1,438 results on '"Rosenstiel P"'
Search Results
2. Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells
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Rieckmann, Lisa-Marie, Spohn, Michael, Ruff, Lisa, Agorku, David, Becker, Lisa, Borchers, Alina, Krause, Jenny, O’Reilly, Roisin, Hille, Jurek, Velthaus-Rusik, Janna-Lisa, Beumer, Niklas, Günther, Armin, Willnow, Lena, Imbusch, Charles D., Iglauer, Peter, Simon, Ronald, Franzenburg, Sören, Winter, Hauke, Thomas, Michael, Bokemeyer, Carsten, Gagliani, Nicola, Krebs, Christian F., Sprick, Martin, Hardt, Olaf, Riethdorf, Sabine, Trumpp, Andreas, Stoecklein, Nikolas H., Peine, Sven, Rosenstiel, Philipp, Pantel, Klaus, Loges, Sonja, and Janning, Melanie
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- 2024
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3. FixNCut: single-cell genomics through reversible tissue fixation and dissociation
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Jiménez-Gracia, Laura, Marchese, Domenica, Nieto, Juan C., Caratù, Ginevra, Melón-Ardanaz, Elisa, Gudiño, Victoria, Roth, Sara, Wise, Kellie, Ryan, Natalie K., Jensen, Kirk B., Hernando-Momblona, Xavier, Bernardes, Joana P., Tran, Florian, Sievers, Laura Katharina, Schreiber, Stefan, van den Berge, Maarten, Kole, Tessa, van der Velde, Petra L., Nawijn, Martijn C., Rosenstiel, Philip, Batlle, Eduard, Butler, Lisa M., Parish, Ian A., Plummer, Jasmine, Gut, Ivo, Salas, Azucena, Heyn, Holger, and Martelotto, Luciano G.
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- 2024
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4. Dynamic changes in extracellular vesicle-associated miRNAs elicited by ultrasound in inflammatory bowel disease patients
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Florian Tran, Alena Scharmacher, Nathan Baran, Neha Mishra, Marek Wozny, Samuel Pineda Chavez, Archana Bhardwaj, Sophia Hinz, Simonas Juzenas, Joana P. Bernardes, Laura Katharina Sievers, Matthias Lessing, Konrad Aden, Arne Lassen, Arne Bergfeld, Hauke Jann Weber, Lennart Neas, Stefania Vetrano, Stefan Schreiber, and Philip Rosenstiel
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Inflammatory bowel disease ,Liquid biopsies ,Extracellular vesicles ,Sonography ,Biomarker discovery ,Medicine ,Science - Abstract
Abstract Blood-based biomarkers that reliably indicate disease activity in the intestinal tract are an important unmet need in the management of patients with IBD. Extracellular vesicles (EVs) are cell-derived membranous microparticles, which reflect the cellular and functional state of their site of site of origin. As ultrasound waves may lead to molecular shifts of EV contents, we hypothesized that application of ultrasound waves on inflamed intestinal tissue in IBD may amplify the inflammation-specific molecular shifts in EVs like altered EV-miRNA expression, which in turn can be detected in the peripheral blood. 26 patients with IBD were included in the prospective clinical study. Serum samples were collected before and 30 min after diagnostic transabdominal ultrasound. Differential miRNA expression was analyzed by sequencing. Candidate inducible EV-miRNAs were functionally assessed in vitro by transfection of miRNA mimics and qPCR of predicted target genes. Serum EV-miRNA concentration at baseline correlated with disease severity, as determined by clinical activity scores and sonographic findings. Three miRNAs (miR-942-5p, mir-5588, mir-3195) were significantly induced by sonography. Among the significantly regulated EV-miRNAs, miR-942-5p was strongly induced in higher grade intestinal inflammation and correlated with clinical activity in Crohn’s disease. Prediction of target regulation and transfection of miRNA mimics inferred a role of this EV-miRNA in regulating barrier function in inflammation. Induction of mir-5588 and mir-3195 did not correlate with inflammation grade. This proof-of-concept trial highlights the principle of induced molecular shifts in EVs from inflamed tissue through transabdominal ultrasound. These inducible EVs and their molecular cargo like miRNA could become novel biomarkers for intestinal inflammation in IBD.
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- 2024
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5. Diagnostic leukapheresis reveals distinct phenotypes of NSCLC circulating tumor cells
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Lisa-Marie Rieckmann, Michael Spohn, Lisa Ruff, David Agorku, Lisa Becker, Alina Borchers, Jenny Krause, Roisin O’Reilly, Jurek Hille, Janna-Lisa Velthaus-Rusik, Niklas Beumer, Armin Günther, Lena Willnow, Charles D. Imbusch, Peter Iglauer, Ronald Simon, Sören Franzenburg, Hauke Winter, Michael Thomas, Carsten Bokemeyer, Nicola Gagliani, Christian F. Krebs, Martin Sprick, Olaf Hardt, Sabine Riethdorf, Andreas Trumpp, Nikolas H. Stoecklein, Sven Peine, Philipp Rosenstiel, Klaus Pantel, Sonja Loges, and Melanie Janning
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Circulating tumor cells ,Non-small cell lung cancer ,Single cell RNA sequencing ,Intratumor heterogeneity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Circulating tumor cells (CTCs) hold immense promise for unraveling tumor heterogeneity and understanding treatment resistance. However, conventional methods, especially in cancers like non-small cell lung cancer (NSCLC), often yield low CTC numbers, hindering comprehensive analyses. This study addresses this limitation by employing diagnostic leukapheresis (DLA) to cancer patients, enabling the screening of larger blood volumes. To leverage DLA’s full potential, this study introduces a novel approach for CTC enrichment from DLAs. Methods DLA was applied to six advanced stage NSCLC patients. For an unbiased CTC enrichment, a two-step approach based on negative depletion of hematopoietic cells was used. Single-cell (sc) whole-transcriptome sequencing was performed, and CTCs were identified based on gene signatures and inferred copy number variations. Results Remarkably, this innovative approach led to the identification of unprecedented 3,363 CTC transcriptomes. The extensive heterogeneity among CTCs was unveiled, highlighting distinct phenotypes related to the epithelial-mesenchymal transition (EMT) axis, stemness, immune responsiveness, and metabolism. Comparison with sc transcriptomes from primary NSCLC cells revealed that CTCs encapsulate the heterogeneity of their primary counterparts while maintaining unique CTC-specific phenotypes. Conclusions In conclusion, this study pioneers a transformative method for enriching CTCs from DLA, resulting in a substantial increase in CTC numbers. This allowed the creation of the first-ever single-cell whole transcriptome in-depth characterization of the heterogeneity of over 3,300 NSCLC-CTCs. The findings not only confirm the diagnostic value of CTCs in monitoring tumor heterogeneity but also propose a CTC-specific signature that can be exploited for targeted CTC-directed therapies in the future. This comprehensive approach signifies a major leap forward, positioning CTCs as a key player in advancing our understanding of cancer dynamics and paving the way for tailored therapeutic interventions.
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- 2024
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6. Effects of lifestyle and associated diseases on serum CC16 suggest complex interactions among metabolism, heart and lungs
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Nathalie Rohmann, Paula Stürmer, Corinna Geisler, Kristina Schlicht, Carina Knappe, Katharina Hartmann, Kathrin Türk, Tim Hollstein, Alexia Beckmann, Anna K. Seoudy, Ulla Becker, Perdita Wietzke-Braun, Ute Settgast, Florian Tran, Philip Rosenstiel, Jan H. Beckmann, Witigo von Schönfels, Stephan Seifert, Jan Heyckendorf, Andre Franke, Stefan Schreiber, Dominik M. Schulte, and Matthias Laudes
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Medicine (General) ,R5-920 ,Science (General) ,Q1-390 - Abstract
Introduction: Clara cell 16-kDa protein (CC16) is an anti-inflammatory, immunomodulatory secreted pulmonary protein with reduced serum concentrations in obesity according to recent data. Objective: Studies focused solely on bodyweight, which does not properly reflect obesity-associated implications of the metabolic and reno-cardio-vascular system. The purpose of this study was therefore to examine CC16 in a broad physiological context considering cardio-metabolic comorbidities of primary pulmonary diseases. Methods: CC16 was quantified in serum samples in a subset of the FoCus (N = 497) and two weight loss intervention cohorts (N = 99) using ELISA. Correlation and general linear regression analyses were applied to assess CC16 effects of lifestyle, gut microbiota, disease occurrence and treatment strategies. Importance and intercorrelation of determinants were validated using random forest algorithms. Results: CC16 A38G gene mutation, smoking and low microbial diversity significantly decreased CC16. Pre-menopausal female displayed lower CC16 compared to post-menopausal female and male participants. Biological age and uricosuric medications increased CC16 (all p
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- 2024
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7. Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability
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Starke, Svenja, Harris, Danielle M. M., Zimmermann, Johannes, Schuchardt, Sven, Oumari, Mhmd, Frank, Derk, Bang, Corinna, Rosenstiel, Philip, Schreiber, Stefan, Frey, Norbert, Franke, Andre, Aden, Konrad, and Waschina, Silvio
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- 2023
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8. Digital measurement of anterolateral knee laxity using strain sensors
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Mayr, Hermann O., Rosenstiel, Nikolaus, Prakash, Karthika S., Comella, Laura M., Woias, Peter, Schmal, Hagen, and Seidenstuecker, Michael
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- 2023
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9. FixNCut: single-cell genomics through reversible tissue fixation and dissociation
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Laura Jiménez-Gracia, Domenica Marchese, Juan C. Nieto, Ginevra Caratù, Elisa Melón-Ardanaz, Victoria Gudiño, Sara Roth, Kellie Wise, Natalie K. Ryan, Kirk B. Jensen, Xavier Hernando-Momblona, Joana P. Bernardes, Florian Tran, Laura Katharina Sievers, Stefan Schreiber, Maarten van den Berge, Tessa Kole, Petra L. van der Velde, Martijn C. Nawijn, Philip Rosenstiel, Eduard Batlle, Lisa M. Butler, Ian A. Parish, Jasmine Plummer, Ivo Gut, Azucena Salas, Holger Heyn, and Luciano G. Martelotto
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Single-cell genomics ,RNA sequencing ,Sample fixation ,Tissue dissociation ,Cellular stress ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract The use of single-cell technologies for clinical applications requires disconnecting sampling from downstream processing steps. Early sample preservation can further increase robustness and reproducibility by avoiding artifacts introduced during specimen handling. We present FixNCut, a methodology for the reversible fixation of tissue followed by dissociation that overcomes current limitations. We applied FixNCut to human and mouse tissues to demonstrate the preservation of RNA integrity, sequencing library complexity, and cellular composition, while diminishing stress-related artifacts. Besides single-cell RNA sequencing, FixNCut is compatible with multiple single-cell and spatial technologies, making it a versatile tool for robust and flexible study designs.
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- 2024
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10. Development of a clinical pathway for bariatric surgery as an integral part of a comprehensive treatment for adolescents with severe obesity in the Netherlands
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Kelly G.H. van de Pas, Anita C.E. Vreugdenhil, Loes Janssen, Wouter K.G. Leclercq, Meeike Kusters, Malika Chegary, Ines von Rosenstiel, Eric J. Hazebroek, Edgar G.A.H. van Mil, Renske Wassenberg, Linda M.W. Hover, Wim G. van Gemert, and François M.H. van Dielen
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Nutrition. Foods and food supply ,TX341-641 ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
Introduction In the Netherlands, bariatric surgery in adolescents is currently only allowed in the context of scientific research. Besides this, there was no clinical pathway for bariatric surgery in adolescents. In this paper, the development of a comprehensive clinical pathway for bariatric surgery in adolescents with severe obesity in the is described. Methods The clinical pathway for bariatric surgery in adolescents consists of an eligibility assessment as well as comprehensive peri- and postoperative care. Regarding the eligibility assessment, the adolescents need to be identified by their attending pediatricians and afterwards be evaluated by specialized pediatric obesity units. If the provided treatment is considered to be insufficiently effective, the adolescent will anonymously be evaluated by a national board. This is an additional diligence procedure specifically established for bariatric surgery in adolescents. The national board consists of independent experts regarding adolescent bariatric surgery, and evaluates whether the adolescents meet the criteria defined by the national professional associations. The final step is an assessment by a multidisciplinary team for adolescent bariatric surgery. The various disciplines (pediatrician, bariatric surgeon, psychologist, dietician) evaluate whether an adolescent is eligible for bariatric surgery. In this decision-making process, it is crucial to assess whether the adolescent is expected to adhere to postoperative behavioral changes and follow-up. When an adolescent is deemed eligible for bariatric surgery, he or she will receive preoperative counselling by a bariatric surgeon to decide on the type of bariatric procedure (Roux-en-Y gastric bypass or sleeve gastrectomy). Postoperative care consists of intensive guidance by the multidisciplinary team for adolescent bariatric surgery. In this guidance, several regular appointments are included and additional care will be provided based on the needs of the adolescent and his or her family. Furthermore, the multidisciplinary lifestyle intervention, in which the adolescents participated before bariatric surgery, continues in coordination with the multidisciplinary team for adolescent bariatric surgery, and this ensures long-term counselling and follow-up. Conclusion The implementation of bariatric surgery as an integral part of a comprehensive treatment for adolescents with severe obesity requires the development of a clinical pathway with a variety of disciplines.
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- 2024
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11. Tryptophan degradation as a systems phenomenon in inflammation – an analysis across 13 chronic inflammatory diseasesResearch in context
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Danielle M.M. Harris, Silke Szymczak, Sven Schuchardt, Johannes Labrenz, Florian Tran, Lina Welz, Hanna Graßhoff, Henner Zirpel, Melike Sümbül, Mhmd Oumari, Nils Engelbogen, Ralf Junker, Claudio Conrad, Diamant Thaçi, Norbert Frey, Andre Franke, Stephan Weidinger, Bimba Hoyer, Philip Rosenstiel, Silvio Waschina, Stefan Schreiber, and Konrad Aden
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Tryptophan ,Inflammation ,Metabolomics ,Metabolism ,Metabolites ,Kynurenine pathway ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Chronic inflammatory diseases (CIDs) are systems disorders that affect diverse organs including the intestine, joints and skin. The essential amino acid tryptophan (Trp) can be broken down to various bioactive derivatives important for immune regulation. Increased Trp catabolism has been observed in some CIDs, so we aimed to characterise the specificity and extent of Trp degradation as a systems phenomenon across CIDs. Methods: We used high performance liquid chromatography and targeted mass spectrometry to assess the serum and stool levels of Trp and Trp derivatives. Our retrospective study incorporates both cross-sectional and longitudinal components, as we have included a healthy population as a reference and there are also multiple observations per patient over time. Findings: We found reduced serum Trp levels across the majority of CIDs, and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Notably, serum Trp was low in several CIDs even in the absence of measurable systemic inflammation. Increases in the kynurenine-to-Trp ratio (Kyn:Trp) suggest that these changes result from increased degradation along the kynurenine pathway. Interpretation: Increases in Kyn:Trp indicate the kynurenine pathway as a major route for CID-related Trp metabolism disruption and the specificity of the network changes indicates excessive Trp degradation relative to other proteogenic amino acids. Our results suggest that increased Trp catabolism is a common metabolic occurrence in CIDs that may directly affect systemic immunity. Funding: This work was supported by the DFG Cluster of Excellence 2167 “Precision medicine in chronic inflammation” (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund “Try-IBD” 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), EKFS (2020_EKCS.11, KA), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings (“Taxonomy, Treatments, Targets and Remission”, 831434, “ImmUniverse”, 853995, “BIOMAP”, 821511).
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- 2024
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12. The short and long-term effects of a lifestyle intervention in children with mental illnesses: a randomized controlled trial (Movementss study)
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van Tetering, Emilie M. A., Muskens, Jet B., Deenik, Jeroen, Pillen, Sigrid, Cahn, Wiepke, von Rosenstiel, Inès, Oomen, Mieke, Rommelse, Nanda N., Staal, Wouter G., and Klip, Helen
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- 2023
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13. Alterations in the hepatocyte epigenetic landscape in steatosis
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Maji, Ranjan Kumar, Czepukojc, Beate, Scherer, Michael, Tierling, Sascha, Cadenas, Cristina, Gianmoena, Kathrin, Gasparoni, Nina, Nordström, Karl, Gasparoni, Gilles, Laggai, Stephan, Yang, Xinyi, Sinha, Anupam, Ebert, Peter, Falk-Paulsen, Maren, Kinkley, Sarah, Hoppstädter, Jessica, Chung, Ho-Ryun, Rosenstiel, Philip, Hengstler, Jan G., Walter, Jörn, Schulz, Marcel H., Kessler, Sonja M., and Kiemer, Alexandra K.
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- 2023
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14. Concept and study protocol of the process evaluation of a pragmatic randomized controlled trial to promote physical activity in outpatients with heterogeneous mental disorders—the ImPuls study
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Fiedler, David Victor, Rosenstiel, Stephanie, Zeibig, Johanna-Marie, Seiffer, Britta, Welkerling, Jana, Frei, Anna Katharina, Studnitz, Thomas, Baur, Julia, Helmhold, Florian, Ray, Andreas, Herzog, Eva, Takano, Keisuke, Nakagawa, Tristan, Kropp, Saskia, Franke, Sebastian, Peters, Stefan, Flagmeier, Anna Lena, Zwanzleitner, Lena, Sundmacher, Leonie, Ramos-Murguialday, Ander, Hautzinger, Martin, Ehring, Thomas, Sudeck, Gorden, and Wolf, Sebastian
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- 2023
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15. Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut
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Björn Becker, Felix Wottawa, Mohamed Bakr, Eric Koncina, Lisa Mayr, Julia Kugler, Guang Yang, Samuel J. Windross, Laura Neises, Neha Mishra, Danielle Harris, Florian Tran, Lina Welz, Julian Schwärzler, Zoltán Bánki, Stephanie T. Stengel, Go Ito, Christina Krötz, Olivia I. Coleman, Christian Jaeger, Dirk Haller, Søren R. Paludan, Richard Blumberg, Arthur Kaser, Luka Cicin-Sain, Stefan Schreiber, Timon E. Adolph, Elisabeth Letellier, Philip Rosenstiel, Johannes Meiser, and Konrad Aden
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Virology ,Microbial metabolism ,Science - Abstract
Summary: Inflammatory bowel diseases are characterized by the chronic relapsing inflammation of the gastrointestinal tract. While the molecular causality between endoplasmic reticulum (ER) stress and intestinal inflammation is widely accepted, the metabolic consequences of chronic ER stress on the pathophysiology of IBD remain unclear. By using in vitro, in vivo models, and patient datasets, we identified a distinct polarization of the mitochondrial one-carbon metabolism and a fine-tuning of the amino acid uptake in intestinal epithelial cells tailored to support GSH and NADPH metabolism upon ER stress. This metabolic phenotype strongly correlates with IBD severity and therapy response. Mechanistically, we uncover that both chronic ER stress and serine limitation disrupt cGAS-STING signaling, impairing the epithelial response against viral and bacterial infection and fueling experimental enteritis. Consequently, the antioxidant treatment restores STING function and virus control. Collectively, our data highlight the importance of serine metabolism to allow proper cGAS-STING signaling and innate immune responses upon gut inflammation.
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- 2024
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16. Fostering positive affective exercise experiences and affect-related competencies for a physically active lifestyle: The FEEL project
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Martin Buehrer, Stephanie Rosenstiel, Gorden Sudeck, and Julia Schmid
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affect regulation ,exercise experiences ,affective responses ,motivation ,health promotion ,Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Introduction Interventions targeting physical inactive individuals have not yielded sufficient impact yet. This may be attributed to two reasons: Firstly, affective processes during physical activity (PA) are often inadequately acknowledged (e. g. shame, feeling bad; Hohberg et al. 2022). Secondly, individuals are often not empowered to PA that positively influences affective wellbeing and mental health (Sudeck & Pfeifer, 2016). The FEEL project addresses these two deficiencies by developing a program promoting pleasant experiences, affect regulation competence, wellbeing and consequently PA. The program is grounded in Ekkekakis et al.’s (2021) conceptual framework on affective exercise experiences and their antecedent appraisals. It consists of [a] an instructor workshop focused on creating an inclusive, socially supportive atmosphere. Additionally, the program features [b] group exercise sessions covering topics such as attentional focus, preferred intensity, and flexible goal setting. Experiential learning is employed during these sessions, encouraging participants to engage not only physically but also to reflect on and in action. Finally, the program incorporates [c] a PA counseling session, during which participants individual motives for exercise are assessed, and suitable activities are discussed (Schorno et al., 2022). Methods We plan a multicenter randomized controlled trial to investigate the impact of the 6-8 week FEEL program. Inactive individuals (meeting less than 75% of recommended PA guidelines) in the age of 16 to 35 will take part in the study. Participants will be recruited via schools, universities, companies, and social work institutions. Around 300 people will be assigned to either the intervention or control group. The control group will undergo a standard fitness program (usual care). The primary outcomes positive affective exercise experiences, affect regulation competence, wellbeing and PA will be measured pre- (0 weeks), post-intervention (6 weeks) and at follow-up (12 weeks). After piloting the FEEL program in April 2024, the main study will start in fall 2024. Discussion This study explores the impact of a multifaceted intervention in a primary care context. It may provide valuable insights for effective considerations of affective processes and related competencies in PA programs. Should the FEEL program showcase positive effects, there may be interest in extending its implementation in diverse settings (e.g., rehabilitation). References Ekkekakis, P., Zenko, Z., & Vazou, S. (2021). Do you find exercise pleasant or unpleasant? The Affective Exercise Experiences (AFFEXX) questionnaire. Psychology of Sport and Exercise, 55, Article 101930. https://doi.org/10.1016/j.psychsport.2021.101930 Hohberg, V., Kreppke, J.‑N., Cody, R., Guthold, R., Woods, C., Brand, R., Dunton, G., Rothman, A., Ketelhut, S., & Nigg, C. (2022). What is needed to promote physical activity? Current Issues in Sport Science, 7, Article 005 https://doi.org/10.36950/2022ciss005 Schorno, N., Gut, V., Conzelmann, A., & Schmid, J. (2022). Effectiveness of individual exercise and sport counseling based on motives and goals: A randomized controlled trial. Journal of Sport and Exercise Psychology, 44(2), 103-115. https://doi.org/10.1123/jsep.2021-0018 Sudeck, G., & Pfeifer, K. (2016). Physical activity-related health competence as an integrative objective in exercise therapy and health sports – Conception and validation of a short questionnaire. Sportwissenschaft, 46, 74–87. https://doi.org/10.1007/s12662-016-0405-4
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- 2024
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17. Verification of Component Fault Trees Using Error Effect Simulations
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Reiter, Sebastian, Zeller, Marc, Hoefig, Kai, Viehl, Alexander, Bringmann, Oliver, and Rosenstiel, Wolfgang
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Computer Science - Software Engineering - Abstract
The growing complexity of safety-relevant systems causes an increasing effort for safety assurance. The reduction of development costs and time-to-market, while guaranteeing safe operation, is therefore a major challenge. In order to enable efficient safety assessment of complex architectures, we present an approach, which combines deductive safety analyses, in form of Component Fault Trees (CFTs), with an Error Effect Simulation (EES) for sanity checks. The combination reduces the drawbacks of both analyses, such as the subjective failure propagation assumptions in the CFTs or the determination of relevant fault scenarios for the EES. Both CFTs and the EES provide a modular, reusable and compositional safety analysis and are applicable throughout the whole design process. They support continuous model refinement and the reuse of conducted safety analysis and simulation models. Hence, safety goal violations can be identified in early design stages and the reuse of conducted safety analyses reduces the overhead for safety assessment.
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- 2021
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18. The short and long-term effects of a lifestyle intervention in children with mental illnesses: a randomized controlled trial (Movementss study)
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Emilie M. A. van Tetering, Jet B. Muskens, Jeroen Deenik, Sigrid Pillen, Wiepke Cahn, Inès von Rosenstiel, Mieke Oomen, Nanda N. Rommelse, Wouter G. Staal, and Helen Klip
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Lifestyle intervention ,Mental illness ,Children ,Treatment ,Short and long-term effects ,Psychiatry ,RC435-571 - Abstract
Abstract Background A lifestyle including poor diet, physical inactivity, excessive gaming and inadequate sleep hygiene is frequently seen among Dutch children. These lifestyle behaviors can cause long-term health problems later in life. Unhealthy lifestyle and poor physical health are even more prevalent among children with mental illness (MI) such as autism, attention-deficit/hyperactivity disorder, depression, and anxiety. However, research on lifestyle interventions among children with MI is lacking. As a result, there are currently no guidelines, or treatment programs where children with MI and poor lifestyle can receive effective support. To address these issues and to provide insight into the effectiveness of lifestyle interventions in children with MI and their families, the Movementss study was designed. This paper describes the rationale, study design, and methods of an ongoing randomized controlled trial (RCT) comparing the short-term (12 weeks) and long-term (1 year) effects of a lifestyle intervention with care as usual (CAU) in children with MI and an unhealthy lifestyle. Methods A total of 80 children (6–12 years) with MI according to DSM-V and an unhealthy lifestyle are randomized to the lifestyle intervention group or CAU at a specialized child and adolescent mental hospital. The primary outcome measure is quality of life measured with the KIDSCREEN. Secondary outcomes include emotional and behavior symptoms, lifestyle parameters regarding diet, physical activity, sleep, and screen time, cognitive assessment (intelligence and executive functions), physical measurements (e.g., BMI), parenting styles, and family functioning, prior beliefs, adherence, satisfaction, and cost-effectiveness. Assessments will take place at the start of the study (T0), after 12 weeks (T1), six months (T2), and 12 months of baseline (T3) to measure long-term effects. Discussion This RCT will likely contribute to the currently lacking knowledge on lifestyle interventions in children with MI. Trial registration trialsearch.who.int/ NL9822. Registered at November 2nd, 2021.
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- 2023
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19. Alterations in the hepatocyte epigenetic landscape in steatosis
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Ranjan Kumar Maji, Beate Czepukojc, Michael Scherer, Sascha Tierling, Cristina Cadenas, Kathrin Gianmoena, Nina Gasparoni, Karl Nordström, Gilles Gasparoni, Stephan Laggai, Xinyi Yang, Anupam Sinha, Peter Ebert, Maren Falk-Paulsen, Sarah Kinkley, Jessica Hoppstädter, Ho-Ryun Chung, Philip Rosenstiel, Jan G. Hengstler, Jörn Walter, Marcel H. Schulz, Sonja M. Kessler, and Alexandra K. Kiemer
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Genetics ,QH426-470 - Abstract
Abstract Fatty liver disease or the accumulation of fat in the liver, has been reported to affect the global population. This comes with an increased risk for the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Yet, little is known about the effects of a diet containing high fat and alcohol towards epigenetic aging, with respect to changes in transcriptional and epigenomic profiles. In this study, we took up a multi-omics approach and integrated gene expression, methylation signals, and chromatin signals to study the epigenomic effects of a high-fat and alcohol-containing diet on mouse hepatocytes. We identified four relevant gene network clusters that were associated with relevant pathways that promote steatosis. Using a machine learning approach, we predict specific transcription factors that might be responsible to modulate the functionally relevant clusters. Finally, we discover four additional CpG loci and validate aging-related differential CpG methylation. Differential CpG methylation linked to aging showed minimal overlap with altered methylation in steatosis.
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- 2023
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20. Concept and study protocol of the process evaluation of a pragmatic randomized controlled trial to promote physical activity in outpatients with heterogeneous mental disorders—the ImPuls study
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David Victor Fiedler, Stephanie Rosenstiel, Johanna-Marie Zeibig, Britta Seiffer, Jana Welkerling, Anna Katharina Frei, Thomas Studnitz, Julia Baur, Florian Helmhold, Andreas Ray, Eva Herzog, Keisuke Takano, Tristan Nakagawa, Saskia Kropp, Sebastian Franke, Stefan Peters, Anna Lena Flagmeier, Lena Zwanzleitner, Leonie Sundmacher, Ander Ramos-Murguialday, Martin Hautzinger, Thomas Ehring, Gorden Sudeck, and Sebastian Wolf
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Implementation research ,Group-based exercise intervention ,Behavior change techniques ,MRC framework ,Outpatient care ,Mental disorders ,Medicine (General) ,R5-920 - Abstract
Abstract Background Evidence suggests that patients suffering from different mental disorders benefit from exercise programs combined with behavior change techniques. Based on this evidence, we have developed an exercise program (ImPuls) specifically designed to provide an additional treatment option in the outpatient mental health care system. The implementation of such complex programs into the outpatient context requires research that goes beyond the evaluation of effectiveness, and includes process evaluation. So far, process evaluation related to exercise interventions has rarely been conducted. As part of a current pragmatic randomized controlled trial evaluating ImPuls treatment effects, we are therefore carrying out comprehensive process evaluation according to the Medical Research Council (MRC) framework. The central aim of our process evaluation is to support the findings of the ongoing randomized controlled trial. Methods The process evaluation follows a mixed-methods approach. We collect quantitative data via online-questionnaires from patients, exercise therapists, referring healthcare professionals and managers of outpatient rehabilitative and medical care facilities before, during, and after the intervention. In addition, documentation data as well as data from the ImPuls smartphone application are collected. Quantitative data is complemented by qualitative interviews with exercise therapists as well as a focus-group interview with managers. Treatment fidelity will be assessed through the rating of video-recorded sessions. Quantitative data analysis includes descriptive as well as mediation and moderation analyses. Qualitative data will be analyzed via qualitative content analysis. Discussion The results of our process evaluation will complement the evaluation of effectiveness and cost-effectiveness and will, for example, provide important information about mechanisms of impact, structural prerequisites, or provider qualification that may support the decision-making process of health policy stakeholders. It might contribute to paving the way for exercise programs like ImPuls to be made successively available for patients with heterogeneous mental disorders in the German outpatient mental health care system. Trial registration The parent clinical study was registered in the German Clinical Trials Register (ID: DRKS00024152, registered 05/02/2021, https://drks.de/search/en/trial/DRKS00024152 ).
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- 2023
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21. Evolution of E. coli in a mouse model of inflammatory bowel disease leads to a disease-specific bacterial genotype and trade-offs with clinical relevance
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Rahul Unni, Nadia Andrea Andreani, Marie Vallier, Silke S. Heinzmann, Jan Taubenheim, Martina A. Guggeis, Florian Tran, Olga Vogler, Sven Künzel, Jan-Bernd Hövener, Philip Rosenstiel, Christoph Kaleta, Astrid Dempfle, Daniel Unterweger, and John F. Baines
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Inflammatory bowel disease ,E. coli ,experimental evolution ,evolutionary trade-offs ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTInflammatory bowel disease (IBD) is a persistent inflammatory condition that affects the gastrointestinal tract and presents significant challenges in its management and treatment. Despite the knowledge that within-host bacterial evolution occurs in the intestine, the disease has rarely been studied from an evolutionary perspective. In this study, we aimed to investigate the evolution of resident bacteria during intestinal inflammation and whether- and how disease-related bacterial genetic changes may present trade-offs with potential therapeutic importance. Here, we perform an in vivo evolution experiment of E. coli in a gnotobiotic mouse model of IBD, followed by multiomic analyses to identify disease-specific genetic and phenotypic changes in bacteria that evolved in an inflamed versus a non-inflamed control environment. Our results demonstrate distinct evolutionary changes in E. coli specific to inflammation, including a single nucleotide variant that independently reached high frequency in all inflamed mice. Using ex vivo fitness assays, we find that these changes are associated with a higher fitness in an inflamed environment compared to isolates derived from non-inflamed mice. Further, using large-scale phenotypic assays, we show that bacterial adaptation to inflammation results in clinically relevant phenotypes, which intriguingly include collateral sensitivity to antibiotics. Bacterial evolution in an inflamed gut yields specific genetic and phenotypic signatures. These results may serve as a basis for developing novel evolution-informed treatment approaches for patients with intestinal inflammation.
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- 2023
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22. The SYSCID map: a graphical and computational resource of molecular mechanisms across rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease
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Marcio Luis Acencio, Marek Ostaszewski, Alexander Mazein, Philip Rosenstiel, Konrad Aden, Neha Mishra, Vibeke Andersen, Prodromos Sidiropoulos, Aggelos Banos, Anastasia Filia, Souad Rahmouni, Axel Finckh, Wei Gu, Reinhard Schneider, and Venkata Satagopam
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inflammatory bowel disease ,rheumatoid arthritis ,systemic lupus erythematosus ,molecular mechanisms ,curation ,pathway biology ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Chronic inflammatory diseases (CIDs), including inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are thought to emerge from an impaired complex network of inter- and intracellular biochemical interactions among several proteins and small chemical compounds under strong influence of genetic and environmental factors. CIDs are characterised by shared and disease-specific processes, which is reflected by partially overlapping genetic risk maps and pathogenic cells (e.g., T cells). Their pathogenesis involves a plethora of intracellular pathways. The translation of the research findings on CIDs molecular mechanisms into effective treatments is challenging and may explain the low remission rates despite modern targeted therapies. Modelling CID-related causal interactions as networks allows us to tackle the complexity at a systems level and improve our understanding of the interplay of key pathways. Here we report the construction, description, and initial applications of the SYSCID map (https://syscid.elixir-luxembourg.org/), a mechanistic causal interaction network covering the molecular crosstalk between IBD, RA and SLE. We demonstrate that the map serves as an interactive, graphical review of IBD, RA and SLE molecular mechanisms, and helps to understand the complexity of omics data. Examples of such application are illustrated using transcriptome data from time-series gene expression profiles following anti-TNF treatment and data from genome-wide associations studies that enable us to suggest potential effects to altered pathways and propose possible mechanistic biomarkers of treatment response.
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- 2023
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23. Design and Implementation of a Wearable System Based on a Flexible Capacitive Sensor, Monitoring Knee Laxity
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Karthika Sheeja Prakash, Erik Andersen, Vicky Chantal vonEinem, Sabari Kannan Muthalagu, Priyank Agarwal, Hermann Otto Mayr, Michael Seidenstuecker, Nikolaus Rosenstiel, Shad Roundy, Peter Woias, and Laura Maria Comella
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anterior cruciate ligament rupture ,battery‐powered system ,bluetooth low energy ,capacitive strain gauge sensors ,flex‐pcb ,knee simulator ,Technology (General) ,T1-995 ,Science - Abstract
Abstract The anterior cruciate ligament (ACL) tear is one of the most common knee injuries causing instability to the knee joint. Current methods of diagnosis fail to meet the ergonomic, reliability, and reproducibility requirements. Thus, the wearable sensors are gaining momentum to overcome current challenges. This paper aims at proposing a wearable capacitive based sensor system that shows a good potential in substituting the currently used methods for the diagnosis of ACL rupture. The developed sensor system measures the internal tibial rotation of the knee. It is compact and lightweight. Being cable free, it can be worn as a patch, without impeding the freedom of movement of the physician. Moreover, it can be powered with a battery or wireless. Both methods make it compact, ergonomic, easy for the patient to wear and for the doctor to use. To analyze the suitability of the developed sensing system, data from a knee simulator setup and three healthy volunteers (2 Males and 1 Female) are compared and analyzed. In all the patients, above 15° for every 5° angle variation, a relative change of capacitance with respect to its initial value of 0.01 is observed. These results are comparable with the knee simulator's data with a max RMSE of 0.002. Below 15° the system is additionally able to measure a gender‐based difference of rotation due to the higher flexibility of ligaments in females. For them the sensitivity below and above 15° is comparable, for male the sensitivity below 15° is lower. The results show that the developed system has good potential in substituting the currently used method for the diagnosis of ACL rupture and paves the way toward the continuous observation in free movement of knee laxity.
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- 2023
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24. Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner
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Camille Chauvin, Katarina Radulovic, Olivier Boulard, Myriam Delacre, Nadine Waldschmitt, Paul Régnier, Gauthier Legris, Clément Bouchez, Mohamed-Yassine Sleimi, Philip Rosenstiel, Guillaume Darrasse-Jèze, Mathias Chamaillard, and Lionel F. Poulin
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lysozyme ,myeloid ,colitis ,cancer-associated colitis ,NOD2 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundCrohn’s disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the NOD2 gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC).MethodsTo ablate Nod2 specifically within the myeloid compartment, we generated LysMCre/+;Nod2fl/fl mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis.ResultsUpon DSS colitis model, LysMCre/+;Nod2fl/fl mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of LysMCre/+;Nod2fl/fl mice, associated with less expression of Tgfb. Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells.ConclusionOur results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
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- 2023
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25. Association studies of the copy-number variable ß-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis
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Taudien Stefan, Gäbel Gabor, Kuss Oliver, Groth Marco, Grützmann Robert, Huse Klaus, Kluttig Alexander, Wolf Andreas, Nothnagel Michael, Rosenstiel Philip, Greiser Karin Halina, Werdan Karl, Krawczak Michael, Pilarsky Christian, and Platzer Matthias
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Defensins ,Single nucleotide variants ,Copy number variation ,Chronic pancreatitis ,Pancreatic ductal adenocarcinoma ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case–control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Results Two groups of PDAC (N=70) and CP (N=60) patients were compared to matched healthy control groups CARLA1 (N=232) and CARLA2 (N=160), respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification. Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively. The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher’s exact test P=0.027), but not between CP and CARLA2 (P=0.867). Conclusion Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.
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- 2012
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26. Accurate variant detection across non-amplified and whole genome amplified DNA using targeted next generation sequencing
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ElSharawy Abdou, Warner Jason, Olson Jeff, Forster Michael, Schilhabel Markus B, Link Darren R, Rose-John Stefan, Schreiber Stefan, Rosenstiel Philip, Brayer James, and Franke Andre
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High-throughput targeted next-generation resequencing ,Microdroplet-based multiplex PCR ,Sample pooling or multiplexing ,Whole-genome amplified DNA samples ,Cost reduction ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Many hypothesis-driven genetic studies require the ability to comprehensively and efficiently target specific regions of the genome to detect sequence variations. Often, sample availability is limited requiring the use of whole genome amplification (WGA). We evaluated a high-throughput microdroplet-based PCR approach in combination with next generation sequencing (NGS) to target 384 discrete exons from 373 genes involved in cancer. In our evaluation, we compared the performance of six non-amplified gDNA samples from two HapMap family trios. Three of these samples were also preamplified by WGA and evaluated. We tested sample pooling or multiplexing strategies at different stages of the tested targeted NGS (T-NGS) workflow. Results The results demonstrated comparable sequence performance between non-amplified and preamplified samples and between different indexing strategies [sequence specificity of 66.0% ± 3.4%, uniformity (coverage at 0.2× of the mean) of 85.6% ± 0.6%]. The average genotype concordance maintained across all the samples was 99.5% ± 0.4%, regardless of sample type or pooling strategy. We did not detect any errors in the Mendelian patterns of inheritance of genotypes between the parents and offspring within each trio. We also demonstrated the ability to detect minor allele frequencies within the pooled samples that conform to predicted models. Conclusion Our described PCR-based sample multiplex approach and the ability to use WGA material for NGS may enable researchers to perform deep resequencing studies and explore variants at very low frequencies and cost.
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- 2012
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27. Improving mapping and SNP-calling performance in multiplexed targeted next-generation sequencing
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ElSharawy Abdou, Forster Michael, Schracke Nadine, Keller Andreas, Thomsen Ingo, Petersen Britt-Sabina, Stade Björn, Stähler Peer, Schreiber Stefan, Rosenstiel Philip, and Franke Andre
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Two-stage mapping ,Read-backmapping ,Software performance ,SNP discovery ,Multiplexed targeted next-generation sequencing ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Compared to classical genotyping, targeted next-generation sequencing (tNGS) can be custom-designed to interrogate entire genomic regions of interest, in order to detect novel as well as known variants. To bring down the per-sample cost, one approach is to pool barcoded NGS libraries before sample enrichment. Still, we lack a complete understanding of how this multiplexed tNGS approach and the varying performance of the ever-evolving analytical tools can affect the quality of variant discovery. Therefore, we evaluated the impact of different software tools and analytical approaches on the discovery of single nucleotide polymorphisms (SNPs) in multiplexed tNGS data. To generate our own test model, we combined a sequence capture method with NGS in three experimental stages of increasing complexity (E. coli genes, multiplexed E. coli, and multiplexed HapMap BRCA1/2 regions). Results We successfully enriched barcoded NGS libraries instead of genomic DNA, achieving reproducible coverage profiles (Pearson correlation coefficients of up to 0.99) across multiplexed samples, with Conclusions We recommend applying our general ‘two-step’ mapping approach for more efficient SNP discovery in tNGS. Our study has also shown the benefit of computing inter-sample SNP-concordances and inspecting read alignments in order to attain more confident results.
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- 2012
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28. Promotion of Physical Activity-Related Health Competence in Physical Education: A Person-Oriented Approach for Evaluating the GEKOS Intervention within a Cluster Randomized Controlled Trial
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Rosenstiel, Stephanie, Volk, Carmen, Schmid, Julia, Wagner, Wolfgang, Demetriou, Yolanda, Höner, Oliver, Thiel, Ansgar, Trautwein, Ulrich, and Sudeck, Gorden
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A central goal of physical education (PE) is to empower students to be physically active in a health-enhancing way. Therefore, using a competence-based approach, the objective of the health- and fitness-related PE intervention 'Promotion of physical activity-related health competence in PE' (GEKOS) was to address practical and theoretical content regarding training, fitness, and health. The aim of this person-oriented study was to examine differential effects of the GEKOS intervention on control competence and related knowledge, skills, abilities, and motivation. A total of 860 ninth graders were randomly assigned to an intervention or control group. Intervention group students received six PE lessons that combined practical and theoretical content regarding training, fitness, and health. Measurements were taken before, directly after, and with a follow-up after 8-12 weeks. Students completed a knowledge test and a fitness test, and filled out scales considering motivation and perceived control competence. Latent profile analysis and multinomial logistic regression were estimated. Five patterns of outcome measures were found. Intervention group students transitioned significantly more often to patterns with improved outcome values. The intervention was especially effective for a subgroup of students who initially had rather low outcome values. For a small proportion of students, the intervention entailed a loss of health-related motivation. The study indicated that students with low control competence and related knowledge, skills, abilities, and motivation can benefit from the GEKOS intervention. Future studies should investigate modes of actions and interventions that explicitly address motivation and vary the content and methods used in PE.
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- 2022
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29. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model
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Rosenstiel Philip, Bewig Burkhard, Hampe Jochen, Häsler Robert, Ellrichmann Mark, Kruse Marie-Luise, Stüber Eckhard, Lange-Grumfeld Julia, Noth Rainer, Schreiber Stefan, and Arlt Alexander
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Abstract Background Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models. Methods To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice. Results By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated. Conclusions This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.
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- 2011
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30. A tissue-specific landscape of sense/antisense transcription in the mouse intestine
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Sina Christian, Kreck Benjamin, Gavrilova Olga, Franke Andre, Häsler Robert, Wittig Michael, Barann Matthias, Klostermeier Ulrich C, Schilhabel Markus B, Schreiber Stefan, and Rosenstiel Philip
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The intestinal mucosa is characterized by complex metabolic and immunological processes driven highly dynamic gene expression programs. With the advent of next generation sequencing and its utilization for the analysis of the RNA sequence space, the level of detail on the global architecture of the transcriptome reached a new order of magnitude compared to microarrays. Results We report the ultra-deep characterization of the polyadenylated transcriptome in two closely related, yet distinct regions of the mouse intestinal tract (small intestine and colon). We assessed tissue-specific transcriptomal architecture and the presence of novel transcriptionally active regions (nTARs). In the first step, signatures of 20,541 NCBI RefSeq transcripts could be identified in the intestine (74.1% of annotated genes), thereof 16,742 are common in both tissues. Although the majority of reads could be linked to annotated genes, 27,543 nTARs not consistent with current gene annotations in RefSeq or ENSEMBL were identified. By use of a second independent strand-specific RNA-Seq protocol, 20,966 of these nTARs were confirmed, most of them in vicinity of known genes. We further categorized our findings by their relative adjacency to described exonic elements and investigated regional differences of novel transcribed elements in small intestine and colon. Conclusions The current study demonstrates the complexity of an archetypal mammalian intestinal mRNA transcriptome in high resolution and identifies novel transcriptionally active regions at strand-specific, single base resolution. Our analysis for the first time shows a strand-specific comparative picture of nTARs in two tissues and represents a resource for further investigating the transcriptional processes that contribute to tissue identity.
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- 2011
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31. Comprehensive assessment of sequence variation within the copy number variable defensin cluster on 8p23 by target enriched in-depth 454 sequencing
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Zhang Xinmin, Petzold Andreas, Raffaelli Francesca, Huse Klaus, Groth Marco, Felder Marius, Szafranski Karol, Taudien Stefan, Rosenstiel Philip, Hampe Jochen, Schreiber Stefan, and Platzer Matthias
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background In highly copy number variable (CNV) regions such as the human defensin gene locus, comprehensive assessment of sequence variations is challenging. PCR approaches are practically restricted to tiny fractions, and next-generation sequencing (NGS) approaches of whole individual genomes e.g. by the 1000 Genomes Project is confined by an affordable sequence depth. Combining target enrichment with NGS may represent a feasible approach. Results As a proof of principle, we enriched a ~850 kb section comprising the CNV defensin gene cluster DEFB, the invariable DEFA part and 11 control regions from two genomes by sequence capture and sequenced it by 454 technology. 6,651 differences to the human reference genome were found. Comparison to HapMap genotypes revealed sensitivities and specificities in the range of 94% to 99% for the identification of variations. Using error probabilities for rigorous filtering revealed 2,886 unique single nucleotide variations (SNVs) including 358 putative novel ones. DEFB CN determinations by haplotype ratios were in agreement with alternative methods. Conclusion Although currently labor extensive and having high costs, target enriched NGS provides a powerful tool for the comprehensive assessment of SNVs in highly polymorphic CNV regions of individual genomes. Furthermore, it reveals considerable amounts of putative novel variations and simultaneously allows CN estimation.
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- 2011
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32. Recent transfer of an iron-regulated gene from the plastid to the nuclear genome in an oceanic diatom adapted to chronic iron limitation
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Schreiber Stefan, Schilhabel Markus, Roy Alexandra-Sophie, Lommer Markus, Rosenstiel Philip, and LaRoche Julie
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Although the importance and widespread occurrence of iron limitation in the contemporary ocean is well documented, we still know relatively little about genetic adaptation of phytoplankton to these environments. Compared to its coastal relative Thalassiosira pseudonana, the oceanic diatom Thalassiosira oceanica is highly tolerant to iron limitation. The adaptation to low-iron conditions in T. oceanica has been attributed to a decrease in the photosynthetic components that are rich in iron. Genomic information on T. oceanica may shed light on the genetic basis of the physiological differences between the two species. Results The complete 141790 bp sequence of the T. oceanica chloroplast genome [GenBank: GU323224], assembled from massively parallel pyrosequencing (454) shotgun reads, revealed that the petF gene encoding for ferredoxin, which is localized in the chloroplast genome in T. pseudonana and other diatoms, has been transferred to the nucleus in T. oceanica. The iron-sulfur protein ferredoxin, a key element of the chloroplast electron transport chain, can be replaced by the iron-free flavodoxin under iron-limited growth conditions thereby contributing to a reduction in the cellular iron requirements. From a comparison to the genomic context of the T. pseudonana petF gene, the T. oceanica ortholog can be traced back to its chloroplast origin. The coding potential of the T. oceanica chloroplast genome is comparable to that of T. pseudonana and Phaeodactylum tricornutum, though a novel expressed ORF appears in the genomic region that has been subjected to rearrangements linked to the petF gene transfer event. Conclusions The transfer of the petF from the cp to the nuclear genome in T. oceanica represents a major difference between the two closely related species. The ability of T. oceanica to tolerate iron limitation suggests that the transfer of petF from the chloroplast to the nuclear genome might have contributed to the ecological success of this species.
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- 2010
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33. NOD2-C2 - a novel NOD2 isoform activating NF-κB in a muramyl dipeptide-independent manner
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Kramer Marcel, Boeck Janne, Reichenbach Daniela, Kaether Christoph, Schreiber Stefan, Platzer Matthias, Rosenstiel Philip, and Huse Klaus
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Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background The innate immune system employs several receptor families that form the basis of sensing pathogen-associated molecular patterns. NOD (nucleotide-binding and oligomerization domain) like receptors (NLRs) comprise a group of cytosolic proteins that trigger protective responses upon recognition of intracellular danger signals. NOD2 displays a tandem caspase recruitment domain (CARD) architecture, which is unique within the NLR family. Findings Here, we report a novel alternative transcript of the NOD2 gene, which codes for a truncated tandem CARD only protein, called NOD2-C2. The transcript isoform is highest expressed in leucocytes, a natural barrier against pathogen invasion, and is strictly linked to promoter usage as well as predominantly to one allele of the single nucleotide polymorphism rs2067085. Contrary to a previously identified truncated single CARD NOD2 isoform, NOD2-S, NOD2-C2 is able to activate NF-κB in a dose dependent manner independently of muramyl dipeptide (MDP). On the other hand NOD2-C2 competes with MDPs ability to activate the NOD2-driven NF-κB signaling cascade. Conclusion NOD2 transcripts having included an alternative exon downstream of exon 3 (exon 3a) are the endogenous equivalents of a previously described in vitro construct with the putative protein composed of only the two N-terminal CARDs. This protein form (NOD2-C2) activates NF-κB independent of an MDP stimulus and is a potential regulator of NOD2 signaling.
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- 2010
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34. Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing
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Rosenstiel Philip, Hampe Jochen, Szafranski Karol, Petzold Andreas, Huse Klaus, Groth Marco, Taudien Stefan, Schreiber Stefan, and Platzer Matthias
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background The beta-defensin gene cluster (DEFB) at chromosome 8p23.1 is one of the most copy number (CN) variable regions of the human genome. Whereas individual DEFB CNs have been suggested as independent genetic risk factors for several diseases (e.g. psoriasis and Crohn's disease), the role of multisite sequence variations (MSV) is less well understood and to date has only been reported for prostate cancer. Simultaneous assessment of MSVs and CNs can be achieved by PCR, cloning and Sanger sequencing, however, these methods are labour and cost intensive as well as prone to methodological bias introduced by bacterial cloning. Here, we demonstrate that amplicon sequencing of pooled individual PCR products by the 454 technology allows in-depth determination of MSV haplotypes and estimation of DEFB CNs in parallel. Results Six PCR products spread over ~87 kb of DEFB and harbouring 24 known MSVs were amplified from 11 DNA samples, pooled and sequenced on a Roche 454 GS FLX sequencer. From ~142,000 reads, ~120,000 haplotype calls (HC) were inferred that identified 22 haplotypes ranging from 2 to 7 per amplicon. In addition to the 24 known MSVs, two additional sequence variations were detected. Minimal CNs were estimated from the ratio of HCs and compared to absolute CNs determined by alternative methods. Concordance in CNs was found for 7 samples, the CNs differed by one in 2 samples and the estimated minimal CN was half of the absolute in one sample. For 7 samples and 2 amplicons, the 454 haplotyping results were compared to those by cloning/Sanger sequencing. Intrinsic problems related to chimera formation during PCR and differences between haplotyping by 454 and cloning/Sanger sequencing are discussed. Conclusion Deep amplicon sequencing using the 454 technology yield thousands of HCs per amplicon for an affordable price and may represent an effective method for parallel haplotyping and CN estimation in small to medium-sized cohorts. The obtained haplotypes represent a valuable resource to facilitate further studies of the biomedical impact of highly CN variable loci such as the beta-defensin locus.
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- 2010
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35. TassDB2 - A comprehensive database of subtle alternative splicing events
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Hampe Jochen, Rosenstiel Philip, Huse Klaus, Szafranski Karol, Friedel Swetlana, Gausmann Ulrike, Jahn Niels, Lenser Thorsten, Sinha Rileen, Schuster Stefan, Hiller Michael, Backofen Rolf, and Platzer Matthias
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Subtle alternative splicing events involving tandem splice sites separated by a short (2-12 nucleotides) distance are frequent and evolutionarily widespread in eukaryotes, and a major contributor to the complexity of transcriptomes and proteomes. However, these events have been either omitted altogether in databases on alternative splicing, or only the cases of experimentally confirmed alternative splicing have been reported. Thus, a database which covers all confirmed cases of subtle alternative splicing as well as the numerous putative tandem splice sites (which might be confirmed once more transcript data becomes available), and allows to search for tandem splice sites with specific features and download the results, is a valuable resource for targeted experimental studies and large-scale bioinformatics analyses of tandem splice sites. Towards this goal we recently set up TassDB (Tandem Splice Site DataBase, version 1), which stores data about alternative splicing events at tandem splice sites separated by 3 nt in eight species. Description We have substantially revised and extended TassDB. The currently available version 2 contains extensive information about tandem splice sites separated by 2-12 nt for the human and mouse transcriptomes including data on the conservation of the tandem motifs in five vertebrates. TassDB2 offers a user-friendly interface to search for specific genes or for genes containing tandem splice sites with specific features as well as the possibility to download result datasets. For example, users can search for cases of alternative splicing where the proportion of EST/mRNA evidence supporting the minor isoform exceeds a specific threshold, or where the difference in splice site scores is specified by the user. The predicted impact of each event on the protein is also reported, along with information about being a putative target for the nonsense-mediated decay (NMD) pathway. Links are provided to the UCSC genome browser and other external resources. Conclusion TassDB2, available via http://www.tassdb.info, provides comprehensive resources for researchers interested in both targeted experimental studies and large-scale bioinformatics analyses of short distance tandem splice sites.
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- 2010
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36. Investigation of innate immunity genes CARD4, CARD8 and CARD15 as germline susceptibility factors for colorectal cancer
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Fölsch Ulrich R, Kalthoff Holger, Röder Christian, Hinz Sebastian, Brosch Mario, Franke Andre, Rosenstiel Philip, Egberts Jan, Sipos Bence, von Kampen Oliver, Buch Stephan, von Schönfels Witigo, Möckelmann Nikolaus, Krawczak Michael, Schreiber Stefan, Bröring Clemens, Tepel Jürgen, Schafmayer Clemens, and Hampe Jochen
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Abstract Background Variation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of the CARD15 gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since the CARD15 gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at the CARD4, CARD8 and CARD15 loci on the risk for sporadic CRC, using a large patient sample from Northern Germany. Methods A total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (≤50 age at diagnosis) were performed for all CARD loci and subgroup analyses for diverse age strata were carried out for CARD15 mutations R702W, G908R and L1007fs. In addition, all SNPs were tested for association with disease presentation and family history of CRC. Results No significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (≤45 age at diagnosis) with early disease manifestation the mutant allele of CARD15 R702W was found to be significantly associated with disease susceptibility (9.7% in cases vs 4.6% in controls; Pallelic = 0.008, Pgenotypic = 0.0008, ORallelic = 2.22 (1.21-4.05) ORressessive = 21.9 (1.96-245.4). Conclusion Variation in the innate immunity genes CARD4, CARD8 and CARD15 is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution of CARD15 for CRC patients with very early disease manifestation, mainly driven by variant R702W.
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- 2009
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37. The expression of the β-defensins hBD-2 and hBD-3 is differentially regulated by NF-κB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis
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Steubesand Nadine, Kiehne Karlheinz, Brunke Gabriele, Pahl Rene, Reiss Karina, Herzig Karl-Heinz, Schubert Sabine, Schreiber Stefan, Fölsch Ulrich R, Rosenstiel Philip, and Arlt Alexander
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis. Results Supernatants of C. albicans or indirect coculture with C. albicans induces upregulation of hBD-2 and hBD-3 expression. PMNs strongly amplifies C. albicans-mediated induction of hBDs. By EMSA we demonstrate that C. albicans activates NF-κB and AP-1 in OE21 cells. Inhibition of these pathways revealed that hBD-2 expression is synergistically regulated by both NF-κB and AP-1. In contrast hBD-3 expression is independent of NF-κB and relies solely on an EGFR/MAPK/AP-1-dependent pathway. Conclusion Our analysis of signal transduction events demonstrate a functional interaction of epithelial cells with PMNs in response to Candida infection involving divergent signalling events that differentially govern hBD-2 and hBD-3 expression.
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- 2009
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38. Functional characterization of two novel 5' untranslated exons reveals a complex regulation of NOD2 protein expression
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Mathew Christopher G, Roberts Roland G, Platzer Cornelia, Reichwald Kathrin, Hampe Jochen, Franke Andre, Huse Klaus, Rosenstiel Philip, Platzer Matthias, and Schreiber Stefan
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background NOD2 is an innate immune receptor for the bacterial cell wall component muramyl-dipeptide. Mutations in the leucine-rich repeat region of NOD2, which lead to an impaired recognition of muramyl-dipeptide, have been associated with Crohn disease, a human chronic inflammatory bowel disease. Tissue specific constitutive and inducible expression patterns of NOD2 have been described that result from complex regulatory events for which the molecular mechanisms are not yet fully understood. Results We have identified two novel exons of the NOD2 gene (designated exon 1a and 1b), which are spliced to the canonical exon 2 and constitute the 5' untranslated region of two alternative transcript isoforms (i.e. exon 1a/1b/2 and exon 1a/2). The two novel transcripts are abundantly expressed and seem to comprise the majority of NOD2 transcripts under physiological conditions. We confirm the expression of the previously known canonical first exon (designated exon 1c) of the gene in unstimulated mononuclear cells. The inclusion of the second alternative exon 1b, which harbours three short upstream open reading frames (uORFs), is downregulated upon stimulation with TNF-α or under pro-inflammatory conditions in the inflamed intestinal mucosa in vivo. Using the different 5' UTR splice forms fused to a firefly luciferase (LUC) reporter we demonstrate a rapamycin-sensitive inhibitory effect of the uORFs on translation efficacy. Conclusion The differential usage of two alternative promoters in the NOD2 gene leads to tissue-specific and context-dependent NOD2 transcript isoform patterns. We demonstrate for the first time that context-dependent alternative splicing is linked to uORF-mediated translational repression. The results suggest complex parallel control mechanisms that independently regulate NOD2 expression in the context of inflammatory signaling.
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- 2007
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39. Role of NOD2/CARD15 in coronary heart disease
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Förster Matti, Rosenstiel Philip, Schäfer Arne, Nebel Almut, Ott Stephan J, El Mokhtari Nour Eddine, Nothnagel Michael, Simon Rüdiger, and Schreiber Stefan
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Genetics ,QH426-470 - Abstract
Abstract Background: Bacterial DNA has been repeatedly detected in atheromatous lesions of coronary heart disease (CHD) patients. Phylogenetic signatures in the atheroma lesions that are similar to those of bacterial biofilms on human barrier organs, including the respiratory or gastrointestinal tract, raise the question of a defective barrier function in CHD. NOD2 plays a major role in defense against bacterial invasion. Genetic variation in the CARD15 gene, which encodes NOD2, was previously shown to result in a barrier defect that causes chronic inflammatory disorders (e.g. Crohn disease). In the present study, we investigated the possible involvement of NOD2/CARD15 in the pathology of CHD by i) analyzing the local expression of NOD2 in atherectomy versus healthy tissue (n = 5 each) using histochemical immunofluorescence and ii) by testing the three major functional CARD15 variants (R702W, G908R and 1007fs) for association with early-onset CHD in 900 German patients and 632 healthy controls. Results: In atherectomy tissue of CHD patients, NOD2 was detected in inflammatory cells at the luminal sides of the lesions. However, the allele and genotype frequencies of the three major CARD15 polymorphisms did not differ between CHD patients and controls. Conclusion: The NOD2 up-regulation in atheroma lesions indicates an involvement of this protein in the pathology of CHD. Although NOD2 could be important in local immune response mechanisms, none of the analyzed CARD15 variants seem to play a significant role in the etiology of CHD.
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- 2007
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40. Cohort profile: the Food Chain Plus (FoCus) cohort
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Geisler, Corinna, Schlicht, Kristina, Knappe, Carina, Rohmann, Nathalie, Hartmann, Katharina, Türk, Kathrin, Settgast, Ute, Schulte, Dominik M., Demetrowitsch, Tobias, Jensen-Kroll, Julia, Pisarevskaja, Alina, Brix, Fynn, Gruber, Bärbel, Rimbach, Gerald, Döring, Frank, Rosenstiel, Philip, Franke, Andre, Schreiber, Stefan, Henning, Christian H. C. A., Lieb, Wolfgang, Nöthlings, Ute, Schwarz, Karin, and Laudes, Matthias
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- 2022
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41. Internal Rotation Measurement of the Knee with Polymer-Based Capacitive Strain Gauges versus Mechanical Rotation Measurement Taking Gender Differences into Account: A Comparative Analysis
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Hermann O. Mayr, Nikolaus Rosenstiel, Karthika S. Prakash, Laura Maria Comella, Peter Woias, Hagen Schmal, and Michael Seidenstuecker
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knee rotation measurement ,polymer-based capacitive strain gauges ,validation ,measurement instruments ,knee laxity ,Laxitester ,Science - Abstract
With the conventional mechanical rotation measurement of joints, only static measurements are possible with the patient at rest. In the future, it would be interesting to carry out dynamic rotation measurements, for example, when walking or participating in sports. Therefore, a measurement method with an elastic polymer-based capacitive measuring system was developed and validated. In our system, the measurement setup was comprised of a capacitive strain gauge made from a polymer, which was connected to a flexible printed circuit board. The electronics integrated into the printed circuit board allowed data acquisition and transmission. As the sensor strip was elongated, it caused a change in the spacing between the strain gauge’s electrodes, leading to a modification in capacitance. Consequently, this alteration in capacitance enabled the measurement of strain. The measurement system was affixed to the knee by adhering the sensor to the skin in alignment with the anterolateral ligament (ALL), allowing the lower part of the sensor (made of silicone) and the circuit board to be in direct contact with the knee’s surface. It is important to note that the sensor should be attached without any prior stretching. To validate the system, an in vivo test was conducted on 10 healthy volunteers. The dorsiflexion of the ankle was set at 2 Nm using a torque meter to eliminate any rotational laxity in the ankle. A strain gauge sensor was affixed to the Gerdii’s tubercle along the course of the anterolateral ligament, just beneath the lateral epicondyle of the thigh. In three successive measurements, the internal rotation of the foot and, consequently, the lower leg was quantified with a 2 Nm torque. The alteration in the stretch mark’s length was then compared to the measured internal rotation angle using the static measuring device. A statistically significant difference between genders emerged in the internal rotation range of the knee (p = 0.003), with female participants displaying a greater range of rotation compared to their male counterparts. The polymer-based capacitive strain gauge exhibited consistent linearity across all measurements, remaining within the sensor’s initial 20% strain range. The comparison between length change and the knee’s internal rotation angle revealed a positive correlation (r = 1, p < 0.01). The current study shows that elastic polymer-based capacitive strain gauges are a reliable instrument for the internal rotation measurement of the knee. This will allow dynamic measurements in the future under many different settings. In addition, significant gender differences in the internal rotation angle were seen.
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- 2024
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42. Allocation of Funds under Title I-A of the Elementary and Secondary Education Act. CRS Report R44461, Version 5. Updated
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Library of Congress, Congressional Research Service (CRS), Skinner, Rebecca R., and Rosenstiel, Leah
- Abstract
The Elementary and Secondary Education Act (ESEA) was comprehensively reauthorized by the Every Student Succeeds Act (ESSA; P.L. 114-95) on December 10, 2015. The Title I-A program is the largest grant program authorized under the ESEA and is funded at $15.8 billion for FY2018. Title I-A of the ESEA authorizes aid to Local education agency's (LEAs) for the education of disadvantaged children. Title I-A grants provide supplementary educational and related services to low-achieving and other students attending pre-kindergarten through grade 12 schools with relatively high concentrations of students from low-income families. Title I-A has also become a vehicle to which a number of requirements affecting broad aspects of public K-12 education for all students have been attached as conditions for receiving Title I-A grants. Under Title I-A, funds are distributed to state educational agencies (SEAs) and (LEAs) based on four formulas. The ESSA made few changes to these formulas. One notable change is an increase in the set-aside for the Bureau of Indian Education (BIE) and Outlying Areas from 1.0% to 1.1%. This change will take effect beginning in FY2017 provided the total amount available for state grants would not be less than the amount available in FY2016. All changes to the Title I-A grant allocation process made by the ESSA will take effect beginning in FY2017. This report provides a detailed discussion of the four Title I-A formulas used to determine grants as modified by the ESSA. Table A-1 in Appendix A offers an overview of the key elements included in the four formulas. Appendix B provides an overview of Title I-A appropriations levels in recent years. [Elizabeth Crowe, former Research Assistant at CRS, also contributed to this report.]
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- 2018
43. Analysis of the Elementary and Secondary Education Act Title I-A Allocation Formulas: Factors, Design Elements, and Allocation Patterns. CRS Report R45141, Version 3. Updated
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Library of Congress, Congressional Research Service (CRS), Skinner, Rebecca R., and Rosenstiel, Leah
- Abstract
The Elementary and Secondary Education Act (ESEA) is the primary source of federal aid to elementary and secondary education. The ESEA was last reauthorized by the Every Student Succeeds Act (ESSA; P.L. 114-95) in 2015. The Title I-A program has always been the largest grant program authorized under the ESEA. Title I-A grants provide supplementary educational and related services to low-achieving and other students attending elementary and secondary schools with relatively high concentrations of students from low-income families. Title I-A grant amounts are primarily driven by the number of "formula children"--principally children from low-income families--in an LEA, although all four formulas also include an expenditure factor based on education expenditures, minimum grant provisions, and hold harmless provisions. Since the initial enactment of Title I-A in 1965, the formula(s) have been criticized for being more favorable to more densely populated and typically urban areas due to how children from low-income families are counted, and for being more favorable to wealthier states due to the inclusion of factors based on education expenditures. This report analyzes issues related to three of the major debates surrounding the Title I-A formulas: (1) the effect of different formula factors and provisions on grant amounts, (2) whether the formulas are more favorable to certain types of LEAs and states, and (3) how effectively the Title I-A formulas target funds on concentrations of poverty. The report is intended to complement CRS Report R44898, "History of the ESEA Title I-A Formulas," which provides a detailed examination of the history of the Title I-A formulas and of the underlying tensions in the policy debates about the design of the formulas from enactment of the original ESEA through enactment of the ESSA.
- Published
- 2018
44. Training Decision Trees as Replacement for Convolution Layers
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Fuhl, Wolfgang, Kasneci, Gjergji, Rosenstiel, Wolfgang, and Kasneci, Enkelejda
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Computer Science - Machine Learning ,Statistics - Machine Learning - Abstract
We present an alternative layer to convolution layers in convolutional neural networks (CNNs). Our approach reduces the complexity of convolutions by replacing it with binary decisions. Those binary decisions are used as indexes to conditional distributions where each weight represents a leaf in a decision tree. This means that only the indices to the weights need to be determined once, thus reducing the complexity of convolutions by the depth of the output tensor. Index computation is performed by simple binary decisions that require fewer cycles compared to conventionally used multiplications. In addition, we show how convolutions can be replaced by binary decisions. These binary decisions form indices in the conditional distributions and we show how they are used to replace 2D weight matrices as well as 3D weight tensors. These new layers can be trained like convolution layers in CNNs based on the backpropagation algorithm, for which we provide a formalization. Our results on multiple publicly available data sets show that our approach performs similar to conventional neuronal networks. Beyond the formalized reduction of complexity and the improved qualitative performance, we show the runtime improvement empirically compared to convolution layers., Comment: Will be published in the proceedings oft he AAAI 2020 conference
- Published
- 2019
45. DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
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Antonella Fazio, Dora Bordoni, Jan W. P. Kuiper, Saskia Weber-Stiehl, Stephanie T. Stengel, Philipp Arnold, David Ellinghaus, Go Ito, Florian Tran, Berith Messner, Anna Henning, Joana P. Bernardes, Robert Häsler, Anne Luzius, Simon Imm, Finn Hinrichsen, Andre Franke, Samuel Huber, Susanna Nikolaus, Konrad Aden, Stefan Schreiber, Felix Sommer, Gioacchino Natoli, Neha Mishra, and Philip Rosenstiel
- Subjects
Science - Abstract
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
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- 2022
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46. Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease
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Neha Mishra, Konrad Aden, Johanna I. Blase, Nathan Baran, Dora Bordoni, Florian Tran, Claudio Conrad, Diana Avalos, Charlot Jaeckel, Michael Scherer, Signe B. Sørensen, Silja H. Overgaard, Berenice Schulte, Susanna Nikolaus, Guillaume Rey, Gilles Gasparoni, Paul A. Lyons, Joachim L. Schultze, Jörn Walter, Vibeke Andersen, SYSCID Consortium, Emmanouil T. Dermitzakis, Stefan Schreiber, and Philip Rosenstiel
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Intestinal inflammation ,Personalized medicine ,Biologics ,Therapy response ,Biomarker ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background and aims Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. Methods We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. Results We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. Conclusions Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.
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- 2022
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47. Measurement of enantiomer percentages for five monoterpenes from six conifer species by cartridge-tube-based passive sampling adsorption–thermal desorption (ps-ATD)
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Y. Wang, W. Luo, T. N. Rosenstiel, and J. F. Pankow
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Environmental engineering ,TA170-171 ,Earthwork. Foundations ,TA715-787 - Abstract
Many monoterpenes have at least two different stereochemical forms, and many biosynthetic pathways are known to favor one product over the other(s). A rapid method was developed and used in the determination of the (-/+)-enantiomeric distributions for α-pinene, β-pinene, camphene, limonene, and β-phellandrene as emitted by plant material from six conifer species. The six species included the two pine species Pseudotsuga menziesii and Pinus ponderosa, as well as the four cypress species Chamaecyparis lawsoniana, Thuja plilcata, Juniperus chinensis, and Thuja occidentalis. The method involved passive sampling adsorption–thermal desorption (ps-ATD). During sampling, the cartridge tube was placed in a 60 mL glass vial with plant material for 1 h. Sample analytes were thermally transferred to a chiral gas chromatography (GC) column. Detection was by mass spectrometry (MS). The six species exhibited different emission patterns for the five monoterpenes in the -/+ totals, although within a given species the distributions among the five monoterpenes were similar across multiple plants. β-pinene dominated in P. menziesii and P. ponderosa, and α-pinene dominated in T. plicata and T. occidentalis. The chiral separations revealed differences in the -/+ enantiomeric distributions among the species. The (−)-enantiomers of α-pinene and β-pinene dominated strongly in P. menziesii and P. ponderosa; the (−)-enantiomer of β-phellandrene dominated in C. lawsoniana. The dependence of the method precision on percent enantiomer abundance is discussed.
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- 2022
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48. Role of glucocorticoid metabolism in childhood obesity-associated hypertension
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Martijn J J Finken, Aleid J G Wirix, Ines A von Rosenstiel-Jadoul, Bibian van der Voorn, Mai J M Chinapaw, Michaela F Hartmann, Joana E Kist-van Holthe, Stefan A Wudy, and Joost Rotteveel
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glucocorticoids ,obesity ,hypertension ,children ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Objective: Childhood obesity is associated with alterations in hypothalamus–pituitary– adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight. Methods: Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n = 38), (2) overweight/non-hypertensive children (n = 83), and (3) non-overweight/non-hypertensive children (n = 56). Results: The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631–1352) vs 839 (609–1123) vs 608 (439–834) μg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11β-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3). Discussion: The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11β-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.
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- 2022
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49. NLRC5 affects diet-induced adiposity in female mice and co-regulates peroxisome proliferator-activated receptor PPARγ target genes
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Sarah Bauer, Vanessa Aeissen, Alena M. Bubeck, Ioannis Kienes, Kornelia Ellwanger, Mona Scheurenbrand, Fjolla Rexhepi, Sheela Ramanathan, Philip Rosenstiel, W. Florian Fricke, and Thomas A. Kufer
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Diet ,Immunology ,Molecular mechanism of gene regulation ,Science - Abstract
Summary: Nucleotide-binding and oligomerization domain containing 5 (NLRC5) is the key transcriptional regulator of major histocompatibility (MHC) class I genes. Recent observations suggest a role for NLRC5 in metabolic traits and in transcriptional regulation beyond MHC class I genes. To understand the function of NLRC5 in metabolic disease, we subjected Nlrc5−/− mice to high-fat diet (HFD) feeding. Female Nlrc5−/− mice presented with higher weight gain and more adipose tissue (AT) compared to wild-type (WT) animals. Mechanistically, we demonstrate that NLRC5 enhanced the expression of peroxisome proliferator-activated receptor (PPAR) γ target genes in human cells. We identify Sin3A and negative elongation factor (NELF) B as two novel NLRC5 interaction partners and show that Sin3A partly modulates the synergistic transcriptional effect of NLRC5 on PPARγ. Collectively, we show that NLRC5 contributes to weight gain in mice, which involves transcriptional enhancement of PPARγ targets by NLRC5 that is co-regulated by Sin3A.
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- 2023
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50. Epithelial Dual Oxidase 2 Shapes the Mucosal Microbiome and Contributes to Inflammatory Susceptibility
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Juan Camilo Castrillón-Betancur, Víctor Alonso López-Agudelo, Nina Sommer, Sven Cleeves, Joana Pimenta Bernardes, Saskia Weber-Stiehl, Philip Rosenstiel, and Felix Sommer
- Subjects
inflammation ,DUOX2 ,ROS ,microbiome ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Reactive oxygen species (ROS) are highly reactive molecules formed from diatomic oxygen. They act as cellular signals, exert antibiotic activity towards invading microorganisms, but can also damage host cells. Dual oxidase 2 (DUOX2) is the main ROS-producing enzyme in the intestine, regulated by cues of the commensal microbiota and functions in pathogen defense. DUOX2 plays multiple roles in different organs and cell types, complicating the functional analysis using systemic deletion models. Here, we interrogate the precise role of epithelial DUOX2 for intestinal homeostasis and host-microbiome interactions. Conditional Duox2∆IEC mice lacking DUOX2, specifically in intestinal epithelial cells, were generated, and their intestinal mucosal immune phenotype and microbiome were analyzed. Inflammatory susceptibility was evaluated by challenging Duox2∆IEC mice in the dextran sodium sulfate (DSS) colitis model. DUOX2-microbiome interactions in humans were investigated by paired analyses of mucosal DUOX2 expression and fecal microbiome data in patients with intestinal inflammation. Under unchallenged conditions, we did not observe any obvious phenotype of Duox2∆IEC mice, although intestinal epithelial ROS production was drastically decreased, and the mucosal microbiome composition was altered. When challenged with DSS, Duox2∆IEC mice were protected from colitis, possibly by inhibiting ROS-mediated damage and fostering epithelial regenerative responses. Finally, in patients with intestinal inflammation, DUOX2 expression was increased in inflamed tissue, and high DUOX2 levels were linked to a dysbiotic microbiome. Our findings demonstrate that bidirectional DUOX2-microbiome interactions contribute to mucosal homeostasis, and their dysregulation may drive disease development, thus highlighting this axis as a therapeutic target to treat intestinal inflammation.
- Published
- 2023
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