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2. Endosome dysfunction leads to gain-of-function TLR7 and human lupus

Author

Mishra, H., Schlack-Leigers, C., Lim, E., Thieck, O., Magg, T., Raedler, J., Wolf, C., Klein, C., Ewers, H., Lee-Kirsch, M., Meierhofer, D., Hauck, F., and Majer, O.

Abstract

Hyperactive Toll-like receptor (TLR) 7 signaling has long been appreciated as a driver of autoimmune disease by breaking tolerance to self-nucleic acids in mouse models1–5. Recently, mutations in TLR7 or its associated regulator UNC93B16, 7, were identified as monogenic causes of human lupus; the unifying feature of these mutations being TLR7 gain-of-function. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes8, 9. Hence, its function depends on intricate transport mechanisms and membrane interactions within the endomembrane network. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here, we show that a dysregulated endosomal compartment leads to unrestricted TLR7 signaling and human lupus. The late endosomal BLOC-1-related protein complex (BORC) together with the small Arf1-like GTPase Arl8b controls TLR7 protein levels, and a direct interaction between Arl8b and Unc93b1 is required to regulate TLR7 turnover. We identified an amino acid insertion in UNC93B1 in a patient with childhood-onset lupus, which reduces the interaction with the BORC-Arl8b complex and leads to endosomal TLR7 accumulation. Therefore, a failure to control the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids in humans. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. As the cellular mechanisms restricting TLR7 signaling can be manifold, identifying and stratifying lupus patients based on a TLR7-driven pathogenesis could be a viable strategy towards a targeted therapy.

Published
2023

4. Gianni Rodari sbarca in America: un viaggio lungo cinquant'anni e oltre

Author

Boero, P., Fava, S., Barsotti, S., Roghi, V., Todaro, L., Campagnaro, M., Sardo, R., Taviani, E., D'Aprile, G., Acone, L., Articoni, A., Strongoli, R.C., Balina, M., Caroli, D., Nicewicz-Staszowska, E., Ewers, H-H., Crisan, M-M., Ilie, E., Truglio, M., Alborghetti, C., Daher, L.M., Gamuzza, A., Leonora, A.M., Mavica, G., Alborghetti, Claudia, claudia alborghetti (ORCID:0000-0001-5019-8383), Boero, P., Fava, S., Barsotti, S., Roghi, V., Todaro, L., Campagnaro, M., Sardo, R., Taviani, E., D'Aprile, G., Acone, L., Articoni, A., Strongoli, R.C., Balina, M., Caroli, D., Nicewicz-Staszowska, E., Ewers, H-H., Crisan, M-M., Ilie, E., Truglio, M., Alborghetti, C., Daher, L.M., Gamuzza, A., Leonora, A.M., Mavica, G., Alborghetti, Claudia, and claudia alborghetti (ORCID:0000-0001-5019-8383)

Abstract

La fama di Gianni Rodari (1920-1980) in traduzione inglese affonda le radici negli anni '60 del Novecento, a seguito della prima pubblicazione delle Favole al telefono con Einaudi editore. Quando poi nel 1970 Rodari vince l'ambito Hans Christian Andersen Award, ecco che il numero di traduzioni verso i paesi di lingua anglofona si moltiplica nelle voci di diversi traduttori. Tuttavia, il viaggio in traduzione di Rodari lo porta in un primo momento verso il Regno Unito, prima di approdare nel 1996 negli Stati Uniti con la Grammatica della fantasia tradotta da Jack Zipes. Prima di allora, gli Stati Uniti avevano solo conosciuto tre brevi favole pubblicate nel noto Cricket Magazine. Grazie alle celebrazioni per il centenario dalla nascita nel 2020, in questo saggio si mostra come sia arrivato un nuovo impulso traduttivo volto a far sentire la voce di questo autore così importante per la letteratura italiana anche in ambito anglofono.

Published
2020

11. Mit dem österreichischen „Heidi“ in die Sechziger Jahre

Author

Maierbäurl, G, Blumesberger, S, Ewers, H H, Rohrwasser, M, Maierbäurl, G ( G ), Blumesberger, S ( S ), Ewers, H H ( H H ), Rohrwasser, M ( M ), Tomkowiak, I; https://orcid.org/0000-0003-3032-8464, Maierbäurl, G, Blumesberger, S, Ewers, H H, Rohrwasser, M, Maierbäurl, G ( G ), Blumesberger, S ( S ), Ewers, H H ( H H ), Rohrwasser, M ( M ), and Tomkowiak, I; https://orcid.org/0000-0003-3032-8464

Published
2010

14. Receptor concentration and diffusivity control multivalent binding of Sv40 to membrane bilayers

Author

Szklarczyk, OM, González-Segredo, N, Kukura, P, Oppenheim, A, Choquet, D, Sandoghdar, V, Helenius, A, Sbalzarini, IF, and Ewers, H

Subjects
Stochastic Processes, Ecologie, viruses, Lipid Bilayers, Computational Biology, Biologie moléculaire, G(M1) Ganglioside, Simian virus 40, Evolution des espèces, Models, Biological, Life sciences, Chemistry, lcsh:Biology (General), ddc:570, ddc:540, Informatique mathématique, Computer Simulation, Biologie, Sciences cognitives, lcsh:QH301-705.5, Research Article, Protein Binding
Abstract

Incoming Simian Virus 40 particles bind to their cellular receptor, the glycolipid GM1, in the plasma membrane and thereby induce membrane deformation beneath the virion leading to endocytosis and infection. Efficient membrane deformation depends on receptor lipid structure and the organization of binding sites on the internalizing particle. To determine the role of receptor diffusion, concentration and the number of receptors required for stable binding in this interaction, we analyze the binding of SV40 to GM1 in supported membrane bilayers by computational modeling based on experimental data. We measure the diffusion rates of SV40 virions in solution by fluorescence correlation spectroscopy and of the receptor in bilayers by single molecule tracking. Quartz-crystal microbalance with dissipation (QCM-D) is used to measure binding of SV40 virus-like particles to bilayers containing the viral receptor GM1. We develop a phenomenological stochastic dynamics model calibrated against this data, and use it to investigate the early events of virus attachment to lipid membranes. Our results indicate that SV40 requires at least 4 attached receptors to achieve stable binding. We moreover find that receptor diffusion is essential for the establishment of stable binding over the physiological range of receptor concentrations and that receptor concentration controls the mode of viral motion on the target membrane. Our results provide quantitative insight into the initial events of virus-host interaction at the nanoscopic level. © 2013 Szklarczyk et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013
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15. Resolving bundled microtubules using anti-tubulin nanobodies

Author

Mikhaylova, M. (Marina), Cloin, B.M.C. (Bas), Finan, K. (Kieran), Berg, R. (Robert) van den, Teeuw, J. (Jalmar), Kijanka, M.M. (Marta M.), Sokolowski, M. (Mikolaj), Katrukha, E.A. (Eugene), Maidorn, M. (Manuel), Opazo, F. (Felipe), Moutel, S. (Sandrine), Vantard, M. (Marylin), Perez, F. (Frank), Van Bergen En Henegouwen, P.M.P. (P. M P), Hoogenraad, C.C. (Casper), Ewers, H. (Helge), Kapitein, L.C. (Lukas), Mikhaylova, M. (Marina), Cloin, B.M.C. (Bas), Finan, K. (Kieran), Berg, R. (Robert) van den, Teeuw, J. (Jalmar), Kijanka, M.M. (Marta M.), Sokolowski, M. (Mikolaj), Katrukha, E.A. (Eugene), Maidorn, M. (Manuel), Opazo, F. (Felipe), Moutel, S. (Sandrine), Vantard, M. (Marylin), Perez, F. (Frank), Van Bergen En Henegouwen, P.M.P. (P. M P), Hoogenraad, C.C. (Casper), Ewers, H. (Helge), and Kapitein, L.C. (Lukas)

Abstract

Microtubules are hollow biopolymers of 25-nm diameter and are key constituents of the cytoskeleton. In neurons, microtubules are organized differently between axons and dendrites, but their precise organization in different compartments is not completely understood. Super-resolution microscopy techniques can detect specific structures at an increased resolution, but the narrow spacing between neuronal microtubules poses challenges because most existing labelling strategies increase the effective microtubule diameter by 20-40 nm and will thereby blend neighbouring microtubules into one structure. Here we develop single-chain antibody fragments (nanobodies) against tubulin to achieve super-resolution imaging of microtubules with a decreased apparent diameter. To test the resolving power of these novel probes, we generate microtubule bundles with a known spacing of 50-70 nm and successfully resolve individual microtubules. Individual bundled microtubules can also be resolved in different mammalian cells, including hippocampal neurons, allowing novel insights into fundamental mechanisms of microtubule organization in cell- and neurobiology.

Published
2015
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16. Lolivetta, Straparola und die Brüder Grimm

Author

Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), Rubini Messerli, Luisa, Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), and Rubini Messerli, Luisa

Published
2015

17. In einem Schloss zu leben ist ganz herrlich. Aschenputtel im Film

Author

Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), Tomkowiak, Ingrid; https://orcid.org/0000-0003-3032-8464, Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), and Tomkowiak, Ingrid; https://orcid.org/0000-0003-3032-8464

Published
2015

18. Mythen in Massen. Überlegungen zu einem Schlagwort in der Tagespresse

Author

Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), Zimmermann, Harm-Peer, Brinker-von der Heyde, Claudia, Ehrhardt, Holger, Ewers, Hans-Heino, Inder, Annekatrin, Brinker-von der Heyde, C ( Claudia ), Ehrhardt, H ( Holger ), Ewers, H ( Hans-Heino ), Inder, A ( Annekatrin ), and Zimmermann, Harm-Peer

Published
2015

23. N-glycolyl GM1 ganglioside as a receptor for Simian virus 40 (SV40)

Author

Campanero-Rhodes, M.A., Smith, A., Chai, W., Sonnino, S., Mauri, L., Childs, R.A., Zhang, Y., Ewers, H., Helenius, A., Imberty, A., Feizi, T., Centre de Recherches sur les Macromolécules Végétales (CERMAV), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

25. Buchbesprechung von: Maren Bonacker (Hg.): Hasenfuss und Löwenherz: Tiere und Tierwesen in der phantastischen Kinder- und Jugendliteratur. Wetzlar: Phantastische Bibliothek Wetzlar, 2011 (= Schriftenreihe und Materialien der Phantastischen Bibliothek Wetzlar; 99), 275 S.

Author

Dolle-Weinkauff, Bernd, Ewers, Hans-Heino, Pohlmann, Carola, Dolle-Weinkauff, B ( Bernd ), Ewers, H ( Hans-Heino ), Pohlmann, C ( Carola ), Schrackmann, Petra, Dolle-Weinkauff, Bernd, Ewers, Hans-Heino, Pohlmann, Carola, Dolle-Weinkauff, B ( Bernd ), Ewers, H ( Hans-Heino ), Pohlmann, C ( Carola ), and Schrackmann, Petra

Published
2012

26. Single particle tracking of alpha7 nicotinic AChR in hippocampal neurons reveals regulated confinement at glutamatergic and GABAergic perisynaptic sites

Author

Bürli, T, Baer, K, Ewers, H, Sidler, C, Fuhrer, Christian; https://orcid.org/0000-0001-8216-8883, Fritschy, J M, Bürli, T, Baer, K, Ewers, H, Sidler, C, Fuhrer, Christian; https://orcid.org/0000-0001-8216-8883, and Fritschy, J M

Abstract

Alpha7 neuronal nicotinic acetylcholine receptors (alpha7-nAChR) form Ca(2+)-permeable homopentameric channels modulating cortical network activity and cognitive processing. They are located pre- and postsynaptically and are highly abundant in hippocampal GABAergic interneurons. It is unclear how alpha7-nAChRs are positioned in specific membrane microdomains, particularly in cultured neurons which are devoid of cholinergic synapses. To address this issue, we monitored by single particle tracking the lateral mobility of individual alpha7-nAChRs labeled with alpha-bungarotoxin linked to quantum dots in live rat cultured hippocampal interneurons. Quantitative analysis revealed different modes of lateral diffusion of alpha7-nAChR dependent on their subcellular localization. Confined receptors were found in the immediate vicinity of glutamatergic and GABAergic postsynaptic densities, as well as in extrasynaptic clusters of alpha-bungarotoxin labeling on dendrites. alpha7-nAChRs avoided entering postsynaptic densities, but exhibited reduced mobility and long dwell times at perisynaptic locations, indicative of regulated confinement. Their diffusion coefficient was lower, on average, at glutamatergic than at GABAergic perisynaptic sites, suggesting differential, synapse-specific tethering mechanisms. Disruption of the cytoskeleton affected alpha7-nAChR mobility and cell surface expression, but not their ability to form clusters. Finally, using tetrodotoxin to silence network activity, as well as exposure to a selective alpha7-nAChR agonist or antagonist, we observed that alpha7-nAChRs cell surface dynamics is modulated by chronic changes in neuronal activity. Altogether, given their high Ca(2+)-permeability, our results suggest a possible role of alpha7-nAChR on interneurons for activating Ca(2+)-dependent signaling in the vicinity of GABAergic and glutamatergic synapses.

Published
2010

34. Even illumination in total internal reflection fluorescence microscopy using laser light.

Author

Fiolka, R., Belyaev, Y., Ewers, H., and Stemmer, A.

Abstract

In modern fluorescence microscopy, lasers are a widely used source of light, both for imaging in total internal reflection and epi-illumination modes. In wide-field imaging, scattering of highly coherent laser light due to imperfections in the light path typically leads to nonuniform illumination of the specimen, compromising image analysis. We report the design and construction of an objective-launch total internal reflection fluorescence microscopy system with excellent evenness of specimen illumination achieved by azimuthal rotation of the incoming illuminating laser beam. The system allows quick and precise changes of the incidence angle of the laser beam and thus can also be used in an epifluorescence mode. Microsc. Res. Tech., 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2008
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36. Innovation-oriented regional policy

Author

Ewers, H. -J. and Wettmann, R. W.

Abstract

Ewers H.-J. and Wettmann R. W. (1980) Innovation-oriented regional policy, Reg. Studies14, 161-179. In a changed macroeconomic situation, it is felt that regional policy is not directed towards the main bottleneck factor constraining growth in the problem regions. Regional innovation potential is shown to be the decisive bottleneck. Existing theories of the spatial diffusion of innovations are reviewed and a theoretical framework, based on an open-system approach to organizations, is considered to deal with spatial influences on innovation processes. A new approach to regional policy by means of innovation-promoting and technology policy instruments is proposed.

Published
1980
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37. [Interactions between nitrous oxide and central depressants]

Author

Stumpf C, Jindra R, Sigismund Huck, and Ewers H

Subjects
Male, Benzodiazepines, Mice, Diazepam, Ethanol, Barbiturates, Nitrous Oxide, Animals, Medazepam, Drug Interactions, Drug Synergism, Flunitrazepam
Abstract

The combined effects on mice of N2O and various central depressants were investigated. A loss of the righting reflex was taken as the criterion for the drug effects. Essential differences could be demonstrated in the type of interaction: diazepam, flunitrazepam, and medazepam have a supra-additive effect in combination with N2O; the solvent of diazepam and an experimental product, Ro 21-3981 (8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-a] [1,4]-benzodiazepine maleate) a simply additive one. However, the interactions between N2O and barbiturates (pentobarbitone and phenobarbitone), and N2O and ethanol were found to be infra-additive. The results of this and previous investigations indicate that additive or supra-additive interactions can only be expected in those cases in which at most one of the two active ingredients in addition to its depressive effect also exhibits an excitatory component.

Published
1979

46. Seeing the forest, tree by tree - Single molecule superresolution microscopy of multiprotein complexes.

Author

Ewers, H.

Subjects
*MOLECULES, *FLUORESCENT proteins, *IMMUNOGLOBULINS
Abstract

Single molecule localization-based superresolution microscopy methods such as PALM or STORM, have been breakthrough techniques of the last years. Until now however, they require special fluorescent proteins to be cloned or high-affinity antibodies to be generated for specific labeling. On the other hand, many laboratories will have most of their constructs in GFP form and entire genomes are available as functional GFP-fusion proteins. Here, we report a method that makes all these constructs available for superresolution microscopy by targeting GFP with tiny, high-affinity antibodies coupled to blinking dyes. It thus combines the molecular specificity of genetic tagging with the high photon yield of organic dyes and minimal linkage error. Direct STORM on microtubules labeled with our novel antibodies showed that indeed the linkage error was minimal, whereas the large size of standard antibodies resulted in an additional error of >10 nm in immunolabeling. The brightness of our labels enabled us to perform rapid time-lapse dSTORM and sptPALM on living neurons expressing the outer membrane protein GPI-GFP. Three-dimensional dSTORM on microtubules using the biplane approach allowed us to distinguish overlapping microtubules with an axial separation of ~100 nm. Using a budding yeast GFP-tag genomic library we could readily image several GFP tagged proteins targeted to specific intra-cellular locations. In summary, targeting of GFP-labeled constructs with tiny antibodies provides fast and simple access to superresolution microscopy of virtually any known protein in cells. Since for several organisms the entire genome is available as GFP-tagged constructs, all these proteins are immediately accessible without the requirement for cloning or the generation of antibodies. Finally, due to a simple one-step labeling protocol, our technique opens the door to high throughput localization analysis of entire genomes at the nanoscopic level in cells. [ABSTRACT FROM AUTHOR]

Published
2013

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