Releasing the Brake: Targeting Cbl-b to Enhance Lymphocyte Effector Functions

The E3 ubiquitin ligase Cbl-b is an established nonredundant negative regulator of T-cell activation. Cbl-b fine-tunes the activation threshold of T cells and uncouples T cells from their vital need of a costimulatory signal to mount a productive immune response. Accordingly, mice deficient in cblb are prone to autoimmunity and reject tumors. The latter has been described to be mediated via CD8+ T cells, which are hyperactive and more abundant in shrinking tumors of cblb-deficient animals. This might at least also in part be mediated by resistance of cblb-deficient T cells to negative cues exerted by tumor-associated immuno-suppressive factors, such as TGF-β and regulatory T cells (Treg). Experiments using cblb-deficient T cells either alone or in combination with vaccines validate the therapeutic concept of enhancing the efficacy of adoptively transferred lymphocytes to treat malignant tumors. This paper summarizes the current knowledge about the negative regulatory role of Cbl-b in T-cell activation and its potential therapeutic implications for cancer immunotherapy

Case studies of three geological archives for rare radionuclide measurements using accelerator mass spectrometry

Long-lived radionuclides in our environment provide important information on natural and anthropogenic processes. Their presence and concentration reflect the balance of production and decay. Geological archives store such information and the nuclides can be chemically extracted from the bulk sample. Accelerator mass spectrometry (AMS) represents a sensitive method to quantify those nuclides at natural levels. Three different terrestrial archives are discussed here as examples for radionuclide extraction using various chemical separation methods for subsequent AMS measurements. We focus on sample preparation for the cosmogenic radionuclides 10Be and 26Al, various anthropogenic actinide isotopes such as U, Pu, and Am as well as the astrophysically interesting nuclides 41Ca, 53Mn, and 60Fe. The processed materials cover samples with masses between a few mg and up to a few hundred kg and protocols are presented for the quantitative extraction of some 10,000 atoms of cosmogenic or interstellar origin per sample and even as low as a few hundred actinide atoms

Zur Stabilität dialektaler Formen.: Eine real- und apparent-time-Analyse remanenter Merkmale in den ruralen Basisdialekten Österreichs

Stability is an essential but frequently underrepresented fact in the study of language variation and change. Although in dialectology the distinction between “primary” and “secondary” dialect features initially led to a certain consideration of stable features as opposed to more dynamic ones, more recent empirical studies have not taken any notice of the former. The question of stability is nevertheless crucial for dialectology. For example, the extent of dialect loss cannot be assessed without establishing which forms are stable. The aim of this study is therefore to address this desideratum by investigating ten dialectal features in Austria’s rural dialects. All ten examples concern variables of the vowel system which show large phonetic differences between dialect and standard variants. On the basis of a comprehensive dialect survey, both a real- and an apparent-time study is conducted to examine the extent and the factors of dialectal stability and change. The study provides evidence for a surprisingly high degree of stability and continuity in Austria’s rural dialects. Changes are not only restricted to a few variables, but also limited (a) to a lexical factor – only a small group of lexemes is not completely stable –, and (b) to a regional factor – only some eastern parts of Austria show a higher degree of change. Other factors, such as the extent of the spatial distribution of a form or the phonetic distance to the standard, do not prove to be relevant for stability and change of the variables

R-process enrichment from a single event in an ancient dwarf galaxy

Elements heavier than zinc are synthesized through the (r)apid and (s)low neutron-capture processes. The main site of production of the r-process elements (such as europium) has been debated for nearly 60 years. Initial studies of chemical abundance trends in old Milky Way halo stars suggested continual r-process production, in sites like core-collapse supernovae. But evidence from the local Universe favors r-process production mainly during rare events, such as neutron star mergers. The appearance of a europium abundance plateau in some dwarf spheroidal galaxies has been suggested as evidence for rare r-process enrichment in the early Universe, but only under the assumption of no gas accretion into the dwarf galaxies. Cosmologically motivated gas accretion favors continual r-process enrichment in these systems. Furthermore, the universal r-process pattern has not been cleanly identified in dwarf spheroidals. The smaller, chemically simpler, and more ancient ultra-faint dwarf galaxies assembled shortly after the first stars formed, and are ideal systems with which to study nucleosynthesis events such as the r-process. Reticulum II is one such galaxy. The abundances of non-neutron-capture elements in this galaxy (and others like it) are similar to those of other old stars. Here, we report that seven of nine stars in Reticulum II observed with high-resolution spectroscopy show strong enhancements in heavy neutron-capture elements, with abundances that follow the universal r-process pattern above barium. The enhancement in this "r-process galaxy" is 2-3 orders of magnitude higher than that detected in any other ultra-faint dwarf galaxy. This implies that a single rare event produced the r-process material in Reticulum II. The r-process yield and event rate are incompatible with ordinary core-collapse supernovae, but consistent with other possible sites, such as neutron star mergers.Comment: Published in Nature, 21 Mar 2016: http://dx.doi.org/10.1038/nature1742

The old, unique C1 chondrite Flensburg - Insight into the first processes of aqueous alteration, brecciation, and the diversity of water-bearing parent bodies and lithologies

On September 12, 2019 at 12:49:48 (UT) a bolide was observed by hundreds of eye-witnesses from the Netherlands, Germany, Belgium, Denmark and the UK. One day later a small meteorite stone was found by accident in Flensburg. The presence of short-lived cosmogenic radionuclides with half-lives as short as 16 days proves the recent exposure of the found object to cosmic rays in space linking it clearly to the bolide event. An exceptionally short exposure time of ~5000 years was determined. The 24.5 g stone has a fresh black fusion crust, a low density of <2 g/cm^3, and a magnetic susceptibility of logX = 4.35 (X in 10^-9 m^3/kg). The rock consists of relict chondrules and clusters of sulfide and magnetite grains set in a fine-grained matrix. The most abundant phases are phyllosilicates. Carbonates (~3.9 vol.%) occur as calcites, dolomites, and a Na-rich phase. The relict chondrules (often surrounded by sulfide laths) are free of anhydrous silicates and contain abundant serpentine. Lithic clasts are also surrounded by similar sulfide laths partly intergrown with carbonates. 53^Mn-^53Cr ages of carbonates in Flensburg indicate that brecciation and contemporaneous formation of the pyrrhotite-carbonate intergrowths by hydrothermal activities occurred no later than 4564.6 +- 1.0 Ma (using the angrite D'Orbigny as the Mn-Cr age anchor). This corresponds to 2.6 +- 1.0 or 3.4 +- 1.0 Ma after formation of CAIs, depending on the exact absolute age of CAIs. This is the oldest dated evidence for brecciation and carbonate formation, which likely occurred during parent body growth and incipient heating due to decay of 26Al. In the three oxygen isotope diagram, Flensburg plots at the 16O-rich end of the CM chondrite field and in the transition field to CV-CK-CR chondrites. The mass-dependent Te isotopic composition of Flensburg is slightly different from mean CM chondrites and is most similar to those of the ungrouped C2 chondrite Tagish Lake. On the other hand, 50Ti and 54Cr isotope anomalies indicate that Flensburg is similar to CM chondrites, as do the ~10 wt.% H2O of the bulk material. Yet, the bulk Zn, Cu, and Pb concentrations are about 30% lower than those of mean CM chondrites. The He, Ne, and Ar isotopes of Flensburg show no solar wind contribution; its trapped noble gas signature is similar to that of CMs with a slightly lower concentration of 20Netr. Based on the bulk H, C, and N elemental abundances and isotopic compositions, Flensburg is unique among chondrites, because it has the lightest bulk H and N isotopic compositions of any type 1 or 2 chondrite investigated so far. Moreover, the number of soluble organic compounds in Flensburg is even lower than that of the brecciated CI chondrite Orgueil. The extraordinary significance of Flensburg is evident from the observation that it represents the oldest chondrite sample in which the contemporaneous episodes of aqueous alteration and brecciation have been preserved. The characterization of a large variety of carbonaceous chondrites with different alteration histories is important for interpreting returned samples from the OSIRIS-REx and Hayabusa 2 missions.This work is partly funded by the Deutsche Forschungs- gemeinschaft (DFG, German Research Foundation) – Project-ID 263649064 – TRR 170 (A.B., C.B., T.K.); this is TRR170 Publication No. 119. M.S. and C.M. thank the Swiss National Science Foundation (SNF) for support. The work of H.B. and M.S. has been in parts carried out within the framework of the NCCR PlanetS supported by SNF. D.H. thanks F. Langenhorst for support and access to the FIB-SEM and TEM facilities at FSU-IGW, which are funded by the DFG via grant LA830/14-1. D.F. (CIW) acknowledges the support of the NASA awards 80NSSC19K0559 and 80NSSC20K0344

Wnt Pathway in Bone Repair and Regeneration – What Do We Know So Far

Wnt signaling plays a central regulatory role across a remarkably diverse range of functions during embryonic development, including those involved in the formation of bone and cartilage. Wnt signaling continues to play a critical role in adult osteogenic differentiation of mesenchymal stem cells. Disruptions in this highly-conserved and complex system leads to various pathological conditions, including impaired bone healing, autoimmune diseases and malignant degeneration. For reconstructive surgeons, critically sized skeletal defects represent a major challenge. These are frequently associated with significant morbidity in both the recipient and donor sites. The Wnt pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for skeletal tissue regeneration and promote bone growth, suggesting that Wnt factors could be used to promote bone healing after trauma. This review summarizes our current understanding of the essential role of the Wnt pathway in bone regeneration and repair

Eicosanoid Release Is Increased by Membrane Destabilization and CFTR Inhibition in Calu-3 Cells

The antiinflammatory protein annexin-1 (ANXA1) and the adaptor S100A10 (p11), inhibit cytosolic phospholipase A2 (cPLA2α) by direct interaction. Since the latter is responsible for the cleavage of arachidonic acid at membrane phospholipids, all three proteins modulate eicosanoid production. We have previously shown the association of ANXA1 expression with that of CFTR, the multifactorial protein mutated in cystic fibrosis. This could in part account for the abnormal inflammatory status characteristic of this disease. We postulated that CFTR participates in the regulation of eicosanoid release by direct interaction with a complex containing ANXA1, p11 and cPLA2α. We first analyzed by plasmon surface resonance the in vitro binding of CFTR to the three proteins. A significant interaction between p11 and the NBD1 domain of CFTR was found. We observed in Calu-3 cells a rapid and partial redistribution of all four proteins in detergent resistant membranes (DRM) induced by TNF-α. This was concomitant with increased IL-8 synthesis and cPLA2α activation, ultimately resulting in eicosanoid (PGE2 and LTB4) overproduction. DRM destabilizing agent methyl-β-cyclodextrin induced further cPLA2α activation and eicosanoid release, but inhibited IL-8 synthesis. We tested in parallel the effect of short exposure of cells to CFTR inhibitors Inh172 and Gly-101. Both inhibitors induced a rapid increase in eicosanoid production. Longer exposure to Inh172 did not increase further eicosanoid release, but inhibited TNF-α-induced relocalization to DRM. These results show that (i) CFTR may form a complex with cPLA2α and ANXA1 via interaction with p11, (ii) CFTR inhibition and DRM disruption induce eicosanoid synthesis, and (iii) suggest that the putative cPLA2/ANXA1/p11/CFTR complex may participate in the modulation of the TNF-α-induced production of eicosanoids, pointing to the importance of membrane composition and CFTR function in the regulation of inflammation mediator synthesis

The instrument control unit of the PLATO payload: design consolidation following the preliminary design review by ESA

PLATO is an M-class mission (M3) of the European Space Agency (ESA) whose launch is scheduled in 2026. The main aim of the mission is the detection and characterization of terrestrial exoplanets orbiting around bright solar-type star. The payload consists of 26 small telescopes: 24 "normal" cameras and 2 "fast" cameras. The huge amount of data produced by the PLATO telescopes is acquired and processed on-board by the Data Processing System (DPS) made up by various processing electronic units. The DPS of the PLATO instrument comprises the Normal and Fast DPUs (Data Processing Units) and a single ICU (Instrument Control Unit), are data routed through a SpaceWire network. The topic of this paper is the description of the architecture of the ICU and its role within the DPS, the status of the Avionic Validation Model (AVM) testing at the end of the Unit Preliminary Design Review (UPDR) performed by ESA and the results of the test of the first engineering model

Die epische Erzähltradition der Ainu: Götterlieder (kamuy yukar) und Heldenepen (yukar)

Die ursprünglich schriftlose Kultur der Ainu – der autochthonen Bevölkerung Nordjapans und des südlichen Bereichs um das ochotskische Meer – hat eine literarische Tradition hervorgebracht, in der Erzählungen über Generationen hinweg rein mündlich überliefert wurden. Diese war bis zum Anfang des 20. Jahrhunderts lebendig, brach dann aber schnell ab, als die Ainu zunehmend an die japanische Gesellschaft assimiliert wurden und ihre eigene Sprache nicht mehr an ihre Kinder und Enkel weitergaben. Dennoch gibt es auch heute noch Erzähler und Rezitatoren, die die alte Kunst nach wie vor beherrschen. Für die seit 2008 international als indigene Bevölkerung Nordjapans anerkannten Ainu gilt darüber hinaus das eigene literarische Erbe als wichtiger Pfeiler bei der Findung einer nationalen Identität. Die orale Literatur der Ainu fand bereits in den frühen Forschungen der Ainu-Kultur ein großes Interesse als sprachliches Korpus und wurde vor allem unter linguistischen Gesichtspunkten analysiert. Literaturwissenschaftliche Untersuchungen gibt es dagegen wenige. Erst seit Beginn des neuen Jahrtausends nimmt die Ainu-Literatur als solche einen größeren Raum in der Ainu-Forschung, aber auch in der Erforschung oraler Literatur allgemein ein. Die vorliegende Arbeit hat zum Ziel, zum einen die orale Ainu-Literatur in der deutschen Forschungslandschaft als Untersuchungsgegenstand einzuführen und zum anderen einen eigenen Forschungsbeitrag im Spannungsfeld zwischen linguistischer und literaturwissenschaftlicher Analyse zu leisten. Nach einer ausführlichen Einführung in die Geschichte und vormoderne Lebenswelt der Ainu stellt die Arbeit die beiden epischen Formen der oralen Ainu-Literatur – die epische Kurzform der Götterlieder (kamuy yukar) und die Langform der Heldenepen (yukar) – vor. Dabei wird auf inhaltliche, sprachliche und strukturelle Charakteristika eingegangen. Einen besonderen Beitrag leistet die Arbeit in Hinblick auf die Übertragung der perspektivistischen Weltsicht nach Viveiros de Castro auf das Glaubenssystem der Ainu, neuen Überlegungen zu den unterschiedlichen Flexionsformen der 1. Person in Umgangssprache, Götterliedern und Heldenepen, und die narratologische Analyse der literaturgeographischen Strukturen der beiden epischen Erzählformen. Teil II schließlich präsentiert eine repräsentative Auswahl von Erzählungen der Ainu-Literatur erstmals in deutscher Übersetzung