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Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy.
β-barrel proteins mediate nutrient uptake in bacteria and serve vital functions in cell signaling and adhesion. For the 14-strand outer membrane protein G of Escherichia coli, opening and closing is pH-dependent. Different roles of the extracellular loops in this process were proposed, and X-ray and solution NMR studies were divergent. Here, we report the structure of outer membrane protein G investigated in bilayers of E. coli lipid extracts by magic-angle-spinning NMR. In total, 1847 inter-residue 1H–1H and 13C–13C distance restraints, 256 torsion angles, but no hydrogen bond restraints are used to calculate the structure. The length of β-strands is found to vary beyond the membrane boundary, with strands 6–8 being the longest and the extracellular loops 3 and 4 well ordered. The site of barrel closure at strands 1 and 14 is more disordered than most remaining strands, with the flexibility decreasing toward loops 3 and 4. Loop 4 presents a well-defined helix.
Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
O artigo apresenta brevemente as possíveis implicações da recusa da clonagem, do DGPI e da eugenia liberal para o formalismo da ética discursiva, pois tal recusa poderia sugerir a eleição de um modo de vida privilegiado, (uma vida humana baseada na “inteireza do patrimônio genético”). Apresentamos os elementos do formalismo ético de Habermas e os argumentos centrais de sua crítica às intervenções eugênicas. Sugerimos que a defesa habermasiana da manutenção da indisponibilidade do patrimônio genético (por seu papel na autocompreensão ética do humano como ser livre e autônomo) situa essa matéria da filosofia moral na tensão entre a ação comunicativa, no qual o debate deveria ter sede, e a ação instrumental, que ameaça monopolizar as decisões sobre o tema.
In the colon, a sophisticated balance between immune reaction and tolerance is absolutely required. Dysfunction may lead to pathologic phenotypes ranging from chronic inflammatory processes to cancer development. Two prominent modulators of colon inflammation are represented by the closely related cytokines interleukin (IL)-12 and IL-23, which initiate adaptive Th1 and Th17 immune responses, respectively. In this study, we investigated the impact of the NADPH oxidase protein p47phox, which negatively regulates IL-12 in dendritic cells, on colon cancer development in a colitis-associated colon cancer model. Initially, we found that IL-12−/− mice developed less severe colitis but are highly susceptible to colon cancer. By contrast, p47phox−/− mice showed lower tumor scores and fewer high grade tumors than wild-type (WT) littermates. Treatment with toll-like receptor 9 ligand CpG2216 significantly enhanced colitis in p47phox−/− mice, whereas tumor growth was simultaneously reduced. In tumor tissue of p47phox−/− mice, the IL-23/IL-17 axis was crucially hampered. IL-23p19 protein expression in tumor tissue correlated with tumor stage. Reconstitution of WT mice with IL-23p19−/− bone marrow protected these mice from colon cancer, whereas transplantation of WT hematopoiesis into IL-23p19−/− mice increased the susceptibility to tumor growth. Our study strengthens the divergent role of IL-12 and IL-23 in colon cancer development. With the characterization of p47phox as a novel modulator of both cytokines our investigation introduces a promising new target for antitumor strategies.
This paper discusses the syntax of relative clauses in European Portuguese (EP) by focussing on the status of the relativizer que in restrictive and appositive relative clauses. We propose a unified account of que in terms of a D-element and discuss the syntactic implications of this assumption for an adequate analysis of relative clauses in EP. We assume that relative que has properties of demonstrative and interrogative determiners. In restrictive object and subject relative clauses, que occurs as a transitive determiner [DP que [NP e]], which selects for a nominal complement, whereas in prepositional and appositive relative clauses, [DP que] is an intransitive determiner parallel to an e-type pronoun. We discuss the position of restrictive relative clauses in the DP containing the modified noun, and propose that they are merged pre-nominally, in the same fashion as demonstratives.
Die Themen Flucht und Migration stehen im Fokus dieser Jahrbuchausgabe. Während Flucht den unfreiwilligen Austritt aus einer gesellschaftlichen Einheit bedeutet, verweist der Begriff Migration auf den Versuch, in ein gesellschaftliches Gefüge einzutreten. Ein zentraler Unterschied liegt somit in sich dichotom gegenüberstehenden Ausgliederungs- und Eingliederungshandlungen. Eine Gemeinsamkeit stellt jedoch die Prozesshaftigkeit dar, die in literarisch sowie bildästhetisch umgesetzten Narrativen, wie zum Beispiel in Form von Graphic Novels, aufgegriffen wird. Die beiden oft aufeinander bezogenen Narrative Flucht und Migration werden in diesem Beitrag getrennt betrachtet und bilden zugleich die beiden zentralen Kapitel des Textes: Zuerst stehen Graphic Novels im Mittelpunkt, die ausschließlich Fluchtnarrative inszenieren, um danach eine spezifische Perspektive auf Migrationsnarrative einnehmen zu können. Gemäß der multimedialen Form dieses Mediums, das dazu tendiert, Fotografie, Illustration (vgl. Hescher 2016, S. 78) sowie Filmtechniken zu verbinden, muss auch die Zugangsweise einen interdisziplinä- ren Ansatz verfolgen, der laut den HerausgeberInnen des Readers Theorien des Comics zu den Stärken der Comicforschung gehöre. (Vgl. Reichert/Eder/Klar 2011, S. 10) Die Comicforschung, insbesondere jener Teilbereich, der sich mit dokumentarisch-grafischen Formen beschäftigt, liefert die Grundlage für die folgenden Überlegungen und die Fragestellung dieses Beitrags: Welche unterschiedlichen ästhetischen Formen werden eingesetzt, um die Themen Flucht und Migration grafisch darzustellen? ...
During the transition from early-modern societies to the nation states of the 19th and 20th centuries, the formation of the territorial state performed an important function. The combining of dominions to form a geographical and political unit could occur through the annexation of the weaker territory by the stronger one, but it could also occur with the mutual agreement of the political decision-makers of both territories. In the case of a union, a distinction emerged very early on between a real union and a personal union (or union of crowns). While in a real union agreements under international law were equally binding for both partners, the personal union assumed a special status, in which the person of the ruler was the only connection between the two states. However, this strictly legal definition only applied to the political institutions. Below the state level, there were forms of transfer that could give a personal union a special, transnational character. Academic opinion remains divided on the extent to which these connections, which are referred to using the term "composite statehood", constitute a Europe-wide development.
This paper considers the trend towards megaregionalism (TTIP, TPP) that became prominent in the trade domain in the last years of the Obama administration. While megaregionalism has fallen by the wayside since Trump’s inauguration, the underlying rationale for such treaties will most likely reassert itself rather soon. So there are structural issues that need to be discussed from a standpoint of global justice. In all likelihood, megaregionalism is detrimental to global justice. TTIP in particular, or anything like it, might derail any possibility for a trade organization to aid the pursuit of justice at the global level, and any possibility that trade will be used to that end. From the standpoint of global justice one must hope that megaregionalism does not replace WTO multilateralism. The global-justice framework used here is the grounds-of-justice approach offered in the author’s 2012 On Global Justice.
In the title compound, C26H24N2O2, the oxazine moiety is fused to a naphthalene ring system. The asymmetric unit consists of one half of the molecule, which lies about an inversion centre. The C atoms of the ethylene spacer group adopt an antiperiplanar arrangement. The oxazine ring adopts a half-chair conformation. In the crystal, supramolecular chains running along the b axis are formed via short C—H⋯π contacts. The crystal studied was a non-merohedral twin with a fractional contribution of 0.168 (2) of the minor twin component.
In the title compound, C17H18N2O, the central carbon atom with the OH substituent and one of the (E)-benzylideneamino substituents are disordered over two sets of sites with occupancies of 0.851 (4) and 0.149 (4). The relative positions of the two disorder components is equivalent to a rotation of approximately 60° about the C—N single bond. In the crystal, the molecules are held together by O—H...N hydrogen bonds, forming simple C(5) chains along the b-axis direction. In addition, pairs of the chains are further aggregated by weak C—H...π interactions.
The asymmetric unit of the title compound, C21H28N4O, consists of two unique molecules linked by an O—H⋯N hydrogen bond. The conformation of both C=N bonds is E and the azomethine functional groups lie close to the plane of their associated benzene rings in each of the independent molecules. The dihedral angles between the two benzene rings are 83.14 (4) and 75.45 (4)°. The plane of the one of the N(CH3)2 units is twisted away from the benzene ring by 18.8 (2)°, indicating loss of conjugation between the lone electron pair and the benzene ring. In the crystal structure, O—H⋯N hydrogen bonds together with C—H⋯O hydrogen bonds link neighbouring supramolecular dimers into a three-dimensional network.
The asymmetric unit of the title co-crystalline adduct, 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD)–4-iodophenol (1/2), C8H16N4·2C6H5IO, comprises a half molecule of the aminal cage polyamine plus a 4-iodophenol molecule. A twofold rotation axis generates the other half of the adduct. The components are linked by two intermolecular O—H⋯N hydrogen bonds. The adducts are further linked into a three-dimensional framework structure by a combination of N⋯I halogen bonds and weak non-conventional C—H⋯O and C—H⋯I hydrogen bonds.
The asymmetric unit of the title compound, C18H18I2N2O2, consists of one half-molecule, completed by the application of inversion symmetry. The molecule adopts the typical structure for this class of bis-benxozazines, characterized by an anti orientation of the two benzoxazine rings around the central C—C bond. The oxazinic ring adopts a half-chair conformation. In the crystal, molecules are linked by C—I⋯N short contacts [I⋯N = 3.378 (2) Å], generating layers lying parallel to the bc plane.
In the face of increasing invasions and limited resources, appropriate management of invasive species requires prioritisation of species for management action. This process often relies on knowledge of species specific impacts. However, as studies explicitly measuring impact of marine alien species are rare, prioritisation of management actions is often based on studies from outside the geographic area of interest. Further, few impact studies account for context dependency (e.g. seasonal variability or distinct environmental regimes), raising the question of how transferrable knowledge about the impact of a species is between invaded ranges. This study addressed this question by using the widespread invasive solitary ascidian Ciona robusta as a case study for assessing impacts across two invaded regions: South Africa and California, USA. We replicated a previously conducted experiment from California that showed that C. robusta depresses local species richness in San Francisco Bay. Our South African experiment showed no effect of C. robusta on species richness, the Shannon-Weiner diversity index or community composition, despite experiments being carried out over two years and at two depths. While these results may reflect strong density dependency in the impact of C. robusta, they serve to highlight context dependency in invasive species impacts. This suggests that until studies of impact in marine systems become common place, context dependency should be explicitly addressed as a source of uncertainty during the prioritisation of species for management action.
Schopenhauer afirma que uma ética não dogmática requer leis demonstráveis derivadas da experiência. Nesse sentido o fundamento de uma ética deve ser uma metafísica imanente, que sustente, na experiência possível, suas afirmações, e que seja, por isso mesmo, capaz de dar de uma vez por todas um fundamento legítimo à moral. A fundamentação da moral schopenhaueriana segue, portanto, uma argumentação muito próxima de uma metodologia científica. Para Schopenhauer a filosofia deve se aproximar mais de uma cosmologia do que da teologia. Max Horkheimer em “O pensamento de Schopenhauer em relação à ciência e à religião” destaca a fecundidade de tal posição filosófica e atualiza a importância de Schopenhauer tanto para sua formação quanto para uma legítima interpretação da modernidade. Acompanhamos, neste artigo tanto os aspectos fundamentais da fundamentação schopenhaueriana da moral, quanto aspectos da interpretação de Horkheimer da empreitada do filósofo.
Recent progress in the synaptic pathophysiology of brain diseases is reviewed. To emphasize the emergence of common motifs in synapse dysfunctions across neurodevelopmental, psychiatric and neurological disorders, conventional clinical boundaries are disregarded and a decidedly trans-diagnostic, potentially unifying view of altered synapse function is promoted. Based on the overlapping genetic architecture of brain disorders, which often converges on genes related to synaptic functions, disease-related changes in basic pre-synaptic and post-synaptic communication, neuromodulation-gated changes in Hebbian plasticity, dynamic interactions between Hebbian and homeostatic plasticity, and changes in synaptic maintenance by autophagy and glial-mediated phagocytosis are highlighted.
The mitophagy receptor Nix interacts with LC3/GABARAP proteins, targeting mitochondria into autophagosomes for degradation. Here we present evidence for phosphorylation-driven regulation of the Nix:LC3B interaction. Isothermal titration calorimetry and NMR indicate a ~100 fold enhanced affinity of the serine 34/35-phosphorylated Nix LC3-interacting region (LIR) to LC3B and formation of a very rigid complex compared to the non-phosphorylated sequence. Moreover, the crystal structure of LC3B in complex with the Nix LIR peptide containing glutamic acids as phosphomimetic residues and NMR experiments revealed that LIR phosphorylation stabilizes the Nix:LC3B complex via formation of two additional hydrogen bonds between phosphorylated serines of Nix LIR and Arg11, Lys49 and Lys51 in LC3B. Substitution of Lys51 to Ala in LC3B abrogates binding of a phosphomimetic Nix mutant. Functionally, serine 34/35 phosphorylation enhances autophagosome recruitment to mitochondria in HeLa cells. Together, this study provides cellular, biochemical and biophysical evidence that phosphorylation of the LIR domain of Nix enhances mitophagy receptor engagement.
In der heutigen Epoche von Radikalismen, politischer und existentieller Unbehaustheit und vermeintlich in die Krise geratener Männlichkeit wird die "vaterlose Gesellschaft" (Matthias Matussek) oft als Ursache für vielfache Fehlentwicklungen insbesondere der Söhne betrachtet und geradezu zur conditio humana der westlichen Welt erklärt. Zwar wird diese 'Vaterlosigkeit' vor allem im rechtskonservativen Lager immer wieder als Verlustgeschichte natürlicher männlicher Vorherrschaft bedauert, aber auch ein kritisch-engagierter Autor wie Milo Rau scheint in seinem Theaterstück Civil Wars ein (Ideal-)Bild normal-autoritärer väterlicher Männlichkeit zu vermitteln, insofern besonders das problematische Verhältnis zum Vater das Stück leitmotivisch durchzieht und als Ursache für die psychosoziale Fehlentwicklung der Figuren aufgeführt wird.
Um 1900 wurde diese heute so oft beklagte vaterlose Gesellschaft aber geradezu herbeigesehnt: Nicht nur die eben erst gegründete bürgerliche Jugendbewegung, sondern auch die reformwillige wilhelminische Elternschaft, die im morbiden Aufbruch der (männlichen) Jugend ihre eigenen politischen Hoffnungen zu realisieren wünschte, erhoben den Vatermord provokativ zum Teil ihres Programms.
Mit dem Ziel einer Re-Politisierung der Selbstbildung im Sinne einer politischen Ökologie legt Katja Rothe das Spiel als ein Gefüge aus, welches das Subjekt auf eine "umweltliche" Weise herstellt, mit sozialen Formen verbindet und kontextualisiert. Ausgehend von einem Überblick über die Bedeutung des Spiels und der Spieltherapien in der psychologischen Praxis von Hermine Hug-Hellmuth über Anna Freud und Melanie Klein, Margaret Lowenfeld und Dora Kalff und deren Vernachlässigung in der Wissenschaftsgeschichte der Psychologie schlägt Rothe vor, Spiele als Formen und Technologien der "Selbst-Bildung" auszulegen, in denen die Interaktion mit Objekten den Ausgangspunkt von offenen bedeutungsgenerierenden Prozessen bildet. Dabei bezieht sich Rothe, wenn sie von Objekten spricht, auf das Konzept des Übergangsobjekts, das im Zentrum von Winnicotts Theorie des Spiels steht. Das zu einem Ort des Übergangs gewordene Objekt beschreibt sie als jenes Element im Spiel, das es erlaubt, etwas zu finden, was man erfunden habe. Das Spiel wird damit als Versammlungsort beschreibbar, an dem sich Subjekt und Objekt in umweltlicher Weise gegenseitig konstituieren.
We investigate the effect of large magnetic fields on the (2 + 1)-dimensional reduced-magnetohydrodynamical expansion of hot and dense nuclear matter produced in √sNN = 200 GeV Au+Au collisions. For the sake of simplicity,we consider the casewhere themagnetic field points in the direction perpendicular to the reaction plane. We also consider this field to be external, with energy density parametrized as a two-dimensional Gaussian. The width of the Gaussian along the directions orthogonal to the beam axis varies with the centrality of the collision. The dependence of the magnetic field on proper time (τ ) for the case of zero electrical conductivity of the QGP is parametrized following Deng et al. [Phys. Rev. C 85, 044907 (2012)], and for finite electrical conductivity following Tuchin [Phys. Rev. C 88, 024911 (2013)].We solve the equations of motion of ideal hydrodynamics for such an external magnetic field. For collisions with nonzero impact parameter we observe considerable changes in the evolution of the momentum eccentricities of the fireball when comparing the case when the magnetic field decays in a conducting QGP medium and when no magnetic field is present. The elliptic-flow coefficient v2 of π− is shown to increase in the presence of an external magnetic field and the increment in v2 is found to depend on the evolution and the initial magnitude of the magnetic field.
Denisovite is a rare mineral occurring as aggregates of fibres typically 200–500 nm diameter. It was confirmed as a new mineral in 1984, but important facts about its chemical formula, lattice parameters, symmetry and structure have remained incompletely known since then. Recently obtained results from studies using microprobe analysis, X-ray powder diffraction (XRPD), electron crystallography, modelling and Rietveld refinement will be reported. The electron crystallography methods include transmission electron microscopy (TEM), selected-area electron diffraction (SAED), high-angle annular dark-field imaging (HAADF), high-resolution transmission electron microscopy (HRTEM), precession electron diffraction (PED) and electron diffraction tomography (EDT). A structural model of denisovite was developed from HAADF images and later completed on the basis of quasi-kinematic EDT data by ab initio structure solution using direct methods and least-squares refinement. The model was confirmed by Rietveld refinement. The lattice parameters are a = 31.024 (1), b = 19.554 (1) and c = 7.1441 (5) Å, β = 95.99 (3)°, V = 4310.1 (5) Å3 and space group P12/a1. The structure consists of three topologically distinct dreier silicate chains, viz. two xonotlite-like dreier double chains, [Si6O17]10−, and a tubular loop-branched dreier triple chain, [Si12O30]12−. The silicate chains occur between three walls of edge-sharing (Ca,Na) octahedra. The chains of silicate tetrahedra and the octahedra walls extend parallel to the z axis and form a layer parallel to (100). Water molecules and K+ cations are located at the centre of the tubular silicate chain. The latter also occupy positions close to the centres of eight-membered rings in the silicate chains. The silicate chains are geometrically constrained by neighbouring octahedra walls and present an ambiguity with respect to their z position along these walls, with displacements between neighbouring layers being either Δz = c/4 or −c/4. Such behaviour is typical for polytypic sequences and leads to disorder along [100]. In fact, the diffraction pattern does not show any sharp reflections with l odd, but continuous diffuse streaks parallel to a* instead. Only reflections with l even are sharp. The diffuse scattering is caused by (100) nanolamellae separated by stacking faults and twin boundaries. The structure can be described according to the order–disorder (OD) theory as a stacking of layers parallel to (100).
In our “House Europe” the exchange of ideas is going on intensively and the multi-cultural societies are in continuous transformation. An interesting example for cultural transfer in a multi-lingual and multi-confessional society is the reception of the St. Martin’s Day combined with the lantern procession organized by the German schools in Transylvania. The schools with German teaching language in Romania became a practice area for intercultural communication. Since 1997, first grade students at German schools in Romania learn from a new reading primer. One of the reading passages, “Our Lantern Festival”, initiated the spreading of a feast which had not been popular before neither with the German speaking minority of the Transylvanian Saxons, nor with the Romanian majority. The Lantern Festival is closely linked to the celebration of St. Martin, who is a European figure of high symbolic power. We can allege that the cultural diversity is an additional value for Europe. In the era of globalization, when migration processes and cultural hybridization are getting more intense, the intercultural communication has to adjust its inherited paradigm to the contemporary dynamics and heterogeneity of cultures.
Local treatment of unresectable colorectal liver metastases : results of a randomized phase II trial
(2017)
Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.
Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.
Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.
Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.
Chemotherapy-induced thrombocytopenia is a common bleeding risk in cancer patients and limits chemotherapy dose and frequency. Recent data from mouse and human platelets revealed that activation of protein kinase A/G (PKA/PKG) not only inhibited thrombin/convulxin-induced platelet activation but also prevented the platelet pro-coagulant state. Here we investigated whether or not PKA/PKG activation could attenuate caspase-dependent apoptosis induced by the anti-cancer drugs ABT-737 (the precursor of navitoclax) and thymoquinone (TQ), thereby potentially limiting chemotherapy-induced thrombocytopenia. This is particularly relevant as activation of cyclic nucleotide signalling in combination chemotherapy is an emerging strategy in cancer treatment. However, PKA/PKG-activation, as monitored by phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), did not block caspase-3-dependent platelet apoptosis induced by the compounds. In contrast, both substances induced PKA activation themselves and PKA activation correlated with platelet inhibition and apoptosis. Surprisingly, ABT-737- and TQ-induced VASP-phosphorylation was independent of cAMP levels and neither cyclases nor phosphatases were affected by the drugs. In contrast, however, ABT-737- and TQ-induced PKA activation was blocked by caspase-3 inhibitors. In conclusion, we show that ABT-737 and TQ activate PKA in a caspase-3-dependent manner, which correlates with platelet inhibition and apoptosis and therefore potentially contributes to the bleeding risk in chemotherapy patients.
First record of a live false killer whale Pseudorca crassidens (Owen, 1846) in Cabo Verdean waters
(2017)
Despite the limited research on cetaceans in Cabo Verde waters, 23 species have been documented (Hazevoet & Wenzel 2000, Hazevoet et al. 2010, Koenen et al. 2013, Berrow et al. 2015). The presence of several species is known only from strandings, such as the false killer whale, which has beached dead twice on Boavista in the 1980s–1990s, and again in 2007 (Hazevoet et al. 2010, Koenen et al. 2013). This is a CITES species, and Data Deficient according to IUCN (Taylor et al. 2008).
Due to its specific features, the German participle has numerous functions and uses in word-formation. As partially deverbalized adjectives, participles take on the syntactic role of an adjective while at the same time retaining the valency of a verb. The paper presents the various steps in an analysis using graded (partial) corpora. Drawing on research into the properties and functions of various participle forms, it explores their specific uses in texts.
In seinem Buch 'Die Verortung der Kultur' analysiert Homi Bhabha das Verhältnis zwischen Literatur, Blasphemie und dem Heiligen. Ihm zufolge ist Blasphemie nicht lediglich eine säkularisierte Fehldarstellung des Heiligen, sondern vielmehr ein Moment, in dem der Inhalt einer kulturellen Tradition im Akt der Übersetzung überwältigt oder verfremdet wird. Bezugnehmend auf Salman Rushdies Roman 'Die Satanischen Verse' stellt Bhabha fest, dass Rushdie einen Raum diskursiver Gegenüberstellung eröffne, der die Autorität des Korans in eine Perspektive des historischen und kulturellen Relativismus hineinstelle.
Zwei Erkenntnisse möchte ich in diesem Ansatz herausheben: Erstens die Kategorie der Übersetzung, die darin besteht, andere artikulatorische Positionen und Möglichkeiten aufzuzeigen. Die zweite Erkenntnis betrifft den historischen und kulturellen Relativismus. Dieser Relativismus ist meines Erachtens für die Heiligkeitsdeutung von entscheidender Bedeutung, da er jegliche festgefahrene und absolute Deutung des Heiligen zunichte macht und die Polyphonie bzw. die Vielfalt der Heiligkeitsauffassungen zulässt. Insbesondere in einem Lebenskontext, der zunehmend von religiöser und kultureller Pluralität gekennzeichnet ist, ist eine solche Vielfalt entscheidend.
Das Buch "Kohelet" des Alten Testaments, auch unter den Titeln "Der Prediger Salomo" oder "Ecclesiastes" überliefert, entstand wahrscheinlich im 3. Jahrhundert vor Christus. Vor allem die Eingangskapitel gehören zu den bekanntesten Texten der sogenannten biblischen Weisheitsbücher. Das kann allein schon die Tradition einiger 'Geflügelter Worte' durch die Jahrhunderte bezeugen wie etwa die folgenden Sätze oder Wendungen: "Es ist alles ganz eitel"; "Nimmersatt"; "Und geschiehet nichts Neues unter der Sonne"; "Ein jegliches hat seine Zeit"; "Sich gütlich tun"; "Viel Büchermachens ist kein Ende".
Spuren eines Einflusses auf das Werk Hofmannsthals scheinen sich etwa im Auftrittsmonolog des "Jedermann" zu finden, wenn er mit seinem stattlichen "Haus", seinem "Hausgesind" oder seinen "Meierhöf voll Vieh" prahlt; denn auch "Kohelet" rühmt sich der von ihm gebauten "Häuser", in denen sein "Gesinde, im Hause geboren" für ihn arbeitet, sowie seiner großen "Habe an Rindern und Schafen".
Diese Übereinstimmungen oder Ähnlichkeiten sind allerdings nur indirekt, weil die direkte Vorlage für Jedermanns Eingangsmonolog eine Dichtung des Hans Sachs ist. Die Textpassage findet sich nicht in Hofmannsthals Hauptquelle, dem "Everyman" aus dem 15. Jahrhundert. So gestaltete sie Hofmannsthal nach seiner zweiten "Jedermann"-Quelle, dem 1549 gedichteten Geistlichen Spiel "Ein comedi von dem reichen sterbenden menschen, der Hecastus genannt".
Borrelia (B.) miyamotoi, an emerging tick-borne relapsing fever spirochete, resists complement-mediated killing. To decipher the molecular principles of immune evasion, we sought to identify determinants contributing to complement resistance. Employing bioinformatics, we identified a gene encoding for a putative Factor H-binding protein, termed CbiA (complement binding and inhibitory protein A). Functional analyses revealed that CbiA interacted with complement regulator Factor H (FH), C3, C3b, C4b, C5, and C9. Upon binding to CbiA, FH retained its cofactor activity for Factor I-mediated inactivation of C3b. The Factor H-binding site within CbiA was mapped to domain 20 whereby the C-terminus of CbiA was involved in FH binding. Additionally, CbiA directly inhibited the activation of the classical pathway and the assembly of the terminal complement complex. Of importance, CbiA displayed inhibitory activity when ectopically produced in serum-sensitive B. garinii G1, rendering this surrogate strain resistant to human serum. In addition, long-term in vitro cultivation lead to an incremental loss of the cbiA gene accompanied by an increase in serum susceptibility. In conclusion, our data revealed a dual strategy of B. miyamotoi to efficiently evade complement via CbiA, which possesses complement binding and inhibitory activities.
Glial cell line-derived neurotrophic factor (GDNF) is a ligand that activates, through co-receptor GDNF family receptor alpha-1 (GFRα1) and receptor tyrosine kinase “RET”, several signaling pathways crucial in the development and sustainment of multiple neuronal populations. We decided to study whether non-mammalian orthologs of these three proteins have conserved their function: can they activate the human counterparts? Using the baculovirus expression system, we expressed and purified Danio rerio RET, and its binding partners GFRα1 and GDNF, and Drosophila melanogaster RET and two isoforms of co-receptor GDNF receptor-like. Our results report high-level insect cell expression of post-translationally modified and dimerized zebrafish RET and its binding partners. We also found that zebrafish GFRα1 and GDNF are comparably active as mammalian cell-produced ones. We also report the first measurements of the affinity of the complex to RET in solution: at least for zebrafish, the Kd for GFRα1-GDNF binding RET is 5.9 μM. Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRα1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli-produced human proteins. These results contradict previous studies suggesting that mammalian GFRα1 and GDNF cannot bind and activate non-mammalian RET and vice versa.
The 33S(n,α)30Si cross section measurement, using 10B(n,α) as reference, at the n_TOF Experimental Area 2 (EAR2) facility at CERN is presented. Data from 0.01 eV to 100 keV are provided and, for the first time, the cross section is measured in the range from 0.01 eV to 10 keV. These data may be used for a future evaluation of the cross section because present evaluations exhibit large discrepancies. The 33S(n,α)30Si reaction is of interest in medical physics because of its possible use as a cooperative target to boron in Neutron Capture Therapy (NCT).
In seinem Buch 'Die Verortung der Kultur' analysiert Homi Bhabha das Verhältnis zwischen Literatur, Blasphemie und dem Heiligen. Ihm zufolge ist Blasphemie nicht lediglich eine säkularisierte Fehldarstellung des Heiligen, sondern vielmehr ein Moment, in dem der Inhalt einer kulturellen Tradition im Akt der Übersetzung überwältigt oder verfremdet wird. Bezugnehmend auf Salman Rushdies Roman 'Die Satanischen Verse' stellt Bhabha fest, dass Rushdie einen Raum diskursiver Gegenüberstellung eröffne, der die Autorität des Korans in eine Perspektive des historischen und kulturellen Relativismus hineinstelle.
Zwei Erkenntnisse möchte ich in diesem Ansatz herausheben: Erstens die Kategorie der Übersetzung, die darin besteht, andere artikulatorische Positionen und Möglichkeiten aufzuzeigen. Die zweite Erkenntnis betrifft den historischen und kulturellen Relativismus. Dieser Relativismus ist meines Erachtens für die Heiligkeitsdeutung von entscheidender Bedeutung, da er jegliche festgefahrene und absolute Deutung des Heiligen zunichte macht und die Polyphonie bzw. die Vielfalt der Heiligkeitsauffassungen zulässt. Insbesondere in einem Lebenskontext, der zunehmend von religiöser und kultureller Pluralität gekennzeichnet ist, ist eine solche Vielfalt entscheidend.
In diesem Beitrag wurden deutsche Entlehnungen in der albanischen Mundart in Kosova untersucht, welche in verschiedenen semantischen Bereichen verwendet werden. Schriftliche Quellen zu diesen Germanismen fehlen völlig, daher wurden sie durch mündliche Befragung von Informanten inventarisiert. Den Schwerpunkt dieser Untersuchung bilden der Bekanntheitsgrad und die Akzeptanz dieser Lehnwörter. Die Befragung hat ergeben, dass die Lehnwörter in den hier untersuchten semantischen Bereichen durchschnittlich von über 70% der Befragten erkannt wurden. Im Allgemeinen konnten keine großen Unterschiede im Erkennungsgrad bei männlichen und weiblichen Befragten festgestellt werden, wohingegen bei der Variable Alter eine etwas größere Diskrepanz beobachtet wurde, was das Erkennen oder Nichterkennen der deutschen Entlehnungen anging.
Este artigo visa discutir os modelos de síntese pressupostos pela dialética negativa de Adorno através de aproximações de temáticas maiores da filosofia de Karl Marx. Isto nos permitirá qualificar melhor a natureza materialista da dialética negativa adorniana, abordando inclusive o impacto político de certas elaborações conceituais.
We present a novel equation of state which is based on the virial expansion for the multicomponent mixtures with hard core repulsion. The suggested equation of state explicitly contains the surface tension which is induced by particle interaction. At high densities such a surface tension vanishes and in this way it switches the excluded volume treatment of hard core repulsion to its eigen volume treatment. The great advantage of the developed model is that the number of equations to be solved is two and it does not depend on the number of independent hard-core radii. Using the suggested equation of state we obtained a high quality fit of the hadron multiplicities measured at AGS, SPS, RHIC and ALICE energies and studied the properties of the nuclear matter phase diagram. It is shown the developed equation of state is softer than the gas of hard spheres and remains causal up to the several normal nuclear densities. Therefore, it could be applied to the neutron star interior modeling.
Short range particle repulsion is rather important property of the hadronic and nuclear matter equations of state. We present a novel equation of state which is based on the virial expansion for the multicomponent mixtures with hard-core repulsion. In addition to the hard-core repulsion taken into account by the proper volumes of particles, this equation of state explicitly contains the surface tension which is induced by another part of the hard-core repulsion between particles. At high densities the induced surface tension vanishes and the excluded volume treatment of hard-core repulsion is switched to its proper volume treatment. Possible applications of this equation of state to a description of hadronic multiplicities measured in A+A collisions, to an investigation of the nuclear matter phase diagram properties and to the neutron star interior modeling are discussed.
The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.
Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.
HADES experiment at GSI is the only high precision experiment probing nuclear matter in the beam energy range of a few AGeV. Pion, proton and ion beams are used to study rare dielectron and strangeness probes to diagnose properties of strongly interacting matter in this energy regime. Selected results from p + A and A + A collisions are presented and discussed.
Schiller and Goethe have very different conceptions of tragedy. In his play Don Carlos, Schiller, especially in the character of Philip II, shows us the conflict between blood and positive law. In Goethe´s novel Elective Affinities, the individual will is ignorant of fate and helpless against it. So to speak, Schiller applies the "Antigone´s Model" and Goethe applies the "Oedipus Model". In his dramatic vision of the conflict, Schiller is inspired by Shakespeare´s plays. However, Goethe´s point of view is based on his reflections on Natural Philosophy.
Land surface and hydrologic models (LSMs/HMs) are used at diverse spatial resolutions ranging from catchment-scale (1–10 km) to global-scale (over 50 km) applications. Applying the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the chosen resolution, i.e., fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent hydrologic parameter fields. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB, and WaterGAP models demonstrate the pitfalls of deficient parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge's 1982 statement on the unsolved problem of parameterization in these models remains true. Based on a review of existing parameter regionalization techniques, we postulate that the multiscale parameter regionalization (MPR) technique offers a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. Herein, we develop a general model protocol to describe how MPR can be applied to a particular model and present an example application using the PCR-GLOBWB model. Finally, we discuss potential advantages and limitations of MPR in obtaining the seamless prediction of hydrological fluxes and states across spatial scales.
Land surface and hydrologic models (LSM/HM) are used at diverse spatial resolutions ranging from 1-10 km in catchment-scale applications to over 50 km in global-scale applications. Application of the same model structure at different spatial scales requires that the model estimates similar fluxes independent of the model resolution and fulfills a flux-matching condition across scales. An analysis of state-of-the-art LSMs and HMs reveals that most do not have consistent and realistic parameter fields for land surface geophysical properties. Multiple experiments with the mHM, Noah-MP, PCR-GLOBWB and WaterGAP models are conducted to demonstrate the pitfalls of poor parameterization practices currently used in most operational models, which are insufficient to satisfy the flux-matching condition. These examples demonstrate that J. Dooge’s 1982 statement on the unsolved problem of parameterization in these models remains true. We provide a short review of existing parameter regionalization techniques and discuss a method for obtaining seamless hydrological predictions of water fluxes and states across multiple spatial resolutions. The multiscale parameter regionalization (MPR) technique is a practical and robust method that provides consistent (seamless) parameter and flux fields across scales. A general model protocol is presented to describe how MPR can be applied to a specific model, with an example of this application using the PCR-GLOBWB model. Applying MPR to PCR-GLOBWB substantially improves the flux-matching condition. Estimation of evapotranspiration without MPR at 5 arcmin and 30 arcmin spatial resolutions for the Rhine river basin results in a difference of approximately 29%. Applying MPR reduce this difference to 9%. For total soil water, the differences without and with MPR are 25% and 7%, respectively.
A booming middle class, new attractive study destinations and a resulting shift in student mobility trends have recently established a new dynamic in international higher education. To stay competitive, countries apply marketing strategies to promote and "sell" their higher education to international students-cum-customers. With the growing use of the Internet to research study destinations, the role of online channels in higher education promotion is becoming increasingly important. The current study investigates the case of Malaysian higher education branding in cyberspace. By applying content analysis to the two major higher education online platforms, this study identifies the core brand values of Malaysian higher education and evaluates their coherence. The research findings demonstrate that both platforms combine nation and higher education branding efforts to create a harmonised image of the national higher education system. Additionally, several suggestions are made concerning the optimisation of the architecture and information presentation of the websites to enhance their attractiveness for users. Finally, the necessity of further investigation into higher education branding for the successful implementation of internationalisation policies in Malaysia is emphasised.
Taxonomically dissimilar epiphyte species can have comparable morphological and physiological traits in similar environmental conditions. However, the degree of trait similarity has not been examined in a comparison of bryophytic and vascular epiphytes across elevational and tree gradients. We assess whether epiphyte species that occupy comparable realised niche spaces within host tree and landscape scale gradients have similarities in taxonomy, morphology or physiology. Vascular and moss epiphytes were surveyed within four height zones at five elevations (300-1100 m asl) in the sub-tropical rainforest of Australia. Epiphyte species distributions were agglomeratively classified using Ward’s method. Chi square tests were used to test for differences in the incidences of taxonomic groups, life forms, leaf thickness, photosynthetic pathways and other drought resistant morphologies between these distributional groups. These traits were also tested for correlation with light and humidity. Six groups were identified based on distribution. Vascular epiphytes with CAM, thickened leaves and other drought-mitigating morphologies were common in the groups that occupied the most xeric situations. All drought resistant traits were associated with high light and low humidity. Vascular species with few to no drought-mitigating characteristics were common in groups that occupied moister situations. Moss morphology was less congruent with environmental conditions than vascular plant morphology, suggesting that moss life forms are responding to a different scale of environmental variation.
O ensaio traz como base a crítica ao capitalismo, no que se refere aos efeitos negativos que ele impõe aos indivíduos, a partir dos estudos da primeira geração da Escola de Frankfurt. Analisar-se-á a história das ideias a partir de Walter Benjamin, Herbert Marcuse, Theodor Adorno e Max Horkheimer. Benjamin afirma que vive-se a perda da aura das obras de arte, já que a sua comercialização faz com que se perca a essência daquelas obras. Ademais, a imposição da novidade às obras e aos produtos consumidos representa uma ferramenta de manipulação do capitalismo, culminando na pobreza da experiência humana. Marcuse afirma que a sociedade vive o princípio do desempenho, que provoca modos de vida uniformizados, baseados numa concepção de trabalho e diversão homogêneos. Adorno propôs que o tempo livre provocava uma sensação de liberdade nos indivíduos, mas, na realidade, tratava-se do exercício de uma não liberdade, já que as formas de diversão seguiam à risca os padrões exigidos pelo capital. A partir do método adotado pela própria Teoria Crítica, afirma-se que a presente discussão teórica só se torna efetiva quando aplicada à prática, à sociedade atual.
The population size and distribution of Phaethon aethereus on Raso Islet was studied from August to December 2016. In total, 42 biometric measures were collected from 38 adults and four juveniles. No recapture was identified although some individuals were ringed in 2014. The means of biometrics variables obtained for the different body segments and eggs were within the ranges of P. aethereus mesonauta from tropical North Atlantic. The two largest agglomerations of P. aethereus identified on Raso were overlapping colonies of brown boobies Sula leucogaster which allowed the maximum direct count of only 90 individuals. The inaccessibility of some breeding areas conditioned the identification and monitoring of just 117 nests. Thus, we estimate the population by the number of nests in more than 100 pairs. However, without an annual census, it is difficult to estimate the population size of this species. So, annual studies are recommended to better understand the population dynamics of P. aethereus on Raso.