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477 results on '"Walther, Paul"'

6. ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Author

Hirschenberger, Maximilian, Lepelley, Alice, Rupp, Ulrich, Klute, Susanne, Hunszinger, Victoria, Koepke, Lennart, Merold, Veronika, Didry-Barca, Blaise, Wondany, Fanny, Bergner, Tim, Moreau, Tatiana, Rodero, Mathieu P., Rösler, Reinhild, Wiese, Sebastian, Volpi, Stefano, Gattorno, Marco, Papa, Riccardo, Lynch, Sally-Ann, Haug, Marte G., Houge, Gunnar, Wigby, Kristen M., Sprague, Jessica, Lenberg, Jerica, Read, Clarissa, Walther, Paul, Michaelis, Jens, Kirchhoff, Frank, de Oliveira Mann, Carina C., Crow, Yanick J., and Sparrer, Konstantin M. J.

Published
2023
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7. NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss

Author

Schlett, Judith Stefanie, Mettang, Melanie, Skaf, Aladdin, Schweizer, Pavel, Errerd, Alina, Mulugeta, Ephraim Alemayehu, Hein, Tabea Melissa, Tsesmelis, Konstantinos, Tsesmelis, Miltiadis, Büttner, Ulrike F. G., Wendt, Heinrich, Abaei, Alireza, Rasche, Volker, Prex, Vivien, Nespoli, Ester, Alami, Najwa Ouali, Tews, Daniel, Walther, Paul, Yilmazer-Hanke, Deniz, Oswald, Franz, Dimou, Leda, Wirth, Thomas, and Baumann, Bernd

Published
2023
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9. The C-terminal 32-mer fragment of hemoglobin alpha is an amyloidogenic peptide with antimicrobial properties

Author

Olari, Lia-Raluca, Bauer, Richard, Gil Miró, Marta, Vogel, Verena, Cortez Rayas, Laura, Groß, Rüdiger, Gilg, Andrea, Klevesath, Raphael, Rodríguez Alfonso, Armando A., Kaygisiz, Kübra, Rupp, Ulrich, Pant, Pradeep, Mieres-Pérez, Joel, Steppe, Lena, Schäffer, Ramona, Rauch-Wirth, Lena, Conzelmann, Carina, Müller, Janis A., Zech, Fabian, Gerbl, Fabian, Bleher, Jana, Preising, Nico, Ständker, Ludger, Wiese, Sebastian, Thal, Dietmar R., Haupt, Christian, Jonker, Hendrik R. A., Wagner, Manfred, Sanchez-Garcia, Elsa, Weil, Tanja, Stenger, Steffen, Fändrich, Marcus, von Einem, Jens, Read, Clarissa, Walther, Paul, Kirchhoff, Frank, Spellerberg, Barbara, and Münch, Jan

Published
2023
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10. Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers

Author

Weil, Tatjana, Groß, Rüdiger, Röcker, Annika, Bravo-Rodriguez, Kenny, Heid, Christian, Sowislok, Andrea, Le, My-Hue, Erwin, Nelli, Dwivedi, Mridula, M., Stephen, Bates, Paul, Wettstein, Lukas, Müller, Janis A, Harms, Mirja, Sparrer, Konstantin, Ruiz-Blanco, Yasser B, Stürzel, Christina M, von Einem, Jens, Lippold, Sina, Read, Clarissa, Walther, Paul, Hebel, Marco, Kreppel, Florian, Klärner, Frank-Gerrit, Bitan, Gal, Ehrmann, Michael, Weil, Tanja, Winter, Roland, Schrader, Thomas, Shorter, James, Sanchez-Garcia, Elsa, and Münch, Jan

Subjects
Engineering, Chemical Sciences, Vaccine Related, Biodefense, Emerging Infectious Diseases, Prevention, Infectious Diseases, Infection, Good Health and Well Being, Acid Phosphatase, Amyloid, Anti-HIV Agents, Antiviral Agents, Arginine, Betacoronavirus, Bridged-Ring Compounds, Cell Membrane, HIV Infections, HIV-1, Humans, Lipids, Lysine, Magnetic Resonance Spectroscopy, Organophosphates, SARS-CoV-2, Seminal Vesicle Secretory Proteins, Structure-Activity Relationship, Viral Envelope Proteins, Zika Virus, General Chemistry, Chemical sciences
Abstract

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.

Published
2020

18. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Author

Müller, Janis A., Groß, Rüdiger, Conzelmann, Carina, Krüger, Jana, Merle, Uta, Steinhart, Johannes, Weil, Tatjana, Koepke, Lennart, Bozzo, Caterina Prelli, Read, Clarissa, Fois, Giorgio, Eiseler, Tim, Gehrmann, Julia, van Vuuren, Joanne, Wessbecher, Isabel M., Frick, Manfred, Costa, Ivan G., Breunig, Markus, Grüner, Beate, Peters, Lynn, Schuster, Michael, Liebau, Stefan, Seufferlein, Thomas, Stenger, Steffen, Stenzinger, Albrecht, MacDonald, Patrick E., Kirchhoff, Frank, Sparrer, Konstantin M. J., Walther, Paul, Lickert, Heiko, Barth, Thomas F. E., Wagner, Martin, Münch, Jan, Heller, Sandra, and Kleger, Alexander

Published
2021
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19. Attenuated replication and damaging effects of SARS‐CoV‐2 Omicron variants in an intestinal epithelial barrier model.

Author

Volcic, Meta, Nchioua, Rayhane, Pastorio, Chiara, Zech, Fabian, Haußmann, Isabell, Sauter, Daniel, Read, Clarissa, Walther, Paul, and Kirchhoff, Frank

Subjects
SARS-CoV-2 Omicron variant, SARS-CoV-2, SARS-CoV-2 Delta variant, INTESTINAL barrier function, COVID-19
Abstract

Many COVID‐19 patients suffer from gastrointestinal symptoms and impaired intestinal barrier function is thought to play a key role in Long COVID. Despite its importance, the impact of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) on intestinal epithelia is poorly understood. To address this, we established an intestinal barrier model integrating epithelial Caco‐2 cells, mucus‐secreting HT29 cells and Raji cells. This gut epithelial model allows efficient differentiation of Caco‐2 cells into microfold‐like cells, faithfully mimics intestinal barrier function, and is highly permissive to SARS‐CoV‐2 infection. Early strains of SARS‐CoV‐2 and the Delta variant replicated with high efficiency, severely disrupted barrier function, and depleted tight junction proteins, such as claudin‐1, occludin, and ZO‐1. In comparison, Omicron subvariants also depleted ZO‐1 from tight junctions but had fewer damaging effects on mucosal integrity and barrier function. Remdesivir, the fusion inhibitor EK1 and the transmembrane serine protease 2 inhibitor Camostat inhibited SARS‐CoV‐2 replication and thus epithelial barrier damage, while the Cathepsin inhibitor E64d was ineffective. Our results support that SARS‐CoV‐2 disrupts intestinal barrier function but further suggest that circulating Omicron variants are less damaging than earlier viral strains. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Functional and Morphological Differences of Muscle Mitochondria in Chronic Fatigue Syndrome and Post-COVID Syndrome.

Author

Bizjak, Daniel Alexander, Ohmayer, Birgit, Buhl, Jasmine Leonike, Schneider, Elisabeth Marion, Walther, Paul, Calzia, Enrico, Jerg, Achim, Matits, Lynn, and Steinacker, Jürgen Michael

Subjects
POST-acute COVID-19 syndrome, CHRONIC fatigue syndrome, PATHOLOGICAL physiology, MITOCHONDRIA, OXIDATIVE phosphorylation
Abstract

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs). Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC. While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis

Author

Burkhalter, Martin D., Sridhar, Arthi, Sampaio, Pedro, Jacinto, Raquel, Burczyk, Martina S., Donow, Cornelia, Investigators, Max AngenendCompetence Network for Congenital Heart Defects, Hempel, Maja, Walther, Paul, Pennekamp, Petra, Omran, Heymut, Lopes, Susana S., Ware, Stephanie M., and Philipp, Melanie

Subjects
Congenital heart defects -- Analysis, Heart diseases -- Analysis, Genes -- Analysis, Medical research -- Analysis, Genetic disorders -- Analysis, Mitochondrial DNA -- Analysis, Biosynthesis, Genomics, Newborn infants, Phenotypes, DNA, Genomes, Cardiovascular diseases, RNA, Health care industry
Abstract

About 1% of all newborns are affected by congenital heart disease (CHD). Recent findings identify aberrantly functioning cilia as a possible source for CHD. Faulty cilia also prevent the development of proper left-right asymmetry and cause heterotaxy, the incorrect placement of visceral organs. Intriguingly, signaling cascades such as mTOR that influence mitochondrial biogenesis also affect ciliogenesis, and can cause heterotaxy-like phenotypes in zebrafish. Here, we identify levels of mitochondrial function as a determinant for ciliogenesis and a cause for heterotaxy. We detected reduced mitochondrial DNA content in biopsies of heterotaxy patients. Manipulation of mitochondrial function revealed a reciprocal influence on ciliogenesis and affected cilia-dependent processes in zebrafish, human fibroblasts and Tetrahymena thermophila. Exome analysis of heterotaxy patients revealed an increased burden of rare damaging variants in mitochondria-associated genes as compared with 1000 Genome controls. Knock down of such candidate genes caused cilia elongation and ciliopathy-like phenotypes in zebrafish, which could not be rescued by RNA encoding damaging rare variants identified in heterotaxy patients. Our findings suggest that ciliogenesis is coupled to the abundance and function of mitochondria. Our data further reveal disturbed mitochondrial function as an underlying cause for heterotaxy- linked CHD and provide a mechanism for unexplained phenotypes of mitochondrial disease., Introduction Cilia are tubulin-based extensions, which can be motile or immotile. Immotile cilia, also known as primary cilia, exist as monocilia emanating from most vertebrate cells upon entry into G0 [...]

Published
2019
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31. Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

Author

Mauler, Maximilian, Herr, Nadine, Schoenichen, Claudia, Witsch, Thilo, Marchini, Timoteo, Härdtner, Carmen, Koentges, Christoph, Kienle, Korbinian, Ollivier, Véronique, Schell, Maximilian, Dorner, Ludwig, Wippel, Christopher, Stallmann, Daniela, Normann, Claus, Bugger, Heiko, Walther, Paul, Wolf, Dennis, Ahrens, Ingo, Lämmermann, Tim, Ho-Tin-Noé, Benoît, Ley, Klaus, Bode, Christoph, Hilgendorf, Ingo, and Duerschmied, Daniel

Published
2019
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50. Mechanical strain of alveolar type II cells in culture: changes in the transcellular cytokeratin network and adaptations

Author

Felder, Edward, Siebenbrunner, Marcus, Busch, Tobias, Fois, Giorgio, Miklavc, Pika, Walther, Paul, and Dietl, Paul

Subjects
Intermediate filament proteins -- Physiological aspects, Pulmonary alveoli -- Physiological aspects, Biological sciences
Abstract

Mechanical forces exert multiple effects in cells, ranging from altered protein expression patterns to cell damage and death. Despite undisputable biological importance, little is known about structural changes in cells subjected to strain ex vivo. Here, we undertake the first transmission electron microscopy investigation combined with fluorescence imaging on pulmonary alveolar type II cells that are subjected to equibiaxial strain. When cells are investigated immediately after stretch, we demonstrate that curved cytokeratin (CK) fibers are straightened out at 10% increase in cell surface area (CSA) and that this is accompanied by a widened extracellular gap of desmosomes-the insertion points of CK fibers. Surprisingly, a CSA increase by 20% led to higher fiber curvatures of CK fibers and a concurrent return of the desmosomal gap to normal values. Since 20% CSA increase also induced a significant phosphorylation of CK8-ser431, we suggest CK phosphorylation might lower the tensile force of the transcellular CK network, which could explain the morphological observations. Stretch durations of 5 min caused membrane injury in up to 24% of the cells stretched by 30%, but the CK network remained surprisingly intact even in dead cells. We conclude that CK and desmosomes constitute a strong transcellular scaffold that survives cell death and hypothesize that phosphorylation of CK fibers is a mechano-induced adaptive mechanism to maintain epithelial overall integrity. mechanical stress; cytoskeleton; desmosome; injury

Published
2008

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