Targeted Proteolysis of Plectin Isoform 1a Accounts for Hemidesmosome Dysfunction in Mice Mimicking the Dominant Skin Blistering Disease EBS-Ogna

Autosomal recessive mutations in the cytolinker protein plectin account for the multisystem disorders epidermolysis bullosa simplex (EBS) associated with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and congenital myasthenia (EBS-CMS). In contrast, a dominant missense mutation leads to the disease EBS-Ogna, manifesting exclusively as skin fragility. We have exploited this trait to study the molecular basis of hemidesmosome failure in EBS-Ogna and to reveal the contribution of plectin to hemidesmosome homeostasis. We generated EBS-Ogna knock-in mice mimicking the human phenotype and show that blistering reflects insufficient protein levels of the hemidesmosome-associated plectin isoform 1a. We found that plectin 1a, in contrast to plectin 1c, the major isoform expressed in epidermal keratinocytes, is proteolytically degraded, supporting the notion that degradation of hemidesmosome-anchored plectin is spatially controlled. Using recombinant proteins, we show that the mutation renders plectin's 190-nm-long coiled-coil rod domain more vulnerable to cleavage by calpains and other proteases activated in the epidermis but not in skeletal muscle. Accordingly, treatment of cultured EBS-Ogna keratinocytes as well as of EBS-Ogna mouse skin with calpain inhibitors resulted in increased plectin 1a protein expression levels. Moreover, we report that plectin's rod domain forms dimeric structures that can further associate laterally into remarkably stable (paracrystalline) polymers. We propose focal self-association of plectin molecules as a novel mechanism contributing to hemidesmosome homeostasis and stabilization

Unidirectional magnetoresistance and spin-orbit torque in NiMnSb

Spin-dependent transport phenomena due to relativistic spin-orbit coupling and broken space-inversion symmetry are often difficult to interpret microscopically, in particular when occurring at surfaces or interfaces. Here we present a theoretical and experimental study of spin-orbit torque and unidirectional magnetoresistance in a model room-temperature ferromagnet NiMnSb with inversion asymmetry in the bulk of this half-Heusler crystal. Aside from the angular dependence on magnetization, the competition of Rashba- and Dresselhaus-type spin-orbit couplings results in the dependence of these effects on the crystal direction of the applied electric field. The phenomenology that we observe highlights potential inapplicability of commonly considered approaches for interpreting experiments. We point out that, in general, there is no direct link between the current-induced nonequilibrium spin polarization inferred from the measured spin-orbit torque and the unidirectional magnetoresistance. We also emphasize that the unidirectional magnetoresistance has not only longitudinal but also transverse components in the electric field: current indices which complicate its separation from the thermoelectric contributions to the detected signals in common experimental techniques. We use the theoretical results to analyze our measurements of the on-resonance and off-resonance mixing signals in microbar devices fabricated from an epitaxial NiMnSb film along different crystal directions. Based on the analysis we extract an experimental estimate of the unidirectional magnetoresistance in NiMnSb

Room-temperature spin-orbit torque in NiMnSb

Materials that crystallize in diamond-related lattices, with Si and GaAs as their prime examples, are at the foundation of modern electronics. Simultaneously, inversion asymmetries in their crystal structure and relativistic spin–orbit coupling led to discoveries of non-equilibrium spin-polarization phenomena that are now extensively explored as an electrical means for manipulating magnetic moments in a variety of spintronic structures. Current research of these relativistic spin–orbit torques focuses primarily on magnetic transition-metal multilayers. The low-temperature diluted magnetic semiconductor (Ga, Mn)As, in which spin–orbit torques were initially discovered, has so far remained the only example showing the phenomenon among bulk non-centrosymmetric ferromagnets. Here we present a general framework, based on the complete set of crystallographic point groups, for identifying the potential presence and symmetry of spin–orbit torques in non-centrosymmetric crystals. Among the candidate room-temperature ferromagnets we chose to use NiMnSb, which is a member of the broad family of magnetic Heusler compounds. By performing all-electrical ferromagnetic resonance measurements in single-crystal epilayers of NiMnSb we detect room-temperature spin–orbit torques generated by effective fields of the expected symmetry and of a magnitude consistent with our ab initio calculations.University of WürzburgThis is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nphys377

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

Observation of time-reversal symmetry breaking in the band structure of altermagnetic RuO 2

Altermagnets are an emerging elementary class of collinear magnets. Unlike ferromagnets, their distinct crystal symmetries inhibit magnetization while, unlike antiferromagnets, they promote strong spin polarization in the band structure. The corresponding unconventional mechanism of time-reversal symmetry breaking without magnetization in the electronic spectra has been regarded as a primary signature of altermagnetism but has not been experimentally visualized to date. We directly observe strong time-reversal symmetry breaking in the band structure of altermagnetic RuO2 by detecting magnetic circular dichroism in angle-resolved photoemission spectra. Our experimental results, supported by ab initio calculations, establish the microscopic electronic structure basis for a family of interesting phenomena and functionalities in fields ranging from topological matter to spintronics, which are based on the unconventional time-reversal symmetry breaking in altermagnets

The role of Merlin in the Hh-cilia axis in meningiomas

Die Rolle von Merlin in der Hh-Zilien Achse im Meningiom Der Tumorsuppressor NF2/Merlin unterdrückt wichtige molekulare Signaltransduktionswege in der Zelle, die das Zellwachstum, die Zellteilung und das Überleben beeinflussen (James et al, 2009; Li et al, 2014; Petrilli & Fernandez-Valle, 2015). Mutationen und/oder Deletionen des NF2 Gens sind häufig in Meningiomen zu finden und repräsentieren ein frühes Stadium in der Tumorentwicklung (Petrilli & Fernandez-Valle, 2015). Der Hedgehog Signalweg ist ein erst seit kürzlich intensiv beforschter Signalweg in der Krebsentstehung und Entwicklung, der durch neue Therapiemöglichkeiten blockierbar ist (Gonnissen et al, 2015; Sekulic et al, 2012). In unserer Studie vermuten wir, dass NF2/Merlin den Hedgehog Signalweg in Meningiomen negativ reguliert. In Gewebsproben von Meningiomen konnten wir gesteigerte Genexpression von Mitgliedern des Hedgehog Singalwegs nachweisen. Nach Einteilung der Gewebsproben durch die WHO Klassifikation, konnten wir eine signifikante Verringerung der Genexpression von Repressoren des Hh Signalwegs wie GLI3 und PTCH1 bei steigender Malignität der Tumoren nachweisen. Nach Unterteilung in NF2/Merlin positive und negative Gewebsproben wiesen wir unterschiedliche Genexpression von Hh Repressor GLI3 und KIF3A, ein essentielles Gen für Zusammenbau und Erhaltung von primären Zilien, nach. In vitro Experimente zeigte eine Liganden-abhängige Überstimulation des Hh Signalwegs in Abwesenheit von NF2/Merlin. Da der Hh Signalweg eng mit dem primären Zilium in der Zelle zusammenhängt, untersuchten wir primären Zilien mittels Immunoflureszenz. Primäre Zilien wurden sowohl von primären Meningiomzellen und meningeale Zellen als auch von etablierten Meningiomzelllinien untersucht. Primäre meningeale Zellen, SF3061 und weit weniger, aber vorhanden in SF4068 und IN-ME-2 zeigten primäre Zilien. Hingegen schienen die Zelllinien KT21, IOMM-Lee und IN-ME-1/3 keine primären Zilien zu besitzen. Interessanterweise löste der Knockdown von NF2 eine Zunahme der primären Zilien in SF4068 Zellen aus. Erst kürzlich bekam ein Hh Signalwegblocker namens Vismodegib die Zulassung für die Behandlung des Basalzellkarzinoms am Menschen. In unseren Experimenten verringerte Vismodegib die Zellproliferation von Menigiomzellen in vitro. Weiters war die Sensitivität der Zellen auf Vismodegib erhöht, wenn die Genexpression von NF2 ausgeschalten wurde. Zusammengefasst beeinflusst NF2/Merlin wahrscheinlich den Hh Signalweg in Meningiomen und Vismodegib könnte ein neue Behandlungsoption für Meningiompatienten sein.The role of Merlin in the Hh-cilia axis in meningioma The tumor suppressor NF2/Merlin represses several crucial molecular signaling pathways within the cell involving cellular growth, proliferation and survival (James et al, 2009; Li et al, 2014; Petrilli & Fernandez-Valle, 2015). Mutations and/or deletions of NF2 are common in meningioma and represent an early stage of tumorigenesis (Petrilli & Fernandez-Valle, 2015). The hedgehog signaling pathway is an emerging pathway in cancer development, and novel, specific treatment options are available (Gonnissen et al, 2015; Sekulic et al, 2012). In our present study, we hypothesize that NF2/Merlin is negatively regulating the hedgehog signaling pathway in meningioma. In meningioma tissue samples, we detected over-expressed hedgehog signaling pathway members. By taking the WHO grading into account, Hh repressors (GLI3 and PTCH1) decreased with malignancy. Subgrouping via NF2 status revealed differently expressed genes including the Hh repressor GLI3 and essential cilia assembly/maintenance gene KIF3A. In vitro work demonstrated ligand-dependent over-stimulation of Hh pathway in absence of NF2. Since the Hh signaling pathway has been closely connected to primary cilia, we further investigated cilia status via immunofluorescence staining. Counting of primary cilia of primary cells and established meningioma cells showed a diverging picture such as detectable cilia in primary meningeal cells, SF3061 and to a lesser degree in SF4068 and IN-ME-2, in contrast to completely abolished primary cilia in KT21, IOMM-Lee and IN-ME-1/3 cells. Interestingly, depletion of NF2 caused primary cilia in SF4068 cells to increase. Recently, novel Hh signaling pathways inhibitors made their way to clinics. One of them, Vismodegib, decreased meningioma cell growth in vitro. Furthermore, sensitivity to Vismodegib treatment was augmented, when NF2 was abolished. Taken together, NF2 may influence the Hh signaling pathway and Vismodegib may be novel treatment option for meningioma patients.Arbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprüftAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2016OeBB(VLID)364470

Predation risk drives social complexity in cooperative breeders

Predation risk is a major ecological factor selecting for group living. It is largely ignored, however, as an evolutionary driver of social complexity and cooperative breeding, which is attributed mainly to a combination of habitat saturation and enhanced relatedness levels. Social cichlids neither suffer from habitat saturation, nor are their groups composed primarily of relatives. This demands alternative ecological explanations for the evolution of advanced social organization. To address this question, we compared the ecology of eight populations of Neolamprologus pulcher, a cichlid fish arguably representing the pinnacle of social evolution in poikilothermic vertebrates. Results show that variation in social organization and behavior of these fish is primarily explained by predation risk and related ecological factors. Remarkably, ecology affects group structure more strongly than group size, with predation inversely affecting small and large group members. High predation and shelter limitation leads to groups containing few small but many large members, which is an effect enhanced at low population densities. Apparently, enhanced safety from predators by cooperative defense and shelter construction are the primary benefits of sociality. This finding suggests that predation risk can be fundamental for the transition toward complex social organization, which is generally undervalued

Large-Scale Drug Screening in Patient-Derived IDHmut Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents

The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDHmut GSCs) resulted in a paucity of preclinical models in IDHmut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDHmut GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDHmut GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC50) below 1 µM and maximum inhibitory effects (Emax) below 25%. These findings were validated in an additional four IDHmut GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC50 values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDHmut gliomas