9 results on '"Aicher S"'
Search Results
2. Species-specific molecular barriers to SARS-CoV-2 replication in bat cells
- Author
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Jordi Serra-Cobo, Olivier Schwartz, Dominique Pontier, Monika Nemcova, Aicher S, Delphine Planas, Nolwenn Jouvenet, Streicher F, Laurent Dacheux, Maxime Chazal, Seidlova, Jiri Pikula, Luo D, Jan Zukal, Julian Buchrieser, and Centre National de la Recherche Scientifique (CNRS)
- Subjects
0303 health sciences ,biology ,030306 microbiology ,viruses ,[SDV]Life Sciences [q-bio] ,Myotis myotis ,medicine.disease_cause ,biology.organism_classification ,Virology ,Virus ,03 medical and health sciences ,Tadarida brasiliensis ,Viral replication ,Viral Receptor ,Interferon ,Cell culture ,medicine ,030304 developmental biology ,Coronavirus ,medicine.drug - Abstract
Bats are natural reservoirs of numerous coronaviruses, including the potential ancestor of SARS-CoV-2. Knowledge concerning the interaction between coronaviruses and bat cells is sparse. We investigated the susceptibility of primary cells from Rhinolophus ferrumequinum and Myotis species, as well as of established and novel cell lines from Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis and Nyctalus noctula, to SARS-CoV-2 infection. None of these cells were sensitive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species. The resistance to infection was overcome by expression of human ACE2 (hACE2) in three cell lines, suggesting that restriction to viral replication was due to a low expression of bat ACE2 (bACE2) or absence of bACE2 binding in these cells. Infectious virions were produced but not released from hACE2-transduced M. myotis brain cells. E. serotinus brain cells and M. myotis nasal epithelial cells expressing hACE2 efficiently controlled viral replication. This ability to control viral replication correlated with a potent interferon response. Our data highlight the existence of species-specific molecular barriers to viral replication in bat cells. These novel chiropteran cellular models are valuable tools to investigate the evolutionary relationships between bats and coronaviruses.Author summaryBats host ancestors of several viruses that cause serious disease in humans, as illustrated by the on-going SARS-CoV-2 pandemic. Progress in investigating bat-virus interactions have been hampered by a limited number of bat cell lines. We have generated primary cells and cell lines from several bat species that are relevant for coronavirus research. The varying susceptibilities of the cells to SARS-CoV-2 infection offered the opportunity to uncover some species-specific molecular restrictions to viral replication. All bat cells exhibited a potent entry-dependent restriction. Once this block was overcome by over-expression of human ACE2, which serves at the viral receptor, two bat cell lines controlled well viral replication, which correlated with the inability of the virus to counteract antiviral responses. Other cells potently inhibited viral release. Our novel bat cellular models contribute to a better understanding of the molecular interplays between bats and viruses.
- Published
- 2021
3. Indirubin analogues inhibit trypanosoma brucei glycogen synthase kinase 3 short and T. Brucei growth
- Author
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Efstathiou, A. Gaboriaud-Kolar, N. Myrianthopoulos, V. Vougogiannopoulou, K. Subota, I. Aicher, S. Mikros, E. Bastin, P. Skaltsounis, A.-L. Soteriadou, K. Smirlis, D.
- Abstract
The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). The disease is fatal if it remains untreated, whereas most drug treatments are inadequate due to high toxicity, difficulties in administration, and low central nervous system penetration. T. brucei glycogen synthase kinase 3 short (TbGSK3s) is essential for parasite survival and thus represents a potential drug target that could be exploited for HAT treatment. Indirubins, effective leishmanicidals, provide a versatile scaffold for the development of potent GSK3 inhibitors. Herein, we report on the screening of 69 indirubin analogues against T. brucei bloodstream forms. Of these, 32 compounds had potent antitrypanosomal activity (half-maximal effective concentration 0.050 to 3.2 M) and good selectivity for the analogues over human HepG2 cells (range, 7.4- to over 641-fold). The majority of analogues were potent inhibitors of TbGSK3s, and correlation studies for an indirubin subset, namely, the 6-bromosubstituted 3=-oxime bearing an extra bulky substituent on the 3= oxime [(6-BIO-3=-bulky)-substituted indirubins], revealed a positive correlation between kinase inhibition and antitrypanosomal activity. Insights into this indirubin-TbGSK3s interaction were provided by structure-activity relationship studies. Comparison between 6-BIO-3=-bulky-substituted indirubin-treated parasites and parasites silenced for TbGSK3s by RNA interference suggested that the above-described compounds may target TbGSK3s in vivo. To further understand the molecular basis of the growth arrest brought about by the inhibition or ablation of TbGSK3s, we investigated the intracellular localization of TbGSK3s. TbGSK3s was present in cytoskeletal structures, including the flagellum and basal body area. Overall, these results give insights into the mode of action of 6-BIO-3=-bulky-substituted indirubins that are promising hits for antitrypanosomal drug discovery. Copyright © 2019 American Society for Microbiology. All Rights Reserved.
- Published
- 2019
4. (102) Corneal hyperalgesia after abrasion injury
- Author
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Aicher, S., primary and Hegarty, D., additional
- Published
- 2017
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5. (Assisted) decision-making in mental health
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Aicher, S
- Subjects
ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Introduction: I am addressing the question how decision-making of people with (mental) health issues can be successful. I argue that assisted decision-making in mental health is often the best way to secure that the interests of the patient are best valued. Method: For this purpose I conducted semi-structured[for full text, please go to the a.m. URL], 4th Research in Medical Education (RIME) Symposium 2015
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- 2015
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6. Refinement of the prognostic impact of somatic CEBPA bZIP domain mutations in acute myeloid leukemia: Results of the AML Study Group (AMLSG).
- Author
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Rücker FG, Corbacioglu A, Krzykalla J, Cocciardi S, Lengerke C, Germing U, Wulf G, Samra MA, Teichmann LL, Lübbert M, Kühn MWM, Bentz M, Westermann J, Bullinger L, Gaidzik VI, Meid A, Aicher S, Stegelmann F, Weber D, Schrade A, Thol F, Heuser M, Ganser A, Benner A, Döhner H, and Döhner K
- Abstract
Competing Interests: Frank G. Rücker reports honoraria from and consultancy for Jazz Pharmaceuticals, Novartis, and BMS/Celgene; travel support from Jazz Pharmaceuticals. Michael Lübbert reports an advisory role for Abbvie, Astex Pharmaceuticals, Imago BioSciences, Janssen, Otsuka, and Syros; research support from Janssen and Cheplapharm. Michael W. M. Kühn reports honoraria from and consultancy for Pfizer, Kura Oncology, Jazz Pharmaceuticals, BMS/Celgene, and Abbvie; speakers bureau of Gilead. Lars Bullinger reports honoraria from Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Roche, and Sanofi; research support from Bayer and Jazz Pharmaceuticals. Verena I. Gaidzik reports an advisory role for Jazz Pharmaceuticals, Abbvie, and Boehringer‐Ingelheim; speakers bureau of Pfizer, Janssen, and Abbvie; and travel support from Abbvie. Frank Stegelmann reports honoraria from and consultancy for AOP Pharma, MorphoSys, BMS/Celgene, Incyte, Novartis, and Pfizer. Felicitas Thol reports an advisory role for Novartis, BMS, Abbvie, Menarini, and Rigel. Michael Heuser reports honoraria from Certara, Jazz Pharmaceuticals, Janssen, Novartis, and Sobi; paid consultancy for Abbvie, Amgen, BMS/Celgene, Glycostem, LabDelbert, Pfizer, PinotBio, and Servier; and research funding to his institution from Abbvie, Agios, Astellas, BMS/Celgene, Glycostem, Jazz Pharmaceuticals, Karyopharm, Loxo Oncology, and PinotBio. Hartmut Döhner declares being in an advisory role for Abbvie, Agios, Amgen, Astellas, AstraZeneca, Berlin Chemie, BMS/Celgene, Daiichi Sankyo, GEMoaB, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Servier, Stemline, and Syndax; research funding from Abbvie, Agios, Amgen, Astellas, BMS/Celgene, Jazz Pharmaceuticals, Kronos Bio, Novartis, and Pfizer. Konstanze Döhner reports an advisory role for Amgen, BMS/Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Roche; research funding from Agios, Astex, Astellas, BMS/Celgene, and Novartis. All other authors declare no competing interest. The remaining authors declared no conflicts of interest.
- Published
- 2024
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7. Real-time imaging of glutamate transients in the extracellular space of acute human brain slices using a single-wavelength glutamate fluorescence nanosensor.
- Author
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Brandner S, Aicher S, Schroeter S, Swierzy I, Kinfe TM, Buchfelder M, Maslarova A, and Stadlbauer A
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- Animals, Brain physiology, Humans, Neurons, Neurotransmitter Agents, Rats, Extracellular Space, Glutamic Acid pharmacology
- Abstract
Glutamate is the most important excitatory neurotransmitter in the brain. The ability to assess glutamate release and re-uptake with high spatial and temporal resolution is crucial to understand the involvement of this primary excitatory neurotransmitter in both normal brain function and different neurological disorders. Real-time imaging of glutamate transients by fluorescent nanosensors has been accomplished in rat brain slices. We performed for the first time single-wavelength glutamate nanosensor imaging in human cortical brain slices obtained from patients who underwent epilepsy surgery. The glutamate fluorescence nanosensor signals of the electrically stimulated human cortical brain slices showed steep intensity increase followed by an exponential decrease. The spatial distribution and the time course of the signal were in good agreement with the position of the stimulation electrode and the dynamics of the electrical stimulation, respectively. Pharmacological manipulation of glutamate release and reuptake was associated with corresponding changes in the glutamate fluorescence nanosensor signals. We demonstrated that the recently developed fluorescent nanosensors for glutamate allow to detect neuronal activity in acute human cortical brain slices with high spatiotemporal precision. Future application to tissue samples from different pathologies may provide new insights into pathophysiology without the limitations of an animal model., (© 2022. The Author(s).)
- Published
- 2022
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8. Indirubin Analogues Inhibit Trypanosoma brucei Glycogen Synthase Kinase 3 Short and T. brucei Growth.
- Author
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Efstathiou A, Gaboriaud-Kolar N, Myrianthopoulos V, Vougogiannopoulou K, Subota I, Aicher S, Mikros E, Bastin P, Skaltsounis AL, Soteriadou K, and Smirlis D
- Subjects
- Animals, Cell Line, Indoles pharmacology, Insecta parasitology, Structure-Activity Relationship, Trypanosomiasis, African drug therapy, Glycogen Synthase Kinase 3 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosoma brucei brucei metabolism
- Abstract
The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT). The disease is fatal if it remains untreated, whereas most drug treatments are inadequate due to high toxicity, difficulties in administration, and low central nervous system penetration. T. brucei glycogen synthase kinase 3 short ( Tb GSK3s) is essential for parasite survival and thus represents a potential drug target that could be exploited for HAT treatment. Indirubins, effective leishmanicidals, provide a versatile scaffold for the development of potent GSK3 inhibitors. Herein, we report on the screening of 69 indirubin analogues against T. brucei bloodstream forms. Of these, 32 compounds had potent antitrypanosomal activity (half-maximal effective concentration = 0.050 to 3.2 μM) and good selectivity for the analogues over human HepG2 cells (range, 7.4- to over 641-fold). The majority of analogues were potent inhibitors of Tb GSK3s, and correlation studies for an indirubin subset, namely, the 6-bromosubstituted 3'-oxime bearing an extra bulky substituent on the 3' oxime [(6-BIO-3'-bulky)-substituted indirubins], revealed a positive correlation between kinase inhibition and antitrypanosomal activity. Insights into this indirubin- Tb GSK3s interaction were provided by structure-activity relationship studies. Comparison between 6-BIO-3'-bulky-substituted indirubin-treated parasites and parasites silenced for Tb GSK3s by RNA interference suggested that the above-described compounds may target Tb GSK3s in vivo To further understand the molecular basis of the growth arrest brought about by the inhibition or ablation of Tb GSK3s, we investigated the intracellular localization of Tb GSK3s. Tb GSK3s was present in cytoskeletal structures, including the flagellum and basal body area. Overall, these results give insights into the mode of action of 6-BIO-3'-bulky-substituted indirubins that are promising hits for antitrypanosomal drug discovery., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
- Full Text
- View/download PDF
9. Differential regulation of the Wnt/β-catenin pathway by hepatitis C virus recombinants expressing core from various genotypes.
- Author
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Aicher S, Kakkanas A, Cohen L, Blumen B, Oprisan G, Njouom R, Meurs EF, Mavromara P, and Martin A
- Subjects
- Active Transport, Cell Nucleus genetics, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular virology, Cell Proliferation genetics, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Neoplastic, Genotype, HEK293 Cells, Hepacivirus pathogenicity, Hepatitis C genetics, Hepatitis C pathology, Hepatitis C virology, Humans, Liver Neoplasms pathology, Liver Neoplasms virology, T Cell Transcription Factor 1 genetics, Wnt Signaling Pathway genetics, Carcinoma, Hepatocellular genetics, Hepacivirus genetics, Liver Neoplasms genetics, beta Catenin genetics
- Abstract
Clinical studies have suggested association of some hepatitis C virus (HCV) subtypes or isolates with progression toward hepatocellular carcinoma (HCC). HCV core protein has been reported to interfere with host Wnt/β-catenin pathway, a cell fate-determining pathway, which plays a major role in HCC. Here, we investigated the impact of HCV core genetic variability in the dysregulation of Wnt/β-catenin pathway. We used both transient expression of core proteins from clinical isolates of HCV subtypes 1a (Cambodia), 4a (Romania) and 4f (Cameroon) and infection systems based on a set of engineered intergenotypic recombinant viruses encoding core from these various clinical strains. We found that TCF transcription factor-dependent reporter activity was upregulated by core in a strain-specific manner. We documented core sequence-specific transcriptional upregulation of several β-catenin downstream target genes associated with cell proliferation and malignant transformation, fibrogenesis or fat accumulation. The extent of β-catenin nuclear translocation varied in accordance with β-catenin downstream gene upregulation in infected cells. Pairwise comparisons of subgenotypic core recombinants and mutated core variants unveiled the critical role of core residues 64 and 71 in these dysregulations. In conclusion, this work identified natural core polymorphisms involved in HCV strain-specific activation of Wnt/β-catenin pathway in relevant infection systems.
- Published
- 2018
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