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The neutron capture cross section of 58Ni was measured at the neutron time of flight facility n_TOF at CERN, from 27 meV to 400 keV neutron energy. Special care has been taken to identify all the possible sources of background, with the so-called neutron background obtained for the first time using high-precision GEANT4 simulations. The energy range up to 122 keV was treated as the resolved resonance region, where 51 resonances were identified and analyzed by a multilevel R-matrix code SAMMY. Above 122 keV the code SESH was used in analyzing the unresolved resonance region of the capture yield. Maxwellian averaged cross sections were calculated in the temperature range of kT = 5 – 100 keV, and their astrophysical implications were investigated.
We performed a survey of grassland communities in the Ukrainian Carpathians with the aim of: (1) syntaxonomically classifying the meso- and subxerophilous grassland vegetation; (2) analysing the main gradients in their species composition; (3) estimating the effect of selected environmental factors on grassland species composition; (4) assessing the species richness of vascular plants and bryophytes in relation to the measured environmental variables. We collected 46 phytosociological relevés during the growing seasons of 2010 and 2011. Species composition and species richness were studied at two spatial scales (1 m² and 16 m²) in relation to soil parameters (soil depth, pH (KCl), content of P, K, Mg, N and C), management regime (mowing, grazing, ploughing in the past and burning), and other factors (altitude, litter cover, open soil, inclination, solar radiation and animal excrement). Seven grassland types were distinguished belonging to 3 classes and 4 alliances, namely the Nardetea strictae including the Violion caninae (mesic pastures at altitudes of 400–600 m mostly on moderate slopes) and the Nardo strictae-Agrostion tenuis (grasslands on moderate slopes at altitudes of 700–900 m usually managed by mowing and grazing the aftermath); the Molinio-Arrhenatheretea, including the Arrhenatherion elatioris (submontane grasslands originated mostly on former fields after their abandonment in the past) and the Cynosurion cristati (intensive pastures); and the Festuco-Brometea including the Cirsio-Brachypodion pinnati (abandoned grasslands dominated by Brachypodium pinnatum and Inula salicina). Detrended correspondence analysis indicated that the major compositional turnover was related to altitude and soil reaction. A canonical correspondence analysis confirmed that altitude had the strongest effect on species composition in the analysed dataset, followed by management treatments (former ploughing, grazing intensity). For vascular plant species richness, regression tree analysis identified grazing intensity as the most important predictor at the 1 m² scale. At the 16 m² scale, soil humus content was evaluated as the most important predictor of vascular plant species richness, followed by litter cover and grazing intensity. The number of bryophytes was not determined by the studied environmental factors at either of the two spatial scales. Although the number of analysed relevés in this study was limited, our results significantly contribute to the understanding of submontane grasslands in the Ukrainian Carpathians.
Background: The treatment of different skin conditions with spa waters is a long tradition dating back to at least late Hellenism. Interestingly, independent scientific examinations studying the effect of spa waters are scarce.
Objective: In the present in vitro study, we compared the effect of culture media supplemented with (a) thermal spa waters (La Roche-Posay, Avène) and (b) two natural mineral drinking waters (Heppinger, Adelholzener) on physiological parameters in HaCaT keratinocytes.
Methods: The different medium preparations were investigated with regard to cell proliferation and cell damage. Moreover, the impact on inflammation parameters with and without ultraviolet B (UVB) irradiation was examined.
Results: Two popular thermal spring waters were found to suppress cell proliferation and cell damage. Moreover, these waters reversed the induction of interleukin-6, as measured using enzyme-linked immunosorbent assay and promoter transactivation, and the formation of reactive oxygen species after UVB stimulation. Of note, the two natural mineral waters, which are distributed as drinking waters, had some effect on the above-mentioned parameters but to a lesser extent.
Conclusion: In summary, our results show that spa waters, and particularly those derived from thermal springs, reduce parameters associated with inflammation. It seems likely that trace elements such as selenium and zinc are critical for the observed effects.
Modern experiments in heavy ion collisions operate with huge data rates that can not be fully stored on the currently available storage devices. Therefore the data flow should be reduced by selecting those collisions that potentially carry the information of the physics interest. The future CBM experiment will have no simple criteria for selecting such collisions and requires the full online reconstruction of the collision topology including reconstruction of short-lived particles.
In this work the KF Particle Finder package for online reconstruction and selection of short-lived particles is proposed and developed. It reconstructs more than 70 decays, covering signals from all the physics cases of the CBM experiment: strange particles, strange resonances, hypernuclei, low mass vector mesons, charmonium, and open-charm particles.
The package is based on the Kalman filter method providing a full set of the particle parameters together with their errors including position, momentum, mass, energy, lifetime, etc. It shows a high quality of the reconstructed particles, high efficiencies, and high signal to background ratios.
The KF Particle Finder is extremely fast for achieving the reconstruction speed of 1.5 ms per minimum-bias AuAu collision at 25 AGeV beam energy on single CPU core. It is fully vectorized and parallelized and shows a strong linear scalability on the many-core architectures of up to 80 cores. It also scales within the First Level Event Selection package on the many-core clusters up to 3200 cores.
The developed KF Particle Finder package is a universal platform for short- lived particle reconstruction, physics analysis and online selection.
Background: The West African country of Burkina Faso (BFA) is an example for the enduring importance of traditional plant use today. A large proportion of its 17 million inhabitants lives in rural communities and strongly depends on local plant products for their livelihood. However, literature on traditional plant use is still scarce and a comprehensive analysis for the country is still missing.
Methods: In this study we combine the information of a recently published plant checklist with information from ethnobotanical literature for a comprehensive, national scale analysis of plant use in Burkina Faso. We quantify the application of plant species in 10 different use categories, evaluate plant use on a plant family level and use the relative importance index to rank all species in the country according to their usefulness. We focus on traditional medicine and quantify the use of plants as remedy against 22 classes of health disorders, evaluate plant use in traditional medicine on the level of plant families and rank all species used in traditional medicine according to their respective usefulness.
Results: A total of 1033 species (50%) in Burkina Faso had a documented use. Traditional medicine, human nutrition and animal fodder were the most important use categories. The 12 most common plant families in BFA differed considerably in their usefulness and application. Fabaceae, Poaceae and Malvaceae were the plant families with the most used species. In this study Khaya senegalensis, Adansonia digitata and Diospyros mespiliformis were ranked the top useful plants in BFA. Infections/Infestations, digestive system disorders and genitourinary disorders are the health problems most commonly addressed with medicinal plants. Fabaceae, Poaceae, Asteraceae, Apocynaceae, Malvaceae and Rubiaceae were the most important plant families in traditional medicine. Tamarindus indica, Vitellaria paradoxa and Adansonia digitata were ranked the most important medicinal plants.
Conclusions: The national-scale analysis revealed systematic patterns of traditional plant use throughout BFA. These results are of interest for applied research, as a detailed knowledge of traditional plant use can a) help to communicate conservation needs and b) facilitate future research on drug screening.
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Using the MAXENT algorithm, we developed risk maps for eight invasive plant species in southern Transylvania, Romania, a region undergoing drastic land-use changes. Our findings show that invasion risk increased with landscape heterogeneity. Roads and agricultural areas were most prone to invasion, whereas forests were least at risk.
Seed production varies from year-to-year in most species. Factors influencing this variation can include pollination and dispersal mechanisms, seed predation and resource availability. Here we examine a long-term (12– year) photographic record of seed cone production for the Australian endemic conifer Wollemia nobilis (Araucariaceae). Coefficient of variation (a commonly used measure of variation in seed production) was low for the two trees analysed, compared with published values for other polycarpic plants. Nevertheless, cone production decreased with increasing spring minimum temperatures (during pollination) and increased with summer total rainfall (during cone initiation). Hence, Wollemia nobilis cone production was correlated with weather, in line with the resource-matching hypothesis. Impacts of variation in cone production on the Wollemia nobilis population are likely to be buffered by the shade-tolerant, slow-growing juvenile life stage of Wollemia nobilis.
The advent of improved experimental and theoretical techniques has brought a lot of attention to the electric dipole (E1) response of atomic nuclei in the last decade. The extensive studies have led to the observation and interpretation of a concentration of E1 strength energetically below the Giant Dipole Resonance in many nuclei. This phenomenon is commonly denoted as Pygmy Dipole Resonance (PDR). This contribution will summarize the most important results obtained using different experimental probes, define the challenges to gain a deeper understanding of the excitations, and discuss the newest experimental developments.
Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complex membrane protein complexes. The enzyme contributes substantially to oxidative energy-conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. Here, we report the X-ray structure of mitochondrial complex I at 3.6- 3.9 Å resolution describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site rendering support for a two-state stabilization-change mechanism of protonpumping.
We investigate charmonium production in Pb + Pb collisions at LHC beam energy Elab=2.76A TeV at fixed-target experiment (√sNN = 72 GeV). In the frame of a transport approach including cold and hot nuclear matter effects on charmonium evolution, we focus on the antishadowing effect on the nuclear modification factors RAA and rAA for the J/ψ yield and transverse momentum. The yield is more suppressed at less forward rapidity (ylab ≃ 2) than that at very forward rapidity (ylab ≃ 4) due to the shadowing and antishadowing in different rapidity bins.
The spider collection of the Zoological Museum of the Iranian Research Institute of Plant Protection was studied during the summer of 2014. A total of 180 specimens, belonging to 25 families, 60 genera and 77 species were documented. Of these, the following nine species could be recorded from Iran for the first time: Alopecosa schmidti (Hahn, 1835), Anyphaena accentuata (Walckenaer, 1802), Crustulina sticta (O. P.-Cambridge, 1861), Enoplognatha mordax (Thorell, 1875), Ero tuberculata (De Geer, 1778), Salticus zebraneus (C. L. Koch, 1837), Pardosa aenigmatica Tongiorgi, 1966, Pardosa nebulosa (Thorell, 1872) and Tmarus piochardi (Simon, 1866). Morphological and geographical data are provided for the newly recorded species. Two species (P. aenigmatica and T. piochardi) are illustrated and a map of localities is given.
Previous study of the setae covering the opisthosoma of ground spiders shows that the morphology of the covering setae is genus-specific. The present study pursues the description of covering setae across the whole Gnaphosidae family using SEM. A detailed morphology of the setae of ground spiders (Araneae, Gnaphosidae) is presented. The six major types of covering setae recognized among gnaphosid spiders are squamose, plumose, lanceolate, pinnate, arborate and sicate setae. Squamose setae are characteristic for Micaria lenzi and Nauhea tapa. Plumose setae are more common in ground spiders and occur in the genera Drassodes, Haplodrassus, Anagraphis, Nodocion, Zelotes and the species Berlandina caspica, Nomisia aussereri, Minosiella intermedia, Sosticus loricatus, Leptodrassus memorialis, Intruda signata, Parasyrisca caucasica, Scopoides catharius, Echemoides tofo, Zimiromus medius, Encoptarthria echemophthalma, Apodrassodes trancas, Apopyllus silvestri, Hemicloea sundevalli, Zelanda erebus, Orodrassus assimilis, Callilepis nocturna and Synaphosus turanicus. The species Matua valida, Anzacia gemmea, Hypodrassodes maoricus, Homoeothele micans and Scotophaeus blackwalli have lanceolate setae. Spiders of the genus Gnaphosa have pinnate setae. Fedotovia uzbekistanica has arborate setae. The species Cesonia bilineata, Herpyllus propinquus, Litopyllus temporarius, Aphantaulax seminigra and Kishidaia conspicua have sicate setae. Some genera, such as Drassodes and Synaphosus, have a combination of different types of setae on their opisthosoma, whereas others, like Eilica sp., Laronius erawan, Urozelotes rusticus, have no covering setae on their opisthosoma at all. This study reveals the existence of different types of covering setae and provides a set of characteristics important for the classification and phylogenetic analysis of Gnaphosidae.
There are only 3 methods for the production of heavy and superheavy (SH) nuclei, namely, fusion reactions, a sequence of neutron capture and beta(-) decay and multinucleon transfer reactions. Low values of the fusion cross sections and very short half-lives of nuclei with Z<120 put obstacles in synthesis of new elements. At the same time, an important area of SH isotopes located between those produced in the cold and hot fusion reactions remains unstudied yet. This gap could be filled in fusion reactions of 48Ca with available lighter isotopes of Pu, Am, and Cm. New neutron-enriched isotopes of SH elements may be produced with the use of a 48Ca beam if a 250Cm target would be prepared. In this case we get a real chance to reach the island of stability owing to a possible beta(+) decay of 291114 and 287112 nuclei formed in this reaction with a cross section of about 0.8 pb. A macroscopic amount of the long-living SH nuclei located at the island of stability may be produced by using the pulsed nuclear reactors of the next generation only if the neutron fluence per pulse will be increased by about three orders of magnitude. Multinucleon transfer processes look quite promising for the production and study of neutron-rich heavy nuclei located in upper part of the nuclear map not reachable by other reaction mechanisms. Reactions with actinide beams and targets are of special interest for synthesis of new neutron-enriched transfermium nuclei and not-yet-known nuclei with closed neutron shell N=126 having the largest impact on the astrophysical r-process. The estimated cross sections for the production of these nuclei allows one to plan such experiments at currently available accelerators.
Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles.
Four new species of the genus Caccothryptus (Coleoptera: Limnichidae) are described: C. taiwanus from Taiwan; C. orion from Okinawa; C. tibetanus and C. chayuensis from Tibet. All the species belong to the testudo species group (sensu Hernando & Ribera 2014). Additional specimen data and an updated species list are also given, and C. testudo Champion, 1923 is newly recorded from Thailand.
This book, the first of its kind on Anglophone Cameroon, brings significant local context into the practice of law particularly at a juncture when civil practice has been radically altered by Cameroon's ongoing effort at harmonization of both the substantive and procedural laws applicable in the courts. The book covers a wide spectrum of topics including: the commencement of civil actions, jurisdiction, simplified recovery procedures and measures of execution, provisional execution and stay of execution. It provides a detailed analysis of the relevant rules of court applicable in both the high court and court of appeal. One of its major strengths lies in its use of recent cases to demonstrate the way Cameroonian judges have dealt with local procedural laws, as well as how the differences between Cameroonian indigenous rules of practice and those imported particularly from Nigeria and England are reconciled.
Methylation of ribose sugars at the 2′-OH group is one of the major chemical modifications in rRNA, and is catalyzed by snoRNA directed C/D box snoRNPs. Previous biochemical and computational analyses of the C/D box snoRNAs have identified and mapped a large number of 2′-OH ribose methylations in rRNAs. In the present study, we systematically analyzed ribose methylations of 18S rRNA in Saccharomyces cerevisiae, using mung bean nuclease protection assay and RP-HPLC. Unexpectedly, we identified a hitherto unknown ribose methylation at position G562 in the helix 18 of 5′ central domain of yeast 18S rRNA. Furthermore, we identified snR40 as being responsible to guide snoRNP complex to catalyze G562 ribose methylation, which makes it only second snoRNA known so far to target three ribose methylation sites: Gm562, Gm1271 in 18S rRNA, and Um898 in 25S rRNA. Our sequence and mutational analysis of snR40 revealed that snR40 uses the same D′ box and methylation guide sequence for both Gm562 and Gm1271 methylation. With the identification of Gm562 and its corresponding snoRNA, complete set of ribose methylations of 18S rRNA and their corresponding snoRNAs have finally been established opening great prospects to understand the physiological function of these modifications.
Protein–protein interactions are at the core of all cellular functions and dynamic alterations in protein interactions regulate cellular signaling. In the last decade, mass spectrometry (MS)-based proteomics has delivered unprecedented insights into human protein interaction networks. Affinity purification-MS (AP-MS) has been extensively employed for focused and high-throughput studies of steady state protein–protein interactions. Future challenges remain in mapping transient protein interactions after cellular perturbations as well as in resolving the spatial organization of protein interaction networks. AP-MS can be combined with quantitative proteomics approaches to determine the relative abundance of purified proteins in different conditions, thereby enabling the identification of transient protein interactions. In addition to affinity purification, methods based on protein co-fractionation have been combined with quantitative MS to map transient protein interactions during cellular signaling. More recently, approaches based on proximity tagging that preserve the spatial dimension of protein interaction networks have been introduced. Here, we provide an overview of MS-based methods for analyzing protein–protein interactions with a focus on approaches that aim to dissect the temporal and spatial aspects of protein interaction networks.
Mechanism of Na+-dependent citrate transport from the structure of an asymmetrical CitS dimer
(2015)
The common human pathogen Salmonella enterica takes up citrate as a nutrient via the sodium symporter SeCitS. Uniquely, our 2.5 Å x-ray structure of the SeCitS dimer shows three different conformations of the active protomer. One protomer is in the outside-facing state. Two are in different inside-facing states. All three states resolve the substrates in their respective binding environments. Together with comprehensive functional studies on reconstituted proteoliposomes, the structures explain the transport mechanism in detail. Our results indicate a six-step process, with a rigid-body 31° rotation of a helix bundle that translocates the bound substrates by 16 Å across the membrane. Similar transport mechanisms may apply to a wide variety of related and unrelated secondary transporters, including important drug targets.
The design of rainwater harvesting based gardens requires considering current climate but also climate change during the lifespan of the facility. The goal of this study is to present an approach for designing garden variants that can be safely supplied with harvested rainwater, taking into account climate change and adaptation measures. In addition, the study presents a methodology to quantify the effects of climate change on rainwater harvesting based gardening. Results of the study may not be accurate due to the assumptions made for climate projections and may need to be further refined. We used a tank flow model and an irrigation water model. Then we established three simple climate scenarios and analyzed the impact of climate change on harvested rain and horticulture production for a semi-arid region in northern Namibia. In the two climate scenarios with decreased precipitation and medium/high temperature increase; adaptation measures are required to avoid substantial decreases in horticulture production. The study found that the most promising adaptation measures to sustain yields and revenues are a more water efficient garden variant and an enlargement of the roof size. The proposed measures can partly or completely compensate the negative impacts of climate change.
Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between multiple neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking the multivariate nature of interactions: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable because of the combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm uses interaction delays reconstructed for directed bivariate interactions to tag potentially spurious edges on the basis of their timing signatures in the context of the surrounding network. Such tagged interactions may then be pruned, which produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation in MATLAB to test the algorithm’s performance on simulated networks as well as networks derived from magnetoencephalographic data. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data-efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible.
In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.
BACKGROUND: Human SAMHD1 is a triphosphohydrolase that restricts the replication of retroviruses, retroelements and DNA viruses in noncycling cells. While modes of action have been extensively described for human SAMHD1, only little is known about the regulation of SAMHD1 in the mouse. Here, we characterize the antiviral activity of murine SAMHD1 with the help of knockout mice to shed light on the regulation and the mechanism of the SAMHD1 restriction and to validate the SAMHD1 knockout mouse model for the use in future infectivity studies.
RESULTS: We found that endogenous mouse SAMHD1 restricts not only HIV-1 but also MLV reporter virus infection at the level of reverse transcription in primary myeloid cells. Similar to the human protein, the antiviral activity of murine SAMHD1 is regulated through phosphorylation at threonine 603 and is limited to nondividing cells. Comparing the susceptibility to infection with intracellular dNTP levels and SAMHD1 phosphorylation in different cell types shows that both functions are important determinants of the antiviral activity of murine SAMHD1. In contrast, we found the proposed RNase activity of SAMHD1 to be less important and could not detect any effect of mouse or human SAMHD1 on the level of incoming viral RNA.
CONCLUSION: Our findings show that SAMHD1 in the mouse blocks retroviral infection at the level of reverse transcription and is regulated through cell cycle-dependent phosphorylation. We show that the antiviral restriction mediated by murine SAMHD1 is mechanistically similar to what is known for the human protein, making the SAMHD1 knockout mouse model a valuable tool to characterize the influence of SAMHD1 on the replication of different viruses in vivo.
In spite of enormous climatic differences between Burkina Faso and Germany, 20 species belong to the spontaneous flora of both countries, i.e. 1% of the flora of Burkina Faso and 0.15 % of the German flora. All of them are either ruderal and segetal species (16) or water and reed plants (4). All of the 16 ruderals/segetals are therophytes. From a recent point of view, most of the 20 species can be classified as cosmopolitan, because they cover three and more floristic zones, and/or at least three climatic zones, and/or are represented in at least three continents. Although Burkina Faso has a semi-arid climate, none of the species can be called a sclero- or xerophyte. Therefore, in Burkina Faso, all are more or less bound to habitats at least temporarily flooded or to humid soils. In Germany, however, the concerned ruderals, with one exception, are indicators of medium dry or dry habitats.
Moving beyond existing approaches that largely deal with the biophysical consequences of climate change realities in Africa, this book explores an alternative perspective that traces climate change as a travelling idea. It focuses on how globally constructed discourses on climate change find their way to the local level in the Bamenda Grassfields of Cameroon, thereby seeking to understand how these discursive practices lead to social transformations, and to new configurations of power. In the translation process from the 'global' to the 'local' level a continuous modification and appropriation of the idea of climate change takes place that finally leads to a concrete implementation of climate change related projects and sensitization campaigns. Hence, it is argued that in this increasingly interconnected and mediated world people in Africa (and elsewhere in the world) do not solely adapt to a changing climate, but also adapt to a changing discourse about the climate. Travelling between traditional rulers and their palaces, to the world of NGOs, journalists and ordinary farmers this study brings the reader on a captivating journey, that reveals how climate change engages in a variety of ways with different lifeworlds, revitalizes local cosmologies, gives birth to a new development paradigm, and moreover how it evokes apocalyptic anxieties and trajectories of blame at the grassroots level.
The demography of the alpine pioneer species Saxifraga aizoides was investigated along a successional gradient at the Rotmoos glacier foreland (2,330–2,450 m a.s.l., Obergurgl, Ötztal, Austria) from recently deglaciated areas to advanced successional stages. A basic hypothesis of our study was that fecundity might play an essential role for population growth rate on the youngest site and become of minor importance at advanced successional stages. A matrix modelling approach was performed to calculate the main demographic parameters on 6, 33, and 81 year old moraines. Our results partly confirmed the prediction of the larger role of fecundity on the youngest sites. Here, seedling mortality was lower compared to the older sites, and the reproductive success was significantly higher. All in all, Saxifraga aizoides mainly follows a "persistence strategy" from the beginning, characterized by the fact that large individuals did not undergo mortality at the recently deglaciated site. However, in the long term a population decline will occur due to plant age and changes of environmental conditions along the successional gradient.
The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of ∼6 μm, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 μm RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.
An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1–47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1–21.0 % and CTM v2: 15.0–32.3 %; CVs at 25 IU/ml: RealTime 17.6–34.9 % and CTM v2 28.2–54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
In many neural systems anatomical motifs are present repeatedly, but despite their structural similarity they can serve very different tasks. A prime example for such a motif is the canonical microcircuit of six-layered neo-cortex, which is repeated across cortical areas, and is involved in a number of different tasks (e.g. sensory, cognitive, or motor tasks). This observation has spawned interest in finding a common underlying principle, a ‘goal function’, of information processing implemented in this structure. By definition such a goal function, if universal, cannot be cast in processing-domain specific language (e.g. ‘edge filtering’, ‘working memory’). Thus, to formulate such a principle, we have to use a domain-independent framework. Information theory offers such a framework. However, while the classical framework of information theory focuses on the relation between one input and one output (Shannon’s mutual information), we argue that neural information processing crucially depends on the combination of multiple inputs to create the output of a processor. To account for this, we use a very recent extension of Shannon Information theory, called partial information decomposition (PID). PID allows to quantify the information that several inputs provide individually (unique information), redundantly (shared information) or only jointly (synergistic information) about the output. First, we review the framework of PID. Then we apply it to reevaluate and analyze several earlier proposals of information theoretic neural goal functions (predictive coding, infomax and coherent infomax, efficient coding). We find that PID allows to compare these goal functions in a common framework, and also provides a versatile approach to design new goal functions from first principles. Building on this, we design and analyze a novel goal function, called ‘coding with synergy’, which builds on combining external input and prior knowledge in a synergistic manner. We suggest that this novel goal function may be highly useful in neural information processing.
Inspiration for artificial biologically inspired computing is often drawn from neural systems. This article shows how to analyze neural systems using information theory with the aim of obtaining constraints that help to identify the algorithms run by neural systems and the information they represent. Algorithms and representations identified this way may then guide the design of biologically inspired computing systems. The material covered includes the necessary introduction to information theory and to the estimation of information-theoretic quantities from neural recordings. We then show how to analyze the information encoded in a system about its environment, and also discuss recent methodological developments on the question of how much information each agent carries about the environment either uniquely or redundantly or synergistically together with others. Last, we introduce the framework of local information dynamics, where information processing is partitioned into component processes of information storage, transfer, and modification – locally in space and time. We close by discussing example applications of these measures to neural data and other complex systems.
Seven different instruments and measurement methods were used to examine the immersion freezing of bacterial ice nuclei from Snomax® (hereafter Snomax), a product containing ice-active protein complexes from non-viable Pseudomonas syringae bacteria. The experimental conditions were kept as similar as possible for the different measurements. Of the participating instruments, some examined droplets which had been made from suspensions directly, and the others examined droplets activated on previously generated Snomax particles, with particle diameters of mostly a few hundred nanometers and up to a few micrometers in some cases. Data were obtained in the temperature range from −2 to −38 °C, and it was found that all ice-active protein complexes were already activated above −12 °C. Droplets with different Snomax mass concentrations covering 10 orders of magnitude were examined. Some instruments had very short ice nucleation times down to below 1 s, while others had comparably slow cooling rates around 1 K min−1. Displaying data from the different instruments in terms of numbers of ice-active protein complexes per dry mass of Snomax, nm, showed that within their uncertainty, the data agree well with each other as well as to previously reported literature results. Two parameterizations were taken from literature for a direct comparison to our results, and these were a time-dependent approach based on a contact angle distribution (Niedermeier et al., 2014) and a modification of the parameterization presented in Hartmann et al. (2013) representing a time-independent approach. The agreement between these and the measured data were good; i.e., they agreed within a temperature range of 0.6 K or equivalently a range in nm of a factor of 2. From the results presented herein, we propose that Snomax, at least when carefully shared and prepared, is a suitable material to test and compare different instruments for their accuracy of measuring immersion freezing.
A new species, Chrysobothris cerceripraeda Westcott and Thomas (Coleoptera: Buprestidae), is described from prey specimens found in nests of the ground-nesting wasp, Cerceris fumipennis Say (Hymenoptera: Crabronidae), near Jacksonville, Florida, USA. A listing for all species of Buprestidae taken as prey of the wasp in that state is provided, four of which, including the species described herein, are new. Notes are also given for
four new state records for Buprestidae.
The chiral phase transition of Quantum Chromo Dynamics (QCD) is investigated with the help of the linear-sigma model and a numerical transport simulation. The scope are non-equilibrium and critical effects of the different type of orders of the transition. Additionally, a mathematical and numerical method is developed which allows to simulate a particle-wave duality and non-continuous interactions, even for classical systems.
A series of photon scattering experiments has been performed on the double-beta decay partners 76Ge and 76Se, in order to investigate their dipole response up to the neutron separation threshold. Gamma-ray beams from bremsstrahlung at the S-DALINAC and from Compton-backscattering at HIGS have been used to measure absolute cross sections and parities of dipole excited states, respectively. The HIGS data allows for indirect measurement of averaged branching ratios, which leads to significant corrections in the observed excitation cross sections. Results are compared to statistical calculations, to test photon strength functions and the Axel-Brink hypothesis.
Evidence for hydrodynamical flow in AA or in pA collisons is to a large extent obtained from the observation of identified hadrons, such as pions, kaons, and protons. But much more information in particular about the late stage can be obtained by also considering unstable particles, which decay during the lifetime of the expanding hadronic matter. We therefore started to use EPOS3, a unified approach for pp, pA, and AA scattering, to investigate the production of stable and unstable particles.
WHILE CLOUD MARKETS PROMISE UNLIMITED RESOURCE SUPPLIES, INDIVIDUAL PROVIDERS MIGHT BE UNABLE TO OFFER SUFFICIENT PHYSICAL CAPACITY TO SERVE LARGE CUSTOMERS. A SOLUTION IS TO FORM CLOUD COLLABORATIONS, IN WHICH MULTIPLE CLOUD PROVIDERS UNITE FORCES IN ORDER TO CONJOINTLY OFFER CAPACITIES WITHIN CLOUD MARKETS. QUALITY OF SERVICE (QOS) AND SECURITY ASPECTS ARE THE PRIMARY CONSIDERATIONS IN BUILDING SUCH COLLABORATIONS. THIS RESEARCH REPORT PRESENTS A CORRESPONDING OPTIMIZATION APPROACH FOR THE SELECTION OF COLLABORATIVE CLOUD PROVIDERS UNDER CONSIDERATION OF FULFILLMENT OF CLOUD USERS’ QOS AND SECURITY REQUIREMENTS.
Myxomycetes (slime moulds) of arid to semi-arid areas of northwest New South Wales, Australia
(2015)
Myxomycetes (plasmodial slime moulds) were studied along an east-west traverse extending across the arid and semi-arid zones in northwest New South Wales bounded by Lake Cargelligo (400 mm annual rainfall), Bourke (400 mm annual rainfall), Tibooburra (200 mm annual rainfall) and Menindee (250 mm annual rainfall). Samples of tree bark were collected from a range of trees, and subsequently myxomycetes were obtained in the laboratory with the use of the moist culture method. A total of 43 species were recognized. The assemblages of myxomycetes recorded did not change significantly across these climate zones, and, for samples with a reasonable number of species present, there was little difference in diversity due to tree-bark type. The assemblage of species present along this traverse is similar to arid and semi-arid zone tree bark assemblages elsewhere in Australia, which is consistent with the occurrence of one assemblage throughout.
About half of this assemblage consists of widely distributed species likely to be recorded anywhere in the world (cosmopolitan), although these species are found in relatively few samples. The other half of the assemblage is made up of species with a more restricted distribution (generally found in one region of the world or relatively rare worldwide); these species were found in most samples. These restricted distribution species have centres of distribution at a similar latitude and climate in the northern hemisphere.
The assemblage of species associated with bark in the higher rainfall areas of Australia has some of the species of the arid and semi-arid zones; it has most of the widely distributed species and very few of the restricted distribution species. The boundary zone between the two assemblages of species is likely to be near the outer margin of the semiarid zone.
Objectives: Previous studies investigating speech perception in noise have typically been conducted with static masker positions. The aim of this study was to investigate the effect of spatial separation of source and masker (spatial release from masking, SRM) in a moving masker setup and to evaluate the impact of adaptive beamforming in comparison with fixed directional microphones in cochlear implant (CI) users.
Design: Speech reception thresholds (SRT) were measured in S0N0 and in a moving masker setup (S0Nmove) in 12 normal hearing participants and 14 CI users (7 subjects bilateral, 7 bimodal with a hearing aid in the contralateral ear). Speech processor settings were a moderately directional microphone, a fixed beamformer, or an adaptive beamformer. The moving noise source was generated by means of wave field synthesis and was smoothly moved in a shape of a half-circle from one ear to the contralateral ear. Noise was presented in either of two conditions: continuous or modulated.
Results: SRTs in the S0Nmove setup were significantly improved compared to the S0N0 setup for both the normal hearing control group and the bilateral group in continuous noise, and for the control group in modulated noise. There was no effect of subject group. A significant effect of directional sensitivity was found in the S0Nmove setup. In the bilateral group, the adaptive beamformer achieved lower SRTs than the fixed beamformer setting. Adaptive beamforming improved SRT in both CI user groups substantially by about 3 dB (bimodal group) and 8 dB (bilateral group) depending on masker type.
Conclusions: CI users showed SRM that was comparable to normal hearing subjects. In listening situations of everyday life with spatial separation of source and masker, directional microphones significantly improved speech perception with individual improvements of up to 15 dB SNR. Users of bilateral speech processors with both directional microphones obtained the highest benefit.
The neutron capture cross section of the s-process branch nucleus 63Ni affects the abundances of other nuclei in its region, especially 63Cu and 64Zn. In order to determine the energy-dependent neutron capture cross section in the astrophysical energy region, an experiment at the Los Alamos National Laboratory has been performed using the calorimetric 4πBaF2 array DANCE. The (n,γ) cross section of 63Ni has been determined relative to the well-known 197Au standard with uncertainties below 15%. Various 63Ni resonances have been identified based on the Q value. Furthermore, the s-process sensitivity of the new values was analyzed with the new network calculation tool NETZ.
The pressure on tax haven countries to engage in tax information exchange shows first effects on capital markets. Empirical research suggests that investors do react to information exchange and partially withdraw from previous secrecy jurisdictions that open up to information exchange. While some of the economic literature emphasizes possible positive effects of tax havens, the present paper argues that proponents of positive effects may have started from questionable premises, in particular when it comes to the effects that tax havens have for emerging markets like China and India.
Greece: threatening recovery
(2015)
Despite the catastrophic phase between 2008 and the end of 2014, much of a previously unsustainable development has been corrected in Greece and there are clear signs that the deterioration came to a halt in 2014. But what is publicly known about the priorities of the newly elected Syriza government suggests that they may be going largely into the wrong direction.
The neural crest gives rise to the neurons and glial cells of the peripheral nervous system (PNS) (Bronner-Fraser and Fraser, 1989; Frank and Sanes, 1991). Self-renewing neural crest-derived stem cells (NCSCs) are present in migratory neural crest and various postmigratory locations, including peripheral ganglia (Duff et al., 1992; Morrison et al., 1999; Kruger er al., 2002). It is demonstrated that NCSCs from embryonic mouse dorsal root ganglia (DRG) are reprogrammed in neurosphere (NS) cultures in the presence of EGF and FGF. Reprogrammed NCSCs (rNCSCs) generate exclusively central nervous system (CNS) progeny, both in vitro and upon transplantation into the mouse brain (Binder et al., 2011). In this study the timing and mechanisms underlying the reprogramming were addressed. Most of the cells acquire CNS characteristics at passage 2, reaching a stable proportion of >90% of Olig2-positive cells at passage 3, which is maintained at least up to passage 10. The PNS marker p75 is completely lacking from passage 3 onwards. Furthermore, it was shown that the reprogramming does not involve a transient pluripotency state. This suggests a direct reprogramming of NCSCs to cells with CNS identity. The reprogramming leads to a stable CNS identity as shown by delayed BMP4 application. This result is in agreement with the previous observation that rNCSCs only generate CNS progeny, in particular mature myelinating oligodendrocytes, upon transplantation into embryonic, postnatal and lesioned adult mouse brains (Binder et al., 2011). Genome wide gene expression profiles of rNCSC NS demonstrates already in culture a complete switch to a (spinal cord stem cell) SCSC CNS identity. These results demonstrate a complete reprogramming of PNS progenitors to CNS identity without genetic modification and imply PNS cells as a source for stem cell-based CNS therapy.
The reprogramming of NCSCs is completely blocked in the presence of BMP4 in NS cultures, as shown by the expression of neural crest markers p75 and Sox10. In addition, BMP4 NCSCs generate PNS neurons (Tuj1/Phox2b- and Peripherin/Tuj1-coexpressing cells) and Schwann cells (O4/p75-coexpressing cells). Genome wide gene expression profiles of BMP NCSCs demonstrate that BMP NCSCs express genes at high levels which are characteristic for neural crest/neural crest derivatives, mesenchymal derivatives of neural crest and perivascular pericytes/MSCs. On the other hand CNS marker genes are restricted to rNCSCs and are only expressed at background or undetectable levels in BMP NCSCs. These findings imply that the CNS versus PNS identity is controlled by antagonistic functions of FGF and BMP4.
The use of rNCSCs for cell therapies requires an accessible source of these cells in the adult organism. Since the DRG is not an easily approachable tissue source, the adult mouse palate, containing NCSCs, was chosen. These results suggest that pNCSCs arise from Sox10-positive neural crest-derived stem cells, that downregulate PNS marker gene expression, such as Sox10 and p75, in NS culture. Contrary to rNCSCs, CNS marker upregulation was not observed. Notably, genome wide gene expression profiles of pNCSCs demonstrate an enrichment of genes expressed by mesenchymal derivatives and perivascular pericytes/mesenchymal stem cells. Since the cranial crest gives rise, besides PNS neural progeny and melanocytes, to mesenchymal derivatives, the results demonstrate that pNCSCs have a restricted developmental potential in comparison to rNCSCs and acquire mostly normal fates of the cranial neural crest.
Taken together, the results demonstrate that rNCSCs acquire a SCSC identity in the presence of EGF and FGF and that the reprogramming can be efficiently blocked by BMP4. On the other hand, NCSCs derived from adult palate rather acquire mesenchymal fates and do not acquire a CNS identity under the conditions used.
Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.
Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5.
Background: Second hand smoke (ETS)-associated particulate matter (PM) contributes considerably to indoor air contamination and constitutes a health risk for passive smokers. Easy to measure, PM is a useful parameter to estimate the dosage of ETS that passive smokers are exposed to. Apart from its suitability as a surrogate parameter for ETS-exposure, PM itself affects human morbidity and mortality in a dose-dependent manner. We think that ETS-associated PM should be considered an independent hazard factor, separately from the many other known harmful compounds of ETS. We believe that brand-specific and tobacco-product-specific differences in the release of PM matter and that these differences are of public interest. Methods: To generate ETS of cigarettes and cigarillos as standardized and reproducible as possible, an automatic second hand smoke emitter (AETSE) was developed and placed in a glass chamber. L&M cigarettes ("without additives", "red label", "blue label"), L&M filtered cigarillos ("red") and 3R4F standard research cigarettes (as reference) were smoked automatically according to a self-developed, standardized protocol until the tobacco product was smoked down to 8 mm distance from the tipping paper of the filter. Results: Mean concentration (Cmean) and area under the curve (AUC) in a plot of PM2.5 against time were measured, and compared. CmeanPM2.5 were found to be 518 μg/m3 for 3R4F cigarettes, 576 μg/m3 for L&M "without additives" ("red"), 448 μg/m3 for L&M "blue label", 547 μg/m3 for L&M "red label", and 755 μg/m3 for L&M filtered cigarillos ("red"). AUCPM2.5-values were 208,214 μg/m3·s for 3R4F reference cigarettes, 204,629 μg/m3·s for L&M "without additives" ("red"), 152,718 μg/m3·s for L&M "blue label", 238,098 μg/m3·s for L&M "red label" and 796,909 μg/m3·s for L&M filtered cigarillos ("red"). Conclusion: Considering the large and significant differences in particulate matter emissions between cigarettes and cigarillos, we think that a favorable taxation of cigarillos is not justifiable.