90 results on '"Frölich, S."'
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2. Etablierung eines Forschungsnetzwerks auf kommunaler Ebene im ÖGD – Unwägbarkeiten und Potenziale am Beispiel der Datenauswertung zur COVID-19 Pandemie
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Hellinckx, J., additional, Diefenbacher, S., additional, Galante-Gottschalk, A., additional, Zöllner, R., additional, Jentzen, L. E., additional, Mischnik, A., additional, Pfahler, M., additional, Behringer, D., additional, Borchert, M., additional, Dyer, C., additional, Kühn, A., additional, Frölich, S., additional, Schneider, M., additional, Tecle, N., additional, Meyer, S., additional, Söller, J., additional, Kiefer, S., additional, Kossow, A., additional, Scharkus, S., additional, Redemann, D., additional, Schmidt, A., additional, Becker, T., additional, Bauer, F., additional, Sigmund, A., additional, Teinert, M., additional, Gleich, S., additional, Savaskan, N., additional, Wüste-Rieback, J., additional, Tinnemann, P., additional, Ehehalt, S., additional, and Rehfuess, E. A., additional
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- 2024
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3. In situ loading and x-ray diffraction quantification of strains in hydroxyapatite particles within a 3D printed scaffold
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Stock, SR, Park, JS, Jakus, A, Birkbak, M, Frølich, S, Birkedal, H, Shah, R, and Almer, JD
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- 2021
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4. POS0401 OSTEOARTHRITIS SYNOVIAL MACROPHAGES HAVE A TOLERIZED PHENOTYPE AND A VERY WEAK CORTICOSTEROID RESPONSE
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Wang, C., primary, De Francesco, R., additional, Lamers, L., additional, Rinzema, S., additional, Frölich, S., additional, Van Lent, P., additional, Logie, C., additional, and Van den Bosch, M., additional
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- 2023
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- View/download PDF
5. genomepy: genes and genomes at your fingertips
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Frölich, S., Sande, M. van der, Schafers, Tilman, Heeringen, S.J. van, Frölich, S., Sande, M. van der, Schafers, Tilman, and Heeringen, S.J. van
- Abstract
Contains fulltext : 292687.pdf (Publisher’s version ) (Open Access)
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- 2023
6. Computational approaches to understand transcription regulation in development
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Sande, M. van der, Frölich, S., Heeringen, S.J. van, Sande, M. van der, Frölich, S., and Heeringen, S.J. van
- Abstract
Item does not contain fulltext
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- 2023
7. Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways
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Wigcheren, G.F. van, Cuenca Escalona, J., Stelloo, S., Brake, J., Peeters, E., Horrevorts, S.K., Frölich, S., Ramos Tomillero, I., Wesseling-Rozendaal, Y., Herpen, C.M.L. van, Stolpe, A. van de, Vermeulen, M., Vries, I.J.M. de, Figdor, C.G., Flórez-Grau, G., Wigcheren, G.F. van, Cuenca Escalona, J., Stelloo, S., Brake, J., Peeters, E., Horrevorts, S.K., Frölich, S., Ramos Tomillero, I., Wesseling-Rozendaal, Y., Herpen, C.M.L. van, Stolpe, A. van de, Vermeulen, M., Vries, I.J.M. de, Figdor, C.G., and Flórez-Grau, G.
- Abstract
Contains fulltext : 298469.pdf (Publisher’s version ) (Open Access)
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- 2023
8. Identification of transcription factors dictating blood cell development using a bidirectional transcription network-based computational framework
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Heuts, B.M.H., Arza-Apalategi, S., Frölich, S., Bergevoet, S.M., Oever, S.N. van den, Heeringen, S.J. van, Reijden, B.A. van der, Martens, J.H.A., Heuts, B.M.H., Arza-Apalategi, S., Frölich, S., Bergevoet, S.M., Oever, S.N. van den, Heeringen, S.J. van, Reijden, B.A. van der, and Martens, J.H.A.
- Abstract
Contains fulltext : 284059.pdf (Publisher’s version ) (Open Access)
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- 2022
9. Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
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Wester, R.A., Voorthuijsen, L. van, Neikes, H.K., Dijkstra, J.J., Frölich, S., Sande, M. van der, Logie, C., Lindeboom, R.G.H., Vermeulen, M., Wester, R.A., Voorthuijsen, L. van, Neikes, H.K., Dijkstra, J.J., Frölich, S., Sande, M. van der, Logie, C., Lindeboom, R.G.H., and Vermeulen, M.
- Abstract
Contains fulltext : 245272.pdf (Publisher’s version ) (Open Access)
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- 2021
10. ANANSE: an enhancer network-based computational approach for predicting key transcription factors in cell fate determination
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Xu, Quan, Georgiou, G., Frölich, S., Sande, M. van der, Veenstra, G.J.C., Zhou, H., Heeringen, S.J. van, Xu, Quan, Georgiou, G., Frölich, S., Sande, M. van der, Veenstra, G.J.C., Zhou, H., and Heeringen, S.J. van
- Abstract
Contains fulltext : 237276.pdf (Publisher’s version ) (Open Access)
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- 2021
11. Combinatorial transcription factor activities on open chromatin induce embryonic heterogeneity in vertebrates
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Bright, A.R., Genesen, S.T. van, Grasso, A., Frölich, S., Sande, M. van der, Heeringen, S.J. van, Veenstra, G.J.C., Bright, A.R., Genesen, S.T. van, Grasso, A., Frölich, S., Sande, M. van der, Heeringen, S.J. van, and Veenstra, G.J.C.
- Abstract
Contains fulltext : 230846.pdf (Publisher’s version ) (Open Access)
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- 2021
12. Design und Qualitätskontrolle der zahnmedizinischen Untersuchung in der NAKO Gesundheitsstudie [Design and quality control of the oral health status examination in the German National Cohort (GNC)]
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Holtfreter, B., Samietz, S., Hertrampf, K., Aarabi, G., Hagenfeld, D., Kim, T.S., Kocher, T., Koos, B., Schmitter, M., Ahrens, W., Alwers, E., Becher, H., Berger, K., Brenner, H., Damms-Machado, A., Ebert, N., Fischer, B., Franzke, C.W., Frölich, S., Greiser, H., Gies, A., Günther, K., Hassan, L., Hoffmann, W., Jaeschke, L., Keil, T., Kemmling, Y., Krause, G., Krist, L., Legath, N., Lieb, W., Leitzmann, M., Linseisen, J., Loeffler, M., Meinke-Franze, C., Michels, K.B., Mikolajczyk, R., Obi, N., Peters, A., Pischon, T., Schipf, S., Schmidt, B., Völzke, H., Waniek, S., Wigmann, C., Wirkner, K., Schmidt, C.O., Kühnisch, J., and Rupf, S.
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stomatognathic diseases ,Cardiovascular and Metabolic Diseases - Abstract
BACKGROUND: Caries and periodontitis are highly prevalent worldwide. Because detailed data on these oral diseases were collected within the framework of the German National Cohort (GNC), associations between oral and systemic diseases and conditions can be investigated. OBJECTIVES: The study protocol for the oral examination was designed to ensure a comprehensive collection of dental findings by trained non-dental staff within a limited examination time. At the mid-term of the GNC baseline examination, a first quality evaluation was performed to check the plausibility of results and to propose measures to improve the data quality. MATERIALS AND METHODS: A dental interview, saliva sampling and oral diagnostics were conducted. As part of the level‑1 examination, the number of teeth and prostheses were recorded. As part of the level‑2 examination, detailed periodontal, cariological and functional aspects were examined. All examinations were conducted by trained non-dental personnel. Parameters were checked for plausibility and variable distributions were descriptively analysed. RESULTS: Analyses included data of 57,967 interview participants, 56,913 level‑1 participants and 6295 level‑2 participants. Percentages of missing values for individual clinical parameters assessed in level 1 and level 2 ranged between 0.02 and 3.9%. Results showed a plausible distribution of the data; rarely, implausible values were observed, e.g. for measurements of horizontal and vertical overbite (overjet and overbite). Intra-class correlation coefficients indicated differences in individual parameters between regional clusters, study centres and across different examiners. CONCLUSIONS: he results confirm the feasibility of the study protocol by non-dental personnel and its successful integration into the GNC's overall assessment program. However, rigorous dental support of the study centres is required for quality management.
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- 2020
13. GPVI and Thromboxane Receptor on Platelets Promote Proinflammatory Macrophage Phenotypes during Cutaneous Inflammation
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Pierre, S., Linke, B., Suo, J., Tarighi, N., Turco, D. del, Thomas, D., Ferreiros, N., Stegner, D., Frölich, S., Sisignano, M., Santos, S.M. dos, Debruin, N., Nüsing, R.M., Deller, T., Nieswandt, B., Geisslinger, G., Scholich, K., and Publica
- Abstract
Platelets are well known for their role in hemostasis but are also increasingly recognized for their supporting role in innate immune responses. Here, we studied the role of platelets in the development of peripheral inflammation and found that platelets colocalize with macrophages in the inflamed tissue outside of blood vessels in different animal models for cutaneous inflammation. Collagen-treatment of macrophages isolated from paws during zymosan-induced inflammation induced thromboxane synthesis through the platelet expressed collagen receptor glycoprotein VI. Deletion of glycoprotein VI or its downstream effector thromboxane A2 receptor (TP) reduced zymosan-induced mechanical allodynia without altering macrophage recruitment or formation of macrophage/platelet complexes. Instead, macrophages in inflamed paws of glycoprotein VI- and TP-deficient mice exhibited an increased expression of anti-inflammatory markers and synthesized less proinflammatory mediators (prostaglandin E-2 and IL6). TP expression on platelets was necessary to mediate increased prostaglandin E2 and IL6 synthesis, whereas TP expression on macrophages was sufficient to decrease the expression of the anti-inflammatory macrophage marker CD206, showing that TP activation on platelets and macrophages regulates different aspects of macrophage activation.
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- 2017
14. Association of dietary patterns with five-year degree and progression of coronary artery calcification in the Heinz Nixdorf Recall study
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Frölich, S., primary, Lehmann, N., additional, Weyers, S., additional, Wahl, S., additional, Dragano, N., additional, Budde, T., additional, Kälsch, H., additional, Mahabadi, A.A., additional, Erbel, R., additional, Moebus, S., additional, Jöckel, K.H., additional, and Schmidt, B., additional
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- 2017
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15. Erste Ergebnisse zur Stillquote einer westdeutschen Kommune ermittelt über die Schuleingangsuntersuchung
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Frölich, S, additional, Wahl, S, additional, and Weyers, S, additional
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- 2017
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16. Die Schuleingangsuntersuchung als Zugang zur Studienteilnahme von Familien in schwierigen Lebenslagen
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Wahl, S, additional, Frölich, S, additional, and Weyers, S, additional
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- 2017
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17. In vivo localization of antibodies raised against Eimeria maxima wall forming bodies during sexual intracellular development
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Frölich, S, Shahparee, A, Wasinger, VC, and Wallach, M
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Coccidiosis ,animal diseases ,Intracellular Space ,Protozoan Proteins ,Antibodies, Protozoan ,Mycology & Parasitology ,Antigens, Protozoan ,parasitic diseases ,Animals ,Humans ,Eimeria ,Immunization ,Chickens ,Toxoplasma ,Poultry Diseases - Abstract
Copyright © 2014 Cambridge University Press. Apicomplexan parasites cause devastating diseases in humans and livestock. Previously we demonstrated that antibodies targeting transmissible forms of the apicomplexan parasite, Eimeria, are effective at reducing parasite shedding thus preventing the transmission of the disease. However, the mechanisms responsible have not been fully defined. Moreover, there is no direct evidence that the parasite-specific IgG antibodies can reach the parasite developing in the enterocytes of the infected chicken host. This study summarizes our efforts using host immunity, parasite proteomics and 3D microscopy to provide a step forward in our understanding of how this immune response works. Eimeria maxima is an important pathogen of poultry and used as a surrogate for a number of human pathogens including Toxoplasma and Plasmodium. Our studies demonstrate that immunization with the purified wall forming bodies (WFBs) results in a production of parasite-specific IgG antibodies, which have the ability to reach in situ gametocytes in the intestinal lumen and permeate the enterocyte/parasite membranes in order to bind to the cytoplasmic Type 1 and Type 2 WFBs. This raises the intriguing possibility that via this process antibodies block the development of Eimeria maxima in vivo.
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- 2014
18. Use of fluorescent nanoparticles to investigate nutrient acquisition by developing Eimeria maxima macrogametocytes
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Frölich, S, Wallach, M, Frölich, S, and Wallach, M
- Abstract
The enteric disease coccidiosis, caused by the unicellular parasite Eimeria, is a major and reoccurring problem for the poultry industry. While the molecular machinery driving host cell invasion and oocyst wall formation has been well documented in Eimeria, relatively little is known about the host cell modifications which lead to acquisition of nutrients and parasite growth. In order to understand the mechanism(s) by which nutrients are acquired by developing intracellular gametocytes and oocysts, we have performed uptake experiments using polystyrene nanoparticles (NPs) of 40 nm and 100 nm in size, as model NPs typical of organic macromolecules. Cytochalasin D and nocodazole were used to inhibit, respectively, the polymerization of the actin and microtubules. The results indicated that NPs entered the parasite at all stages of macrogametocyte development and early oocyst maturation via an active energy dependent process. Interestingly, the smaller NPs were found throughout the parasite cytoplasm, while the larger NPs were mainly localised to the lumen of large type 1 wall forming body organelles. NP uptake was reduced after microfilament disruption and treatment with nocodazole. These observations suggest that E. maxima parasites utilize at least 2 or more uptake pathways to internalize exogenous material during the sexual stages of development.
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- 2016
19. The spatial organization and extraction of the wall-forming bodies of Eimeria maxima
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Frölich, S, Johnson, M, Robinson, M, Entzeroth, R, and Wallach, M
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Proteomics ,Microscopy, Confocal ,Microscopy, Fluorescence ,Immunoblotting ,Oocysts ,Protozoan Proteins ,Animals ,Mycology & Parasitology ,Eimeria - Abstract
Eimeria maxima has been used as a model apicomplexan parasite to study sexual stage development and oocyst wall formation. A complete understanding of the wall's biochemical and biophysical properties is of great interest in research on all apicomplexan parasites. Purified gametocytes, zygotes and oocysts were analysed by three-dimensional confocal microscopy, and wide-field fluorescent microscopy was used to investigate the appearance and spatial organization of the 2 types of wall-forming bodies (WFBs). In addition, a variety of staining procedures and immunoassays were used to assess the biosynthesis, metabolic activity, intactness and molecular composition of the WFBs in situ. WFBs were extracted from gametocytes/zygotes and their composition was assessed by microscopy and SDS-PAGE analysis. It was concluded that isolated gametocytes are intact and metabolically active. Additionally, it was observed that the Type 1 WFBs are aligned at the periphery of the parasite and fuse together producing neutral lipid rich patches that appear to be inserted into the space between 2 parasite-specific membranes. Finally, it was shown that the WFBs extracted from purified gametocytes had the same shape, size and staining properties as those observed in situ, and contained the major glycoprotein antigens known to be present in these organelles. Copyright © Cambridge University Press 2013.
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- 2013
20. OSTEOARTHRITIS SYNOVIAL MACROPHAGES HAVE A TOLERIZED PHENOTYPE AND A VERY WEAK CORTICOSTEROID RESPONSE.
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Wang, C., De Francesco, R., Lamers, L., Rinzema, S., Frölich, S., Van Lent, P., Logie, C., and Van den Bosch, M.
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- 2023
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21. Brain Morphometry in Pontocerebellar Hypoplasia Type 2
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Groeschel, S., primary, Ekert, K., additional, Sánchez Albisua, I., additional, Frölich, S., additional, and Krägeloh-Mann, I., additional
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- 2014
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22. Comparison of protective immune responses to apicomplexan parasites.
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Frölich, S, Entzeroth, R, Wallach, M, Frölich, S, Entzeroth, R, and Wallach, M
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Members of the phylum Apicomplexa, which includes the species Plasmodium, Eimeria, Toxoplasma, and Babesia amongst others, are the most successful intracellular pathogens known to humankind. The widespread acquisition of antimicrobial resistance to most drugs used to date has sparked a great deal of research and commercial interest in the development of vaccines as alternative control strategies. A few antigens from the asexual and sexual stages of apicomplexan development have been identified and their genes characterised; however, the fine cellular and molecular details of the effector mechanisms crucial for parasite inhibition and stimulation of protective immunity are still not entirely understood. This paper provides an overview of what is currently known about the protective immune response against the various types of apicomplexan parasites and focuses mainly on the similarities of these pathogens and their host interaction. Finally, the evolutionary relationships of these parasites and their hosts, as well as the modulation of immune functions that are critical in determining the outcome of the infection by these pathogenic organisms, are discussed.
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- 2012
23. Comparison of protective immune responses to apicomplexan parasites
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Wallach, M, Frölich, S, Entzeroth, R, Wallach, M, Frölich, S, and Entzeroth, R
- Abstract
Members of the phylum Apicomplexa, which includes the species Plasmodium, Eimeria, Toxoplasma, and Babesia amongst others, are the most successful intracellular pathogens known to humankind. The widespread acquisition of antimicrobial resistance to most drugs used to date has sparked a great deal of research and commercial interest in the development of vaccines as alternative control strategies. A few antigens from the asexual and sexual stages of apicomplexan development have been identified and their genes characterised; however, the fine cellular and molecular details of the effector mechanisms crucial for parasite inhibition and stimulation of protective immunity are still not entirely understood. This paper provides an overview of what is currently known about the protective immune response against the various types of apicomplexan parasites and focuses mainly on the similarities of these pathogens and their host interaction. Finally, the evolutionary relationships of these parasites and their hosts, as well as the modulation of immune functions that are critical in determining the outcome of the infection by these pathogenic organisms, are discussed.
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- 2012
24. O39 – 1826 Natural course of pontocerebellar hypoplasia type 2
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Sánchez-Albisua, I, primary, Frölich, S, additional, and Krägeloh-Mann, I, additional
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- 2013
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25. Ungewöhnliche Häufung periklitoraler Vulvakarzinome – Vergleich mit der Literatur und Hinweise zum operativen Management
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Frölich, S, primary, Suerken, A, additional, and Dall, P, additional
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- 2007
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26. Platelet 3H-imipramine binding in chronic non-cancer pain patients compared with healthy controls
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Jensen, N.H., Mellerup, E., Lauritzen, L., Eriksen, J., Frolich, S., Plenge, P., and Lunde, M.
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- 1990
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27. Corrigendum: Interaction between habits as action sequences and goal-directed behavior under time pressure.
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Frölich S, Esmeyer M, Endrass T, Smolka MN, and Kiebel SJ
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[This corrects the article DOI: 10.3389/fnins.2022.996957.]., (Copyright © 2024 Frölich, Esmeyer, Endrass, Smolka and Kiebel.)
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- 2024
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28. Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response.
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Wang C, De Francesco R, Lamers LA, Rinzema S, Frölich S, van Lent PLEM, Logie C, and van den Bosch MHJ
- Abstract
Objectives: It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of OA-Mf., Methods: We determined the genome-wide transcriptomic response to corticosteroids of end-stage osteoarthritic joint synovial macrophages (OA-Mf). This was compared with LPS-tolerized and β-glucan-trained circulating blood monocyte-derived macrophage models., Results: Upon corticosteroid stimulation, the trained and tolerized macrophages significantly alter the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf have a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, -2, -3 and -10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf Interleukin 1 (IL1), chemokine (CXCL) and cytokine (CCL) family member profiles resemble the tolerized macrophage model, with the exception that OA-Mf show high levels of CCL20., Conclusion: Terminal osteoarthritis joints therefore harbor macrophages with an inflammatory state that closely resembles the tolerized macrophage state and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2024
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29. Shigella flexneri remodeling and consumption of host lipids during infection.
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Ascari A, Frölich S, Zang M, Tran ENH, Wilson DW, Morona R, and Eijkelkamp BA
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- Humans, Fatty Acids metabolism, Lipids, Bacterial Proteins metabolism, Shigella flexneri metabolism
- Abstract
Importance: Bacterial pathogens have vastly distinct sites that they inhabit during infection. This requires adaptation due to changes in nutrient availability and antimicrobial stress. The bacterial surface is a primary barrier, and here, we show that the bacterial pathogen Shigella flexneri increases its surface decorations when it transitions to an intracellular lifestyle. We also observed changes in bacterial and host cell fatty acid homeostasis. Specifically, intracellular S. flexneri increased the expression of their fatty acid degradation pathway, while the host cell lipid pool was significantly depleted. Importantly, bacterial proliferation could be inhibited by fatty acid supplementation of host cells, thereby providing novel insights into the possible link between human malnutrition and susceptibility to S. flexneri ., Competing Interests: The authors declare no conflict of interest.
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- 2023
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30. Seq2science: an end-to-end workflow for functional genomics analysis.
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van der Sande M, Frölich S, Schäfers T, Smits JGA, Snabel RR, Rinzema S, and van Heeringen SJ
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- Workflow, Genomics, Chromatin Immunoprecipitation Sequencing, Software, High-Throughput Nucleotide Sequencing
- Abstract
Sequencing databases contain enormous amounts of functional genomics data, making them an extensive resource for genome-scale analysis. Reanalyzing publicly available data, and integrating it with new, project-specific data sets, can be invaluable. With current technologies, genomic experiments have become feasible for virtually any species of interest. However, using and integrating this data comes with its challenges, such as standardized and reproducible analysis. Seq2science is a multi-purpose workflow that covers preprocessing, quality control, visualization, and analysis of functional genomics sequencing data. It facilitates the downloading of sequencing data from all major databases, including NCBI SRA, EBI ENA, DDBJ, GSA, and ENCODE. Furthermore, it automates the retrieval of any genome assembly available from Ensembl, NCBI, and UCSC. It has been tested on a variety of species, and includes diverse workflows such as ATAC-, RNA-, and ChIP-seq. It consists of both generic as well as advanced steps, such as differential gene expression or peak accessibility analysis and differential motif analysis. Seq2science is built on the Snakemake workflow language and thus can be run on a range of computing infrastructures. It is available at https://github.com/vanheeringen-lab/seq2science., Competing Interests: The authors declare that they have no competing interests., (© 2023 van der Sande et al.)
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- 2023
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31. Myeloid-derived suppressor cells and tolerogenic dendritic cells are distinctively induced by PI3K and Wnt signaling pathways.
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van Wigcheren GF, Cuenca-Escalona J, Stelloo S, Brake J, Peeters E, Horrevorts SK, Frölich S, Ramos-Tomillero I, Wesseling-Rozendaal Y, van Herpen CML, van de Stolpe A, Vermeulen M, de Vries IJM, Figdor CG, and Flórez-Grau G
- Subjects
- Humans, Immunomodulation immunology, Immunotherapy, Neoplasms immunology, Neoplasms therapy, Proto-Oncogene Proteins c-akt immunology, Tumor Cells, Cultured, Dendritic Cells immunology, Myeloid-Derived Suppressor Cells immunology, Phosphatidylinositol 3-Kinases immunology, Signal Transduction immunology, Wnt Signaling Pathway immunology
- Abstract
Imbalanced immune responses are a prominent hallmark of cancer and autoimmunity. Myeloid cells can be overly suppressive, inhibiting protective immune responses or inactive not controlling autoreactive immune cells. Understanding the mechanisms that induce suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), can facilitate the development of immune-restoring therapeutic approaches. MDSCs are a major barrier for effective cancer immunotherapy by suppressing antitumor immune responses in cancer patients. TolDCs are administered to patients to promote immune tolerance with the intent to control autoimmune disease. Here, we investigated the development and suppressive/tolerogenic activity of human MDSCs and TolDCs to gain insight into signaling pathways that drive immunosuppression in these different myeloid subsets. Moreover, monocyte-derived MDSCs (M-MDSCs) generated in vitro were compared to M-MDSCs isolated from head-and-neck squamous cell carcinoma patients. PI3K-AKT signaling was identified as being crucial for the induction of human M-MDSCs. PI3K inhibition prevented the downregulation of HLA-DR and the upregulation of reactive oxygen species and MerTK. In addition, we show that the suppressive activity of dexamethasone-induced TolDCs is induced by β-catenin-dependent Wnt signaling. The identification of PI3K-AKT and Wnt signal transduction pathways as respective inducers of the immunomodulatory capacity of M-MDSCs and TolDCs provides opportunities to overcome suppressive myeloid cells in cancer patients and optimize therapeutic application of TolDCs. Lastly, the observed similarities between generated- and patient-derived M-MDSCs support the use of in vitro-generated M-MDSCs as powerful model to investigate the functionality of human MDSCs., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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32. Atlas of Plasmodium falciparum intraerythrocytic development using expansion microscopy.
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Liffner B, Cepeda Diaz AK, Blauwkamp J, Anaguano D, Frölich S, Muralidharan V, Wilson DW, Dvorin J, and Absalon S
- Abstract
Apicomplexan parasites exhibit tremendous diversity in much of their fundamental cell biology, but study of these organisms using light microscopy is often hindered by their small size. Ultrastructural expansion microscopy (U-ExM) is a microscopy preparation method that physically expands the sample ~4.5x. Here, we apply U-ExM to the human malaria parasite Plasmodium falciparum during the asexual blood stage of its lifecycle to understand how this parasite is organized in three-dimensions. Using a combination of dye-conjugated reagents and immunostaining, we have catalogued 13 different P. falciparum structures or organelles across the intraerythrocytic development of this parasite and made multiple observations about fundamental parasite cell biology. We describe that the outer centriolar plaque and its associated proteins anchor the nucleus to the parasite plasma membrane during mitosis. Furthermore, the rhoptries, Golgi, basal complex, and inner membrane complex, which form around this anchoring site while nuclei are still dividing, are concurrently segregated and maintain an association to the outer centriolar plaque until the start of segmentation. We also show that the mitochondrion and apicoplast undergo sequential fission events while maintaining an association with the outer centriolar plaque during cytokinesis. Collectively, this study represents the most detailed ultrastructural analysis of P. falciparum during its intraerythrocytic development to date, and sheds light on multiple poorly understood aspects of its organelle biogenesis and fundamental cell biology., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.
- Published
- 2023
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33. scANANSE gene regulatory network and motif analysis of single-cell clusters.
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Smits JGA, Arts JA, Frölich S, Snabel RR, Heuts BMH, Martens JHA, van Heeringen SJ, and Zhou H
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- Sequence Analysis, RNA methods, Software, Transcription Factors genetics, Gene Regulatory Networks, Leukocytes, Mononuclear
- Abstract
The recent development of single-cell techniques is essential to unravel complex biological systems. By measuring the transcriptome and the accessible genome on a single-cell level, cellular heterogeneity in a biological environment can be deciphered. Transcription factors act as key regulators activating and repressing downstream target genes, and together they constitute gene regulatory networks that govern cell morphology and identity. Dissecting these gene regulatory networks is crucial for understanding molecular mechanisms and disease, especially within highly complex biological systems. The gene regulatory network analysis software ANANSE and the motif enrichment software GimmeMotifs were both developed to analyse bulk datasets. We developed scANANSE, a software pipeline for gene regulatory network analysis and motif enrichment using single-cell RNA and ATAC datasets. The scANANSE pipeline can be run from either R or Python. First, it exports data from standard single-cell objects. Next, it automatically runs multiple comparisons of cell cluster data. Finally, it imports the results back to the single-cell object, where the result can be further visualised, integrated, and interpreted. Here, we demonstrate our scANANSE pipeline on a publicly available PBMC multi-omics dataset. It identifies well-known cell type-specific hematopoietic factors. Importantly, we also demonstrated that scANANSE combined with GimmeMotifs is able to predict transcription factors with both activating and repressing roles in gene regulation., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Smits JGA et al.)
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- 2023
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34. genomepy: genes and genomes at your fingertips.
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Frölich S, van der Sande M, Schäfers T, and van Heeringen SJ
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- Genomics methods, Computational Biology, Molecular Sequence Annotation, Software, Genome
- Abstract
Motivation: Analyzing a functional genomics experiment, such as ATAC-, ChIP-, or RNA-sequencing, requires genomic resources such as a reference genome assembly and gene annotation. These data can generally be retrieved from different organizations and in different versions. Most bioinformatic workflows require the user to supply this genomic data manually, which can be a tedious and error-prone process., Results: Here, we present genomepy, which can search, download, and preprocess the right genomic data for your analysis. Genomepy can search genomic data on NCBI, Ensembl, UCSC, and GENCODE, and inspect available gene annotations to enable an informed decision. The selected genome and gene annotation can be downloaded and preprocessed with sensible, yet controllable, defaults. Additional supporting data can be automatically generated or downloaded, such as aligner indexes, genome metadata, and blacklists., Availability and Implementation: Genomepy is freely available at https://github.com/vanheeringen-lab/genomepy under the MIT license and can be installed through pip or Bioconda., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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35. Computational approaches to understand transcription regulation in development.
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van der Sande M, Frölich S, and van Heeringen SJ
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- Gene Regulatory Networks, Genome, Computational Biology, Gene Expression Regulation, Transcription Factors metabolism
- Abstract
Gene regulatory networks (GRNs) serve as useful abstractions to understand transcriptional dynamics in developmental systems. Computational prediction of GRNs has been successfully applied to genome-wide gene expression measurements with the advent of microarrays and RNA-sequencing. However, these inferred networks are inaccurate and mostly based on correlative rather than causative interactions. In this review, we highlight three approaches that significantly impact GRN inference: (1) moving from one genome-wide functional modality, gene expression, to multi-omics, (2) single cell sequencing, to measure cell type-specific signals and predict context-specific GRNs, and (3) neural networks as flexible models. Together, these experimental and computational developments have the potential to significantly impact the quality of inferred GRNs. Ultimately, accurately modeling the regulatory interactions between transcription factors and their target genes will be essential to understand the role of transcription factors in driving developmental gene expression programs and to derive testable hypotheses for validation., (© 2023 The Author(s).)
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- 2023
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36. Interaction between habits as action sequences and goal-directed behavior under time pressure.
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Frölich S, Esmeyer M, Endrass T, Smolka MN, and Kiebel SJ
- Abstract
Human behavior consists in large parts of action sequences that are often repeated in mostly the same way. Through extensive repetition, sequential responses become automatic or habitual, but our environment often confronts us with events to which we have to react flexibly and in a goal-directed manner. To assess how implicitly learned action sequences interfere with goal-directed control, we developed a novel behavioral paradigm in which we combined action sequence learning through repetition with a goal-directed task component. So-called dual-target trials require the goal-directed selection of the response with the highest reward probability in a fast succession of trials with short response deadlines. Importantly, the response primed by the learned action sequence is sometimes different from that required by the goal-directed task. As expected, we found that participants learned the action sequence through repetition, as evidenced by reduced reaction times (RT) and error rates (ER), while still acting in a goal-directed manner in dual-target trials. Specifically, we found that the learned action sequence biased choices in the goal-directed task toward the sequential response, and this effect was more pronounced the better individuals had learned the sequence. Our novel task may help shed light on the acquisition of automatic behavioral patterns and habits through extensive repetition, allows to assess positive features of habitual behavior (e.g., increased response speed and reduced error rates), and importantly also the interaction of habitual and goal-directed behaviors under time pressure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frölich, Esmeyer, Endrass, Smolka and Kiebel.)
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- 2023
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37. Targeting malaria parasites with novel derivatives of azithromycin.
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Burns AL, Sleebs BE, Gancheva M, McLean KT, Siddiqui G, Venter H, Beeson JG, O'Handley R, Creek DJ, Ma S, Frölich S, Goodman CD, McFadden GI, and Wilson DW
- Subjects
- Animals, Humans, Azithromycin pharmacology, Plasmodium falciparum, Chloroquine pharmacology, Chloroquine therapeutic use, Antimalarials pharmacology, Parasites, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Malaria drug therapy, Malaria parasitology
- Abstract
Introduction: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development., Methods: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans)., Results: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi , respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment., Discussion: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burns, Sleebs, Gancheva, McLean, Siddiqui, Venter, Beeson, O’Handley, Creek, Ma, Frölich, Goodman, McFadden and Wilson.)
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- 2022
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38. Changes in patterns of eating habits and food intake during the first German COVID-19 lockdown: results of a cross-sectional online survey.
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Bühlmeier J, Frölich S, Ludwig C, Knoll-Pientka N, Schmidt B, Föcker M, and Libuda L
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- Adult, Communicable Disease Control, Cross-Sectional Studies, Eating, Feeding Behavior psychology, Female, Humans, Male, Pandemics, COVID-19 epidemiology
- Abstract
Purpose: The COVID-19 pandemic and public measures have a direct impact on the nutrition situation; studies show changes in food consumption, eating behavior or body weight but complex pattern analyses of changes rarely exist., Methods: During the first German lockdown, a web-based survey was conducted among adults. It included 33 questions about changes in food intake, eating habits and physical activity, as well as anthropometrics and sociodemographic factors. Patterns of change were calculated based on changes in food intake and eating habits using two-step cluster analysis. To identify influencing factors for assignment to the patterns of change, binary logistic regression analyses were performed., Results: Data from 2103 participants (81% female, 40 ± 14 years) were considered for analysis. Increased stockpiling, cooking, and variation in preparation was reported by 50-70%. The constant pattern (C-P, 36%) reported little change besides the above. The health-oriented pattern (HO-P; 37%) reported eating more healthy foods, avoiding unhealthy foods, and eating less and less frequently. The emotional-driven pattern (ED-P; 28%) exhibits higher influence of emotions on eating behavior, less avoidance of unhealthy foods, and increased consumption of sweets, pastries, and alcohol. The odds of changing eating behavior either to HO-P or ED-P were higher in women, people with migration background, younger participants, and increased with BMI categories., Conclusion: Both, the ED-P and HO-P, exhibit distinctive reactions in eating habits and food intake when dealing with a distressing experience. In subgroups, these may lead to disturbances in eating behavior and increase the risk for eating disorders and obesity., (© 2022. The Author(s).)
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- 2022
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39. Correction to: Changes in patterns of eating habits and food intake during the first German COVID-19 lockdown: results of a cross-sectional online survey.
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Bühlmeier J, Frölich S, Ludwig C, Knoll-Pientka N, Schmidt B, Föcker M, and Libuda L
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- 2022
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40. Cell biological analysis reveals an essential role for Pfcerli2 in erythrocyte invasion by malaria parasites.
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Liffner B, Balbin JM, Shami GJ, Siddiqui G, Strauss J, Frölich S, Heinemann GK, Edwards EM, Alder A, Wichers JS, Creek DJ, Tilley L, Dixon MWA, Gilberger TW, and Wilson DW
- Subjects
- Animals, Erythrocytes parasitology, Humans, Phylogeny, Protozoan Proteins metabolism, Malaria, Parasites metabolism
- Abstract
Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Here we characterise P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 2 (PfCERLI2), as a rhoptry bulb protein that is essential for merozoite invasion. Phylogenetic analyses show that cerli2 arose through an ancestral gene duplication of cerli1. We show that PfCERLI2 is essential for blood-stage growth and localises to the cytosolic face of the rhoptry bulb. Inducible knockdown of PfCERLI2 led to a proportion of merozoites failing to invade and was associated with elongation of the rhoptry organelle during merozoite development and inhibition of rhoptry antigen processing. These findings identify PfCERLI2 as a protein that has key roles in rhoptry biology during merozoite invasion., (© 2022. The Author(s).)
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- 2022
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41. Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication.
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Shue B, Chiramel AI, Cerikan B, To TH, Frölich S, Pederson SM, Kirby EN, Eyre NS, Bartenschlager RFW, Best SM, and Beard MR
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- A549 Cells, Aedes, Animals, COVID-19, Chlorocebus aethiops, Culicidae, Dengue Virus genetics, Genome-Wide Association Study, HEK293 Cells, Host-Pathogen Interactions genetics, Humans, RNA, Small Interfering metabolism, RNA, Viral metabolism, SARS-CoV-2, Vero Cells, West Nile virus genetics, Zika Virus genetics, Zika Virus Infection virology, CRISPR-Cas Systems, Flavivirus genetics, Neoplasm Proteins genetics, Receptors for Activated C Kinase genetics, Virus Replication
- Abstract
Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles. IMPORTANCE Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knockout screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.
- Published
- 2021
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42. Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer.
- Author
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Wester RA, van Voorthuijsen L, Neikes HK, Dijkstra JJ, Lamers LA, Frölich S, van der Sande M, Logie C, Lindeboom RGH, and Vermeulen M
- Abstract
Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant transformation, and disease progression in the intestine remain incompletely understood. Here, we report, in agreement with previous findings, that activation of the Retinoic Acid Receptor and the Retinoid X Receptor results in enhanced transcription of enterocyte-specific genes in mouse small intestinal organoids. Conversely, inhibition of this pathway results in reduced expression of genes associated with the absorptive lineage. Strikingly, this latter effect is conserved in a human organoid model for colorectal cancer (CRC) progression. We further show that RXR motif accessibility depends on progression state of CRC organoids. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic target in CRC., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
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43. ANANSE: an enhancer network-based computational approach for predicting key transcription factors in cell fate determination.
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Xu Q, Georgiou G, Frölich S, van der Sande M, Veenstra GJC, Zhou H, and van Heeringen SJ
- Subjects
- Cell Differentiation genetics, Chromatin Immunoprecipitation Sequencing, Epithelial Cells cytology, Epithelial Cells metabolism, Humans, Organ Specificity genetics, RNA-Seq methods, Transcription Factors metabolism, Algorithms, Computational Biology methods, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Gene Regulatory Networks, Transcription Factors genetics
- Abstract
Proper cell fate determination is largely orchestrated by complex gene regulatory networks centered around transcription factors. However, experimental elucidation of key transcription factors that drive cellular identity is currently often intractable. Here, we present ANANSE (ANalysis Algorithm for Networks Specified by Enhancers), a network-based method that exploits enhancer-encoded regulatory information to identify the key transcription factors in cell fate determination. As cell type-specific transcription factors predominantly bind to enhancers, we use regulatory networks based on enhancer properties to prioritize transcription factors. First, we predict genome-wide binding profiles of transcription factors in various cell types using enhancer activity and transcription factor binding motifs. Subsequently, applying these inferred binding profiles, we construct cell type-specific gene regulatory networks, and then predict key transcription factors controlling cell fate transitions using differential networks between cell types. This method outperforms existing approaches in correctly predicting major transcription factors previously identified to be sufficient for trans-differentiation. Finally, we apply ANANSE to define an atlas of key transcription factors in 18 normal human tissues. In conclusion, we present a ready-to-implement computational tool for efficient prediction of transcription factors in cell fate determination and to study transcription factor-mediated regulatory mechanisms. ANANSE is freely available at https://github.com/vanheeringen-lab/ANANSE., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
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44. Neuronal Sequence Models for Bayesian Online Inference.
- Author
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Frölich S, Marković D, and Kiebel SJ
- Abstract
Various imaging and electrophysiological studies in a number of different species and brain regions have revealed that neuronal dynamics associated with diverse behavioral patterns and cognitive tasks take on a sequence-like structure, even when encoding stationary concepts. These neuronal sequences are characterized by robust and reproducible spatiotemporal activation patterns. This suggests that the role of neuronal sequences may be much more fundamental for brain function than is commonly believed. Furthermore, the idea that the brain is not simply a passive observer but an active predictor of its sensory input, is supported by an enormous amount of evidence in fields as diverse as human ethology and physiology, besides neuroscience. Hence, a central aspect of this review is to illustrate how neuronal sequences can be understood as critical for probabilistic predictive information processing, and what dynamical principles can be used as generators of neuronal sequences. Moreover, since different lines of evidence from neuroscience and computational modeling suggest that the brain is organized in a functional hierarchy of time scales, we will also review how models based on sequence-generating principles can be embedded in such a hierarchy, to form a generative model for recognition and prediction of sensory input. We shortly introduce the Bayesian brain hypothesis as a prominent mathematical description of how online, i.e., fast, recognition, and predictions may be computed by the brain. Finally, we briefly discuss some recent advances in machine learning, where spatiotemporally structured methods (akin to neuronal sequences) and hierarchical networks have independently been developed for a wide range of tasks. We conclude that the investigation of specific dynamical and structural principles of sequential brain activity not only helps us understand how the brain processes information and generates predictions, but also informs us about neuroscientific principles potentially useful for designing more efficient artificial neuronal networks for machine learning tasks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Frölich, Marković and Kiebel.)
- Published
- 2021
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45. The impact of severe rare chronic neurological disease in childhood on the quality of life of families-a study on MLD and PCH2.
- Author
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Ammann-Schnell L, Groeschel S, Kehrer C, Frölich S, and Krägeloh-Mann I
- Subjects
- Child, Chronic Disease, Female, Humans, Olivopontocerebellar Atrophies, Parents, Surveys and Questionnaires, Leukodystrophy, Metachromatic, Quality of Life
- Abstract
Background: Rare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this study was to investigate the impact of such diseases on the family, especially on the quality of life and life perspectives of parents, but also on the families' everyday life, based on the model of two diseases which have been well described in recent years with respect to symptoms and course: metachromatic leukodystrophy (MLD) and pontocerebellar hypoplasia type 2 (PCH2). PCH2 is a primary severe developmental disorder, while children with MLD initially develop normally and then progressively deteriorate., Methods: Using a semi-standardized questionnaire, 43 families with children suffering from MLD (n = 30) or PCH2 (n = 19) reported data on the severity of the illness/symptoms, on family support and the care situation, as well as on the circumstances of non-affected siblings and the parents' work situation. In addition, the quality of life of parents and general family functioning was assessed using the PedsQL™ Family Impact Module [23]. Results for the latter were compared to published data from families with children without any chronic condition using student's t-tests for independent samples. Potential factors influencing the PedsQL™ scores were analyzed using Spearman's rank correlation., Results: Parents of children with MLD and PCH2 reported significantly lower health-related quality of life (HRQOL) compared to parents of healthy children (P < 0.001). Mothers showed significantly poorer HRQOL (P < 0.05) and were significantly more dissatisfied with their professional development (P < 0.05) than fathers, and this was seen in relation to their child's disease. Neither the form of disease ('primary' symptomatic PCH2 or 'secondary' symptomatic MLD), nor the severity of the child's illness (in terms of gross motor and speech function) had a specific impact on HRQOL in families. However, the time from diagnosis and advanced symptoms in the terminal disease stage were experienced as especially distressing., Conclusions: This study illustrates that MLD and PCH2 affect mothers in particular, but also the entire family. This underlines the need for personalized care and counselling of parents and families, especially following diagnosis and during the end stage in a child with a severe, rare chronic neurological disorder.
- Published
- 2021
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46. Combinatorial transcription factor activities on open chromatin induce embryonic heterogeneity in vertebrates.
- Author
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Bright AR, van Genesen S, Li Q, Grasso A, Frölich S, van der Sande M, van Heeringen SJ, and Veenstra GJC
- Subjects
- Animals, Body Patterning, Chromatin metabolism, Gastrulation, Gene Expression Profiling, Gene Expression Regulation, Developmental, Sequence Analysis, RNA, Xenopus genetics, Xenopus Proteins metabolism, Chromatin genetics, Single-Cell Analysis methods, Transcription Factors metabolism, Xenopus embryology, Xenopus Proteins genetics
- Abstract
During vertebrate gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal-ventral patterning and establishing of the dorsal axis. We applied single-cell chromatin accessibility and transcriptome analyses to explore the emergence of cellular heterogeneity during gastrulation in Xenopus tropicalis. Transcriptionally inactive lineage-restricted genes exhibit relatively open chromatin in animal caps, whereas chromatin accessibility in dorsal marginal zone cells more closely reflects transcriptional activity. We characterized single-cell trajectories and identified head and trunk organizer cell clusters in early gastrulae. By integrating chromatin accessibility and transcriptome data, we inferred the activity of transcription factors in single-cell clusters and tested the activity of organizer-expressed transcription factors in animal caps, alone or in combination. The expression profile induced by a combination of Foxb1 and Eomes most closely resembles that observed in the head organizer. Genes induced by Eomes, Otx2, or the Irx3-Otx2 combination are enriched for maternally regulated H3K4me3 modifications, whereas Lhx8-induced genes are marked more frequently by zygotically controlled H3K4me3. Taken together, our results show that transcription factors cooperate in a combinatorial fashion in generally open chromatin to orchestrate zygotic gene expression., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2021
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47. Development of Automated Microscopy-Assisted High-Content Multiparametric Assays for Cell Cycle Staging and Foci Quantitation.
- Author
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Frölich S, Robker R, and Russell D
- Subjects
- Cell Cycle, Humans, Telomere, Transcription Factors, Microscopy, Nuclear Proteins genetics
- Abstract
The investigation of cell cycle stage-dependent processes in a population of cells is often performed using flow cytometry. While this approach is high-throughput, it is relatively low in resolution and unable to measure phenotypic changes or processes occurring in subcellular compartments. We integrated automated microscopy with newly developed informatics workflow that enabled the quantitation of multiple fluorescent markers from specific subnuclear regions throughout a population of cells. Telomeres protect chromosome termini and prevent cellular aging. Cancer cells lengthen telomeres by synthesizing new TTAGGG repeats by the enzyme telomerase, while others activate recombination-dependent alternative lengthening of telomeres (ALT). A key feature of the ALT pathway is the specific clustering of promyelocytic leukemia (PML) nuclear bodies at telomeres. These ALT-associated PML bodies (APBs) common in tumors of mesenchymal origin have gained in diagnostic use in the past decade. Here we applied recent improvements in automated microscopy and developed novel informatics workflows for quantitation of multiple fluorescent markers from specific subnuclear regions at the single cell level. Key to this workflow are customized machine learning algorithms within HCS Studio™ Cell Analysis which automatically identify and segment cells into defined regions of interest based on fluorescent markers, measure marker intensities and compute marker colocalizations in specific segmented regions. These multiparametric cellular assays assess cell cycle dynamics as well as the interactome of APBs, are amenable to adherent cells and histological sections, and are adaptable for use with additional markers. In the future we anticipate exploiting these algorithms for a wide range of research questions related to telomere biology with potential to facilitate clinical development of ALT detection assays to benefit patients with these often-poor prognosis tumors. © 2020 International Society for Advancement of Cytometry., (© 2020 International Society for Advancement of Cytometry.)
- Published
- 2020
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48. [Design and quality control of the oral health status examination in the German National Cohort (GNC)].
- Author
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Holtfreter B, Samietz S, Hertrampf K, Aarabi G, Hagenfeld D, Kim TS, Kocher T, Koos B, Schmitter M, Ahrens W, Alwers E, Becher H, Berger K, Brenner H, Damms-Machado A, Ebert N, Fischer B, Franzke CW, Frölich S, Greiser H, Gies A, Günther K, Hassan L, Hoffmann W, Jaeschke L, Keil T, Kemmling Y, Krause G, Krist L, Legath N, Lieb W, Leitzmann M, Linseisen J, Loeffler M, Meinke-Franze C, Michels KB, Mikolajczyk R, Obi N, Peters A, Pischon T, Schipf S, Schmidt B, Völzke H, Waniek S, Wigmann C, Wirkner K, Schmidt CO, Kühnisch J, and Rupf S
- Subjects
- Cohort Studies, Germany, Humans, Quality Assurance, Health Care, Quality Control, Data Collection standards, Dental Caries epidemiology, Mouth Diseases, Oral Health
- Abstract
Background: Caries and periodontitis are highly prevalent worldwide. Because detailed data on these oral diseases were collected within the framework of the German National Cohort (GNC), associations between oral and systemic diseases and conditions can be investigated., Objectives: The study protocol for the oral examination was designed to ensure a comprehensive collection of dental findings by trained non-dental staff within a limited examination time. At the mid-term of the GNC baseline examination, a first quality evaluation was performed to check the plausibility of results and to propose measures to improve the data quality., Materials and Methods: A dental interview, saliva sampling and oral diagnostics were conducted. As part of the level‑1 examination, the number of teeth and prostheses were recorded. As part of the level‑2 examination, detailed periodontal, cariological and functional aspects were examined. All examinations were conducted by trained non-dental personnel. Parameters were checked for plausibility and variable distributions were descriptively analysed., Results: Analyses included data of 57,967 interview participants, 56,913 level‑1 participants and 6295 level‑2 participants. Percentages of missing values for individual clinical parameters assessed in level 1 and level 2 ranged between 0.02 and 3.9%. Results showed a plausible distribution of the data; rarely, implausible values were observed, e.g. for measurements of horizontal and vertical overbite (overjet and overbite). Intra-class correlation coefficients indicated differences in individual parameters between regional clusters, study centres and across different examiners., Conclusions: The results confirm the feasibility of the study protocol by non-dental personnel and its successful integration into the GNC's overall assessment program. However, rigorous dental support of the study centres is required for quality management.
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- 2020
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49. PfCERLI1 is a conserved rhoptry associated protein essential for Plasmodium falciparum merozoite invasion of erythrocytes.
- Author
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Liffner B, Frölich S, Heinemann GK, Liu B, Ralph SA, Dixon MWA, Gilberger TW, and Wilson DW
- Subjects
- Humans, Merozoites genetics, Merozoites growth & development, Organelles parasitology, Plasmodium falciparum genetics, Plasmodium falciparum metabolism, Protozoan Proteins genetics, Erythrocytes parasitology, Malaria, Falciparum parasitology, Merozoites metabolism, Plasmodium falciparum growth & development, Protozoan Proteins metabolism
- Abstract
The disease-causing blood-stage of the Plasmodium falciparum lifecycle begins with invasion of human erythrocytes by merozoites. Many vaccine candidates with key roles in binding to the erythrocyte surface and entry are secreted from the large bulb-like rhoptry organelles at the apical tip of the merozoite. Here we identify an essential role for the conserved protein P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 1 (PfCERLI1) in rhoptry function. We show that PfCERLI1 localises to the cytosolic face of the rhoptry bulb membrane and knockdown of PfCERLI1 inhibits merozoite invasion. While schizogony and merozoite organelle biogenesis appear normal, biochemical techniques and semi-quantitative super-resolution microscopy show that PfCERLI1 knockdown prevents secretion of key rhoptry antigens that coordinate merozoite invasion. PfCERLI1 is a rhoptry associated protein identified to have a direct role in function of this essential merozoite invasion organelle, which has broader implications for understanding apicomplexan invasion biology.
- Published
- 2020
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50. Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.
- Author
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Han M, Napier CE, Frölich S, Teber E, Wong T, Noble JR, Choi EHY, Everett RD, Cesare AJ, and Reddel RR
- Subjects
- Animals, Cell Death, Cell Line, Tumor, Cricetinae, Herpes Simplex pathology, Humans, Immediate-Early Proteins genetics, Immunity, Innate genetics, Kidney pathology, Mutation genetics, Oncolytic Virotherapy, Promyelocytic Leukemia Protein genetics, Telomere Homeostasis, Ubiquitin-Protein Ligases genetics, Herpes Simplex metabolism, Herpesvirus 1, Human physiology, Immediate-Early Proteins metabolism, Kidney metabolism, Promyelocytic Leukemia Protein metabolism, Ubiquitin-Protein Ligases metabolism, X-linked Nuclear Protein deficiency
- Abstract
Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)
- Published
- 2019
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