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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.