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Distributional records of the 71 tiger beetle species and subspecies known for Argentina are given together with a key and habitus photos (Coleoptera: Cicindelidae). Brasiella (Brasiella) cuyabaensis Mandl, 1970 and Brasiella (Gaymara) rotundatodilatata (Horn, 1925) are reported as new for the fauna of Argentina. Brasiella (Brasiella) stamatovi (Sumlin, 1979) is transferred to Cylindera (Plectographa), becoming C. (P.) stamatovi (Sumlin), new combination. Cylindera (Plectographa) siccalacicola (Sumlin, 1979) is placed into synonymy under Cylindera (Plectographa) hassenteufeli (Mandl, 1960), new synonymy. A lectotype is designated for Cylindera (Plectographa) patagonica bergiana (Horn, 1895).
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.
Money is more than memory
(2014)
Impersonal exchange is the hallmark of an advanced society. One key institution for impersonal exchange is money, which economic theory considers just a primitive arrangement for monitoring past conduct in society. If so, then a public record of past actions — or memory — supersedes the function performed by money. This intriguing theoretical postulate remains untested. In an experiment, we show that the suggested functional equality between money and memory does not translate into an empirical equivalence. Monetary systems perform a richer set of functions than just revealing past behaviors, which proves to be crucial in promoting large-scale cooperation.
Five new species of Cerambycidae (Coleoptera) from Peru and Bolivia, and two new records for Peru
(2014)
The following four new species of Cerambycidae are described from Bolivia: Chrysoprasis imitatrix (Heteropsini); Carneades vigneaulti (Colobotheini); Colobothea larriveei (Colobotheini); Colobothea boliviana (Colobotheini). Esthlogena (Pseudotaxia) bella (Pteropliini) is described from Peru. A key to species of Carneades Bates, 1869 is provided. The other new species are included in previously published keys. Additionally, two new country records are reported for the fauna of Peru.
Emotions-at-risk: an experimental investigation into emotions, option prices and risk perception
(2014)
This paper experimentally investigates how emotions are associated with option prices and risk perception. Using a binary lottery, we find evidence that the emotion ‘surprise’ plays a significant role in the negative correlation between lottery returns and estimates of the price of a put option. Our findings shed new light on various existing theories on emotions and affect. We find gratitude, admiration, and joy to be positively associated with risk perception, although the affect heuristic predicts a negative association. In contrast with the predictions of the appraisal tendency framework (ATF), we document a negative correlation between option price and surprise for lottery winners. Finally, the results show that the option price is not associated with risk perception as commonly used in psychology.
This chapter analyzes the risk and return characteristics of investments in artists from the Middle East and Northern Africa (MENA) region over the sample period 2000 to 2012. With hedonic regression modeling we create an annual index that is based on 3,544 paintings created by 663 MENA artists. Our empirical results prove that investing in such a hypothetical index provides strong financial returns. While the results show an exponential growth in sales since 2006, the geometric annual return of the MENA art index is a stable13.9 percent over the whole period. We conclude that investing in MENA paintings would have been profitable but also note that we examined the performance of an emerging art market that has only seen an upward trend without any correction, yet.
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.
This paper investigates the impact of news media sentiment on financial market returns and volatility in the long-term. We hypothesize that the way the media formulate and present news to the public produces different perceptions and, thus, incurs different investor behavior. To analyze such framing effects we distinguish between optimistic and pessimistic news frames. We construct a monthly media sentiment indicator by taking the ratio of the number of newspaper articles that contain predetermined negative words to the number of newspaper articles that contain predetermined positive words in the headline and/or the lead paragraph. Our results indicate that pessimistic news media sentiment is positively related to global market volatility and negatively related to global market returns 12 to 24 months in advance. We show that our media sentiment indicator reflects very well the financial market crises and pricing bubbles over the past 20 years.
Since the 2008 financial crisis, in which the Reserve Primary Fund “broke the buck,” money market funds (MMFs) have been the subject of ongoing policy debate. Many commentators view MMFs as a key contributor to the crisis because widespread redemption demands during the days following the Lehman bankruptcy contributed to a freeze in the credit markets. In response, MMFs were deemed a component of the nefarious shadow banking industry and targeted for regulatory reform. The Securities and Exchange Commission’s (SEC) misguided 2014 reforms responded by potentially exacerbating MMF fragility while potentially crippling large segments of the MMF industry.
Determining the appropriate approach to MMF reform has been difficult. Banks regulators supported requiring MMFs to trade at a floating net asset value (NAV) rather than a stable $1 share price. By definition, a floating NAV prevents MMFs from breaking the buck but is unlikely to eliminate the risk of large redemptions in a time of crisis. Other reform proposals have similar shortcomings. More fundamentally, the SEC’s reforms may substantially reduce the utility of MMFs for many investors, which could, in turn, affect the availability of short term credit.
The shape of MMF reform has been influenced by a turf war among regulators as the SEC has battled with bank regulators both about the need for additional reforms and about the structure and timing of those reforms. Bank regulators have been influential in shaping the terms of the debate by using banking rhetoric to frame the narrative of MMF fragility. This rhetoric masks a critical difference between banks and MMFs – asset segregation. Unlike banks, MMF sponsors have assets and operations that are separate from the assets of the MMF itself. This difference has caused the SEC to mistake sponsor support as a weakness rather than a key stability-enhancing feature. As a result, the SEC mistakenly adopted reforms that burden sponsor support instead of encouraging it.
As this article explains, required sponsor support offers a novel and simple regulatory solution to MMF fragility. Accordingly this article proposes that the SEC require MMF sponsors explicitly to guarantee the $1 share price. Taking sponsor support out of the shadows embraces rather than ignores the advantage that MMFs offer over banks through asset partitioning. At the same time, sponsor support harnesses market discipline as a constraint against MMF risk-taking and moral hazard.
A new species of Nephus Mulsant (Coleoptera: Coccinellidae) from southern Florida is described: Nephus (Nephus) alyssae. This represents the fi rst member of the subgenus Nephus reported in the southeastern United States. Florida species previously placed in the genus Nephus, now placed in Scymnobius Casey, are compared with the new species.
A newly discovered population of Xystocheir brachymacris Shelley, 1996 (Polydesmida: Xystodesmidae: Xystocheirini), in Placer County (Co.), California, exhibits an unusual grayish-black color dorsally with mottled, ovoid patches at paranotal bases; it cons titutes northern generic and specifi c range extensions of ~28.4 km (17.6 mi). The gonopods differ from those in the El Dorado Co. population in having shorter/acuminate prefemoral processes and blade-like, rather than spatulate, processes “B” that angle away from the solenomere instead of overhanging it. Additionally, a strong distomedial prefemoral lobe, absent from the El Dorado population, arises from the stem in Placer Co. males. Authorship of Xystocheirini is properly attributed to Hoffman, 1980.
The rediscovery of an older available name threatens the stability of the long accepted name of Strategus oblongus (Palisot de Beauvois, 1807) (Coleoptera: Scarabaeidae) from Hispaniola. Using Article 23.9 of the International Code of Zoological Nomenclature, Scarabaeus monoceros Nicolson, 1776 is designated a nomen oblitum to maintain nomenclatural stability while its junior synonym, Scarabaeus oblongus Palisot de Beauvois, 1807, is designated a nomen protectum.
Multiple sources of confusion surround the identity of Ochodaeus grandiceps Fairmaire, 1897, from Sichuan, China (Coleoptera: Ochodaeidae). Herein the type specimen is illustrated to solve these taxonomic issues. Examination of the holotype indicates that the species must be transferred to the genus Nothochodaeus Nikolajev, 2005, resulting in a new combination. The genus Mimochodaeus Nikolajev, 2009, based on a misidentifi cation of O. grandiceps as its purported type species, is discussed. Finally, Cuban specimens had been treated erroneously as belonging to O. grandiceps, and so the species had remained undescribed. A new species, Parochodaeus perdidus, is described to accommodate them.
A gomphid male from west-central Wisconsin (Eau Claire County, North Fork Eau Claire River, 11 June 1994, K. J. Tennessen leg) with characters that are intermediate between Ophiogomphus carolus Needham, 1897 and Ophiogomphus rupinsulensis (Walsh), 1862 is described and illustrated. The specimen appears to be a hybrid based on intermediate character states of 1) color pattern (slightly closer to O. carolus), 2) hamule morphology (shaped slightly more like those of O. carolus), and 3) anal appendage morphology (slightly more like those of O. rupinsulensis).
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.
An adventive female Julidae (Julida), discovered in a moist, grassy depression in the Peninsula de Brunswick south of Punta Arenas, Chile, and assigned to Cylindroiulus Verhoeff, 1894, is the fi rst vouchered milliped from southern Patagonia. The southernmost milliped ever collected in Chile, South America, and the Western Hemisphere, it may also constitute the southernmost in the world as the site is only ~1,176 km (735 mi) northwest of the Antarctic Peninsula. Records are consolidated of the two families, three genera, and fi ve species of this Holarctic order that are known from South America. They are documented from Argentina, Chile, and southern Peru and Brazil; three species are known from the Juan Fernandez Islands.
US data and new stockholding data from fifteen European countries and China exhibit a common pattern: stockholding shares increase in household income and wealth. Yet, there is a multitude of numbers to match through models. Using a single utility function across households (parsimony), we suggest a strategy for fitting stockholding numbers, while replicating that saving rates increase in wealth, too. The key is introducing subsistence consumption to an Epstein-Zin-Weil utility function, creating endogenous risk-aversion differences across rich and poor. A closed-form solution for the model with insurable labor-income risk serves as calibration guide for numerical simulations with uninsurable labor-income risk.
Eleven Neotropical species of Laemophloeus Dejean with antennal clubs composed of three antennomeres are reviewed, diagnosed, and illustrated. Six of the species are described as new: L. capitesculptus Thomas, n. sp., L. corporeflavus Thomas, n. sp., L. dozieri Thomas, n. sp., L. insulatestudinorum Thomas, n. sp., L. planaclavatus Thomas, n. sp., and L. taurus Thomas, n. sp. Four new synonymies are proposed: L. catharinensis Kessel (=L. incisus Sharp), new synonym; L. similans Kessel (=L. incisus Sharp), new synonym; L. distinguendus Sharp (=L. megacephalus Grouvelle), new synonym, and L. chevrolati Grouvelle (=L. lecontei Grouvelle), new synonym. A key to the species is provided.
The crape myrtle aphid Sarucallis kahawaluokalani (Kirkaldy) (Hemiptera: Aphididae) collected on Lagerstroemia indica (Lythraceae) is herein reported as a new invasive species in the city of Palmira, State of Valle del Cauca, and on San Andres island, in the State of San Andres, Old Providence and Santa Catalina, Colombia. The species is illustrated and diagnosed. A brief review of recent invasive species in Colombia, i.e., Ceroplastes rubens Maskell (Hemiptera: Coccidae), Crypticerya multicicatrices Kondo and Unruh (Hemiptera: Monophlebidae) [invasive on the island of San Andres], Diaphorina citri Kuwayama (Hemiptera: Liviidae), Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae), Maconellicoccus hirsutus (Green) (Hemiptera: Pseudococcidae) and Singhiella simplex (Singh) (Hemiptera: Aleyrodidae); and other adventive (but non-invasive) species in Colombia, i.e., Anagyrus kamali Moursi (Hymenoptera: Encyrtidae), Gyranusoidea indica Shafee, Alam and Agarwal (Hymenoptera: Encyrtidae), and Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae) is provided.
New North American records of Pyraloidea (Lepidoptera: Crambidae, Pyralidae) from southern Florida
(2014)
We report six new North American records, one new state record, and one rare record of pyraloid moths from southern Florida, together with diagnostic characters for all taxa. We transfer Ennomosia Amsel from Spilomelinae to Glaphyriinae, Cangetta micralis (Hampson) n. comb. from Deuterophysa Warren, and Microthyris lelex (Cramer) n. comb. from Cyclocena Möschler. We revise Pseudocabotia Blanchard and Knudson rev. stat. to a subgenus of Ancylosis Zeller, with its type species A. (P.) balconiensis (Blanchard and Knudson) n. comb., and discuss the classifi cation of Cabotia Ragonot as a subgenus of Ancylosis.
Two new species and a new genus of Cerambycidae are described from South America: Cotyclytus arriagadai sp. nov., from Bolivia; and Lembu dieguezi, gen. nov., sp. nov., from Paraguay. Orthomegas irroratus (Lameere, 1915) is redescribed, based on the second and third known specimens, and its distribution is expanded to include Ecuador. The male of Jamesia fuscofasciata Dillon and Dillon, 1952 is described and illustrated for the fi rst time, and the distribution of the species is expanded to Peru. Thirty-two new country records (twelve for Paraguay, fi fteen for Peru, two for Ecuador, three for Bolivia) and one new province record (Argentina) are presented.
Four new species and one new genus of Cerambycinae are described from French Guiana: Sphagoeme premarginata sp. nov. and Atenizus apicalis sp. nov. (Oemini); Paraniophis signatipes gen. nov., sp. nov., and Niophis brusteli sp. nov. (Ectenessini). Three new country records for French Guiana are provided: Sphagoeme paraensis Martins, 1977, Atenizus simplex Bates, 1884, and Macroeme vittipennis (Melzer, 1934). All taxa are illustrated.
Tumor cell plasticity is an event that has been observed in several malignancies. In fact, most of the solid tumors are characterized by cellular heterogeneity and undergo constant changes as the tumor develops. The increased plasticity displayed by these cells allows them to acquire additional properties, enabling epithelial-mesenchymal transitions, dedifferentiation and the acquisition of stem cell-like properties. Here we discuss the particular importance of an inflammatory microenvironment for the bidirectional control of cellular plasticity and the potential for therapeutic intervention.
Background: Oral anticoagulation (OAC) with coumarins and new anticoagulants are highly effective in preventing thromboembolic complications. However, some studies indicate that over- and under-treatment with anticoagulants are fairly common. The aim of this paper is to assess the appropriateness of treatment in patients with a long-term indication for OAC, and to describe the corresponding characteristics of such patients on the basis of screening results from the cluster randomized PICANT trial.
Methods: Randomly selected family practices in the federal state of Hesse, Germany, were visited by study team members. Eligible patients were screened using an anonymous patient list that was generated by the general practitioners? software according to predefined instructions. A documentation sheet was filled in for all screened patients. Eligible patients were classified into 3 categories (1: patients with a long-term indication for OAC and taking anticoagulants, 2: patients with a long-term indication for OAC but not taking anticoagulants, 3: patients without a long-term indication for OAC but taking an anticoagulant on a permanent basis). IBM SPSS Statistics 20 was used for descriptive statistical analysis.
Results: We screened 2,036 randomly selected, potentially eligible patients from 52 family practices. 275 patients could not be assigned to one of the 3 categories and were therefore not considered for analysis. The final study sample comprised 1,761 screened patients, 1,641 of whom belonged to category 1, 78 to category 2, and 42 to category 3. INR values were available for 1,504 patients of whom 1,013 presented INR values within their therapeutic ranges. The majority of screened patients had very good compliance, as assessed by the general practitioner. New antithrombotic drugs were prescribed in 6.1% of cases.
Conclusions: The screening results showed that a high proportion of patients were receiving appropriate anticoagulation therapy. The numbers of patients with a long-term indication for OAC therapy that were not receiving oral anticoagulants, and without a long-term indication that were receiving OAC, were considerably lower than expected. Most patients take coumarins, and the quality of OAC control is reasonably high.
We study the equilibrium properties of strongly-interacting infinite parton-hadron matter, characterized by the transport coefficients such as shear and bulk viscosity and electric conductivity, and the non-equilibrium dynamics of heavy-ion collisions within the Parton-Hadron-String Dynamics (PHSD) transport approach, which incorporates explicit partonic degrees of freedom in terms of strongly interacting quasiparticles (quarks and gluons) in line with an equation of state from lattice QCD as well as the dynamical hadronization and hadronic collision dynamics in the final reaction phase. We discuss in particular the possible origin for the strong elliptic flow v2 of direct photons observed at RHIC energies.
Reaction times to previously ignored information are often delayed, a phenomenon referred to as negative priming (NP). Rothermund et al. (2005) proposed that NP is caused by the retrieval of incidental stimulus-response associations when consecutive displays share visual features but require different responses. In two experiments we examined whether the features (color, shape) that reappear in consecutive displays, or their level of processing (early-perceptual, late-semantic) moderate the likelihood that stimulus-response associations are retrieved. Using a perceptual matching task (Experiment 1), NP occurred independently of whether responses were repeated or switched. Only when implementing a semantic-matching task (Experiment 2), negative priming was determined by response-repetition as predicted by response-retrieval theory. The results can be explained in terms of a task-dependent temporal discrimination process (Milliken et al., 1998): Response-relevant features are encoded more strongly and/or are more likely to be retrieved than irrelevant features.
Reintroductions of plant species are increasingly popular in conservation practice. Steppe grasslands contain many rare and endangered plant species that are potential objects for such reintroductions. Most reintroduction projects, however, can only target a restricted number of species, which raises the question of how species should be prioritised. Here, we present a method to select priority species for reintroduction based on species' characteristics that are widely used in conservation practice. We first determined the local species pool containing those vascular plant species that occurred both in our target region (Thuringia, Germany) and target habitat (steppe grasslands), yielding 369 species. With the help of an a priori filter that selected currently endangered species with limited distribution, 136 potential target species were determined. These potential target species had experienced stronger decline, had a narrower phytosociological amplitude and were more likely to be species of the Festuco-Brometea class and the Festucetalia valesiacae order than non-target species. Potential target species were then ranked by a points system based on ten conservation-relevant characteristics of the species from the categories "threat and protection status", "distribution and decline", and "habitat affiliation". In the ranking, six steppe grassland plant species (Astragalus exscapus, Bothriochloa ischaemum, Prunella laciniata, Pulsatilla pratensis subsp. nigricans, Scorzonera purpurea, and Seseli hippomarathrum) achieved the highest scores. An additional seven species not specifically characteristic for steppe grasslands also scored highly. A post hoc evaluation of these 13 highest scoring species based on additional conservation criteria left five species (Astragalus exscapus, Linum leonii, Orchis morio, Pulsatilla pratensis subsp. nigricans and Scorzonera purpurea) as species with highest priority for reintroductions and another five species as highly suitable for reintroductions. Associations between the ranking order and different ranking criteria revealed that a species’ threat and rarity in Thuringia and its protection status had the highest representation in the ranking, followed by threat in Germany, regional decline and habitat affiliation. In contrast, international threat and responsibility of Thuringia for its conservation had only low representation in the ranking, probably because these characteristics applied to only a few species. The ranking list gives a selection of species for reintroductions, which combined with additional information based on comprehensive local and floristic knowledge, allows the identification of the species with the highest priority. Our method can be transferred to other regions or habitat types.
Central European dry grasslands are remarkably diverse plant communities that occur at the western edge of the Eurasian forest-steppe zone and harbour many species of continental distribution. Although their plant community types have been described in detail, the diversity patterns and their environmental determinants are still poorly known for these grasslands. Here, we study environmental drivers of species composition and richness in dry grasslands of northern Bohemia (České středohoří Mts) and central Bohemia (Křivoklát region), both in the Czech Republic. In vegetation plots of 100 m2 we recorded all vascular plant species, measured soil chemistry variables, above-ground biomass production and nutrient concentrations in biomass. Species richness in these plots ranged from 13 to 55. The relationships between species composition and the environment were explored using detrended correspondence analysis and canonical correspondence analysis, while the relationships between species richness and the environment were assessed using univariate and multiple regression models. In both regions, species composition and richness strongly responded to the soil pH (ranging from 4.0 to 7.8), which was positively correlated with calcium and magnesium concentrations and negatively with annual precipitation. The response of species richness to soil pH was unimodal with a peak at pH of about 6.5 in the České středohoří Mts, and positive in the Křivoklát region. Plots on soils with a pH higher than 5 consistently contained more than 35 species. In the České středohoří Mts, species richness was positively related to the aboveground biomass production, whereas in the Křivoklát region, this relationship was only significant for graminoid species. In both areas, plots with soils deeper than 20 cm and with aboveground biomass dry weight above 200 g/m2 harboured more than 40 species per 100 m2. Moreover, in the České středohoří Mts, nitrogen concentrations in the biomass had considerable effects on both species composition and richness: species numbers were lower at sites with higher nitrogen concentration. This indicates a threat to diversity of these dry grasslands under currently high atmospheric nitrogen deposition coupled with the absence of management at most of the studied sites.
Cryophytic steppes in the Minusinskaya intermountain basin containing plant species that are predominantly distributed in the alpine zone such as Androsace dasyphylla, Dryas oxyodonta, Festuca sphagnicola, Kobresia myosuroides, K. filifolia, Minuartia verna, Oxytropis bracteata, Sagina saginoides, Papaver nudicaule, Patrinia sibirica, Pedicularis lasiostachys, Pulsatilla ambigua, Saussurea schanginiana, which are considered remnants of the Pleistocene vegetation. Based on 89 relevés, we classified cryophytic steppes using the Braun-Blanquet method within two phytosociological classes: Central Asian steppes of the Cleistogenetea squarrosae and West Palearctic steppes of the Festuco-Brometea. Three associations (Androsaco dasyphyllae-Caricetum pediformis, Pulsatillo patentis-Caricetum pediformis and Bupleuro multinervi-Helictotrichetum desertori) with three subassociations and three variants were described with respect to their phytosociological affinities and ecology. DCA ordination showed floristic differences between syntaxa, while correlations of DCA axes and floristic and environmental variables detected substrate type and temperature regime as presumably main drivers for vegetation differentiation. Another driver for vegetation differentiation seems to be continentality of the climate. Small scale distribution of cryophytic steppes were mapped using satellite images with resolution of 1.8 m. Cryophytic steppes always occupy only small areas in landscapes, on convex parts of undulated microrelief of mountain slopes and summits characterised by drought in summer and deep soil freezing in winter. These special micro-ecological conditions play an essential role for the existence of alpine flora in the Minusinskaya intermountain basin.
We present the data of the 2nd research expedition of the European Dry Grassland Group (EDGG), which was conducted in 2010 in Central Podolia, Ukraine. The aim was to collect plot data to compare Ukrainian dry grasslands with those of other parts of Europe in terms of syntaxonomy and biodiversity. We sampled 21 nested-plot series (0.0001–100 m2) and 184 normal plots (10 m2) covering the full variety of dry grassland types occurring in the study region. For all plots, we recorded species composi-tion of terrestrial vascular plants, bryophytes and lichens, while for the 226 10-m2 plots we estimated and measured percentage cover of all species, structural, topographic, soil and landuse parameters. The 10-m² plots were used for phytosociological classification based on iteratively refined TWINSPAN classification as well as for DCA ordination. Differences between the derived vegetation types with respect to environmental conditions and species richness were assessed with ANOVAs. We assigned our plots to nine association-level units but refrained from placing them into formal associations with two exceptions. In the study area, dry grasslands of the Festuco-Brometea were far more common than those of the Koelerio-Corynephoretea. Among the Festuco-Brometea, xeric Festucetalia valesiacae grasslands were more frequent and represented by the Festucion valesiacae (2 associations, including the Allio taurici-Dichanthietum ischaemi ass. nova) and the Stipion lessingianae (1) compared to the Brachypodietalia pinnati with the Agrostio vinealis-Avenulion schellianae (3). The Koelerio-Corynephoretea were represented by three associations, each from a different order and alliance: basiphilous outcrops (Alysso alyssoidis-Sedetalia: Alysso alyssoidis-Sedion?), acidophilous outcrops (Sedo-Scleranthetalia: Veronico dillenii-Sedion albi?) and mesoxeric sandy grasslands (Trifolio arvensis-Festucetalia ovinae: Agrostion vinealis). We discuss the issue of the mesoxeric order Galietalia veri placed within the Molinio-Arrhenatheretea by Ukrainian authors and conclude that the content of that order would probably be better placed in the mesoxeric orders of the Koelerio-Corynephoretea and Festuco-Brometea. Other syntaxonomic questions could not be solved with our geographically limited dataset and await a supraregional analysis, e.g. whether the Ukrainian outcrop communities should be assigned to the same alliances as known from Central Europe or rather represent new vicariant units. The analysis of the biodiversity patterns showed that at a grain size of 10 m2, Podolian Koelerio-Corynephoretea communities were overall richer than Festuco-Brometea communities (46.4 vs. 40.6 species). This difference was due to the Koelerio-Corynephoretea containing twice as many bryophytes and nine times more lichens, while vascular plant species richness did not differ significantly between classes. The orders within the classes showed no real differences in species richness. The richness patterns observed in Podolia were almost the opposite of those usually found in dry grasslands, where Brachypodietalia pinnati are richer than Festucetalia valesiacae, and these richer than stands of the Koelerio-Corynpehoretea – and we do not have a good explanation for these idiosyncrasies. In conclusion, Podolian dry grasslands behave quite unexpectedly regarding biodiversity, and their syntaxonomy is still poorly understood. These knowledge gaps can only be addressed with supranational analyses based on comprehensive datasets.
An extensive survey of the relevant literature of dry grassland communities described for the territory of Serbia allowed us to check the validity and legitimacy of the nomenclature of this vegetation. Nomenclature rules of the International Code of Phytosociological Nomenclature were strictly followed. The syntaxonomic affiliation of communities to higher syntaxa was assessed according to existing syntaxonomic schemes for Serbia and the position determined by the original source. Higher syntaxa followed the synsystem of the socalled “EuroVegChecklist”. We have highlighted problems and some disagreement with the existing classification of dry grassland communities in Europe. A total of 134 dry grassland communities have so far been registered for Serbia. This list of syntaxa may serve for further research of grassland vegetation and its appropriate positioning within a syntaxonomical scheme of Europe.
Der diesjährige 9. Trockenrasen-Sonderteil von Tuexenia beginnt mit einem Bericht über die aktuellen Aktivitäten der European Dry Grassland Group (EDGG). Zunächst geben wir einen Überblick über die Entwicklung der Mitgliederzahl. Dann berichten wir vom letzten European Dry Grassland Meeting in Zamość (Polen, 2013) und vom letzten European Dry Grassland Field Workshop in Chakassien (Russland, 2013) und informieren über künftige Veranstaltungen der EDGG. Anschließend erläutern wir die Publikationsaktivitäten der EDGG. Im zweiten Teil des Editorials geben wir eine Einführung zu den fünf Artikeln des diesjährigen Trockenrasen-Sonderteils: Zwei davon beschäftigen sich mit der Syntaxonomie von Trockenrasen in Osteuropa: Der eine Artikel präsentiert erstmalig eine nach internationalen Nomenklaturregeln gültige Liste der Trockenrasengesellschaften Serbiens während der andere die Ergebnisse des zweiten EDGG-Field Workshop 2010 nach Podolien (Ukraine) vorstellt. Im dritten Artikel werden kryophytische Steppen in Südsibirien (Russland) analysiert. Der vierte Artikel analysiert in Böhmen (Tschechien) die bestimmenden Kräfte für Artenreichtum und Artenzusammensetzung der Trockenrasen. Der fünfte Artikel befasst sich mit der Auswahl von Wiederansiedlungsarten am Beispiel der Steppenrasen in Thüringen (Deutschland).
The Feldbach district is situated near the town of Feldbach in the southeastern province of Styria, Austria. Since 2007, a climate observation network of 151 climate stations within an area of approximately 20 x 15 km (grid cell 1.4 × 1.4 km) has provided a unique collection of spatial and temporal meteorological data. Examining short-lived ruderal and arable weed communities, we search for correlations and spatial patterns between the community composition and climate data. Do such plant communities respond to temperature differences within an agricultural landscape and on a regional scale? Data of 277 relevés from short-lived weed communities were collected across the investigated area during the summer of 2011. Relevés were assigned to the corresponding climate stations and classified. Average Ellenberg indicator values for temperature were calculated for each relevé and community cluster. Measured temperature data were assigned and correlated with community data by applying linear regression and redundancy analyses (RDA). The classification resulted in six associations; the two most frequently observed associations were divided into subtypes resulting in 13 vegetation clusters that could be analyzed further. A significant relationship could be found only between the clusters of arable weed communities and the average winter temperatures. Site variables explain twice as much variance as measured climate variables; this ratio changes to 50 : 50 when we analyzed only arable field community data. No clear spatial patterns concerning mean annual temperature were visible. However, the Setaria faberi subtype of the Echinochloo-Setarietum and the Sorghum halepense subtype of the Convolvulo-Agropyretum show a tendency toward a temperature-induced spatial pattern, such that both were sensitive to winter temperature. On a regional scale, the occurrence and composition of short-lived ruderal plant communities correlated weakly with climate variables. However, the studied arable weed communities showed a certain tendency to follow small-scale temperature differences, especially those of average winter temperature. We conclude that short-lived weed communities have the potential to be indicators for global warming, but the spatial temperature gradients are not clear enough in our approach to allow the production of better regression models and elucidation of distinct spatial patterns.
Background: IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.
Methods: Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.
Results: Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.
Conclusion: IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
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.
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.
Introduction: Curare is one of the best-examined neurotoxins of the world, which has empirically been used for centuries by American Indigenes. Research on curare has been performed much later, a global scientometric analysis on curare research or its derivates does not yet exist. This bibliometric analysis is part of the global NewQis-project and should illuminate both toxic and historic issues of research on curare.
Methods: The ISI Web of Science was searched for data covering 1900 to 2013 using a term which included as many original articles on curare as possible. 3,867 articles were found and analyzed for common bibliometric items such as the number of citations, language of the articles or the (modified) Hirsch-Index (h-index). Results are illustrated utilizing modern density equalizing map projections (DEMP) or beam diagrams.
Results: Most publications were located in North America and Europe. The USA has the highest number of publications as well as the highest h-index. The number of publications overall rose until the late 1990s and later decreased. Furthermore, sudden increases of research activity are ascribable to historic events, like the first use of curare as muscle relaxant during surgery.
Discussion: This scientometric analysis of curare research reflects several tendencies as previously seen in other bibliometric investigations, i.e. the scientific quality standard of North America and Europe. Research on curare decreased however, due to the declining attention towards this muscle relaxant. This work exemplifies also how scientometric methods can be used to illuminate historic circumstances immediately stimulating scientific research.
Introduction: To determine the esthetic outcome of implant-based reconstructions after autologous and allogeneic bone grafting.
Methods: From 2003 to 2009, 67 patients underwent alveolar ridge augmentation and were enrolled in the study, 41 meet the inclusion criteria and 31 agreed to take part in the study. Patients were 18-69 years old (mean: 49.3 ± 13.8 years), and predominantly female. Patients received bone block grafts either autologous (n = 48) (AUBB) or allografts (ABB) (n = 19). Implants were inserted 4-7 months (autografts) or 5-6 months (allografts) after bone grafting. The Pink Esthetic Score (PES) as well as radiographic and subjective assessments were employed for the outcome analysis. The PES was assessed twice within one month based on digital photographic images that were randomly rearranged between evaluations by three independent, experienced investigators.
Results: Across all observations and investigators, the average PES was 7.5 ± 2.6 without differences between implants inserted in auto- and allografted bone, respectively. Patients assessed the allograft procedures as less painful and would have repeated it more often. The intra-rater reliability was excellent (correlation coefficients 0.7-0.9). The inter-observer agreement was lower (correlation coefficients 0.6-0.8).
Conclusions: Bone grafting with ABB allografts yields equivalent results to autologous grafting, and patients appreciate the omission of bone harvesting. The PES is a reliable method but should be performed by the same individual.
In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-benzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.
Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
1D-3D hybrid modeling : from multi-compartment models to full resolution models in space and time
(2014)
Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator—which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.
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.
Epicutanoeus immunotherapy as a novel prophylactic and therapeutic strategy for birch pollen allergy
(2014)
The development of a convenient, effective and safe allergen-specific immunotherapy (SIT) for birch pollen allergy, one of the most prevalent allergic diseases in Northern Europe, North America and Northern Japan, is of crucial importance. Epicutaneous immunotherapy (EPIT) has gained attention as a safe and non-invasive alternative for subcutaneous immunotherapy, a conventional SIT. However, clinical studies showed a limited effcacy of EPIT, indicating the necessity of improvement of the treatment regime. In this study, we hypothesized that a combination of a hypoallergen with an appropriate adjuvant could be a strategy to improve EPIT. To verify this hypothesis, we aimed at investigating the efficacy of epicutaneous treatment with rBet v 1, the major birch pollen allergen, plus Toll-like receptor (TLR) agonists for prophylaxis and therapy of birch pollen allergy using a murine model of birch pollen-induced allergic asthma. Furthermore, the efficacy of rBet v 1B2, a hypoallergenic variant of Bet v 1, as a therapeutic allergen in EPI was pre-clinically investigated. TLRs recognize conserved microbial molecules (like PAMPs), and are known to promote the counter-regulation of TH2 responses by the induction of TH1-type and/or regulatory cytokines by immune cells. The hypoallergen Bet v 1B2 is a folding-variant of the wild-type allergen rBet v 1 with reduced allergenicity, but retained T-cell immunogenicity. The low allergenicity, could allow the application of hypoallergens in higher doses, and therefore provide a safer and more effective treatment to regulate T-cell immune responses. First, the expression and purification of recombinant Bet v 1 and Bet v 1B2 was optimized. Compared to natural proteins, recombinant proteins offer the possibility to use well-defined molecules with a consistent pharmaceutical quality. Using optimal Escherichia coli expression strains in combination with immobilized metal chelate affinity chromatography (IMAC) and size exclusion chromatography (SEC), we successfully prepared a large amount of rBet v 1 and rBet v 1B2 with a high purity. The allergenic potency of rBet v 1 and the hypoallergenic characteristics of rBet v 1B2 were confirmed by measurement of IgE reactivity and mediator release capacity using ELISA and basophil activation tests, respectively. In a second part, a murine model of birch pollen-induced allergic asthma was established. It was shown that intraperetoneal sensitization with an optimal dose of rBet v 1 and intranasal challenge with birch pollen extract induced elevated IgE levels, airway eosinophilia and pulmonary inflammation in BALB/c mice. The clinical features are comparable to those in patients with allergic asthma, indicating that sensitized and challenged mice could be used for a pre-clinical study to assess the efficacy of the treatment for birch pollen allergy. Next, we investigated the adjuvant effects of Polyadenylic:polyuridylic acid (Poly(A:U)), a TLR3 agonist, and R848 (resiquimod), a TLR7 agonist, in prophylactic EPI with rBet v 1 to intervene with birch pollen allergy. Here, we hypothesized that TLR3 and TLR7 could be possible target receptors to induce adjuvant effects in EPI, since these receptors are expressed in Langerhans cells and dermal dendritic cells, persistent antigen presenting cells in the cutaneous tissues. BALB/c mice received EPI with rBet v 1 alone, or plus Poly(A:U), or R848 on their depilated back using patches. Mice treated epicutaneously were then sensitized with rBet v 1 plus ALUM and intranasally challenged with birch pollen extract. We found that prophylactic EPI with rBet v 1 plus R848 inhibited the production of Bet v 1-specific IgE antibodies in sensitization, suppressed pulmonary inflammation and airway hyperreactivity upon challenge. In contrast to R848, no adjuvant effect of Poly(A:U) on suppression of asthmatic features was observed. Our results indicated that R848, but not Poly(A:U), could be a potential adjuvant for prophylactic EPI of birch pollen induced allergic asthma. Finally, the therapeutic potency of EPI with rBet v 1, or rBet v 1B2 alone, or plus R848 was assessed. After sensitization and challenge, mice received therapeutic EPI with rBet v 1 alone, or plus R848, and re-challenge with birch pollen extract. We found that therapeutic treatment with Bet v 1B2 reduced established Bet v 1-specific IgE antibodies, pulmonary inflammation and airway hyperreactivity upon re-challenge. Therapeutic treatment with the recombinant wild-type allergen does not influence these key characteristics of allergic asthma. In contrast to the findings in the prophylactic treatment with rBet v 1 plus R848,no therapeutic benefit was found upon combination with R848. This could be due to the high number of treatment days. Reduction of this number may lead to a beneficial effect. However, these findings indicate that Bet v 1B2 could be a potential therapeutic agent for the treatment of established birch pollen induced allergic asthma. In conclusion, this study demonstrates for the first time that prophylactic EPI with the recombinant form of Bet v 1 in combination with R848 could prevent and suppress asthmatic features in an established birch pollen allergy. Not only therapeutic, but also prophylactic applications of EPI could be of importance to prevent allergic sensitization, considering the high prevalence of allergic diseases. R848 could be a potential adjuvant for enhancing the prophylactic potential of EPI for the treatment of birch pollen allergy. Furthermore, the beneficial use of the hypoallergen Bet v 1B2 in therapeutic EPI was demonstrated by intervention of established asthmatic features. In the future, a combination of hypoallergens alone or together with adjuvants in EPIT could lead to a more convenient and effective therapeutic treatment of established birch pollen induced allergic asthma.
The laser-driven acceleration of protons from thin foils irradiated by hollow high-intensity laser beams in the regime of target normal sheath acceleration is reported for the first time. The use of hollow beams aims at reducing the initial emission solid angle of the TNSA source, due to a flattening of the electron sheath at the target rear side. The experiments were conducted at the PHELIX laser facility at the GSI Helmholtzzentrum für Schwerionenforschung GmbH with laser intensities in the range from 10^18 to 10^20 W/cm^2. We observed an average reduction of the half opening angle by (3.07±0.42)° or (13.2±2)% when the targets have a thickness between 12 to 14 μm. In addition, the highest proton energies were achieved with the hollow laser beam in comparison to the typical Gaussian focal spot.
Background: Birch pollen-allergic subjects produce polyclonal cross-reactive IgE antibodies that mediate pollen-associated food allergies. The major allergen Bet v 1 and its homologs in plant foods bind IgE in their native protein conformation. Information on location, number and clinical relevance of IgE epitopes is limited. We addressed the use of an allergen-related protein model to identify amino acids critical for IgE binding of PR-10 allergens.
Method: Norcoclaurine synthase (NCS) from meadow rue is structurally homologous to Bet v 1 but does not bind Bet v 1-reactive IgE. NCS was used as the template for epitope grafting. NCS variants were tested with sera from 70 birch pollen allergic subjects and with monoclonal antibody BV16 reported to compete with IgE binding to Bet v 1.
Results: We generated an NCS variant (Δ29NCSN57/I58E/D60N/V63P/D68K) harboring an IgE epitope of Bet v 1. Bet v 1-type protein folding of the NCS variant was evaluated by 1H-15N-HSQC NMR spectroscopy. BV16 bound the NCS variant and 71% (50/70 sera) of our study population showed significant IgE binding. We observed IgE and BV16 cross-reactivity to the epitope presented by the NCS variant in a subgroup of Bet v 1-related allergens. Moreover BV16 blocked IgE binding to the NCS variant. Antibody cross-reactivity depended on a defined orientation of amino acids within the Bet v 1-type conformation.
Conclusion: Our system allows the evaluation of patient-specific epitope profiles and will facilitate both the identification of clinically relevant epitopes as biomarkers and the monitoring of therapeutic outcomes to improve diagnosis, prognosis, and therapy of allergies caused by PR-10 proteins.
Background: Tracks of pigeons homing to the Frankfurt loft revealed an odd phenomenon: whereas birds returning from the North approach their loft more or less directly in a broad front, pigeons returning from the South choose, from 25 km from home onward, either of two corridors, a direct one and one with a considerable detour to the West. This implies differences in the navigational process.
Methodology/Principle Findings: Pigeons released at sites at the beginning of the westerly corridor and in this corridor behave just like pigeons returning from farther south, deviating to the west before turning towards their loft. Birds released at sites within the straight corridors, in contrast, take more or less straight routes. The analysis of the short-term correlation dimension, a quantity reflecting the complexity of the system and with it, the number of factors involved in the navigational process, reveals that it is significantly larger in pigeons choosing the westerly corridor than in the birds flying straight - 3.03 vs. 2.85. The difference is small, however, suggesting a different interpretation of the same factors, with some birds apparently preferring particular factors over others.
Conclusions: The specific regional distribution of the factors which pigeons use to determine their home course seems to provide ambiguous information in the area 25 km south of the loft, resulting in the two corridors. Pigeons appear to navigate by deriving their routes directly from the locally available navigational factors which they interpret in an individual way. The fractal nature of the correlation dimensions indicates that the navigation process of pigeons is chaotic-deterministic; published tracks of migratory birds suggest that this may apply to avian navigation in general.
Background: Highly infectious diseases (HIDs) are (i) easily transmissible from person to person; (ii) cause a life-threatening illness with no or few treatment options; and (iii) pose a threat for both personnel and the public. Hence, even suspected HID cases should be managed in specialised facilities minimizing infection risks but allowing state-of-the-art critical care. Consensus statements on the operational management of isolation facilities have been published recently. The study presented was set up to compare the operational management, resources, and technical equipment among European isolation facilities. Due to differences in geography, population density, and national response plans it was hypothesized that adherence to recommendations will vary.
Methods and Findings: Until mid of 2010 the European Network for Highly Infectious Diseases conducted a cross-sectional analysis of isolation facilities in Europe, recruiting 48 isolation facilities in 16 countries. Three checklists were disseminated, assessing 44 items and 148 specific questions. The median feedback rate for specific questions was 97.9% (n = 47/48) (range: n = 7/48 (14.6%) to n = 48/48 (100%). Although all facilities enrolled were nominated specialised facilities' serving countries or regions, their design, equipment and personnel management varied. Eighteen facilities fulfilled the definition of a High Level Isolation Unit'. In contrast, 24 facilities could not operate independently from their co-located hospital, and five could not ensure access to equipment essential for infection control. Data presented are not representative for the EU in general, as only 16/27 (59.3%) of all Member States agreed to participate. Another limitation of this study is the time elapsed between data collection and publication; e.g. in Germany one additional facility opened in the meantime.
Conclusion: There are disparities both within and between European countries regarding the design and equipment of isolation facilities. With regard to the International Health Regulations, terminology, capacities and equipment should be standardised.
Introduction: On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance.
Aim: To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis.
Methods: We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays.
Results: Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR.
Conclusion: Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.
There has been a considerable debate about whether disaster models can rationalize the equity premium puzzle. This is because empirically disasters are not single extreme events, but long-lasting periods in which moderate negative consumption growth realizations cluster. Our paper proposes a novel way to explain this stylized fact. By allowing for consumption drops that can spark an economic crisis, we introduce a new economic channel that combines long-run and short-run risk. First, we document that our model can match consumption data of several countries. Second, it generates a large equity risk premium even if consumption drops are of moderate size.
We analyze the implications of the structure of a network for asset prices in a general equilibrium model. Networks are represented via self- and mutually exciting jump processes, and the representative agent has Epstein-Zin preferences. Our approach provides a exible and tractable unifying foundation for asset pricing in networks. The model endogenously generates results in accordance with, e.g., the robust-yetfragile feature of financial networks shown in Acemoglu, Ozdaglar, and Tahbaz-Salehi (2014) and the positive centrality premium documented in Ahern (2013). We also show that models with simpler preference assumptions cannot generate all these findings simultaneously.
Using data from the US Health and Retirement Study, we study the causal effect of increased health insurance coverage through Medicare and the associated reduction in health-related background risk on financial risk-taking. Given the onset of Medicare at age 65, we identify our effect of interest using a regression discontinuity approach. We find that getting Medicare coverage induces stockholding for those with at least some college education, but not for their less-educated counterparts. Hence, our results indicate that a reduction in background risk induces financial risk-taking in individuals for whom informational and pecuniary stock market participation costs are relatively low.
A phytosociological survey of weed (segetal) vegetation in Slovakia was performed. A total of 508 relevés were sampled in 2002–2008. The aims of this study were to determine the actual distribution of the segetal communities, to analyze their floristic structure, and to evaluate their relationships to selected environmental factors. Thirteen plant communities of the class Stellarietea mediae were distinguished by cluster analysis; 11 communities were included in the subclass Violenea arvensis (Lathyro tuberosi-Adonidetum aestivalis, Consolido-Anthemidetum austriacae, Euphorbio exiguae-Melandrietum noctiflori, Veronicetum trilobae-triphyllidi, Lamio amplexicauli-Thlaspietum arvensis, Taraxacum sect. Ruderalia community, Spergulo arvensis-Scleranthetum annui, Myosotido-Sonchetum arvensis, Echinochloo-Setarietum pumilae, Galinsogo-Setarietum, and Stachyo annui-Setarietum pumilae) and two in the subclass Sisymbrienea (Portulacetum oleraceae and Setario viridis-Erigeronetum canadensis). Communities were characterized by diagnostic, constant, and dominant species and their structure, ecology, and distribution were estimated. The species composition of these communities was documented in synoptic and association tables. DCA ordination and analysis of variance was used to determine the main environmental factors of floristic differentiation and to determine ecological and structural differences among the communities. The analyses showed that the most important factors affecting floristic composition and classification of the weed communities are their time of development (agroecophase), the type of crops and altitude.
River corridor plants in Central Europe account for an above-average proportion of endangered species. The main objective of this study was to examine the effects of habitat fragmentation and abiotic conditions on the survival and changes in population size of four endangered, long-lived river corridor plant species (Euphorbia palustris, Pseudolysimachion longifolium, Sanguisorba officinalis, and Senecio paludosus) over the course of at least ten years. We sampled altogether 138 populations in the Weser and Elbe river systems in Northwestern Germany.
Overall, 33% of the populations went extinct during the study period. Extinction rates and changes in population size were related to initial population sizes, but not to population isolation and only marginally so to habitat quality. Large populations (> 100 individuals) had a much higher probability to survive or increase in size (to > 1000 individuals) than smaller populations. There was no general decline in population size in surviving populations, and extinction rates and changes in population size were independent of time. We therefore conclude that the high extinction rates in small populations are best explained by sudden short-term environmental events, such as changes in land use, rather than by long-term negative effects of, for example, genetic deterioration. A projection matrix for the next 117 years, however, predicted that 85% of the surveyed populations will have gone extinct. Since any establishment of new populations in the study area is unlikely owing to the lack of potential habitats and dispersal limitation, river corridor plants will probably continue to decline. Apart from preventing further habitat deterioration it will be crucial to maintain or establish an appropriate management, and to avoid sudden and adverse changes in land use.
The small libellulid genus Rhodothemis is restricted to Asia and Australia. Two of the four included species were described relatively recently by Lohmann (1984) but much previously documented material was never re-identified and the distribution of species in the Indospecies in the Indo-Australian Archipelago remained poorly known. All material available in the Naturalis Biodiversity Center (RMNH) from the eastern part of the Indo-Australian Archipelago was studied and is here brought on record. Key characters are illustrated and SEM images of the genital ligula are presented.
Wet meadows are transitional habitats between wetlands and dry-mesophilous grasslands; thus, they are vital in sustaining biodiversity as sources, stepping stones and green corridors of species dispersal. It is especially valid for inland alkali vegetation, where high landscapescale patchiness is typical and rapid shifts between vegetation types occur frequently. Solonetz meadows (Beckmannion eruciformis) are among the bestpreserved open habitats in Europe harbouring a unique flora including several endemics. Besides their importance, studies on the vegetation of solonetz meadows are scarce even though this knowledge would be vital for their effective conservation and management. Using own records and literature data, we provide a synthesis of the alliance Beckmannion eruciformis to characterise its associations floristically and ecologically in five regions along the river Tisza, East Hungary. We studied three associations of the alliance: (i) Agrostio stoloniferae-Alopecuretum pratensis, (ii) Agrostio stoloniferae-Beckmannietum eruciformis and (iii) Agrostio stoloniferae-Glycerietum pedicellatae. We found that solonetz meadow associations were separated along a moisture gradient with Agrostio stoloniferae-Alopecuretum pratensis at the drier end and Agrostio stoloniferae-Glycerietum pedicellateae at the wet end. This gradient was also justified by the distribution of the phytosociological groups. The proportion of species of Festuco-Brometea division was the highest in Agrostio stoloniferae-Alopecuretum pratensis, while the proportion of Cypero-Phragmitetea species was the highest in Agrostio stoloniferae-Glycerietum pedicellateae. Species of Puccinellio-Salicornetea had the highest proportion in Agrostio stoloniferae-Beckmannietum eruciformis, indicating the high soil salinity of this association. Our results suggest that Agrostio stoloniferae-Alopecuretum pratensis association plays an important role in preserving the continental flora elements of the surrounding dry grasslands. The ecological indicator values for soil moisture and salinity suggest that in case of the studied solonetz meadow associations, humidity increases with decreasing elevation, while salinity is highest at medium elevations. Our results suggest that Agrostio stoloniferae-Beckmannietum eruciformis is a transition towards salt marsh associations, while Agrostio stoloniferae-Glycerietum pedicellatae is a transition towards freshwater marshes. Our results show that preserving solonetz meadows is an important task for nature conservation as they have a crucial role in maintaining landscapescale species and habitat diversity and act as buffer zones around wetlands.
Fluctuations of the water level at the edges of temporary water bodies provide favourable living conditions for annual plant communities of the phytosociological class Isoëto-Nanojuncetea. Such communities of periodically flooded ponds within the agricultural landscape of NE Germany are particularly rich in rare plant species of that class. During the past decades drainage, fertilisation and herbicides in the surrounding arable fields have led to a severe decline in diversity of these species. To develop efficient conservation strategies it is essential to understand the factors driving the species composition. Therefore, we studied how varying water regimes, soil properties and agricultural practices affect the diversity and species composition of these temporary ponds. The study was carried out in seven ponds on a conventionally managed farm in NE Brandenburg. At each of these wetlands mixed soil samples were taken to determine the pH, total nitrogen and phosphorus concentration. The plant species were recorded in 177 plots, each covering 1 x 1 m2. For each plot, the water level was recorded in April, July and August 2013, respectively, resulting in five "water level regimes". Total species number and percentages of Isoëto-Nanojuncetea species were determined per plot, to evaluate water level effects on the vegetation. In addition, mean Ellenberg indicator values for light, moisture and nutrients were calculated to assess the environmental conditions.
Large herbivores are significant vectors for the long distance dispersal of seeds in various habitats, both attached to animals (epizoochory) and via gut passage (endozoochory). The majority of studies on epizoochory have examined dispersal in the fur of domesticated ungulates. Studies on wild ungulates are important to understand dispersal processes in many habitats, but rare due to methodological constraints. We studied epizoochory of seeds by European bison in an open-forest-mosaic (nutrient poor grassland and heathland, mixed forest) in NW Germany, where bison had been introduced for the purpose of nature conservation. At the study site it was possible to apply a method by which hoof material of freeranging bison was non-invasively collected. We identified a total of 1082 seeds from 32 plant species in the hoof material. The three most abundant species were Polygonum aviculare, Agrostis capillaris and Betula spp. Seed species originated from various habitat types of the study area, while the majority of seeds derived from trampled areas. Compared to the non-dispersed plant species of the study area, dispersed plant species had a higher seed longevity index, suggesting that many seeds were picked up from the soil seed bank. Epizoochory ranking indices of dispersed seed species, classifying the importance of epizoochory, revealed that transport in the fur may be of minor importance for many species, i.e. epizoochory by the hooves turned out to be negatively correlated to epizoochory in the fur. We conclude that European bison disperses a considerable number of seed species through trampling. Further research should consider epizoochory via the hooves and include integrative approaches to understand the different dispersal mechanisms by ungulates and their longterm synergetic effect on plant communities.
Translation of mRNA into a polypeptide chain is a highly accurate process. Many prokaryotic and eukaryotic viruses, however, use leaky termination of translation to optimize their coding capacity. Although growing evidence indicates the occurrence of ribosomal readthrough also in higher organisms, a biological function for the resulting extended proteins has been elucidated only in very few cases. Here, we report that in human cells programmed stop codon readthrough is used to generate peroxisomal isoforms of cytosolic enzymes. We could show for NAD-dependent lactate dehydrogenase B (LDHB) and NAD-dependent malate dehydrogenase 1 (MDH1) that translational readthrough results in C-terminally extended protein variants containing a peroxisomal targeting signal 1 (PTS1). Efficient readthrough occurs at a short sequence motif consisting of a UGA termination codon followed by the dinucleotide CU. Leaky termination at this stop codon context was observed in fungi and mammals. Comparative genome analysis allowed us to identify further readthrough-derived peroxisomal isoforms of metabolic enzymes in diverse model organisms. Overall, our study highlights that a defined stop codon context can trigger efficient ribosomal readthrough to generate dually targeted protein isoforms. We speculate that beyond peroxisomal targeting stop codon readthrough may have also other important biological functions, which remain to be elucidated.
Dendritic morphology has been shown to have a dramatic impact on neuronal function. However, population features such as the inherent variability in dendritic morphology between cells belonging to the same neuronal type are often overlooked when studying computation in neural networks. While detailed models for morphology and electrophysiology exist for many types of single neurons, the role of detailed single cell morphology in the population has not been studied quantitatively or computationally. Here we use the structural context of the neural tissue in which dendritic trees exist to drive their generation in silico. We synthesize the entire population of dentate gyrus granule cells, the most numerous cell type in the hippocampus, by growing their dendritic trees within their characteristic dendritic fields bounded by the realistic structural context of (1) the granule cell layer that contains all somata and (2) the molecular layer that contains the dendritic forest. This process enables branching statistics to be linked to larger scale neuroanatomical features. We find large differences in dendritic total length and individual path length measures as a function of location in the dentate gyrus and of somatic depth in the granule cell layer. We also predict the number of unique granule cell dendrites invading a given volume in the molecular layer. This work enables the complete population-level study of morphological properties and provides a framework to develop complex and realistic neural network models.
Freshwater ecosystems are increasingly impacted by alien invasive species which have the potential to alter various ecological interactions like predator-prey and host-parasite relationships. Here, we simultaneously examined predator-prey interactions and parasitization patterns of the highly invasive round goby (Neogobius melanostomus) in the rivers Rhine and Main in Germany. A total of 350 N. melanostomus were sampled between June and October 2011. Gut content analysis revealed a broad prey spectrum, partly reflecting temporal and local differences in prey availability. For the major food type (amphipods), species compositions were determined. Amphipod fauna consisted entirely of non-native species and was dominated by Dikerogammarus villosus in the Main and Echinogammarus trichiatus in the Rhine. However, the availability of amphipod species in the field did not reflect their relative abundance in gut contents of N. melanostomus. Only two metazoan parasites, the nematode Raphidascaris acus and the acanthocephalan Pomphorhynchus sp., were isolated from N. melanostomus in all months, whereas unionid glochidia were only detected in June and October in fish from the Main. To analyse infection pathways, we examined 17,356 amphipods and found Pomphorhynchus sp. larvae only in D. villosus in the river Rhine at a prevalence of 0.15%. Dikerogammarus villosus represented the most important amphipod prey for N. melanostomus in both rivers but parasite intensities differed between rivers, suggesting that final hosts (large predatory fishes) may influence host-parasite dynamics of N. melanostomus in its introduced range.
Pseudoperonospora cubensis, an obligate biotrophic oomycete causing devastating foliar disease in species of the Cucurbitaceae family, was never reported in seeds or transmitted by seeds. We now show that P. cubensis occurs in fruits and seeds of downy mildew-infected plants but not in fruits or seeds of healthy plants. About 6.7% of the fruits collected during 2012–2014 have developed downy mildew when homogenized and inoculated onto detached leaves and 0.9% of the seeds collected developed downy mildew when grown to the seedling stage. This is the first report showing that P. cubensis has become seed-transmitted in cucurbits. Species-specific PCR assays showed that P. cubensis occurs in ovaries, fruit seed cavity and seed embryos of cucurbits. We propose that international trade of fruits or seeds of cucurbits might be associated with the recent global change in the population structure of P. cubensis.
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.
We examine both the degree and the structural stability of inflation persistence at different quantiles of the conditional inflation distribution. Previous research focused exclusively on persistence at the conditional mean of the inflation rate. As economic theory provides reasons for inflation persistence to differ across conditional quantiles, this is a potentially severe constraint. Conventional studies of inflation persistence cannot identify changes in persistence at selected quantiles that leave persistence at the median of the distribution unchanged. Based on post-war US data we indeed find robust evidence for a structural break in persistence at all quantiles of the inflation process in the early 1980s. While prior to the 1980s inflation was not mean reverting, quantile autoregression based unit root tests suggest that since the end of the Volcker disinflation the unit root can be rejected at every quantile of the conditional inflation distribution.
Background: Emergency ultrasound is gaining importance in medical education. Widespread teaching methods are frontal presentations and hands-on training. The primary goal of our study was to evaluate the impact of frontal presentations (PS) by analysis of retained knowledge rate (RKR) and learning load (LL).
Methods: Our study was conducted during four introductory courses in emergency ultrasound covering Extended Focused Assessment with Sonography for Trauma (E-FAST) and Focused Echocardiography Evaluation in Life Support (FEEL). Standardized PS (length of 10 to 50 min) were presented by experienced trainers, who were asked to provide keywords, key messages, and images and assign a score to each. Group 1 consisted of 11 medical students with no prior ultrasound experience, and group 2 consisted of 80 physicians. Each group was audience to seven to eight standard PS and requested to answer a free text questionnaire after 0 h, 2.5 h, 24 h, and 14 days.
Results: In group 1, 168/176 questionnaires were analyzed, and 161/202 were analyzed in group 2. RKR in group 1 was 32.5%, 15%, 16%, and 12% at 0 h, 2.5 h, 24 h, and 2 weeks. The physicians' RKR were 23%, 20.5%, and 22.4% after 0, 2.5, and 24 h of a respective PS. The LL was 1.6/min for students and 1.2/min for physicians. There was no difference in RKR when comparing PS with higher and lower LL for both groups; shorter or case-based PS were associated with a higher RKR (p < 0.01).
Conclusions: Our study provides evidence that only a limited amount of information can be processed at a time. Only 12% of knowledge is retained after 2 weeks. Presentations of short duration can increase the retained knowledge rate. Therefore, frontal presentations and classroom-based ultrasound training and teaching should be adapted.
Background: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.
Findings: PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
Conclusion: PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
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.
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.
Background: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123).
Methods: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31).
Results: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years.
Conclusion: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up.
Background: Evaluation of automated attenuation-based tube potential selection and its impact on image quality and radiation dose in CT (computed tomography) examinations for cancer staging.
Methods: A total of 110 (59 men, 51 women) patients underwent chest-abdomen-pelvis CT examinations; 55 using a fixed tube potential of 120 kV/current of 210 Reference mAs (using CareDose4D), and 55 using automated attenuation-based tube potential selection (CAREkV) also using a current of 210 Reference mAs. This evaluation was performed as a single-centre, observer-blinded retrospective analysis. Image quality was assessed by two readers in consensus. Attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured or calculated for objective image evaluation. For the evaluation of radiation exposure, dose-length-product (DLP) values were compared and Size-specific dose estimates (SSDE) values were calculated.
Results: Diagnostic image quality was obtained from all patients. The median DLP (703.5 mGy · cm, range 390–2203 mGy · cm) was 7.9% lower when using the algorithm compared with the standard 120 kV protocol (median 756 mGy · cm, range 345–2267 mGy · cm). A reduction in potential to 100 kV occurred in 32 cases; therefore, these patients received significantly lower radiation exposure compared with the 120 kV protocol.
Conclusion: Automated attenuation-based tube potential selection produces good diagnostic image quality in chest-abdomen-pelvis CT and reduces the patient’s overall radiation dose by 7.9% compared to the standard 120 kV protocol.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
The European Central Bank (ECB) has finalized its comprehensive assessment of the solvency of the largest banks in the euro area and on October 26 disclosed the results of this assessment. In the present paper, Acharya and Steffen compare the outcomes of the ECB's assessment to their own benchmark stress tests conducted for 39 publically listed financial institutions that are also included in the ECB's regulatory review. The authors identify a negative correlation between their benchmark estimates for capital shortfalls and the regulatory capital shortfall, but a positive correlation between their benchmark estimates for losses under stress both in the banking book and in the trading book. They conclude that the regulatory stress test outcomes are potentially heavily affected by discretion of national regulators in measuring what is capital, and especially the use of risk-weighted assets in calculating the prudential capital requirement.
Robustness, validity, and significance of the ECB's asset quality review and stress test exercise
(2014)
As we are moving toward a eurozone banking union, the European Central Bank (ECB) is going to take over the regulatory oversight of 128 banks in November 2014. To that end, the ECB conducted a comprehensive assessment of these banks, which included an asset quality review (AQR) and a stress test. The fundamental question is how accurately will the financial condition of these banks have been assessed by the ECB when it commences its regulatory oversight? And, can the comprehensive assessment lead to a full repair of banks’ balance sheets so that the ECB takes over financially sound banks and is the necessary regulation in place to facilitate this? Overall, the evidence presented in this paper based on the design of the comprehensive assessment as well as own stress test exercises suggest that the ECB’s assessment might not comprehensively deal with the problems in the financial sector and risks may remain that will pose substantial threats to financial stability in the eurozone.
On average, "young" people underestimate whereas "old" people overestimate their chances to survive into the future. We adopt a Bayesian learning model of ambiguous survival beliefs which replicates these patterns. The model is embedded within a non-expected utility model of life-cycle consumption and saving. Our analysis shows that agents with ambiguous survival beliefs (i) save less than originally planned, (ii) exhibit undersaving at younger ages, and (iii) hold larger amounts of assets in old age than their rational expectations counterparts who correctly assess their survival probabilities. Our ambiguity-driven model therefore simultaneously accounts for three important empirical findings on household saving behavior.
This paper investigates extensions of the method of endogenous gridpoints (ENDGM) introduced by Carroll (2006) to higher dimensions with more than one continuous endogenous state variable. We compare three different categories of algorithms: (i) the conventional method with exogenous grids (EXOGM), (ii) the pure method of endogenous gridpoints (ENDGM) and (iii) a hybrid method (HYBGM). ENDGM comes along with Delaunay interpolation on irregular grids. Comparison of methods is done by evaluating speed and accuracy. We find that HYBGM and ENDGM both dominate EXOGM. In an infinite horizon model, ENDGM also always dominates HYBGM. In a finite horizon model, the choice between HYBGM and ENDGM depends on the number of gridpoints in each dimension. With less than 150 gridpoints in each dimension ENDGM is faster than HYBGM, and vice versa. For a standard choice of 25 to 50 gridpoints in each dimension, ENDGM is 1.4 to 1.7 times faster than HYBGM in the finite horizon version and 2.4 to 2.5 times faster in the infinite horizon version of the model.
When markets are incomplete, social security can partially insure against idiosyncratic and aggregate risks. We incorporate both risks into an analytically tractable model with two overlapping generations and demonstrate that they interact over the life-cycle. The interactions appear even though the two risks are orthogonal and they amplify the welfare consequences of introducing social security. On the one hand, the interactions increase the welfare benefits from insurance. On the other hand, they can in- or decrease the welfare costs from crowding out of capital formation. This ambiguous effect on crowding out means that the net effect of these two channels is positive, hence the interactions of risks increase the total welfare benefits of social security.
We outline a procedure for consistent estimation of marginal and joint default risk in the euro area financial system. We interpret the latter risk as the intrinsic financial system fragility and derive several systemic fragility indicators for euro area banks and sovereigns, based on CDS prices. Our analysis documents that although the fragility of the euro area banking system had started to deteriorate before Lehman Brothers' file for bankruptcy, investors did not expect the crisis to affect euro area sovereigns' solvency until September 2008. Since then, and especially after November 2009, joint sovereign default risk has outpaced the rise of systemic risk within the banking system.
This paper studies the effect of graduating from college on lifetime earnings. We develop a quantitative model of college choice with uncertain graduation. Departing from much of the literature, we model in detail how students progress through college. This allows us to parameterize the model using transcript data. College transcripts reveal substantial and persistent heterogeneity in students’ credit accumulation rates that are strongly related to graduation outcomes. From this data, the model infers a large ability gap between college graduates and high school graduates that accounts for 54% of the college lifetime earnings premium.
his paper distils three lessons for bank regulation from the experience of the 2009-12 euro-area financial crisis. First, it highlights the key role that sovereign debt exposures of banks have played in the feedback loop between bank and fiscal distress, and inquires how the regulation of banks’ sovereign exposures in the euro area should be changed to mitigate this feedback loop in the future. Second, it explores the relationship between the forbearance of non-performing loans by European banks and the tendency of EU regulators to rescue rather than resolving distressed banks, and asks to what extent the new regulatory framework of the euro-area “banking union” can be expected to mitigate excessive forbearance and facilitate resolution of insolvent banks. Finally, the paper highlights that capital requirements based on the ratio of Tier-1 capital to banks’ risk-weighted assets were massively gamed by large banks, which engaged in various forms of regulatory arbitrage to minimize their capital charges while expanding leverage. This argues in favor of relying on a set of simpler and more robust indicators to determine banks’ capital shortfall, such as book and market leverage ratios.
We study a model where some investors ("hedgers") are bad at information processing, while others ("speculators") have superior information-processing ability and trade purely to exploit it. The disclosure of financial information induces a trade externality: if speculators refrain from trading, hedgers do the same, depressing the asset price. Market transparency reinforces this mechanism, by making speculators' trades more visible to hedgers. As a consequence, issuers will oppose both the disclosure of fundamentals and trading transparency. Issuers may either under- or over-provide information compared to the socially efficient level if speculators have more bargaining power than hedgers, while they never under-provide it otherwise. When hedgers have low financial literacy, forbidding their access to the market may be socially efficient.
Most simulated micro-founded macro models use solely consumer-demand aggregates in order to estimate deep economy-wide preference parameters, which are useful for policy evaluation. The underlying demand-aggregation properties that this approach requires, should be easy to empirically disprove: since household-consumption choices differ for households with more members, aggregation can be rejected if appropriate data violate an affine equation regarding how much individuals benefit from within-household sharing of goods. We develop a survey method that tests the validity of this equation, without utility-estimation restrictions via models. Surprisingly, in six countries, this equation is not rejected, lending support to using consumer-demand aggregates.
Riley (1979)'s reactive equilibrium concept addresses problems of equilibrium existence in competitive markets with adverse selection. The game-theoretic interpretation of the reactive equilibrium concept in Engers and Fernandez (1987) yields the Rothschild-Stiglitz (1976)/Riley (1979) allocation as an equilibrium allocation, however multiplicity of equilibrium emerges. In this note we imbed the reactive equilibrium's logic in a dynamic market context with active consumers. We show that the Riley/Rothschild-Stiglitz contracts constitute the unique equilibrium allocation in any pure strategy subgame perfect Nash equilibrium.
Background: According to current taxonomy only three out of 27 Sinohimalayan leaf warbler species (Phylloscopidae) are considered genetically uniform across their entire breeding range along the Southeastern margin of the Qinghai-Tibetan Plateau, the Buff-barred Warbler (Phylloscopus pulcher) being one of them. Because marked differentiation among Himalayan and Chinese populations has been recently demonstrated for a number of Phylloscopus species (or sister species) we investigated the intraspecific variation of a mitochondrial gene, songs and morphology of P. pulcher in a phylogeographic approach.
Methods: We sequenced a fragment of the mitochondrial cytochrome b, reconstructed haplotype networks and analyzed DNA polymorphism among Himalayan and Chinese populations. We measured time and frequency parameters of two distinct song types and analyzed among population-differentiation in a principal component analysis and a discriminant analysis. We also compared measurements of body size dimensions taken from museum specimens.
Results: The mitochondrial haplotype network (cytb) was divided into two distinct clusters corresponding to geographic origin of samples. Pairwise genetic distances among Himalayan and Chinese mtDNA lineages account for 1.3% which coincides with Pleistocene lineage separation at roughly 650,000 years ago. Genetic diversity is slightly higher in the Chinese part of the species’ range with respect to haplotype and nucleotide diversity while the less diversified Himalayan population lineage shows signs of recent range expansion. The vocal repertoire of P. pulcher comprises two distinct verse types that are combined with short interspersed click notes to long continuous song displays. Trill verse types showed significant differences among regions in almost all measured frequency and time parameters: Chinese males displayed more rapid and more broad-banded trills at a lower pitch. In contrast, warbling verse types showed a distinctively different structure among regions: Himalayan songs consisted of repeated syllables while Chinese songs comprised repetitions of single, long and strongly modulated elements. Subtle morphological differences among specimens from the two study regions could only be confirmed for plumage coloration but not for metric characters.
Conclusions: Based on the genetic and bioacoustic distinctiveness of Chinese Buff-barred Warbler populations, we recommend that the name Phylloscopus pulcher vegetus Bangs, 1913 should be re-validated for this taxon.
Herbaceous ground vegetation is an important pool of biomass and nutrients, which is also used as the major forage source for wild ungulates. Up to now no standard methods exist to estimate herbaceous biomass on a landscape level for temperate forests, which are characterised by deciduous trees with closed canopies. Quantity and quality of the herbaceous forage accessible to herbivores can be estimated from estimated cover in vegetation plot data and information on biomass and element concentrations in plant species. Vegetation was sampled stratified by community types and forest developmental phases in Bavarian Forst National Park, Germany. We adopted the PhytoCalc model to estimate biomass and bioelement stocks from vegetation plot data and adjusted species assignments and absolute levels of biomass to the conditions in the national park. We categorised attractiveness of plant species as forage for red deer (Cervus elaphus) and roe deer (Capreolus capreolus). Multiple controls of total biomass and of plant groups (graminoids, ferns, herbs, Vaccinium, Rubus) were studied by stepwise regression against stand and environmental predictors. Herbaceous mass had a highly skewed distribution in the park, with 75% of plots having less than 231 g*m-2 of biomass or 24 g*m-2 of raw protein. Contributions of plant groups were site-dependent and variable, but decreased in the order Vaccinium-graminoids-Rubus-herbs-ferns. Biomass appeared to be controlled by deciduous tree cover, by total cover of canopy and coarse woody debris and by site quality, with nutrient-poor, high elevation sites having higher herb biomass. As a consequence, montane beech forests offered less forage mass than coniferous communities of high elevations and mires. Stand disturbances by bark beetles and the corresponding forest developmental phases had no systematic effects on total biomass.
The endemic Floridian milliped genus, Floridobolus Causey, 1957, more closely related to tylobolinines in the western United States (US), Mexico, and Guatemala than syntopic spirobolines, is incorporated into Spirobolidae (Spirobolida: Spirobolidea). With taxonomic priority by one year, its monotypic family is reduced to Floridobolinae, n. stat., comprising Floridobolini and Tylobolini, n. stats., the counterpart to Spirobolinae, comprising Spirobolini and Aztecolini, n. tribe; relationships are Floridobolini + (Tylobolini + (Aztecolini + Spirobolini)). Like F. penneri Causey, 1957, 208 km (130 mi) to the south in the Lake Wales Ridge, Polk and Highlands counties (cos.), F. orini n. sp., inhabits “Big Scrub” environments in the Ocala National Forest, Marion Co. Biogeographic reconstructions, compatible with broader hypotheses on the class’ evolutionary history, indicate that, from a presumptive source area in northern Mexico where the subfamilies overlap, spirobolid stock penetrated the “proto-US” four times, once per tribe, before the Western Interior Seaway developed in the Cretaceous Period, Mesozoic Era. Three expansions headed northeastward into future “Appalachia,” from which taxa spread southward as the Seaway receded. Floridobolini, the fi rst invader, had to be in “proto-Georgia” and positioned to penetrate Florida when the sand dunes that comprise the “Central Highlands” emerged from the sea in the Oligocene (Cenozoic), ~25 mya. As sea levels rose and fell, the dunes fragmented into islands and the subcontinuous Floridobolus population was partitioned. The southernmost became F. penneri; F. orini inhabited a northern island; and a graduate student is investigating other insular remnants for additional species. Shortly after Floridobolini began spreading, Hiltonius/ Tylobolini arose and expanded both southward to Guatemala and northwestward to California; Tylobolus Cook, 1904, diverged in the latter area and dispersed northward to Washington and eastward to Utah/Arizona. The third invader, and the second to disperse northeastward, was Aztecolini, which probably eradicated Floridobolini from some of its established range and was partitioned into Mexican (Aztecolus Chamberlin, 1943) and US (Chicobolus Chamberlin, 1947) taxa by the Seaway. The fi nal invader, Spirobolini, dispersed northwestward and northeastward to both the Pacifi c and Atlantic coasts; instead of Trans-Beringia, we prefer penetration of the Asian part of “Asiamerica,” when it temporarily formed during the Cretaceous, to explain the Mongolian fossil genus, Gobiulus Dzik, 1975, herein assigned to Tylobolini, and the occurrence of Spirobolus Brandt, 1833, in China and Taiwan today. In the east, Narceus Rafi nesque, 1820, spread across Appalachia, eradicated most remaining populations of Floridobolus and Chicobolus, and expanded to Maine and Québec after retreat of the Wisconsin glaciation. Chicobolus and Narceus also penetrated earliest Florida; the former established itself in the Central Highlands, spread through the widening peninsula as sea levels fell, and remained on insular refugia when waters rose. Apparently fueled by the different Floridian environments, Narceus underwent time-consuming speciation; consequently, Floridobolus and Chicobolus still survive on the peninsula, and an allopatric population of the latter inhabits coastal South Carolina. However, N. gordanus (Chamberlin, 1943) occurs syntopically with both in peninsular Florida and may be actively eradicating them from their last stronghold. Trigoniulus niger, takahasii, and segmentatus, all by Takakuwa, 1940, are removed from Spirobolidae and returned toTrigoniulidae (Trigoniulidea). New records in the Appendix include the fi rst of Aztecolus from Durango and Jalisco, Mexico.
Background: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
Methods: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.
Results: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
Conclusions: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/− irinotecan in stage II/III colorectal cancer.
Background: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330].
Methods: Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72.
Results: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study.
Conclusions: Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.
Background: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV.
Methods: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population.
Results: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients.
Conclusion: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents.
Background: The federal state of Hesse, Germany, introduced a laboratory-based reporting scheme for carbapenem-resistant organisms (CROs).
Method: The results of the first year of mandated reporting of CROs from April 2012 through March 2013 to the Public Health Authority of Frankfurt/Main, responsible for a population of 700,000 inhabitants, are described.
Results: Within a period of 12 months 243 CROs were notified to the health authority. Of these 213 isolates had been reported from 16 of the 17 hospitals in Frankfurt/Main, 6 from ambulatory settings and 24 from clinics outside of Frankfurt/Main. Mean incidence rate per 1,000 patient days in hospitals was 0.138 (range 0.02-0.28).
Conclusion: In Frankfurt/Main almost all hospitals have reported CROs in the study period though the frequency of isolation varies strongly and many facilities only report CROs sporadically. Molecular data indicate a high diversity of different carbapenemases. Autochthonous transmission must be assumed despite the absence of major outbreaks. Rapid and coordinated efforts by clinicians and health departments are crucial to control the spread of CRO infections. The mandatory reporting scheme provides important data to guide the implementation of preventive measures.
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.
(Micro)plastics in the aquatic environment are an issue of emerging concern. However, to date, there is considerable lack of knowledge on the abundance and toxicity of plastic debris in aquatic ecosystems, especially with regard to the freshwater situation. In this editorial, we briefly discuss important aspects of the research on environmental (micro)plastics to stimulate research and call for papers.
Background: Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication.
Findings: Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages.
Conclusions: These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity.