAMIC WORK ENVIRONMENTS DRIVEN BY CLOUD COMPUTING OR MOBILE DEVICES. SPECIFICALLY, IN MINDFUL ORGANIZATIONS, SUCH AS FINANCIAL INSTITUTIONS, RELIABLE OUTCOMES ARISE FROM OM IN THE FACE OF COMPLEX INFORMATION SYSTEMS. HOWEVER, EXTANT IS RESEARCH HAS DISREGARDED THE MULTILEVEL STRUCTURE OF MINDFULNESS, ESPECIALLY THEIMPORTANCE OF MINDFUL ORGANIZING (MO) ON LOWER HIERARCHICAL LEVELS. BASED ON DATA FROM 256 USERS OF AN ORGANIZATION WIDE CLOUD-BASED DESKTOP-AS-A-SERVICE SYSTEM, WE FOUND A SIGNIFICANTLY POSITIVE INFLUENCE OF THE COMBINATION OF OM AND MO AS WELL AS DIFFERENTIAL EFFECTS FOR BOTH ON JOB PERFORMANCE.
The LPJ-GUESS dynamic vegetation model uniquely combines an individual- and patch-based representation of vegetation dynamics with ecosystem biogeochemical cycling from regional to global scales. We present an updated version that includes plant and soil N dynamics, analysing the implications of accounting for C–N interactions on predictions and performance of the model. Stand structural dynamics and allometric scaling of tree growth suggested by global databases of forest stand structure and development were well reproduced by the model in comparison to an earlier multi-model study. Accounting for N cycle dynamics improved the goodness of fit for broadleaved forests. N limitation associated with low N-mineralisation rates reduces productivity of cold-climate and dry-climate ecosystems relative to mesic temperate and tropical ecosystems. In a model experiment emulating free-air CO2 enrichment (FACE) treatment for forests globally, N limitation associated with low N-mineralisation rates of colder soils reduces CO2 enhancement of net primary production (NPP) for boreal forests, while some temperate and tropical forests exhibit increased NPP enhancement. Under a business-as-usual future climate and emissions scenario, ecosystem C storage globally was projected to increase by ca. 10%; additional N requirements to match this increasing ecosystem C were within the high N supply limit estimated on stoichiometric grounds in an earlier study. Our results highlight the importance of accounting for C–N interactions in studies of global terrestrial N cycling, and as a basis for understanding mechanisms on local scales and in different regional contexts.
A recent proposal by the Financial Stability Board (FSB) suggests a new risk capital buffer for globally operating systemically important financial institutions. The suggested metric, “Total Loss Absorbing Capacity“ (TLAC), is composed of Tier-1 capital and loss absorbing debt. In a crisis situation, “bail-in-able” debt is to be written down or converted into equity. Jan Krahnen argues that the credibility of bail-in, in the case of systemically important financial institutions, hinges crucially on the design of TLAC and the requirements that will be placed on loss absorbing “bail-in-able” debt.The fear of direct systemic consequences through bail-in could be overcome, if a holding ban were placed on the “bail-in-bonds” of financial institutions. The holding ban would stipulate that these bonds cannot be held by other institutions within the banking sector.
Background: In primary care, patients with multiple chronic conditions are the rule rather than the exception. The Chronic Care Model (CCM) is an evidence-based framework for improving chronic illness care, but little is known about the extent to which it has been implemented in routine primary care. The aim of this study was to describe how multimorbid older patients assess the routine chronic care they receive in primary care practices in Germany, and to explore the extent to which factors at both the practice and patient level determine their views.
Methods: This cross-sectional study used baseline data from an observational cohort study involving 158 general practitioners (GP) and 3189 multimorbid patients. Standardized questionnaires were employed to collect data, and the Patient Assessment of Chronic Illness Care (PACIC) questionnaire used to assess the quality of care received. Multilevel hierarchical modeling was used to identify any existing association between the dependent variable, PACIC, and independent variables at the patient level (socio-economic factors, weighted count of chronic conditions, instrumental activities of daily living, health-related quality of life, graded chronic pain, no. of contacts with GP, existence of a disease management program (DMP) disease, self-efficacy, and social support) and the practice level (age and sex of GP, years in current practice, size and type of practice).
Results: The overall mean PACIC score was 2.4 (SD 0.8), with the mean subscale scores ranging from 2.0 (SD 1.0, subscale goal setting/tailoring) to 3.5 (SD 0.7, delivery system design). At the patient level, higher PACIC scores were associated with a DMP disease, more frequent GP contacts, higher social support, and higher autonomy of past occupation. At the practice level, solo practices were associated with higher PACIC values than other types of practice.
Conclusions: This study shows that from the perspective of multimorbid patients receiving care in German primary care practices, the implementation of structured care and counseling could be improved, particularly by helping patients set specific goals, coordinating care, and arranging follow-up contacts. Studies evaluating chronic care should take into consideration that a patient’s assessment is associated not only with practice-level factors, but also with individual, patient-level factors.
To overcome poor treatment response of pediatric high-risk acute lymphoblastic leukemia (ALL), novel treatment strategies are required to reactivate programmed cell death in this malignancy. Therefore, we take advantage of using small-molecule antagonists of Inhibitor of apoptosis (IAP) proteins, so called Smac mimetics such as BV6, which are described to overcome apoptosis resistance and thereby sensitize tumor cells for several apoptotic stimuli. To address the question whether redox alterations can sensitize leukemic cells for Smac mimetic-mediated cell death, we interfered with the cellular redox status in different ALL cell lines. Here, we show for the first time that redox alterations, mediated by the glutathione depleting agent Buthioninesulfoximine (BSO), prime ALL cells for BV6-induced apoptosis. Besides ALL cell lines, BV6/BSO cotreatment similarly synergizes in cell death induction in patient-derived primary leukemic samples. In contrast, the combination treatment does not exert any cytotoxicity against peripheral blood lymphocytes (PBLs) or mesenchymal stroma cells (MSCs) from healthy donors, suggesting some tumor selectivity of this treatment. We also identify the underlying molecular mechanism of the novel synergistic drug interaction of BSO and BV6. We demonstrate that both agents act in concert to increase reactive oxygen species (ROS) production, lipid peroxidation and finally apoptotic cell death. Enhanced ROS levels in the combination treatment account for cell death induction, since several ROS scavengers, like NAC, MnTBAP and Trolox attenuate BSO/BV6-induced apoptosis. BSO/BV6-induced ROS can be mainly classified as lipid peroxides, since the vitamin E derivate α-Tocopherol as well as Glutathione peroxidase 4 (GPX4), which both specifically reduce lipid-membrane peroxides, prevent lipid peroxidation, caspase activation and cell death induction. Vice versa, GPX4 knockdown and pharmacological inhibition of GPX4 by RSL3 or Erastin enhance BV6-induced cell death. Importantly, cell death induction critically depends on the formation of a complex consisting of RIP1/FADD/Caspase-8, since all complex components are required for ROS production, lipid peroxidation and cell death induction. Taken together, we demonstrate that BSO and BV6 cooperate to induce ROS production and lipid peroxidation which are eventually required for caspase activation and cell death execution. Collectively, findings of this study indicate that BV6-induced apoptosis is mediated via redox alterations offering promising new treatment strategy to overcome apoptosis resistance in ALL.
Objective: The objective of this study was to describe and analyze the effects of depression on health care utilization and costs in a sample of multimorbid elderly patients.
Method: This cross-sectional analysis used data of a prospective cohort study, consisting of 1,050 randomly selected multimorbid primary care patients aged 65 to 85 years. Depression was defined as a score of six points or more on the Geriatric Depression Scale (GDS-15). Subjects passed a geriatric assessment, including a questionnaire for health care utilization. The impact of depression on health care costs was analyzed using multiple linear regression models. A societal perspective was adopted.
Results: Prevalence of depression was 10.7%. Mean total costs per six-month period were €8,144 (95% CI: €6,199-€10,090) in patients with depression as compared to €3,137 (95% CI: €2,735-€3,538; p<0.001) in patients without depression. The positive association between depression and total costs persisted after controlling for socio-economic variables, functional status and level of multimorbidity. In particular, multiple regression analyses showed a significant positive association between depression and pharmaceutical costs.
Conclusion: Among multimorbid elderly patients, depression was associated with significantly higher health care utilization and costs. The effect of depression on costs was even greater than reported by previous studies conducted in less morbid patients.
Gene transfer vectors such as lentiviral vectors offer versatile possibilities to express transgenic antigens for vaccination purposes. However, viral vaccines leading to broad transduction and transgene expression in vivo, are undesirable. Therefore, strategies capable of directing gene transfer only to professional antigen-presenting cells would increase the specific activity and safety of genetic vaccines. A lentiviral vector pseudotype specific for murine major histocompatibilty complex class II (LV-MHCII) was recently developed and the present study aims to characterize the in vivo biodistribution profile and immunization potential of this vector in mice. Whereas the systemic administration of a vector pseudotyped with a ubiquitously-interacting envelope led to prominent detection of vector copies in the liver of animals, the injection of an equivalent amount of LV-MHCII resulted in a more specific biodistribution of vector and transgene. Copies of LV-MHCII were found only in secondary lymphoid organs, essentially in CD11c+ dendritic cells expressing the transgene whereas B cells were not efficiently targeted in vivo, contrary to expectations based on in vitro testing. Upon a single injection of LV-MHCII, naive mice mounted specific effector CD4 and CD8 T cell responses against the intracelllular transgene product with the generation of Th1 cytokines, development of in vivo cytotoxic activity and establishment of T cell immune memory. The targeting of dendritic cells by recombinant viral vaccines must therefore be assessed in vivo but this strategy is feasible, effective for immunization and cross-presentation and constitutes a potentially safe alternative to limit off-target gene expression in gene-based vaccination strategies with integrative vectors.
The Institute for Monetary and Financial Stability (IMFS) is a research center of the Johann Wolfgang Goethe University, Frankfurt am Main, located in the "House of Finance". The Institute was established as implementation of the project "Currency and Financial Stability" funded by a grant of the Stiftung Geld und Währung (Foundation of Monetary and Financial Stability). The Foundation of Monetary and Financial Stability was created January 1, 2002 by federal law. ...
Physical Biology is a field of life sciences dealing with the extraction of quantitative data from biophysical or molecular biological experiments with different levels of complexity. Such data are further used as parameters for mathematical models of the biological system. These models allow to predict reactions on external stimuli by describing the relevant molecular interactions and are therefore used for example to generate a deeper comprehension of complex human diseases. An essential technique in biophysical research on human diseases is fluorescence microscopy. This is a constantly developed toolbox comprising a large number of specific labeling strategies, as well as a broad spectrum of fluorescent probes. It is further minimal invasive and therefore suitable for measurements in living cells or organisms. The sensitivity of modern photo-detectors even allows for the detection of a single fluorescent probe with an accuracy of approximately 10 nm.
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The model-prediction was further verified by two color SMLM experiments. In this work the development and application of imaging-systems are described which provide quantitative data with single-molecule resolution for systems biological model approaches with a low degree of abstractness. In the near future, the impact of mathematical models in the research field of complex human diseases will increase. The predictions of these models will be more exact, the more detailed and accurate the input parameters will become. This work gives an impression of how quantitative data obtained by SMLM may serve as input parameters for mathematical models at the single-cell level.
Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E–deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A–induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E–deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells
(2014)
The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.
Identity politics redux
(2014)
Pornography reappropriated by feminist and queer pornographers is being reimagined as a site of activist productions, be it through the reshaping of desire or engaging with wider discussions of representational politics. Here, K. Heintzman takes up Shine Louise Houston's feature length film, "The Wild Search", as a unique case study for addressing the relationship between debates of identity politics and queer activist practice.
The flourishing of literature and thought during the age of Goethe may have inspired German nationalism in the 1930s, but Walter Benjamin identified other values in the period worth defending. 'Deutsche Menschen' is a short collection of edited letters by well-known German authors which Benjamin published in 1936 under the pseudonym Detlef Holz in order to hide his Jewish identity. In his inscription to Scholem's copy of the book, Benjamin wrote, "May you, Gerhard, find a chamber in this ark - which I built when the Fascist flood started to rise - for the memories of your youth," and in his sister’s copy Benjamin wrote, "This ark, built after a Jewish model, for Dora - From Walter." This essay considers what Benjamin may have meant by those inscriptions. Looking beyond discussions of "German," "Jewish," and even "German-Jewish" identity, this essay explores Benjamin's descriptions of his letter collection, asking how he conceptualized and framed it at first and how it may have changed between 1931 and 1936. The categories of tradition and agency will be my focus, which I will develop in the context of Benjamin's other writings and his particular interests in quotation and materialism. &e formation and reception of 'Deutsche Menschen' reveal a complex, ambitious project that combines many of Benjamin's ideas and goals.
RNA modifications are present in all three kingdoms of life and detected in all classes of cellular RNAs. RNA modifications are diverse, with more than 100 types of chemical modifications identified to date. These chemical modifications expand the topological repertoire of RNAs and are expected to fine-tune their functions. Ribosomal RNA (rRNA) contains two types of covalent modifications, either methylation on the sugar (Nm) or bases (mN), or base isomerization (conversion of uridine into pseudouridines, "). Pseudouridylations and ribose methylations are catalyzed by site-specific H/ACA and C/D box snoRNPs, respectively. The RNA component (snoRNA) of both types of snoRNPs is responsible for the site selection by base pairing with the rRNA substrate, whereas the protein component catalyzes the modification reaction: Nop1 in C/D box and Cbf5 in H/ACA box snoRNPs. Contrastingly, base methylations are performed by snoRNA independent, ‘protein-only’, methyltransferases (MTases). rRNA modifications occur at highly conserved positions, all clustering around functional ribosomal sites. Mutations in factors involved in rRNA modification have been linked to severe human diseases (e.g. X-linked Dyskeratosis congenita). Emerging evidences indicate that heterogeneity in RNA modification prevails, i.e. not all positions are modified at all time, and the concept of ‘specialized ribosomes’ has been coined. rRNA modification heterogeneity has been correlated with disease etiology (cancer), and shown to play a role in cell differentiation(hematopoiesis). Remarkably, alteration in rRNA modification patterns profoundly affects the preference of ribosomes for cap- versus IRESdependent translation initiation, with major consequences on cell physiology.
Smac (second mitochondria-derived activator of caspase) mimetics are considered as promising anticancer therapeutics and used to induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are often abundantly expressed in cancer cells. Here, we identify interferon regulatory factor 1 (IRF1) as a novel critical regulator of Smac mimetic BV6-induced apoptosis and proinflammatory cytokine secretion with impact on the immune response. IRF1 knockdown rescues cells from BV6-induced apoptosis and attenuates BV6-stimulated upregulation of tumor necrosis factor-α (TNFα), indicating that IRF1 mediates BV6-triggered cell death, at least in part, by inducing TNFα. This notion is supported by data showing that exogenous supply of TNFα restores BV6-induced cell death in IRF-knockdown cells. Interestingly, IRF1 selectively controls the induction of nuclear factor-κB (NF-κB) target genes, as IRF1 depletion attenuates BV6-stimulated upregulation of TNFα and interleukin-8 (IL-8) but not p100 and RelB. Concomitant knockdown of IRF1 and p65 cooperate to inhibit BV6-induced cell death, implying a cooperative interaction of IRF1 and NF-κB. In addition, IRF1 silencing hampers TNFα induction by TNFα itself as an another prototypical NF-κB stimulus. Importantly, IRF1 depletion impedes BV6-stimulated secretion of additional proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IL-6 and monocyte chemoattractant protein-1, and migration of primary monocytes to BV6-treated tumor cells. In conclusion, this identification of IRF1 as a dual regulator of BV6-induced apoptosis and inflammatory cytokine secretion provides novel insights into determinants of sensitivity towards Smac mimetic and possible implications of Smac mimetic treatment on tumor microenvironment and immune response.
Myxobacteria are on order of Gram-negative, soil dwelling bacteria that feature an impressive number of properties: they can glide on solid surfaces by using two different motility motors, subsist by preying on other microorganisms, are often producers of multiple natural products, and upon adverse environmental conditions, they are able to form multicellular structures called “fruiting bodies”. The process, in which these macroscopically visible structures arise from independent single cells, has been the predominant subject of myxobacterial research for many decades. More precisely, researchers have strived for the discovery of genes, proteins and small molecules that act as signals, receivers or modulators of this complex process. In this regard, the species Myxococcus xanthus has evolved into the model organism due to its relatively simple and reliable handling in a laboratory environment. The research underlying this thesis focused on the identification and biosynthesis of lipids that may act as intercellular signaling molecules during the course of fruiting body formation of the myxobacterium Myxococcus xanthus as part of the “E-signal” system. In general, lipids containing branched-chain fatty acids with an uneven number of carbon atoms were found to be important players in this particular process. Nevertheless, their exact roles remain largely unknown as of this day. The first publication that is part of this thesis deals with an aspect that even strengthened the importance of role of iso-branched compounds in myxobacteria: myxobacterial metabolism is able to transform precursors of iso-lipids to isoprenoids. It addresses the question whether isoprenoids in general are important for fruiting body formation. Phenotypic analysis of mutants impaired in the biosynthesis of the central isoprenoid precursor 3-hydroxymethylglutaryl-Coenzyme A (3-HMG-CoA) from acetate and/or branched chain keto acids and their genetic and metabolic complementation clearly showed that isoprenoids are essential for fruiting body formation and confirmed that leucine derived isovalerate is an important source for isoprenoid precursors in myxobacteria. The second, and by far and away most tedious and sophisticated study, addressed the question as to how myxobacteria form fatty acid derived iso-branched ether lipids and to what extent they are important for fruiting body formation and sporulation. In a previous study, those unusual lipids were identified as specific biomarkers for myxobacterial development. No biochemical pathways to ether lipids specific for prokaryotes were known by then. In this study, a putative candidate gene that may be in involved in ether lipid biosynthesis was investigated. A combination of gene disruption and complementation experiments, phenotypic analysis and monitoring of ether lipid formation by means of GC-MS demonstrated its involvement in myxobacterial ether lipid biosynthesis and the importance of these lipids for the developmental process. Heterologous expression and biochemical testing of this gene together with in-silico sequence analysis and docking experiments confirmed the functions of its predicted domains. The discussion section provides an additional suggestion on how the ether bond formation is performed. Furthermore and most importantly, iso-branched ether lipids were found to be essential for sporulation but not for fruiting body formation. In summary, one or several molecules derived from an iso-branched alkylglycerol seem to play a role during sporulation in M. xanthus and a multidomain enzyme unique for myxobacteria is involved in their biosynthesis. The last manuscript addresses the complexity of lipid metabolism in myxobacteria. Prior to this work, there was limited knowledge about the exact composition of the myxobacterial lipidome and no method was available to monitor putative changes in the myxobacterial lipidome down to the single molecular species for studying lipid biosynthesis or regulation. An ultra-performance liquid chromatography coupled with mass spectrometry based method with electrospray ionization (UPLC-ESI-MS) utilizing standard equipment and a water/acetonitrile/isopropanol based eluent system proved to be geared for the construction of lipid profiles for wild type and mutant cells of M. xanthus and to show their differences. Fragmentation spectra based structure elucidation of lipid molecular species resulted in the identification of 99 molecular species comprising glycerophosphoethanolamines, glycerophosphoglycerols, glycerolipids, ceramides and ceramide phosphoinositols. The latter have never been described for any prokaryotes before. Three dimensional plots were created from the relative intensity differences of the single molecular ion species between the different samples to provide an efficient and versatile visualization of the data and enable the researcher to quickly detect differences.
Guanine quadruplex (G-quadruplex) motifs in the 5′ untranslated region (5′-UTR) of mRNAs were recently shown to influence the efficiency of translation. In the present study, we investigate the interaction between cellular proteins and the G-quadruplexes located in two mRNAs (MMP16 and ARPC2). Formation of the G-quadruplexes was confirmed by biophysical characterization and the inhibitory activity on translation was shown by luciferase reporter assays. In experiments with whole cell extracts from different eukaryotic cell lines, G-quadruplex-binding proteins were isolated by pull-down assays and subsequently identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. The binding partners of the RNA G-quadruplexes we discovered included several heterogenous nuclear ribonucleoproteins, ribosomal proteins, and splicing factors, as well as other proteins that have previously not been described to interact with nucleic acids. While most of the proteins were specific for either of the investigated G-quadruplexes, some of them bound to both motifs. Selected candidate proteins were subsequently produced by recombinant expression and dissociation constants for the interaction between the proteins and RNA G-quadruplexes in the low nanomolar range were determined by surface plasmon resonance spectroscopy. The present study may thus help to increase our understanding of the mechanisms by which G-quadruplexes regulate translation.
A novel xanthomonadin-dialkylresorcinol hybrid named arcuflavin was identified in Azoarcus sp. BH72 by a combination of feeding experiments, HPLC-MS and MALDI-MS and gene clusters encoding the biosynthesis of this non-isoprenoid aryl-polyene containing pigment are reported. A chorismate-utilizing enzyme from the XanB2-type producing 3- and 4-hydroxybenzoic acid and an AMP-ligase encoded by these gene clusters were characterized, that might perform the first two steps of the polyene biosynthesis. Furthermore, a detailed analysis of the already known or novel biosynthesis gene clusters involved in the biosynthesis of polyene containing pigments like arcuflavin, flexirubin and xanthomonadin revealed the presence of similar gene clusters in a wide range of bacterial taxa, suggesting that polyene and polyene-dialkylresorcinol pigments are more widespread than previously realized.
Hypoxia enhances the antiglioma cytotoxicity of b10, a glycosylated derivative of betulinic acid
(2014)
B10 is a glycosylated derivative of betulinic acid with promising activity against glioma cells. Lysosomal cell death pathways appear to be essential for its cytotoxicity. We investigated the influence of hypoxia, nutrient deprivation and current standard therapies on B10 cytotoxicity. The human glioma cell lines LN-308 and LNT-229 were exposed to B10 alone or together with irradiation, temozolomide, nutrient deprivation or hypoxia. Cell growth and viability were evaluated by crystal violet staining, clonogenicity assays, propidium iodide uptake and LDH release assays. Cell death was examined using an inhibitor of lysosomal acidification (bafilomycin A1), a cathepsin inhibitor (CA074-Me) and a short-hairpin RNA targeting cathepsin B. Hypoxia substantially enhanced B10-induced cell death. This effect was sensitive to bafilomycin A1 and thus dependent on hypoxia-induced lysosomal acidification. Cathepsin B appeared to mediate cell death because either the inhibitor CA074-Me or cathepsin B gene silencing rescued glioma cells from B10 toxicity under hypoxia. B10 is a novel antitumor agent with substantially enhanced cytotoxicity under hypoxia conferred by increased lysosomal cell death pathway activation. Given the importance of hypoxia for therapy resistance, malignant progression, and as a result of antiangiogenic therapies, B10 might be a promising strategy for hypoxic tumors like malignant glioma.
HIV vaccine preclinical testing is difficult because HIV’s only relevant hosts are humans and no correlates of protection are known. To this end, we are working on the humanization of different mouse strains with human peripheral blood mononuclear cells (PBMCs) as well as human hematopoietic stem cells (HSC) to generate a useful small animal model.
We generated immune deficient mice (NOD Scid IL2gc -/- /NOD Rag1-/- IL2gc -/-) expressing human MHC class II (HLA-DQ8) on a mouse class II deficient background (Ab-/-). Here, the human HLA-DQ8 should interact with the matching T cell receptors of transferred matching human PBMCs and therefore could support the functionality of the transferred human CD4+ cells in the mice.
Mice that were adoptively transferred with human HLA-DQ8 PBMCs only showed engraftment of CD3+ T cells. Surprisingly, the presence of HLA class II did not significantly change the repopulation rates in the mice. Also, the presence of HLA class II did not advance B cell engraftment, such that humoral immune responses were undetectable. However, the overall survival of DQ8-expressing mice was significantly prolonged, compared to mice expressing mouse MHC class II molecules, and correlated with an increased time span until onset of GvHD.
To avoid GVHD and to increase and maintain the level of human cell reconstitution over a long period of time, the same mouse strains were reconstituted with human HSC. Compared to PBMC-repopulated mice, HSC-reconstituted mice develop almost all subpopulations of the human immune system detectable at week 12 after HSC transfer. These mice developed adaptive immune responses after Tetanus Toxoide (TT) immunizations. In addition, we are testing the susceptibility of these humanized mice to different HIV strains with a detailed look at immune responses.
The genetic treatment of neurodegenerative diseases still remains a challenging task since many approaches fail to deliver the therapeutic material in relevant concentrations into the brain. As viral vectors comprise the risk of immune and inflammatory responses, human serum albumin (HSA) nanoparticles were found to represent a safer and more convenient alternative. Their ability to cross the blood-brain barrier (BBB) and deliver drugs into the brain in order to enhance gene-based therapy has been previously demonstrated. The present study deals with the development of pGL3-PEI-coated HSA nanoparticles and subsequent in vitro testing in cerebellar granular and HeLa cells. The luciferase control vector pGL3 was chosen as reporter plasmid encoding for the firefly luciferase protein, linear polyethylenimine (22 kDa) as endosomolytic agent for enhancing the cells’ transfection. Studies on particle characteristics, their cellular uptake into aforementioned cell lines and on subcellular localisation, and transfection efficiency in the cerebellar cells proved the feasibility of nanoparticle-based gene delivery.
We characterize optimal redistribution in a dynastic family model with human capital. We show how a government can improve the trade-off between equality and incentives by changing the amount of observable human capital. We provide an intuitive decomposition for the wedge between human-capital investment in the laissez faire and the social optimum. This wedge differs from the wedge for bequests because human capital carries risk: its returns depend on the non-diversi
able risk of children's ability. Thus, human capital investment is encouraged more than bequests in the social optimum if human capital is a bad hedge for consumption risk.
Objective: To investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received surgery and cisplatin-based postoperative radiochemotherapy.
Materials and methods: For 221 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium, the impact of HPV DNA, p16 overexpression and p53 expression on outcome were retrospectively analysed. The primary endpoint was loco-regional tumour control; secondary endpoints were distant metastases and overall survival.
Results: In the total patient population, univariate analyses revealed a significant impact of HPV16 DNA positivity, p16 overexpression, p53 positivity and tumour site on loco-regional tumour control. Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma (p = 0.02) but not in the oral cavity carcinoma group. Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival (p < 0.01) but not with distant metastases.
Conclusions: HPV16 DNA status appears to be a strong prognosticator of loco-regional tumour control after postoperative cisplatin-based radiochemotherapy of locally advanced oropharyngeal carcinoma and is now being explored in a prospective validation trial.
Reciprocal exchanges can be understood as the updating of an initial belief about a partner. This initial level of trust is essential when it comes to establishing cooperation with an unknown partner, as cooperation cannot arise without a minimum of trust not justified by previous successful exchanges with this partner. Here we demonstrate the existence of a representation of the initial trust level before an exchange with a partner has occurred. Specifically, we can predict the Investor’s initial investment—i.e. his initial level of trust toward the unknown trustee in Round 1 of a standard 10-round Trust Game—from resting-state functional connectivity data acquired several minutes before the start of the Trust Game. Resting-state functional connectivity is, however, not significantly associated with the level of trust in later rounds, potentially mirroring the updating of the initial belief about the partner. Our results shed light on how the initial level of trust is represented. In particular, we show that a person’s initial level of trust is, at least in part, determined by brain electrical activity acquired well before the beginning of an exchange.
How to abolish cyberwar
(2014)
Part III of our series "Cyberpeace: Dimensionen eines Gegenentwurfs" on cyberpeace: Cyberwar is like a discursive plague. After years and years of writing texts about it and against it, the concept is still scary, still spreading, still harmful. Its power is such that it is not simply being used in discourse – but is in fact forcing its specific discursive structures and rules on us. In short, we may keep questioning this concept, but we will never get rid of it...
In ‘Strafe für fremde Schuld’ Harald Maihold uncovered how a doctrine of surrogate punishment in the legal treatises of the Salamanca school gradually gave way to the principle of guilt. This meant that punishment eventually could only be inflicted upon a culprit and no longer upon an innocent. We will use René Girard’s philosophy of (the disruption of) scapegoat mechanisms and sacrifice to develop a coherent interpretation not only of how this institution of surrogate punishment functioned, how it selected its victims and the way it was legitimated, but also of the theology that formed its background. We argue that most of what surrogate punishment is about can be grasped in two words: sacrificial logic. The elimination of surrogation from criminal law would then correspond to the rejection of this logic, an evolution which could be interpreted as a desacralisation or secularisation of criminal law under the influence of the upcoming principle of guilt.
How special are they? - Targeting systemic risk by regulating shadow banking : (October 5, 2014)
(2014)
This essay argues that at least some of the financial stability concerns associated with shadow banking can be addressed by an approach to financial regulation that imports its functional foundations more vigorously into the interpretation and implementation of existing rules. It shows that the general policy goals of prudential banking regulation remain constant over time despite dramatic transformations in the financial and technological landscape. Moreover, these overarching policy goals also legitimize intervention in the shadow banking sector. On these grounds, this essay encourages a more normative construction of available rules that potentially limits both the scope for regulatory arbitrage and the need for ever more rapid updates and a constant increase in the complexity of the regulatory framework. By tying the regulatory treatment of financial innovation closely to existing prudential rules and their underlying policy rationales, the proposed approach potentially ends the socially wasteful race between hare and tortoise that signifies the relation between regulators and a highly dynamic industry. In doing so it does not generally hamper market participants’ efficient discoveries where disintermediation proves socially beneficial. Instead, it only weeds-out rent-seeking circumventions of existing rules and standards.
How special are they? - Targeting systemic risk by regulating shadow banking : (October 5, 2014)
(2014)
This essay argues that at least some of the financial stability concerns associated with shadow banking can be addressed by an approach to financial regulation that imports its functional foundations more vigorously into the interpretation and implementation of existing rules. It shows that the general policy goals of prudential banking regulation remain constant over time despite dramatic transformations in the financial and technological landscape. Moreover, these overarching policy goals also legitimize intervention in the shadow banking sector. On these grounds, this essay encourages a more normative construction of available rules that potentially limits both the scope for regulatory arbitrage and the need for ever more rapid updates and a constant increase in the complexity of the regulatory framework. By tying the regulatory treatment of financial innovation closely to existing prudential rules and their underlying policy rationales, the proposed approach potentially ends the socially wasteful race between hare and tortoise that signifies the relation between regulators and a highly dynamic industry. In doing so it does not generally hamper market participants’ efficient discoveries where disintermediation proves socially beneficial. Instead, it only weeds-out rent-seeking circumventions of existing rules and standards.
Before the 2007–09 crisis, standard risk measurement methods substantially underestimated the threat to the financial system. One reason was that these methods didn’t account for how closely commercial banks, investment banks, hedge funds, and insurance companies were linked. As financial conditions worsened in one type of institution, the effects spread to others. A new method that more accurately accounts for these spillover effects suggests that hedge funds may have been central in generating systemic risk during the crisis.
How much additional tax revenue can the government generate by increasing labor income taxes? In this paper we provide a quantitative answer to this question, and study the importance of the progressivity of the tax schedule for the ability of the government to generate tax revenues. We develop a rich overlapping generations model featuring an explicit family structure, extensive and intensive margins of labor supply, endogenous accumulation of labor market experience as well as standard intertemporal consumption-savings choices in the presence of uninsurable idiosyncratic labor productivity risk. We calibrate the model to US macro, micro and tax data and characterize the labor income tax Laffer curve under the current choice of the progressivity of the labor income tax code as well as when varying progressivity. We find that more progressive labor income taxes significantly reduce tax revenues. For the US, converting to a flat tax code raises the peak of the Laffer curve by 6%, whereas converting to a tax system with progressivity similar to Denmark would lower the peak by 7%. We also show that, relative to a representative agent economy tax revenues are less sensitive to the progressivity of the tax code in our economy. This finding is due to the fact that labor supply of two earner households is less elastic (along the intensive margin) and the endogenous accumulation of labor market experience makes labor supply of females less elastic (around the extensive margin) to changes in tax progressivity.
Rising powers are fundamentally shifting the relations of power in the global economic and political landscape. International political theory, however, has so far failed to evaluate this nascent multipolarity. This article fills this lacuna by synthesizing empirical and normative modes of inquiry. It examines the transformation of sovereignty exercised by emerging democracies and focuses especially on the case of Brazil. The paper shows that – in stark contrast to emerging democracies' foreign policy rhetoric – the "softening" of sovereignty, which means that emerging powers gain as well as lose certain aspects of sovereignty, has become the norm. The paper explores this softening of sovereignty from the perspective of global justice by assessing it on the basis of globalist, statist, and internationalist conceptions of global justice. We find that the emergent multipolarity contributes in various ways to the realization of the distinct socioeconomic and political criteria of these three conceptions of global justice. However, we also point out that the transformation of sovereignty generates particular problems for the realization of all three conceptions.
This paper studies the geometry and the thermodynamics of a holographic screen in the framework of the ultraviolet self-complete quantum gravity. To achieve this goal we construct a new static, neutral, nonrotating black hole metric, whose outer (event) horizon coincides with the surface of the screen. The spacetime admits an extremal configuration corresponding to the minimal holographic screen and having both mass and radius equalling the Planck units. We identify this object as the spacetime fundamental building block, whose interior is physically unaccessible and cannot be probed even during the Hawking evaporation terminal phase. In agreement with the holographic principle, relevant processes take place on the screen surface. The area quantization leads to a discrete mass spectrum. An analysis of the entropy shows that the minimal holographic screen can store only one byte of information, while in the thermodynamic limit the area law is corrected by a logarithmic term.
This study describes the Holocene sedimentary lagoonal deposition history, including event sedimentation and benthic foraminiferal analyzes, from about 10 kyrs BP until today. This is the first study describing the sedimentation of a Maldivian atoll lagoon in such detail. Thirty-nine sediment cores have been recovered from the deep Rasdhoo Atoll lagoon of the Maldives (4°N/73°W). Seventeen sediment cores were opened, described, and 296 sediment samples have been collected and analyzed. Different methods have been used to evaluate the coarse- and fine-grained carbonate components and a total of fifty-eight samples have been dated radiometrically by Beta Analytic Inc., Miami, Florida. In general, the Rasdhoo Atoll lagoon sediments can be divided into (1) a Late Pleistocene soil, (2) an early Holocene peat layer composed of mangrove deposits which mark the beginning inundation of the atoll lagoon by the rising Holocene sea-level at 10,320 ± 100 yrs BP, and (3) carbonate sediments starting to fill up the lagoon 7850 ± 140 yrs BP until today. The transition from peat to carbonate is characterized by a considerable hiatus. Six different carbonate sediment facies are classified by statistical analyses, listed in decreasing abundance:
(1) mollusk-coral-algal floatstone to rudstone (30%)
(2) mollusk-coral-red algae rudstone (23%)
(3) mollusk-coral-algal wackestone to floatstone (23%)
(4) mollusk-coral wackestone (13%)
(5) mollusk-coral mudstone to wackestone (9%)
(6) mollusk mudstone (2%)
Based on grain-sizes in combination with coral identification, the facies represent both lagoonal background sedimentation (mostly fine-grained sediments (matrix >50%)) and event sedimentation (coarse-grained sediment layers composing reefal components).
Six coarser grained layers in muddy background sediments of the Rasdhoo Atoll lagoon were interpreted as Holocene tsunami events, based on the increase of allochthonous skeletal material with shallow-water reef affinity such as fragments of shallow-water coral species, coralline red algae, and reef-dwelling foraminifera in these layers, as well as AMS dating:
• Event 1: 420 - 890 yrs BP (655 yrs BP)
• Event 2: 890 - 1560 yrs BP (1225 yrs BP)
• Event 3: 2040 - 2340 yrs BP (2190 yrs BP)
• Event 4: 2420 - 3380 yrs BP (2900 yrs BP)
• Event 5: 3890 - 4330 yrs BP (4110 yrs BP)
• Event 6: 5480 - 5760 yrs BP (5620 yrs BP)
Five of the six layers may be correlated to previously published tsunami events at adjacent coastal research sites. The mid-late Holocene atoll lagoon archive is incomplete though based on the assumption that major earthquakes at the Indonesian subduction zone generated more than six major tsunamis during the past 6.5 kyrs.
According to Gischler (2006), the sediments of the Rasdhoo Atoll lagoon can be divided into two areas: (1) a central to marginal deep lagoon with a lateral west-to-east gradient of sediment facies distribution, visible in sections <4 kyrs BP with sedimentary facies of mudstone to wackestone in the western part (e.g., cores 16, 18, and 34) and coarse-grained coral and algal-rich sediments in the eastern part of the lagoon (e.g., cores 30 and 31). (2) A northern enclosed and shallow area between the sand apron and the sand spit accumulating “sandy” sediments of wackestone facies (cores 2, 19, 25, and 26).
Comparing the sediment accumulation data of the lagoon with two reconstructed local sea-level curves, three different sequence-stratigraphical systems tracts are visible: (1) a lowstand systems tract (LST) >10 kyrs BP. Pleistocene brownish soil superposing subaerially exposed Pleistocene reef limestone. (2) A transgressive systems tract (TST) 10-6.5 kyrs BP. A peat layer marks the beginning of the inundation, and the carbonate sedimentation starts with very low sedimentation rates of 0.02 m/kyr. (3) A highstand systems tract (HST) 6.5-0 kyrs BP, further divided into three stages (6.5-3, 3-1, 1-0 kyrs BP). The sea-level rise slowed down, sedimentation rates are increasing continuously up to a maximum of 1.4 m/kyr, the sand spit developed some 4 kyrs BP, the lagoonal circulation got restricted, and the lateral west-to-east gradient of grain-size accumulation started. From 1-0 kyrs BP the sedimentation rates slowed down to modern mean sedimentation rates of 0.6 m/kyr.
Two cores, one core from the center of the lagoon (core 16) and one core from the northern margin of the lagoon (core 19), have been analyzed on diversity and assemblages of benthic foraminifera in high-resolution. The transitions of Ammonia spp. to a more even and diverse fauna marks a significant environmental change at 7.0 kyrs BP in core 16 (onset of a stable environment in the deep lagoon after the sea-level rise slowed down at HST stage 1) and at 4.0 kyrs BP in core 19. A continuing environmental change after 1.4 kyrs BP in core 16 caused the fauna to become more even, a recovery of diversity and a permanent decline of foraminiferal accumulation rate. The changes in the faunas at 4.0 kyrs BP and at 1.4 kyrs BP could be explained with the sand spit formation in the northwestern and western lagoon. The sand spit has apparently acted as an obstacle in lagoonal circulation and might have caused unstable environmental conditions due to a more rapid circulation at the shallow marine site of core 19 and a slowdown of bottom water circulation in the main lagoon (core 16) leading to higher residence times and to lower oxygen and higher nutrient concentrations.
This publication is the result of a baseline study of the state of the higher education systems in the five Portuguese speaking countries in Africa (PALOP): Angola, Cape Verde, Guinea-Bissau, Mozambique and Sao Tome and Principe. The project was undertaken by an African international expert in the field of higher education studies and was fully sponsored and supported by the Association for the Development of Education in Africa (ADEA). The report offers a historical overview of the development of higher education in PALOP from colonial times to the present. The main objective of this baseline study is to map the landscape and dynamics of change in the higher education systems of PALOP countries. It focuses on describing the latest developments of trends of expansion, financing, governance and policy reforms closely linked to the development of higher education systems in these countries. Furthermore, the study will facilitate an informed debate and the dissemination of knowledge on the role of higher education for development in Africa.
Background: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance.
Methods: In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
Results: A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
Conclusion: In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
In this paper we argue that very high marginal labor income tax rates are an effective tool for social insurance even when households have preferences with high labor supply elasticity, make dynamic savings decisions, and policies have general equilibrium effects. To make this point we construct a large scale Overlapping Generations Model with uninsurable labor productivity risk, show that it has a wealth distribution that matches the data well, and then use it to characterize fiscal policies that achieve a desired degree of redistribution in society. We find that marginal tax rates on the top 1% of the earnings distribution of close to 90% are optimal. We document that this result is robust to plausible variation in the labor supply elasticity and holds regardless of whether social welfare is measured at the steady state only or includes transitional generations.
Species distributed across vast continental areas and across major biomes provide unique model systems for studies of biotic diversification, yet also constitute daunting financial, logistic and political challenges for data collection across such regions. The tree frog Dendropsophus minutus (Anura: Hylidae) is a nominal species, continentally distributed in South America, that may represent a complex of multiple species, each with a more limited distribution. To understand the spatial pattern of molecular diversity throughout the range of this species complex, we obtained DNA sequence data from two mitochondrial genes, cytochrome oxidase I (COI) and the 16S rhibosomal gene (16S) for 407 samples of D. minutus and closely related species distributed across eleven countries, effectively comprising the entire range of the group. We performed phylogenetic and spatially explicit phylogeographic analyses to assess the genetic structure of lineages and infer ancestral areas. We found 43 statistically supported, deep mitochondrial lineages, several of which may represent currently unrecognized distinct species. One major clade, containing 25 divergent lineages, includes samples from the type locality of D. minutus. We defined that clade as the D. minutus complex. The remaining lineages together with the D. minutus complex constitute the D. minutus species group. Historical analyses support an Amazonian origin for the D. minutus species group with a subsequent dispersal to eastern Brazil where the D. minutus complex originated. According to our dataset, a total of eight mtDNA lineages have ranges >100,000 km2. One of them occupies an area of almost one million km2 encompassing multiple biomes. Our results, at a spatial scale and resolution unprecedented for a Neotropical vertebrate, confirm that widespread amphibian species occur in lowland South America, yet at the same time a large proportion of cryptic diversity still remains to be discovered.
High lipoprotein expression and potent activation of host Toll-like receptor-2 (TLR2) are characteristic features of the staphylococcal species. Expression of TLR2 in the host is important for clearance of Staphylococcus aureus infection and host survival. Thus, we hypothesized that bacterial regulation of its intrinsic TLR2-stimulatory capacity could represent a means for immune evasion or host adaptation. We, therefore, compared clinical S. aureus isolates in regards to their TLR2 activation potential and assessed the bacterial factors that modulate TLR2-mediated recognition. S. aureus isolates displayed considerable variability in TLR2-activity with low to absent TLR2-activity in 64% of the isolates tested (68/106). Notably, strain-specific TLR2-activity was independent of the strain origin, e.g. no differences were found between strains isolated from respiratory specimen from cystic fibrosis patients or those isolated from invasive disease specimen. TLR2-activity correlated with protein A expression but not with the agr status. Capsule expression and small colony variant formation had a negative impact on TLR2-activity but any disruption of cell wall integrity enhanced TLR2 activation. Altogether, heterogeneity in host TLR2-activity reflects differences in metabolic activity and cell wall synthesis and/or remodeling.
Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.
Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.
Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.
Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
Halting biological invasions in Europe : from data to decisions ; a message from NEOBIOTA 2012
(2014)
The NEOBIOTA conferences initiated by the European Group on Biological Invasions represents a forum for exchange of ideas and discussion of topics related to biological invasions as well as an interface between science, application and policies (Kowarik and Starfinger 2009). The 7th NEOBIOTA conference (http://neobiota2012.blogspot.com.es/), held in Pontevedra (Spain) from 12–14 September 2012, brought together 288 participants (ecologists, conservationists, representatives of governmental agencies and stake-holders), from 24 European countries and 9 non-European ones (namely, Australia, Brazil, Canada, Chile, Colombia, New Zealand, South Africa, United States and Venezuela).
Halophilic archaea cultivated from surface sterilized middle-late Eocene rock salt are polyploid
(2014)
Live bacteria and archaea have been isolated from several rock salt deposits of up to hundreds of millions of years of age from all around the world. A key factor affecting their longevity is the ability to keep their genomic DNA intact, for which efficient repair mechanisms are needed. Polyploid microbes are known to have an increased resistance towards mutations and DNA damage, and it has been suggested that microbes from deeply buried rock salt would carry several copies of their genomes. Here, cultivable halophilic microbes were isolated from a surface sterilized middle-late Eocene (38–41 million years ago) rock salt sample, drilled from the depth of 800 m at Yunying salt mine, China. Eight unique isolates were obtained, which represented two haloarchaeal genera, Halobacterium and Halolamina. We used real-time PCR to show that our isolates are polyploid, with genome copy numbers of 11–14 genomes per cell in exponential growth phase. The ploidy level was slightly downregulated in stationary growth phase, but the cells still had an average genome copy number of 6–8. The polyploidy of halophilic archaea living in ancient rock salt might be a factor explaining how these organisms are able to overcome the challenge of prolonged survival during their entombment.
It was long assumed that translation initiation in prokaryotes generally occurs via the so-called Shine Dalgarno (SD) mechanism. Recently, it became clear that translation initiation in prokaryotes is more heterogeneous. In the haloarchaeon Haloferax volcanii, the majority of transcripts is leaderless and most transcripts with a 5′-UTR lack a SD motif. Nevertheless, a bioinformatic analysis predicted that 20–30% of all genes are preceded by a SD motif in haloarchaea. To analyze the importance of the SD mechanism for translation initiation in haloarchaea experimentally the monocistronic sod gene was chosen, which contains a 5′-UTR with an extensive SD motif of seven nucleotides and a length of 19 nt, the average length of 5′UTRs in this organism. A translational fusion of part of the sod gene with the dhfr reporter gene was constructed. A mutant series was generated that matched the SD motif from zero to eight positions, respectively. Surprisingly, there was no correlation between the base pairing ability between transcripts and 16S rRNA and translational efficiency in vivo under several different growth conditions. Furthermore, complete replacement of the SD motif by three unrelated sequences did not reduce translational efficiency. The results indicate that H. volcanii does not make use of the SD mechanism for translation initiation in 5′-UTRs. A genome analysis revealed that while the number of SD motifs in 5′-UTRs is rare, their fraction within open reading frames is high. Possible biological functions for intragenic SD motifs are discussed, including re-initiation of translation at distal genes in operons.
The simultaneous description of the hadronic yields, pion, kaon and proton spectra, elliptic flows and femtoscopy scales in hydrokinetic model of A+A collisions is presented at different centralities for the top RHIC and LHC energies. The hydrokinetic model is used in its hybrid version that allows one to switch correctly to the UrQMD cascade at the isochronic hypersurface which separates the cascade stage and decaying hydrodynamic one. The results are compared with pure hybrid model where hydrodynamics and hadronic cascade are matching just at the non-space-like hypersurface of chemical freeze-out. The initial conditions are based on both Glauber- and KLN- Monte-Carlo simulations and results are compared. It seems that the observables, especially femtoscopy data, prefer the Glauber initial conditions. The modification of the particle number ratios caused, in particular, by the particle annihilations at the afterburn stage is analyzed.
In many markets, design is one of the key factors in determining a product’s success. The present research offers insights into the role of design for the success of cars, and offers procedures to measure the quality of the designs objectively. The authors show that visual design plays a major role in a product’s success in the automobile market. In the study, two visual design aspects were already sufficient to significantly improve traditional sales forecasting models for cars. Visual prototypicality and visual complexity both had a positive impact on sales, and designs that were perceived as both prototypical and complex were the ones that displayed the best results. Most design evaluation used to be based on subjective measures, but the researcher applied a new, objective procedure to measure prototypicality and complexity. While the latter was detected by the disk space needed by the compressed image file, the new approach for measuring prototypicality was even more sophisticated. It relied on the technique of image morphing. Morphing is a technique that allows the construction of a visual synthesis – or average picture – from a number of individual pictures. Once a car morph is developed, one can determine the visual similarity of different car models to the morph in order to obtain its prototypicality. In principle, this procedure can be automated completely, and including a large number of versions is possible. These measures therefore seem suitable for supporting design decision processes in practice.
In Growing up with Tanzania. Karim Hirji, a renowned Professor of Medical Statistics and Fellow of the Tanzania Academy of Science, presents a multi-faceted, evocative portrait of his joyous but conflicted passage to adulthood during colonial and early-Uhuru Tanzania. His smooth style engages the reader with absorbing true tales, cultural currents, critical commentary and progressive possibilities. By vibrantly contrasting the hope-filled sixties with the cynical modern era, he also lays bare the paradoxes of personal life and society, past and present.
We study the dispersion of debt maturities across time, which we call "granularity of corporate debt,'' using a model in which a firm's inability to roll over expiring debt causes inefficiencies, such as costly asset sales or underinvestment. Since multiple small asset sales are less costly than a single large one, firms diversify debt rollovers across maturity dates. We construct granularity measures using data on corporate bond issuers for the 1991-2012 period and establish a number of novel findings. First, there is substantial variation in granularity in that we observe both very concentrated and highly dispersed maturity structures. Second, observed variation in granularity supports the model's predictions, i.e. maturities are more dispersed for larger and more mature firms, for firms with better investment oppo
God was African
(2014)
When Kendem, a varsity instructor, returns to his native Lewoh countryside where he spent his childhood, he is seeking relief from the complexity of human civilization after attending the Fulbright Institute in the United States. Instead, he is confronted with two seething issues: how to reveal to his sick and troubled mother the situation in which he finds his elder brother, the successor of Mbe Tanju-Ngong's household, who travelled to the United States many years before and had never returned and the dispute over Fuo Beyano's funeral which is tearing the land apart, whether the deceased village chief, should be given a Christian burial or he should, according to the age-old tradition of Lewoh people, go through a ritual to enable him return and continue ruling his people.
Halobacillus halophilus, a moderately halophilic bacterium isolated from salt marshes, produces various compatible solutes to cope with osmotic stress. Glutamate and glutamine are dominant compatible solutes at mild salinities. Glutamine synthetase activity in cell suspensions of Halobacillus halophilus wild type was shown to be salt dependent and chloride modulated. A possible candidate to catalyze glutamine synthesis is glutamine synthetase A2, whose transcription is stimulated by chloride. To address the role of GlnA2 in the biosynthesis of the osmolytes glutamate and glutamine, a deletion mutant (ΔglnA2) was generated and characterized in detail. We compared the pool of compatible solutes and performed transcriptional analyses of the principal genes controlling the solute production in the wild type strain and the deletion mutant. These measurements did not confirm the hypothesized role of GlnA2 in the osmolyte production. Most likely the presence of another, yet to be identified enzyme has the main contribution in the measured activity in crude extracts and probably determines the total chloride-modulated profile. The role of GlnA2 remains to be elucidated.