350 research outputs found

    Deepening democratisation? Exploring the declared motives for ‘late’ lustration in Poland

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    Lustration was one of, if not the, most important and controversial transitional justice methods to be used in post-communist Central and Eastern Europe, and Poland is an archetypal case of late and recurring lustration. Many of the attempts in the literature to tackle such changes of lustration trajectory divide between those who focus on the partisan and electoral-strategic drivers of its protagonists, and those who ascribe more ideological-programmatic motives to them. The re-emergence of the lustration issue in the Polish case was entwined with broader debates about the quality of post-communist democracy more generally and often felt to be indicative of the need to deepen the democratisation process

    A proteasome-resistant fragment of NIK mediates oncogenic NF-ÎșB signaling in schwannomas

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    Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ÎșB)-inducing kinase (NIK) as a potential drug target driving NF-ÎșB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-ÎșB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-ÎșB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-ÎșB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential

    Hydrogen bonding of nitroxide spin labels in membrane proteins

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    On the basis of experiments at 275 GHz, we reconsider the dependence of the continuous-wave EPR spectra of nitroxide spin-labeled protein sites in sensory- and bacteriorhodopsin on the micro-environment. The high magnetic field provides the resolution necessary to disentangle the effects of hydrogen bonding and polarity. In the gxx region of the 275 GHz EPR spectrum, bands are resolved that derive from spin-label populations carrying no, one or two hydrogen bonds. The gxx value of each population varies hardly from site to site, significantly less than deduced previously from studies at lower microwave frequencies. The fractions of the populations vary strongly, which provides a consistent description of the variation of the average gxx and the average nitrogen-hyperfine interaction Azz from site to site. These variations reflect the difference in the proticity of the micro-environment, and differences in polarity contribute marginally. Concomitant W-band ELDOR- detected NMR experiments on the corresponding nitroxide in perdeuterated water resolve population-specific nitrogen-hyperfine bands, which underlies the interpretation for the proteins

    Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

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    E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

    Density data for Lake Ontario benthic invertebrate assemblages from 1964 to 2018

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    Benthic invertebrates are important trophic links in aquatic food webs and serve as useful bioindicators of environmental conditions because their responses integrate the effects of both water and sediment qualities. However, long-term data sets for benthic invertebrate assemblages across broad geographic areas are rare and, even if collected, historic data sets are often not readily accessible. This data set provides densities of benthic macroinvertebrates for all taxa collected during lake-wide surveys in Lake Ontario, a Laurentian Great Lake, from 1964 to 2018. This information resulted from surveys funded by the governments of the United States and Canada to investigate the status and changes of Lake Ontario benthic community. Of the 13 lake-wide benthic surveys conducted in Lake Ontario over the course of 54 yr, we were able to acquire taxonomic data to the species level for 11 of the surveys and data to the group level for the other two surveys. Density data are provided for taxa representing the Annelida, Arthropoda, Mollusca, Cnidaria, Nemertea, and Platyhelminthes phyla. Univariate and multivariate analyses revealed that the compositional structure of Lake Ontario invertebrate assemblages differed markedly by depth and were also significantly altered by the Dreissena spp. invasion in early 1990s. The introduction of invasive dreissenids has changed the community historically dominated by Diporeia, Oligochaeta, and Sphaeriidae, to a community dominated by quagga mussels and Oligochaeta. Considering the rarity of long-term benthic data of high taxonomic resolution in lake ecosystems, this data set could be useful to explore broader aspects of ecological theory, including effects of different environmental factors and invasive species on community organization, functional and phylogenetic diversity, and spatial scale of variation in community structure. The data set could also be useful for studies on individual species including abundance and distribution, species co-occurrence, and how the patterns of dominance and rarity change over space and time. Use of this data set for academic or educational purposes is encouraged as long as the data source is properly cited using the title of this Data Paper, the names of the authors, the year of publication, the journal name, and the article number

    Influence of Diporeia Density on Diet Composition, Relative Abundance, and Energy Density of Planktivorous Fishes in Southeast Lake Michigan

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    The benthic amphipod Diporeia spp. is an important prey for many fish in offshore areas of the Great Lakes, but its abundance has been rapidly decreasing. To assess the influence of Diporeia availability on the food habits, relative abundance, and energetics of planktivorous fish, the diet composition, catch per unit effort (CPUE), and energy density of plantkivorous fish in southeast Lake Michigan during 2000–2001 were compared among locations with different Diporeia densities. Diporeia densities at St. Joseph, Michigan, were near 0/m2 over much of the bottom but averaged more than 3,800/m2 at Muskegon and Little Sable Point, Michigan. Consistent with these differences in Diporeia density, fish diet composition, CPUE, and energy density varied spatially. For example, alternative prey types comprised a larger fraction of the diets of bloater Coregonus hoyi, large (>100 mm total length) alewife Alosa pseudoharengus, and slimy sculpin Cottus cognatus at St. Joseph than at Muskegon and Little Sable Point. This pattern was seasonally dependent for alewives and bloaters because Diporeia were eaten mainly in June. Food biomass per stomach was not lower at St. Joseph than elsewhere, suggesting that the spatial variation in diet composition was due to greater consumption of alternative prey by fish at St. Joseph. Although slimy sculpin and bloaters were able to feed on alternative prey, the CPUE of these species at certain depths was considerably lower at St. Joseph than at Muskegon or Little Sable Point, indicating that Diporeia availability may also influence fish abundance and distribution. Finally, a link between Diporeia density and fish energetics was suggested by the comparatively low energy density of deepwater sculpin Myoxocephalus thompsonii and large alewives at St. Joseph, a result that may reflect the low energy content of other prey relative to Diporeia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141042/1/tafs0588.pd

    Impact of Dreissena fouling on the physiological condition of native and invasive bivalves : interspecific and temporal variations

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    The impact of Dreissena fouling on unionids has hardly been studied in Europe, despite the fact that in some ecosystems (e.g. Lake Balaton, Hungary) infestations of several hundreds to a thousand individuals per unionid have been observed. At present, the zebra mussel Dreissena polymorpha is a dominant species in Lake Balaton and in the last decade three other invasive bivalves were introduced, potentially increasing the pressure on native unionid survival. We examined whether the fouling of dreissenids (zebra and quagga (D. rostriformis bugensis) mussels) has a negative impact on native (Anodonta anatina, Unio pictorum and U. tumidus) and invasive (Corbicula fluminea and Sinanodonta woodiana) bivalves and whether there are any interspecific and temporal variations in fouling intensity and physiological condition measured by standard condition index and glycogen content. A significant negative impact was detected on native unionids only in July and September (no impact was detected in May), when the fouling rate was high. For invasive species, a significant negative impact was detected on S. woodiana with a high level of dressenid infestation; whereas no significant impact was detected on C. fluminea. Overall, this study confirms that Dreissena may threaten unionid species including the invasive S. woodiana, although high interspecific and temporal variations were observed. This situation should be taken into account in future ecological and conservational assessments because species respond differently to Dreissena fouling and effects seem to be more pronounced in late summer/early autumn. In addition, this study provides the first evidence that the invasive C. fluminea appear to be less vulnerable to dressenid fouling.The study was supported by the Hungarian Scientific Fund (KTIA-OTKA) under the contract No. CNK80140

    Click and detect: Versatile ampicillin aptasensor enabled by click chemistry on a graphene-alkyne derivative

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    Tackling the current problem of antimicrobial resistance (AMR) requires fast, inexpensive, and effective methods for controlling and detecting antibiotics in diverse samples at the point of interest. Cost-effective, disposable, point-of care electrochemical biosensors are a particularly attractive option. However, there is a need for conductive and versatile carbon-based materials and inks that enable effective bioconjugation under mild conditions for the develop ment of robust, sensitive, and selective devices. This work describes a simple and fast methodology to construct an aptasensor based on a novel graphene derivative equipped with alkyne groups prepared via fluorographene chem istry. Using click chemistry, an aptamer is immobilized and used as a suc cessful platform for the selective determination of ampicillin in real samples in the presence of interfering molecules. The electrochemical aptasensor displayed a detection limit of 1.36 nM, high selectivity among other antibi otics, the storage stability of 4 weeks, and is effective in real samples. Addi tionally, structural and docking simulations of the aptamer shed light on the ampicillin binding mechanism. The versatility of this platform opens up wide possibilities for constructing a new class of aptasensor based on disposable screen-printed carbon electrodes usable in point-of-care devices.Web of Scienc

    A discrete firefly algorithm to solve a rich vehicle routing problem modelling a newspaper distribution system with recycling policy

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    A real-world newspaper distribution problem with recycling policy is tackled in this work. In order to meet all the complex restrictions contained in such a problem, it has been modeled as a rich vehicle routing problem, which can be more specifically considered as an asymmetric and clustered vehicle routing problem with simultaneous pickup and deliveries, variable costs and forbidden paths (AC-VRP-SPDVCFP). This is the first study of such a problem in the literature. For this reason, a benchmark composed by 15 instances has been also proposed. In the design of this benchmark, real geographical positions have been used, located in the province of Bizkaia, Spain. For the proper treatment of this AC-VRP-SPDVCFP, a discrete firefly algorithm (DFA) has been developed. This application is the first application of the firefly algorithm to any rich vehicle routing problem. To prove that the proposed DFA is a promising technique, its performance has been compared with two other well-known techniques: an evolutionary algorithm and an evolutionary simulated annealing. Our results have shown that the DFA has outperformed these two classic meta-heuristics
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