101 results on '"Interdisciplinary Centre for Clinical Research (IZKF)"'
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2. S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis
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Estelle Remion, Thomas Vogl, Coralie Martin, Indulekha Karunakaran, Stefan J. Frohberger, Jayagopi Surendar, Marc P. Hübner, Alexandra Ehrens, Wiebke Stamminger, Frédéric Fercoq, Anna-Lena Neumann, Achim Hoerauf, University Hospital Bonn, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Centre for Clinical Research (IZKF), Institute of Immunology-Westfälische Wilhelms-Universität Münster (WWU), and Université de Bordeaux (UB)
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0301 basic medicine ,Life Cycles ,Chemokine ,Neutrophils ,RC955-962 ,White Blood Cells ,Mice ,Larvae ,0302 clinical medicine ,Animal Cells ,Arctic medicine. Tropical medicine ,Medicine and Health Sciences ,Intradermal injection ,Nematode Infections ,Immune Response ,Lung ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,biology ,T Cells ,Elastase ,Filariasis ,3. Good health ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Infectious Diseases ,Lymphatic system ,medicine.anatomical_structure ,Larva ,Cellular Types ,medicine.symptom ,Public aspects of medicine ,RA1-1270 ,Research Article ,Immune Cells ,Immunology ,030231 tropical medicine ,Cytotoxic T cells ,Inflammation ,Granulocyte ,S100A9 ,Microbiology ,03 medical and health sciences ,Immune system ,Parasitic Diseases ,medicine ,Animals ,Calgranulin B ,Calgranulin A ,Filarioidea ,Blood Cells ,Macrophages ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Cell Biology ,Eosinophils ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,Developmental Biology - Abstract
Neutrophils are essentially involved in protective immune responses against invading infective larvae of filarial nematodes. The present study investigated the impact of S100A8/S100A9 on protective immune responses against the rodent filarial nematode Litomosoides sigmodontis. S100A9 forms with S100A8 the heterodimer calprotectin, which is expressed by circulating neutrophils and monocytes and mitigates or amplifies tissue damage as well as inflammation depending on the immune environment. Mice deficient for S100A8/A9 had a significantly reduced worm burden in comparison to wildtype (WT) animals 12 days after infection (dpi) with infective L3 larvae, either by the vector or subcutaneous inoculation, the latter suggesting that circumventing natural immune responses within the epidermis and dermis do not alter the phenotype. Nevertheless, upon intradermal injection of L3 larvae, increased total numbers of neutrophils, eosinophils and macrophages were observed within the skin of S100A8/A9-/- mice. Furthermore, upon infection the bronchoalveolar and thoracic cavity lavage of S100A8/A9-/- mice showed increased concentrations of CXCL-1, CXCL-2, CXCL-5, as well as elastase in comparison to the WT controls. Neutrophils from S100A8/A9-/- mice exhibited an increased in vitro activation and reduced L3 larval motility more effectively in vitro compared to WT neutrophils. The depletion of neutrophils from S100A8/A9-/- mice prior to L. sigmodontis infection until 5dpi abrogated the protective effect and led to an increased worm burden, indicating that neutrophils mediate enhanced protective immune responses against invading L3 larvae in S100A8/A9-/- mice. Interestingly, complete circumvention of protective immune responses in the skin and the lymphatics by intravenous injection of L3 larvae reversed the phenotype and resulted in an increased worm burden in S100A8/A9-/- mice. In summary, our results reveal that lack of S100A8/S100A9 triggers L3-induced inflammatory responses, increasing chemokine levels, granulocyte recruitment as well as neutrophil activation and therefore impairs larval migration and susceptibility for filarial infection., Author summary Human pathogenic filariae are responsible for several devastating diseases such as lymphatic filariasis and onchocerciasis. Neutrophils are essentially involved in protective immune responses against invading infective L3 larvae of filarial nematodes. The S100A8/S100A9 heterodimer, also known as calprotectin, is abundantly expressed by neutrophils and markedly increased during infection, tissue damage, neutrophil extracellular trap formation (NETosis) and cellular necrosis. However, calprotectin is also known to have an anti-inflammatory or protective role during infection and inflammation and there is an ongoing controversy on whether S100A8/A9 is pathogenic or rather protective. The present study investigated the impact of calprotectin on protective immune responses against the rodent filarial nematode Litomosoides sigmodontis. Investigations in L. sigmodontis-infected mice deficient in S100A8/S100A9 and wild-type controls demonstrate that the lack of S100A8/S100A9 promotes protective responses that trigger L3-induced inflammation by increasing chemokine production, granulocyte recruitment and neutrophil activation, triggering transient inflammatory responses and therefore impairing larval migration and worm recovery.
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- 2020
3. Ubiquitination of Listeria virulence factor InlC contributes to the host response to infection
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Damien Balestrino, Francis Impens, Thomas Vogl, Yves Jacob, Orhan Rasid, Véronique Villiers, Stevenn Volant, Pascale Cossart, Edith Gouin, Olivier Dussurget, Marie-Anne Nahori, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Interdisciplinary Centre for Clinical Research (IZKF), Institute of Immunology-Westfälische Wilhelms-Universität Münster (WWU), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Our work has been supported by the Institut Pasteur, Inserm, INRA, Université Paris-Diderot, the Laboratory of Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID), ERA-NET Infect-ERA ProAntiLis (ANR-13-IFEC-0004-02), the Fondation Balzan, the Fondation Le Roch, and the European Research Council (advanced grant awards 233348 and 670823 to Pascale Cossart)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-13-IFEC-0004,PROANTILIS,Subversive pro- and anti-inflammation trade-offs promote infection by Listeria monocytogenes(2013), European Project: 233348,EC:FP7:ERC,ERC-2008-AdG,MODELIST(2009), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institute of Immunology-Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Nahori, marie-anne, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, ERA-NET Infect-ERA - Subversive pro- and anti-inflammation trade-offs promote infection by Listeria monocytogenes - - PROANTILIS2013 - ANR-13-IFEC-0004 - IFEC - VALID, Understanding the infection by the bacterium Listeria monocytogenes as a way to address key issues in biology - MODELIST - - EC:FP7:ERC2009-06-01 - 2015-05-31 - 233348 - VALID, and Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID
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EXPRESSION ,listeria monocytogenes ,[SDV]Life Sciences [q-bio] ,Virulence ,IκB kinase ,Listeria infection ,medicine.disease_cause ,ubiquitination ,Microbiology ,Virulence factor ,03 medical and health sciences ,Immune system ,Listeria monocytogenes ,MRP14 ,Virology ,LIGASE COMPLEX ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Medicine and Health Sciences ,L-MONOCYTOGENES ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Internalin ,030304 developmental biology ,REQUIRES ,0303 health sciences ,biology ,SURFACE PROTEIN ,030306 microbiology ,pathogenesis ,INTERNALIN ,BOX ,alarmin ,medicine.disease ,biology.organism_classification ,GENE ,QR1-502 ,3. Good health ,[SDV] Life Sciences [q-bio] ,inflammation ,ENTRY ,Listeria - Abstract
International audience; Listeria monocytogenes is a pathogenic bacterium causing potentially fatal foodborne infections in humans and animals. While the mechanisms used by Listeria to manipulate its host have been thoroughly characterized, how the host controls bacterial virulence factors remains to be extensively deciphered. Here, we found that the secreted Listeria virulence protein InlC is monoubiquitinated by the host cell machinery on K224, restricting infection. We show that the ubiquitinated form of InlC interacts with the intracellular alarmin S100A9, resulting in its stabilization and in increased reactive oxygen species production by neutrophils in infected mice. Collectively, our results suggest that posttranslational modification of InlC exacerbates the host response upon Listeria infection. IMPORTANCE The pathogenic potential of Listeria monocytogenes relies on the production of an arsenal of virulence determinants that have been extensively characterized , including surface and secreted proteins of the internalin family. We have previously shown that the Listeria secreted internalin InlC interacts with IB kinase ␣ to interfere with the host immune response (E. Gouin, M. Adib-Conquy, D. Balestrino, M.-A. Nahori, et al., Proc Natl Acad Sci USA, 107:17333-17338, 2010, https://doi.org/10 .1073/pnas.1007765107). In the present work, we report that InlC is monoubiquitinated on K 224 upon infection of cells and provide evidence that ubiquitinated InlC interacts with and stabilizes the alarmin S100A9, which is a critical regulator of the immune response and inflammatory processes. Additionally, we show that ubiquitination of InlC causes an increase in reactive oxygen species production by neutrophils in mice and restricts Listeria infection. These findings are the first to identify a posttranscriptional modification of an internalin contributing to host defense.
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- 2019
4. Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels
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M.C. ter Huurne, Christian Jorgensen, Johannes Roth, P.L.E.M. van Lent, Thomas Vogl, W.B. van den Berg, R. Schelbergen, Danièle Noël, S. van Dalen, Arjen B. Blom, F.A.J. van de Loo, Radboud University Medical Center [Nijmegen], Radboud university [Nijmegen], University of Münster, Interdisciplinary Centre for Clinical Research (IZKF), Westfälische Wilhelms-Universität Münster (WWU)-Institute of Immunology, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), 1. The authors would like to thank Birgitte Walgreen, Monique Helsen and Elly Vitters (Dept. Experimental Rheumatology, Radboud umc Nijmegen) and Niels Cremers (Dept. of orthodontics and craniofacial biology, Radboud umc, Nijmegen) for their excellent technical assistance.2. This study was financially supported by EU Framework Programme 7 ADIPOA ( Health-2009-1.4-3-241719 ) and by the Dutch Arthritis foundation (Reumafonds) no. 12-2-405.3. The funding source indicated above had no role in study design, in collection, analysis or interpretation of data, nor in writing the manuscript or decision to submit the manuscript., European Project: 241719,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,ADIPOA(2010), Hennaut, Odile, ADIPOSE DERIVED STROMAL CELLS FOR OSTEOARTHRITIS - ADIPOA - - EC:FP7:HEALTH2010-01-01 - 2014-06-30 - 241719 - VALID, Radboud University [Nijmegen], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Immunology-Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institute of Immunology-Westfälische Wilhelms-Universität Münster (WWU)
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Cartilage, Articular ,Pathology ,Synovitis ,[SDV]Life Sciences [q-bio] ,Interleukin-1beta ,Adipose tissue ,Osteoarthritis ,Menisci, Tibial ,Mice ,0302 clinical medicine ,Orthopedics and Sports Medicine ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Stem Cells ,Synovial Membrane ,Osteoarthritis, Knee ,Pathophysiology ,Animal models ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Adipose Tissue ,medicine.symptom ,Stem cell ,Medial meniscus ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,S100 ,medicine.medical_specialty ,Biomedical Engineering ,Inflammation ,Experimental OA ,S100A8 ,03 medical and health sciences ,Rheumatology ,medicine ,Animals ,Calgranulin B ,Calgranulin A ,Collagenases ,RNA, Messenger ,Molecular Biology ,030304 developmental biology ,030203 arthritis & rheumatology ,business.industry ,medicine.disease ,Arthritis, Experimental ,Adipose stem cells ,Disease Models, Animal ,business ,Stem Cell Transplantation - Abstract
Contains fulltext : 137118.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Synovitis is evident in a substantial subpopulation of patients with osteoarthritis (OA) and is associated with development of pathophysiology. Recently we have shown that adipose-derived stem cells (ASC) inhibit joint destruction in collagenase-induced experimental OA (CIOA). In the current study we explored the role of synovitis and alarmins S100A8/A9 in the immunomodulatory capacity of ASCs in experimental OA. METHOD: CIOA, characterized by synovitis, and surgical DMM (destabilization of medial meniscus) OA were treated locally with ASCs. Synovial activation, cartilage damage and osteophyte size were measured on histological sections. Cytokines in synovial washouts and serum were determined using Luminex or enzyme-linked immunosorbent assay (S100A8/A9), mRNA levels with reverse-transcriptase (RT)-qPCR. RESULTS: Local administration of ASCs at various time-points (days 7 or 14) after DMM induction had no effect on OA pathology. At day 7 of CIOA, already 6 h after ASC injection mRNA expression of pro-inflammatory mediators S100A8/A9, interleukin-1beta (IL-1beta) and KC was down-regulated in the synovium. IL-1beta protein, although low, was down-regulated by ASC-treatment of CIOA. S100A8/A9 protein levels were very high at 6 and 48 h and were decreased by ASC-treatment. The protective action of ASC treatment in CIOA was only found when high synovial inflammation was present at the time of deposition which was reflected by high serum S100A8/A9 levels. Finally, successful treatment resulted in significantly lower levels of serum S100A8/A9. CONCLUSION: Our study indicates that synovial activation rapidly drives anti-inflammatory and protective effects of intra-articularly deposited ASCs in experimental OA which is reflected by decreased S100A8/A9 levels. 9 p.
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- 2014
5. Responsiveness in Rheumatoid Arthritis. A Report from the OMERACT 11 Ultrasound Workshop
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Ingrid Möller, Sarah Ohrndorf, Marina Backhaus, Philippe Aegerter, Sibel Zehra Aydin, Wolfgang A. Schmidt, Sandrine Jousse-Joulin, Frédérique Gandjbakhch, Peter Mandl, Andrea Delle Sedie, Emilio Filippucci, Annamaria Iagnocco, Damien Loeuille, Stephanie Finzel, Maria Antonietta D'Agostino, George A W Bruyn, Johannes Roth, Silvia Magni-Manzoni, Philip G. Conaghan, C. Pineda, Paz Collado, Lene Terslev, Richard J. Wakefield, Hilde Berner-Hammer, Esperanza Naredo, Peter V. Balint, Gurjit S. Kaeley, Niolay Tzaribachev, Academic Unit of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, Chapel Allerton Hospital, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Instituto Poal de Reumatologia, Barcelona, Laboratoire Universitaire Santé Environnement Vieillissement, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Santé Publique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], University of Vienna [Vienna], Interdisciplinary Centre for Clinical Research (IZKF), Institute of Immunology-Westfälische Wilhelms-Universität Münster (WWU), and Service de Rhumatologie
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musculoskeletal diseases ,rheumatoid arthritis ,medicine.medical_specialty ,Settore MED/16 - REUMATOLOGIA ,responsiveness ,rheumatoid ,Immunology ,Juvenile ,Arthritis ,Severity of Illness Index ,Arthritis, Rheumatoid ,Rheumatology ,omeract ,Synovitis ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Ultrasonography ,Clinical Trials as Topic ,Tenosynovitis ,business.industry ,ultrasound ,Ultrasound ,Doppler ,Reproducibility of Results ,Ultrasonography, Doppler ,medicine.disease ,Arthritis, Juvenile ,3. Good health ,Clinical trial ,Treatment Outcome ,arthritis ,Rheumatoid arthritis ,Cohort ,Physical therapy ,Joints ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Objective.To summarize the work performed by the Outcome Measures in Rheumatology (OMERACT) Ultrasound (US) Task Force on the validity of different US measures in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) presented during the OMERACT 11 Workshop.Methods.The Task Force is an international group aiming to iteratively improve the role of US in arthritis clinical trials. Recently a major focus of the group has been the assessment of responsiveness of a person-level US synovitis score in RA: the US Global Synovitis Score (US-GLOSS) combines synovial hypertrophy and power Doppler signal in a composite score detected at joint level. Work has also commenced examining assessment of tenosynovitis in RA and the role of US in JIA.Results.The US-GLOSS was tested in a large RA cohort treated with biologic therapy. It showed early signs of improvement in synovitis starting at Day 7 and increasing to Month 6, and demonstrated sensitivity to change of the proposed grading. Subsequent voting questions concerning the application of the US-GLOSS were endorsed by > 80% of OMERACT delegates. A standardized US scoring system for detecting and grading severity of RA tenosynovitis and tendon damage has been developed, and acceptable reliability data were presented from a series of exercises. A preliminary consensus definition of US synovitis in pediatric arthritis has been developed and requires further testing.Conclusion.At OMERACT 11, consensus was achieved on the application of the US-GLOSS for evaluating synovitis in RA; and work continues on development of RA tenosynovitis scales as well as in JIA synovitis.
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- 2014
6. Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis
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Helmut Wittkowski, Johannes Roth, Vanita Shah, Lucy R. Wedderburn, Thomas Vogl, Kiran Nistala, Kamel Mamchaoui, Petra Krol, Paul A. Brogan, Hemlata Varsani, Rheumatology Unit, UCL Institute of Child Health, Department of General Pediatrics, Münster University Children Hospital, Interdisciplinary Centre for Clinical Research (IZKF), Westfälische Wilhelms-Universität Münster (WWU)-Institute of Immunology, Charles University [Prague] (CU), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), University Children's Hospital Muenster, Institute of Immunology-Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Department of Pediatrics and Adolescent Medicine, Charles University [Prague] (CU)-First Faculty of Medicine-General University Hospital in Prague, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The JDM Cohort Study and this work have been supported by generous grants from the Wellcome Trust UK (085860), Action Medical Research UK, (SP4252), and The Henry Smith Charity. LW is supported in part by the Great Ormond Street Hospital Children's Charity. KN is a Wellcome Trust Intermediate Clinical Fellow (097259). TV and JR were supported by grants from the Interdisciplinary Centre for Clinical Research at the University of Muenster (Vo2/014/09 to T.V. as well as grant Ro2/004/10 to J.R) and the Deutsche Forschungsgemeinschaft (DFG project RO 1190/9-1)., BMC, Ed., and HAL UPMC, Gestionnaire
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Male ,Myeloid ,Biopsy ,Gene Expression ,0302 clinical medicine ,Interferon ,Immunology and Allergy ,Myocyte ,Child ,Chemokine CCL2 ,Juvenile dermatomyositis ,0303 health sciences ,[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Muscles ,Endoplasmic Reticulum Stress ,Immunohistochemistry ,3. Good health ,medicine.anatomical_structure ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,Child, Preschool ,Cytokines ,Female ,Inflammation Mediators ,Research Article ,medicine.drug ,Muscle tissue ,Adolescent ,Myoblasts, Skeletal ,Immunology ,Antigens, Differentiation, Myelomonocytic ,Dermatomyositis ,Cell Line ,03 medical and health sciences ,[SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics ,Rheumatology ,Downregulation and upregulation ,Antigens, CD ,medicine ,Calgranulin B ,Humans ,Calgranulin A ,Muscle Strength ,Interleukin 6 ,030304 developmental biology ,030203 arthritis & rheumatology ,[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics ,Interleukin-6 ,business.industry ,Macrophages ,medicine.disease ,Microscopy, Fluorescence ,biology.protein ,business - Abstract
International audience; IntroductionThe aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood. In particular the contribution of monocytes or macrophages, which are frequently observed to be an infiltrate within muscle tissue very early in the disease process, is unknown. We hypothesised that these cells secrete the pro-inflammatory myeloid related protein (MRP) 8/14 which may then contribute to muscle pathology in JDM.MethodsIn this study of 56 JDM patients, serum MRP8/14 levels were compared with clinical measures of disease activity. Muscle biopsies taken early in disease were assessed by immunohistochemistry to determine the frequency and identity of MRP-expressing cells. The effects of MRP stimulation and endoplasmic reticulum (ER) stress on muscle were tested in vitro. Serum or supernatant levels of cytokines were analyzed by multiplex immunoassay.ResultsSerum MRP8/14 correlated with physician's global assessment of disease activity in JDM (R = 0.65, p = 0.0003) and muscle strength/endurance, childhood myositis assessment score (CMAS, R = −0.55, p = 0.004). MRP8/14 was widely expressed by CD68+ macrophages in JDM muscle tissue. When cultured with human myoblasts, MRP8 led to the secretion of MCP-1 and IL-6, which was enhanced by ER stress. Both inflammatory mediators were detected in significantly higher levels in the serum of JDM patients compared to healthy controls.ConclusionsThis study is the first to identify serum MRP8/14 as a potential biomarker for disease activity in JDM. We propose that tissue infiltrating macrophages secreting MRP8/14 may contribute to myositis, by driving the local production of cytokines directly from muscle.
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- 2013
7. PLoS One
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Madeleine Schönherr, Manfred Blessing, Susanna Marg, Janina Bär, Johannes Hirrlinger, Amrit Mann, Markus Moser, Klemens Rottner, Claudia Tanja Mierke, Wolfgang H. Ziegler, Mirko Himmel, Ulrike Winkler, Marcello Sestu, and Faculty of Medicine, Interdisciplinary Centre for Clinical Research (IZKF) Leipzig, University of Leipzig, Leipzig, Germany.
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animal structures ,Science ,Immunoblotting ,macromolecular substances ,Biology ,Mice ,Cell Biology/Cytoskeleton ,Animals ,Protein Isoforms ,Cell adhesion ,Cytoskeleton ,Tissue homeostasis ,Actin ,Cells, Cultured ,Multidisciplinary ,Developmental Biology/Morphogenesis and Cell Biology ,Reverse Transcriptase Polymerase Chain Reaction ,Signal transducing adaptor protein ,Fluorescence recovery after photobleaching ,Vinculin ,Fibroblasts ,musculoskeletal system ,Embryo, Mammalian ,Molecular biology ,Actins ,Cell biology ,Cell Biology/Cell Adhesion ,biology.protein ,Medicine ,Ectopic expression ,Research Article ,Protein Binding - Abstract
BackgroundThe cytoskeletal adaptor protein vinculin plays a fundamental role in cell contact regulation and affects central aspects of cell motility, which are essential to both embryonal development and tissue homeostasis. Functional regulation of this evolutionarily conserved and ubiquitously expressed protein is dominated by a high-affinity, autoinhibitory head-to-tail interaction that spatially restricts ligand interactions to cell adhesion sites and, furthermore, limits the residency time of vinculin at these sites. To date, no mutants of the vinculin protein have been characterized in animal models.Methodology/principal findingsHere, we investigate vinculin-DeltaEx20, a splice variant of the protein lacking the 68 amino acids encoded by exon 20 of the vinculin gene VCL. Vinculin-DeltaEx20 was found to be expressed alongside with wild type protein in a knock-in mouse model with a deletion of introns 20 and 21 (VCL-DeltaIn20/21 allele) and shows defective head-to-tail interaction. Homozygous VCL-DeltaIn20/21 embryos die around embryonal day E12.5 showing cranial neural tube defects and exencephaly. In mouse embryonic fibroblasts and upon ectopic expression, vinculin-DeltaEx20 reveals characteristics of constitutive head binding activity. Interestingly, the impact of vinculin-DeltaEx20 on cell contact induction and stabilization, a hallmark of the vinculin head domain, is only moderate, thus allowing invasion and motility of cells in three-dimensional collagen matrices. Lacking both F-actin interaction sites of the tail, the vinculin-DeltaEx20 variant unveils vinculin's dynamic binding to cell adhesions independent of a cytoskeletal association, and thus differs from head-to-tail binding deficient mutants such as vinculin-T12, in which activated F-actin binding locks the protein variant to cell contact sites.Conclusions/significanceVinculin-DeltaEx20 is an active variant supporting adhesion site stabilization without an enhanced mechanical coupling. Its presence in a transgenic animal reveals the potential of splice variants in the vinculin gene to alter vinculin function in vivo. Correct control of vinculin is necessary for embryonic development.
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- 2010
8. Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions
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Himmel, Mirko, Ritter, Anett, Rothemund, Sven, Pauling, Björg V, Rottner, Klemens, Gingras, Alexandre R, Ziegler, Wolfgang H, and Interdisciplinary Centre for Clinical Research (IZKF) Leipzig, Faculty of Medicine, University of Leipzig, D-04103 Leipzig, Germany.
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Talin ,Focal Adhesions ,Integrins ,animal structures ,Binding Sites ,macromolecular substances ,Models, Biological ,Actins ,Protein Structure, Secondary ,Cell Line ,Protein Structure, Tertiary ,Mice ,Cell Adhesion ,Animals ,Cytoskeleton - Abstract
In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.
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- 2009
9. Targeted lipid nanoparticles to prevent trans-placental passage in the ex vivo human placental cotyledon perfusion model.
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van Kammen C, van Hove H, Kapsokalyvas D, Greupink R, Schiffelers R, Lely T, and Terstappen F
- Abstract
Medication use during pregnancy poses risks to both the mother and the fetus. These risks include an elevated potential for fetotoxicity due to placental drug transport. Nanomedicines offer a promising solution by potentially preventing trans-placental passage. Targeted nanomedicines could enhance safety and efficacy in treating maternal or placental pathophysiology. Our study investigates placental transfer kinetics of targeted lipid nanoparticles (LNPs) in an ex vivo human placenta cotyledon perfusion model. We collected human placentas for dual-side ex vivo placental perfusions. Targeted LNPs with a fluorescence tag were introduced into the maternal circuit of each placenta. To establish if there was trans-placental passage of LNPs to the fetal circuit, we collected samples from maternal and fetal circuits throughout the six hours of the perfusion. We determined the fluorescence signal using a multi-mode microplate reader and Multiphoton microscopy to localize the LNPs in the placenta tissue. Data from perfused placenta tissue showed no significant transfer of the fluorescently labeled LNPs across the placental barrier to the fetal circuit. Localization of targeted LNPs in tissue samples is mainly observed in the maternal blood space of the placenta. Our results suggest that targeted LNPs present a promising strategic approach to prevent trans-placental passage to the fetus. Our future perspectives involve investigating the efficacy of targeted LNPs as well as loading targeted LNPs with nucleic acid-based therapeutics to investigate their therapeutic potential., (© 2024. The Author(s).)
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- 2024
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10. Cellular metabolism changes in atherosclerosis and the impact of comorbidities.
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Dai Y, Junho CVC, Schieren L, Wollenhaupt J, Sluimer JC, van der Vorst EPC, and Noels H
- Abstract
Cell activation and nutrient dysregulation are common consequences of atherosclerosis and its preceding risk factors, such as hypertension, dyslipidemia, and diabetes. These diseases may also impact cellular metabolism and consequently cell function, and the other way around, altered cellular metabolism can impact disease development and progression through altered cell function. Understanding the contribution of altered cellular metabolism to atherosclerosis and how cellular metabolism may be altered by co-morbidities and atherosclerosis risk factors could support the development of novel strategies to lower the risk of CVD. Therefore, we briefly review disease pathogenesis and the principles of cell metabolic pathways, before detailing changes in cellular metabolism in the context of atherosclerosis and comorbidities. In the hypoxic, inflammatory and hyperlipidemic milieu of the atherosclerotic plaque riddled with oxidative stress, metabolism shifts to increase anaerobic glycolysis, the pentose-phosphate pathway and amino acid use. We elaborate on metabolic changes for macrophages, neutrophils, vascular endothelial cells, vascular smooth muscle cells and lymphocytes in the context of atherosclerosis and its co-morbidities hypertension, dyslipidemia, and diabetes. Since causal relationships of specific key genes in a metabolic pathway can be cell type-specific and comorbidity-dependent, the impact of cell-specific metabolic changes must be thoroughly explored in vivo , with a focus on also systemic effects. When cell-specific treatments become feasible, this information will be crucial for determining the best metabolic intervention to improve atherosclerosis and its interplay with co-morbidities., Competing Interests: Author HN is founding shareholder of AMICARE Development GmbH. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dai, Junho, Schieren, Wollenhaupt, Sluimer, van der Vorst and Noels.)
- Published
- 2024
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11. Specific Compounds Derived from Traditional Chinese Medicine Ameliorate Lipid-Induced Contractile Dysfunction in Cardiomyocytes.
- Author
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Wang F, Neumann D, Kapsokalyvas D, Hoes MF, Schianchi F, Glatz JFC, Nabben M, and Luiken JJFP
- Subjects
- Animals, Rats, Insulin Resistance, Myocardial Contraction drug effects, Glucose metabolism, Drugs, Chinese Herbal pharmacology, Lipid Metabolism drug effects, Oxidative Stress drug effects, Glucose Transporter Type 4 metabolism, Glucose Transporter Type 4 genetics, Mice, Cell Line, CD36 Antigens metabolism, CD36 Antigens genetics, Proto-Oncogene Proteins c-akt metabolism, Male, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Medicine, Chinese Traditional methods
- Abstract
Chronic lipid overconsumption, associated with the Western diet, causes excessive cardiac lipid accumulation, insulin resistance, and contractile dysfunction, altogether termed lipotoxic cardiomyopathy (LCM). Existing treatments for LCM are limited. Traditional Chinese Medicine (TCM) has been shown as beneficial in diabetes and its complications. The following compounds-Resveratrol, Quercetin, Berberine, Baicalein, and Isorhamnetin-derived from TCM and often used to treat type 2 diabetes. However, virtually nothing is known about their effects in the lipid-overexposed heart. Lipid-induced insulin resistance was generated in HL-1 cardiomyocytes and adult rat cardiomyocytes by 24 h exposure to high palmitate. Upon simultaneous treatment with each of the TCM compounds, we measured myocellular lipid accumulation, insulin-stimulated fatty acid and glucose uptake, phosphorylation levels of AKT and ERK1/2, plasma membrane appearance of GLUT4 and CD36, and expression of oxidative stress-/inflammation-related genes and contractility. In lipid-overloaded cardiomyocytes, all the selected TCM compounds prevented lipid accumulation. These compounds also preserved insulin-stimulated CD36 and GLUT4 translocation and insulin-stimulated glucose uptake in an Akt-independent manner. Moreover, all the TCM compounds prevented and restored lipid-induced contractile dysfunction. Finally, some (not all) of the TCM compounds inhibited oxidative stress-related SIRT3 expression, and others reduced inflammatory TNFα expression. Their ability to restore CD36 trafficking makes all these TCM compounds attractive natural supplements for LCM treatment.
- Published
- 2024
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12. TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2.
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Ahmed N, Preisinger C, Wilhelm T, and Huber M
- Subjects
- Humans, Cell Line, Tumor, Membrane Proteins metabolism, Valosin Containing Protein metabolism, Valosin Containing Protein genetics, Endoplasmic Reticulum-Associated Degradation genetics, Endoribonucleases metabolism, Leukemia, Mast-Cell metabolism, Leukemia, Mast-Cell pathology, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics
- Abstract
The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α-MTDH-VCP complex(es) might enable the treatment of MCL.
- Published
- 2024
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13. Serum/Plasma Proteome in Non-Malignant Liver Disease.
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Fu L, Guldiken N, Remih K, Karl AS, Preisinger C, and Strnad P
- Subjects
- Humans, Proteomics methods, Biomarkers metabolism, Proteome metabolism, Liver Diseases
- Abstract
The liver is the central metabolic organ and produces 85-90% of the proteins found in plasma. Accordingly, the plasma proteome is an attractive source of liver disease biomarkers that reflects the different cell types present in this organ, as well as the processes such as responses to acute and chronic injury or the formation of an extracellular matrix. In the first part, we summarize the biomarkers routinely used in clinical evaluations and their biological relevance in the different stages of non-malignant liver disease. Later, we describe the current proteomic approaches, including mass spectrometry and affinity-based techniques, that allow a more comprehensive assessment of the liver function but also require complex data processing. The many approaches of analysis and interpretation and their potential caveats are delineated. While these advances hold the promise to transform our understanding of liver diseases and support the development and validation of new liver-related drugs, an interdisciplinary collaboration is needed.
- Published
- 2024
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14. Synergistic lethality in chronic myeloid leukemia - targeting oxidative phosphorylation and unfolded protein response effectively complements tyrosine kinase inhibitor treatment.
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Häselbarth L, Gamali S, Saul D, Krumbholz M, Böttcher-Loschinski R, Böttcher M, Zou D, Metzler M, Karow A, and Mougiakakos D
- Subjects
- Humans, Fusion Proteins, bcr-abl, Oxidative Phosphorylation, Thapsigargin pharmacology, Thapsigargin therapeutic use, Drug Resistance, Neoplasm, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Enzyme Inhibitors pharmacology, Oligomycins pharmacology, Adenosine Triphosphate metabolism, Apoptosis, Tyrosine Kinase Inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
- Abstract
Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKIs), targeting the BCR::ABL1 oncoprotein. Still, resistance to therapy, relapse after treatment discontinuation, and side effects remain significant issues of long-term TKI treatment. Preliminary studies have shown that targeting oxidative phosphorylation (oxPhos) and the unfolded protein response (UPR) are promising therapeutic approaches to complement CML treatment. Here, we tested the efficacy of different TKIs, combined with the ATP synthase inhibitor oligomycin and the ER stress inducer thapsigargin in the CML cell lines K562, BV173, and KU812 and found a significant increase in cell death. Both, oligomycin and thapsigargin, triggered the upregulation of the UPR proteins ATF4 and CHOP, which was inhibited by imatinib. We observed comparable effects on cell death when combining TKIs with the ATP synthase inhibitor 8-chloroadenosine (8-Cl-Ado) as a potentially clinically applicable therapeutic agent. Stress-related apoptosis was triggered via a caspase cascade including the cleavage of caspase 3 and the inactivation of poly ADP ribose polymerase 1 (PARP1). The inhibition of PARP by olaparib also increased CML death in combination with TKIs. Our findings suggest a rationale for combining TKIs with 8-Cl-Ado or olaparib for future clinical studies in CML., (© 2023. The Author(s).)
- Published
- 2023
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15. The unknown functions of a known protein: the case of coagulation factor XI.
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van der Vorst EPC and Badimon L
- Subjects
- Factor XI, Blood Coagulation
- Abstract
Competing Interests: Conflict of interest L.B. declares to have acted as SAB/speaker for Sanofi, Novo Nordisk, and Ionis; and to have founded the spin-offs Glycardial Diagnostics SL and Ivastatin Therapeutics SL (all unrelated to this work).
- Published
- 2023
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16. Microgels as Platforms for Antibody-Mediated Cytokine Scavenging.
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Boesveld S, Kittel Y, Luo Y, Jans A, Oezcifci B, Bartneck M, Preisinger C, Rommel D, Haraszti T, Centeno SP, Boersma AJ, De Laporte L, Trautwein C, Kuehne AJC, and Strnad P
- Subjects
- Humans, Cytokines, Tumor Necrosis Factor-alpha, Antibodies, HT29 Cells, Microgels
- Abstract
Therapeutic antibodies are the key treatment option for various cytokine-mediated diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, systemic injection of these antibodies can cause side effects and suppress the immune system. Moreover, clearance of therapeutic antibodies from the blood is limiting their efficacy. Here, water-swollen microgels are produced with a size of 25 µm using droplet-based microfluidics. The microgels are functionalized with TNFα antibodies to locally scavenge the pro-inflammatory cytokine TNFα. Homogeneous distribution of TNFα-antibodies is shown throughout the microgel network and demonstrates specific antibody-antigen binding using confocal microscopy and FLIM-FRET measurements. Due to the large internal accessibility of the microgel network, its capacity to bind TNFα is extremely high. At a TNFα concentration of 2.5 µg mL
-1 , the microgels are able to scavenge 88% of the cytokine. Cell culture experiments reveal the therapeutic potential of these microgels by protecting HT29 colorectal adenocarcinoma cells from TNFα toxicity and resulting in a significant reduction of COX II and IL8 production of the cells. When the microgels are incubated with stimulated human macrophages, to mimic the in vivo situation of inflammatory bowel disease, the microgels scavenge almost all TNFα that is produced by the cells., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)- Published
- 2023
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17. Resting-state functional connectivity patterns associated with childhood maltreatment in a large bicentric cohort of adults with and without major depression.
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Goltermann J, Winter NR, Meinert S, Sindermann L, Lemke H, Leehr EJ, Grotegerd D, Winter A, Thiel K, Waltemate L, Breuer F, Repple J, Gruber M, Richter M, Teckentrup V, Kroemer NB, Brosch K, Meller T, Pfarr JK, Ringwald KG, Stein F, Heindel W, Jansen A, Kircher T, Nenadić I, Dannlowski U, Opel N, and Hahn T
- Subjects
- Humans, Adult, Child, Depression, Retrospective Studies, Limbic System, Magnetic Resonance Imaging methods, Depressive Disorder, Major diagnostic imaging, Child Abuse
- Abstract
Background: Childhood maltreatment (CM) represents a potent risk factor for major depressive disorder (MDD), including poorer treatment response. Altered resting-state connectivity in the fronto-limbic system has been reported in maltreated individuals. However, previous results in smaller samples differ largely regarding localization and direction of effects., Methods: We included healthy and depressed samples [ n = 624 participants with MDD; n = 701 healthy control (HC) participants] that underwent resting-state functional MRI measurements and provided retrospective self-reports of maltreatment using the Childhood Trauma Questionnaire. A-priori defined regions of interest [ROI; amygdala, hippocampus, anterior cingulate cortex (ACC)] were used to calculate seed-to-voxel connectivities., Results: No significant associations between maltreatment and resting-state connectivity of any ROI were found across MDD and HC participants and no interaction effect with diagnosis became significant. Investigating MDD patients only yielded maltreatment-associated increased connectivity between the amygdala and dorsolateral frontal areas [ p
FDR < 0.001; η2 partial = 0.091; 95%-CI (0.038-0.166)). Weaker evidence - not surviving correction for multiple ROI analyses - was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment.n = 264; pFDR < 0.001; η2 partial = 0.091; 95%-CI (0.038-0.166)). Weaker evidence - not surviving correction for multiple ROI analyses - was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment., Conclusions: The majority of previous resting-state connectivity correlates of CM could not be replicated in this large-scale study. The strongest evidence was found for clinically relevant maltreatment associations with altered adult amygdala-dorsolateral frontal connectivity in depression. Future studies should explore the relevance of this pathway for a maltreated subgroup of MDD patients.- Published
- 2023
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18. Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib.
- Author
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Häselbarth L, Karow A, Mentz K, Böttcher M, Roche-Lancaster O, Krumbholz M, Jitschin R, Mougiakakos D, and Metzler M
- Subjects
- Humans, Dasatinib pharmacology, Dasatinib therapeutic use, Imatinib Mesylate pharmacology, Imatinib Mesylate therapeutic use, Protein-Tyrosine Kinases, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyrimidines pharmacology, Fusion Proteins, bcr-abl, Drug Resistance, Neoplasm, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
- Abstract
T cell function is central to immune reconstitution and control of residual chronic myeloid leukemia (CML) cells after treatment initiation and is associated with achieving deep molecular response as a prerequisite for treatment-free remission, the ultimate therapeutic goal in CML. ATP-pocket-binding tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib are widely used for treating CML, but they have shown to inhibit T cell function as an "off-target" effect. Therefore, we tested asciminib, the first-in-class BCR::ABL1 fusion protein inhibitor specifically targeting the ABL myristoyl pocket (STAMP) and compared its effects on T cell function with imatinib, dasatinib, and nilotinib. Whereas all four TKIs inhibited the expression of the co-stimulatory protein CD28, the amino acid transporter CD98, proliferation, and secretion of pro-inflammatory cytokines IFNγ, IL-6, and IL-17A upon T cell stimulation, asciminib had less impact on PD-1, activation markers, and IL-2 secretion. T cells treated with asciminib and the other TKIs maintained their ability to mobilize their respiratory capacity and glycolytic reserve, which is an important surrogate for metabolic fitness and flexibility. Overall, we found milder inhibitory effects of asciminib on T cell activation, which might be beneficial for the immunological control of residual CML cells., (© 2023. The Author(s).)
- Published
- 2023
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19. Genetic, individual, and familial risk correlates of brain network controllability in major depressive disorder.
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Hahn T, Winter NR, Ernsting J, Gruber M, Mauritz MJ, Fisch L, Leenings R, Sarink K, Blanke J, Holstein V, Emden D, Beisemann M, Opel N, Grotegerd D, Meinert S, Heindel W, Witt S, Rietschel M, Nöthen MM, Forstner AJ, Kircher T, Nenadic I, Jansen A, Müller-Myhsok B, Andlauer TFM, Walter M, van den Heuvel MP, Jamalabadi H, Dannlowski U, and Repple J
- Subjects
- Humans, Diffusion Tensor Imaging, Genetic Predisposition to Disease, Magnetic Resonance Imaging methods, Brain, Depressive Disorder, Major, Connectome
- Abstract
Many therapeutic interventions in psychiatry can be viewed as attempts to influence the brain's large-scale, dynamic network state transitions. Building on connectome-based graph analysis and control theory, Network Control Theory is emerging as a powerful tool to quantify network controllability-i.e., the influence of one brain region over others regarding dynamic network state transitions. If and how network controllability is related to mental health remains elusive. Here, from Diffusion Tensor Imaging data, we inferred structural connectivity and inferred calculated network controllability parameters to investigate their association with genetic and familial risk in patients diagnosed with major depressive disorder (MDD, n = 692) and healthy controls (n = 820). First, we establish that controllability measures differ between healthy controls and MDD patients while not varying with current symptom severity or remission status. Second, we show that controllability in MDD patients is associated with polygenic scores for MDD and psychiatric cross-disorder risk. Finally, we provide evidence that controllability varies with familial risk of MDD and bipolar disorder as well as with body mass index. In summary, we show that network controllability is related to genetic, individual, and familial risk in MDD patients. We discuss how these insights into individual variation of network controllability may inform mechanistic models of treatment response prediction and personalized intervention-design in mental health., (© 2023. The Author(s).)
- Published
- 2023
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20. Definition and Quantification of Three-Dimensional Imaging Targets to Phenotype Pre-Eclampsia Subtypes: An Exploratory Study.
- Author
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Hermans S, Pilon J, Eschweiler D, Stegmaier J, Severens-Rijvers CAH, Al-Nasiry S, van Zandvoort M, and Kapsokalyvas D
- Subjects
- Humans, Pregnancy, Female, Imaging, Three-Dimensional, Trophoblasts, Phenotype, Placenta blood supply, Pre-Eclampsia
- Abstract
Pre-eclampsia is a severe placenta-related complication of pregnancy with limited early diagnostic and therapeutic options. Aetiological knowledge is controversial, and there is no universal consensus on what constitutes the early and late phenotypes of pre-eclampsia. Phenotyping of native placental three-dimensional (3D) morphology offers a novel approach to improve our understanding of the structural placental abnormalities in pre-eclampsia. Healthy and pre-eclamptic placental tissues were imaged with multiphoton microscopy (MPM). Imaging based on inherent signal (collagen, and cytoplasm) and fluorescent staining (nuclei, and blood vessels) enabled the visualization of placental villous tissue with subcellular resolution. Images were analysed with a combination of open source (FIJI, VMTK, Stardist, MATLAB, DBSCAN), and commercially (MATLAB) available software. Trophoblast organization, 3D-villous tree structure, syncytial knots, fibrosis, and 3D-vascular networks were identified as quantifiable imaging targets. Preliminary data indicate increased syncytial knot density with characteristic elongated shape, higher occurrence of paddle-like villous sprouts, abnormal villous volume-to-surface ratio, and decreased vascular density in pre-eclampsia compared to control placentas. The preliminary data presented indicate the potential of quantifying 3D microscopic images for identifying different morphological features and phenotyping pre-eclampsia in placental villous tissue.
- Published
- 2023
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21. Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice.
- Author
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van der Vorst EPC, Maas SL, Theodorou K, Peters LJF, Jin H, Rademakers T, Gijbels MJ, Rousch M, Jansen Y, Weber C, Lehrke M, Lebherz C, Yildiz D, Ludwig A, Bentzon JF, Biessen EAL, and Donners MMPC
- Abstract
Introduction: The transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a "pattern regulatory function," by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo ., Methods and Results: Endothelial Adam10 deficiency ( Adam10
ecko ) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro , ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo , as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes., Discussion: Collectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van der Vorst, Maas, Theodorou, Peters, Jin, Rademakers, Gijbels, Rousch, Jansen, Weber, Lehrke, Lebherz, Yildiz, Ludwig, Bentzon, Biessen and Donners.)- Published
- 2023
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22. In Vitro (Trans)Migration Experiment Using Chemokines as Stimulatory Factor.
- Author
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Maas SL and van der Vorst EPC
- Subjects
- Animals, Mice, Cell Movement, Chemotactic Factors, Chemotaxis, Chemokines metabolism
- Abstract
Transmigration assays, and the use of the Boyden chamber, became one of the most used tools to assess cell motility, invasion, and chemotaxis. The classical Boyden chamber consists of two compartments separated by a membrane representing a physical barrier, which cells have to overcome by active migration. A large variety of Boyden chambers are available and can be customized to fit the experiment by choosing pore size, density, and membrane type. The method described in this chapter intends to measure the migration of mouse T cells towards the chemoattractant CCL25, as a practical example of such (trans)migration experiment that can be further adopted to individual needs and requirements., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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23. Ex Vivo Perfusion System to Analyze Chemokine-Driven Leukocyte Adhesion.
- Author
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Maas SL, Megens RTA, and van der Vorst EPC
- Subjects
- Mice, Animals, Cell Adhesion physiology, Carotid Arteries, Perfusion, Endothelium, Vascular physiology, Leukocytes physiology, Chemokines
- Abstract
At the moment, many researchers are using in vitro techniques to investigate chemokine-driven leukocyte adhesion/recruitment, for example, by using a transwell or flow chamber system. Here we describe a more physiologically relevant, sophisticated, and highly flexible method to study leukocyte adhesion ex vivo in fresh murine carotid arteries under arterial flow conditions. This model mimics an in vivo situation and allows the combination of leukocytes and arteries isolated from different donors in one experiment, generating information on both vascular and leukocyte adhesive properties of both donors. This method provides a versatile, highly physiologically relevant model to investigate leukocyte adhesion., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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24. Finding the culprit for the failure of the immune clock as time goes by.
- Author
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van der Vorst EPC and Lecour S
- Subjects
- Circadian Rhythm, Transcription Factors
- Abstract
Competing Interests: Conflict of interest: None declared.
- Published
- 2022
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25. Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease.
- Author
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Wollenhaupt J, Frisch J, Harlacher E, Wong DWL, Jin H, Schulte C, Vondenhoff S, Moellmann J, Klinkhammer BM, Zhang L, Baleanu-Curaj A, Liehn EA, Speer T, Kazakov A, Werner C, van der Vorst EPC, Selejan SR, Hohl M, Böhm M, Kramann R, Biessen EAL, Lehrke M, Marx N, Jankowski J, Maack C, Boor P, Prates Roma L, and Noels H
- Subjects
- Adenine, Animals, Anti-Inflammatory Agents, Apolipoproteins E, Disease Models, Animal, Fibrosis, Hypertrophy, Left Ventricular, Mice, Mice, Inbred C57BL, Oxidative Stress, Cardiomyopathies, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic metabolism
- Abstract
Aims: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD., Methods and Results: CKD of different severity and duration was induced by subtotal nephrectomy or adenine-rich diet in various strains (C57BL/6J, C57BL/6 N, hyperlipidemic C57BL/6J ApoE
-/- , 129/Sv), followed by the analysis of kidney function and morphology, blood pressure, cardiac function, cardiac hypertrophy, fibrosis, myocardial calcification and inflammation using functional, histological and molecular techniques, including cardiac gene expression profiling supplemented by oxidative stress analysis. Intriguingly, despite uremia of variable degree, neither cardiac dysfunction, hypertrophy nor interstitial fibrosis were observed. However, already moderate CKD altered cardiac oxidative stress responses and enhanced oxidative stress markers in each mouse strain, with cardiac RNA sequencing revealing activation of oxidative stress signaling as well as anti-inflammatory feedback responses., Conclusion: This study considerably expands the knowledge on strain- and protocol-specific differences in the field of cardiorenal research and reveals that several weeks of at least moderate experimental CKD increase oxidative stress responses in the heart in a broad spectrum of mouse models. However, this was insufficient to induce relevant systolic or diastolic dysfunction, suggesting that additional "hits" are required to induce uremic cardiomyopathy., Translational Perspective: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular adverse events and exhibit myocardial changes, overall referred to as 'uremic cardiomyopathy'. We revealed that CKD increases cardiac oxidative stress responses in the heart. Nonetheless, several weeks of at least moderate experimental CKD do not necessarily trigger cardiac dysfunction and remodeling, suggesting that additional "hits" are required to induce uremic cardiomyopathy in the clinical setting. Whether the altered cardiac oxidative stress balance in CKD may increase the risk and extent of cardiovascular damage upon additional cardiovascular risk factors and/or events will be addressed in future studies., Competing Interests: Declaration of competing interest CM received honoraria for consulting and/or speeches from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Novo Nordisk, Novartis, Pfizer, Servier. The other authors report that no conflict of interest exists., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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26. Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling.
- Author
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Neupane B, Pradhan K, Ortega-Ramirez AM, Aidery P, Kucikas V, Marks M, van Zandvoort MAMJ, Klingel K, Witte KK, Gründer S, Marx N, and Gramlich M
- Abstract
Background: Mutations in the Lamin A/C ( LMNA ) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course., Methods: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fraction and NYHA functional class IV despite optimal heart failure treatment. Whole-exome sequencing revealed an LMNA E161K missense mutation as the pathogenetic cause for DCM in this patient. We generated a patient-specific LMNA -knock in ( LMNA -KI) in vitro model using mES cells., Results: Beta adrenergic stimulation of cardiomyocytes derived from LMNA -KI mES cells resulted in augmented mTOR signaling and increased dysregulation of action potentials, which could be effectively prevented by the mTOR-inhibitor rapamycin. A cardiac biopsy confirmed strong activation of the mTOR-signaling pathway in the patient. An off-label treatment with oral rapamycin was initiated and resulted in an improvement in left ventricular ejection fraction (27.8% to 44.5%), NT-BNP (8120 ng/L to 2210 ng/L) and NYHA functional class., Conclusion: We have successfully generated the first in vitro model to recapitulate a patient-specific LMNA E161K mutation which leads to a severe form of DCM. The model may serve as a template for individualized and specific treatment of heart failure.
- Published
- 2022
- Full Text
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27. White matter fiber microstructure is associated with prior hospitalizations rather than acute symptomatology in major depressive disorder.
- Author
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Meinert S, Leehr EJ, Grotegerd D, Repple J, Förster K, Winter NR, Enneking V, Fingas SM, Lemke H, Waltemate L, Stein F, Brosch K, Schmitt S, Meller T, Linge A, Krug A, Nenadić I, Jansen A, Hahn T, Redlich R, Opel N, Schubotz RI, Baune BT, Kircher T, and Dannlowski U
- Subjects
- Humans, Diffusion Tensor Imaging methods, Cross-Sectional Studies, Anisotropy, Brain pathology, Depressive Disorder, Major pathology, White Matter pathology
- Abstract
Background: Eighty percent of all patients suffering from major depressive disorder (MDD) relapse at least once in their lifetime. Thus, understanding the neurobiological underpinnings of the course of MDD is of utmost importance. A detrimental course of illness in MDD was most consistently associated with superior longitudinal fasciculus (SLF) fiber integrity. As similar associations were, however, found between SLF fiber integrity and acute symptomatology, this study attempts to disentangle associations attributed to current depression from long-term course of illness., Methods: A total of 531 patients suffering from acute ( N = 250) or remitted ( N = 281) MDD from the FOR2107-cohort were analyzed in this cross-sectional study using tract-based spatial statistics for diffusion tensor imaging. First, the effects of disease state (acute v . remitted), current symptom severity (BDI-score) and course of illness (number of hospitalizations) on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity were analyzed separately. Second, disease state and BDI-scores were analyzed in conjunction with the number of hospitalizations to disentangle their effects., Results: Disease state ( p
FWE 0.032) were associated with decreased FA and increased MD and RD in the bilateral SLF. A trend was found for the BDI-score ( pFWE < 0.032) were associated with decreased FA and increased MD and RD in the bilateral SLF. A trend was found for the BDI-score ( pFWE > 0.067). When analyzed simultaneously only the effect of course of illness remained significant ( pFWE < 0.040) mapping to the right SLF., Conclusions: Decreased FA and increased MD and RD values in the SLF are associated with more hospitalizations when controlling for current psychopathology. SLF fiber integrity could reflect cumulative illness burden at a neurobiological level and should be targeted in future longitudinal analyses.- Published
- 2022
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28. Enolase of Staphylococcus lugdunensis Is a Surface-Exposed Moonlighting Protein That Binds to Extracellular Matrix and the Plasminogen/Plasmin System.
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Hussain M, Kohler C, and Becker K
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The coagulase-negative staphylococcal (CoNS) species Staphylococcus lugdunensis is unique in causing serious infections in humans that resemble those of Staphylococcus aureus rather than those of other CoNS species. The colonization and invasion of host tissue presupposes the presence of adherence factors, but only a few proteins mediating adhesion of S. lugdunensis to biotic surfaces are known yet. Here, we report on the functionality of the S. lugdunensis enolase (SlEno), which performs two distinct roles, first, as the metabolic enzyme of the glycolysis, and second, as an adherence factor to the extracellular matrix (ECM) of cells. Phylogenetic analyses of the SlEno confirmed their high conservation to enolases of other species and revealed a closer relationship to Staphylococcus epidermidis than to S. aureus . Using matrix-assisted laser desorption/ionization time of flight mass spectrometry and Western blot experiments, we identified SlEno to be located in the cytoplasm as well as on the cell surface of S. lugdunensis . Recombinantly generated and surface-associated SlEno showed the usual enolase activity by catalyzing the conversion of 2-phosphoglycerate to phosphoenolpyruvate but, in addition, also displayed strong binding to immobilized laminin, fibronectin, fibrinogen, and collagen type IV in a dose-dependent manner. We also showed a strong binding of SlEno to plasminogen (Plg) and observed a tissue plasminogen activator (tPA)-dependent conversion of Plg to plasmin (Pln) whereby the Plg activation significantly increased in the presence of SlEno. This interaction might be dependent on lysines of the SlEno protein as binding to Plg was inhibited by ε-aminocaproic acid. Furthermore, the enhanced activation of the Plg/Pln system by SlEno enabled S. lugdunensis to migrate through a fibrin matrix. This migration was about 10-fold higher than without exogenously added SlEno. Finally, we observed a significantly higher clearance of S. lugdunensis by freshly prepared granulocytes and in the presence of anti-SlEno antibodies. In conclusion, these data demonstrate for the first time a moonlighting function of the S. lugdunensis enolase, which is an underrated virulence factor for colonization and invasion of tissues. Hence, SlEno might be a potential vaccine candidate to prevent severe infections caused by this pathogen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hussain, Kohler and Becker.)
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- 2022
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29. The Course of Disease in Major Depressive Disorder Is Associated With Altered Activity of the Limbic System During Negative Emotion Processing.
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Lemke H, Probst S, Warneke A, Waltemate L, Winter A, Thiel K, Meinert S, Enneking V, Breuer F, Klug M, Goltermann J, Hülsmann C, Grotegerd D, Redlich R, Dohm K, Leehr EJ, Repple J, Opel N, Brosch K, Meller T, Pfarr JK, Ringwald K, Schmitt S, Stein F, Krug A, Jansen A, Nenadic I, Kircher T, Hahn T, and Dannlowski U
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- Cross-Sectional Studies, Emotions physiology, Female, Humans, Limbic System, Magnetic Resonance Imaging, Male, Depressive Disorder, Major
- Abstract
Background: Brain functional alterations during emotion processing in patients with major depressive disorder (MDD) compared with healthy control subjects (HCs) are frequently reported. However, evidence for functional correlates of emotion processing with regard to MDD trajectories is scarce. This study investigates the role of lifetime disease course for limbic brain activation during negative emotional face processing in patients with MDD., Methods: In a large sample of patients with MDD (n = 333; 58.55% female) and HCs (n = 333; 60.06% female), brain activation was investigated during a negative emotional face-processing task within a cross-sectional design. Differences between HC and MDD groups were analyzed. Previous disease course, characterized by 2 components, namely hospitalization and duration of illness, was regressed on brain activation of the amygdala, (para-)hippocampus, and insula in patients with MDD., Results: Patients with MDD showed increased activation in the amygdala, insula, and hippocampus compared with HCs (all p values corrected for familywise error [p
FWE ] < .045). The hospitalization component showed negative associations with brain activation in the bilateral insula (right: pFWE = .026, left: pFWE = .019) and (para-)hippocampus (right: pFWE = .038, left: pFWE = .031). No significant association was found for the duration of illness component (all pFWE > .057)., Conclusions: This study investigated negative emotion processing in a large sample of patients with MDD and HCs. Our results confirm limbic hyperactivation in patients with MDD during negative emotion processing; however, this hyperactivation may resolve with a more severe lifetime disease course in the insula and (para-)hippocampus-brain regions involved in emotion processing and regulation. These findings need further replication in longitudinal studies., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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30. A systematic review and meta-analysis of murine models of uremic cardiomyopathy.
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Soppert J, Frisch J, Wirth J, Hemmers C, Boor P, Kramann R, Vondenhoff S, Moellmann J, Lehrke M, Hohl M, van der Vorst EPC, Werner C, Speer T, Maack C, Marx N, Jankowski J, Roma LP, and Noels H
- Subjects
- Animals, Disease Models, Animal, Fibrosis, Mice, Mice, Inbred C57BL, Cardiomyopathies genetics, Renal Insufficiency, Chronic complications
- Abstract
Chronic kidney disease (CKD) triggers the risk of developing uremic cardiomyopathy as characterized by cardiac hypertrophy, fibrosis and functional impairment. Traditionally, animal studies are used to reveal the underlying pathological mechanism, although variable CKD models, mouse strains and readouts may reveal diverse results. Here, we systematically reviewed 88 studies and performed meta-analyses of 52 to support finding suitable animal models for future experimental studies on pathological kidney-heart crosstalk during uremic cardiomyopathy. We compared different mouse strains and the direct effect of CKD on cardiac hypertrophy, fibrosis and cardiac function in "single hit" strategies as well as cardiac effects of kidney injury combined with additional cardiovascular risk factors in "multifactorial hit" strategies. In C57BL/6 mice, CKD was associated with a mild increase in cardiac hypertrophy and fibrosis and marginal systolic dysfunction. Studies revealed high variability in results, especially regarding hypertrophy and systolic function. Cardiac hypertrophy in CKD was more consistently observed in 129/Sv mice, which express two instead of one renin gene and more consistently develop increased blood pressure upon CKD induction. Overall, "multifactorial hit" models more consistently induced cardiac hypertrophy and fibrosis compared to "single hit" kidney injury models. Thus, genetic factors and additional cardiovascular risk factors can "prime" for susceptibility to organ damage, with increased blood pressure, cardiac hypertrophy and early cardiac fibrosis more consistently observed in 129/Sv compared to C57BL/6 strains., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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31. Which traits predict elevated distress during the Covid-19 pandemic? Results from a large, longitudinal cohort study with psychiatric patients and healthy controls.
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Brosch K, Meller T, Pfarr JK, Stein F, Schmitt S, Ringwald KG, Waltemate L, Lemke H, Thiel K, Schrammen E, Hülsmann C, Meinert S, Dohm K, Leehr EJ, Opel N, Krug A, Dannlowski U, Nenadić I, and Kircher T
- Subjects
- Anxiety, Cohort Studies, Communicable Disease Control, Depression, Humans, Longitudinal Studies, SARS-CoV-2, COVID-19, Pandemics
- Abstract
The Covid-19 pandemic resulted in repeated, prolonged restrictions in daily life. Social distancing policies as well as health anxiety are thought to lead to mental health impairment. However, there is lack of longitudinal data identifying at-risk populations particularly vulnerable for elevated Covid-19-related distress. We collected data of N = 1268 participants (n = 622 healthy controls (HC), and n = 646 patients with major depression, bipolar disorder, schizophrenia or schizoaffective disorder) at baseline before (2014-2018) and during (April-May 2020) the first lockdown in Germany. We obtained information on Covid-19 restrictions (number and subjective impact of Covid-19 events), and Covid-19-related distress (i.e., subjective fear and isolation). Using multiple linear regression models including trait variables and individual Covid-19 impact, we sought to predict Covid-19-related distress. HC and patients reported similar numbers of Covid-19-related events, and similar subjective impact rating. They did not differ in Covid-19-related subjective fear. Patients reported significantly higher subjective isolation. 30.5% of patients reported worsened self-rated symptoms since the pandemic. Subjective fear in all participants was associated with trait anxiety (STAI-T), conscientiousness (NEO-FFI), Covid-19 impact, and sex. Subjective isolation in HC was associated with social support (FSozu), Covid-19 impact, age, and sex; in patients, it was associated with social support and Covid-19 impact. Our data shed light on differential effects of the pandemic in psychiatric patients and HC. Low social support, high conscientiousness and high trait anxiety are associated with elevated distress during the pandemic. These variables might be valuable for the creation of risk profiles of Covid-19-related distress for direct translation into clinical practice., (Copyright © 2021. Published by Elsevier B.V.)
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- 2022
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32. An uncertainty-aware, shareable, and transparent neural network architecture for brain-age modeling.
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Hahn T, Ernsting J, Winter NR, Holstein V, Leenings R, Beisemann M, Fisch L, Sarink K, Emden D, Opel N, Redlich R, Repple J, Grotegerd D, Meinert S, Hirsch JG, Niendorf T, Endemann B, Bamberg F, Kröncke T, Bülow R, Völzke H, von Stackelberg O, Sowade RF, Umutlu L, Schmidt B, Caspers S, Kugel H, Kircher T, Risse B, Gaser C, Cole JH, Dannlowski U, and Berger K
- Abstract
The deviation between chronological age and age predicted from neuroimaging data has been identified as a sensitive risk marker of cross-disorder brain changes, growing into a cornerstone of biological age research. However, machine learning models underlying the field do not consider uncertainty, thereby confounding results with training data density and variability. Also, existing models are commonly based on homogeneous training sets, often not independently validated, and cannot be shared because of data protection issues. Here, we introduce an uncertainty-aware, shareable, and transparent Monte Carlo dropout composite quantile regression (MCCQR) Neural Network trained on N = 10,691 datasets from the German National Cohort. The MCCQR model provides robust, distribution-free uncertainty quantification in high-dimensional neuroimaging data, achieving lower error rates compared with existing models. In two examples, we demonstrate that it prevents spurious associations and increases power to detect deviant brain aging. We make the pretrained model and code publicly available.
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- 2022
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33. Correction: Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders.
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Opel N, Thalamuthu A, Milaneschi Y, Grotegerd D, Flint C, Leenings R, Goltermann J, Richter M, Hahn T, Woditsch G, Berger K, Hermesdorf M, McIntosh A, Whalley HC, Harris MA, MacMaster FP, Walter H, Veer IM, Frodl T, Carballedo A, Krug A, Nenadic I, Kircher T, Aleman A, Groenewold NA, Stein DJ, Soares JC, Zunta-Soares GB, Mwangi B, Wu MJ, Walter M, Li M, Harrison BJ, Davey CG, Cullen KR, Klimes-Dougan B, Mueller BA, Sämann PG, Penninx B, Nawijn L, Veltman DJ, Aftanas L, Brak IV, Filimonova EA, Osipov EA, Reneman L, Schrantee A, Grabe HJ, Van der Auwera S, Wittfeld K, Hosten N, Völzke H, Sim K, Gotlib IH, Sacchet MD, Lagopoulos J, Hatton SN, Hickie I, Pozzi E, Thompson PM, Jahanshad N, Schmaal L, Baune BT, and Dannlowski U
- Published
- 2021
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34. PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo.
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Sundararaman SS, Peters LJF, Nazir S, Marquez AB, Bouma JE, Bayasgalan S, Döring Y, and van der Vorst EPC
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- Animals, Atherosclerosis metabolism, Atherosclerosis pathology, Atherosclerosis veterinary, Cytokines blood, Cytokines genetics, Cytokines metabolism, Endothelial Cells cytology, Endothelial Cells metabolism, Humans, Leukocytes cytology, Leukocytes metabolism, Lipopolysaccharides pharmacology, Liver metabolism, Macrophages, Peritoneal cytology, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle metabolism, Proprotein Convertase 9 blood, Proprotein Convertase 9 genetics, Receptors, Chemokine genetics, Proprotein Convertase 9 metabolism, Receptors, Chemokine metabolism
- Abstract
Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.
- Published
- 2021
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35. The nucleoporin Nup50 activates the Ran guanine nucleotide exchange factor RCC1 to promote NPC assembly at the end of mitosis.
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Holzer G, De Magistris P, Gramminger C, Sachdev R, Magalska A, Schooley A, Scheufen A, Lennartz B, Tatarek-Nossol M, Lue H, Linder MI, Kutay U, Preisinger C, Moreno-Andres D, and Antonin W
- Subjects
- Animals, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Female, Guanine Nucleotide Exchange Factors genetics, HeLa Cells, Humans, Nuclear Pore Complex Proteins genetics, Nuclear Proteins genetics, Transcription Factors genetics, Xenopus laevis, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Guanine Nucleotide Exchange Factors metabolism, Mitosis, Mutation, Nuclear Pore Complex Proteins metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
During mitotic exit, thousands of nuclear pore complexes (NPCs) assemble concomitant with the nuclear envelope to build a transport-competent nucleus. Here, we show that Nup50 plays a crucial role in NPC assembly independent of its well-established function in nuclear transport. RNAi-mediated downregulation in cells or immunodepletion of Nup50 protein in Xenopus egg extracts interferes with NPC assembly. We define a conserved central region of 46 residues in Nup50 that is crucial for Nup153 and MEL28/ELYS binding, and for NPC interaction. Surprisingly, neither NPC interaction nor binding of Nup50 to importin α/β, the GTPase Ran, or chromatin is crucial for its function in the assembly process. Instead, an N-terminal fragment of Nup50 can stimulate the Ran GTPase guanine nucleotide exchange factor RCC1 and NPC assembly, indicating that Nup50 acts via the Ran system in NPC reformation at the end of mitosis. In support of this conclusion, Nup50 mutants defective in RCC1 binding and stimulation cannot replace the wild-type protein in in vitro NPC assembly assays, whereas excess RCC1 can compensate the loss of Nup50., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2021
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36. Technical feasibility and adherence of the Remote Monitoring Application in Psychiatry (ReMAP) for the assessment of affective symptoms.
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Emden D, Goltermann J, Dannlowski U, Hahn T, and Opel N
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- Anxiety, Feasibility Studies, Humans, Smartphone, Affective Symptoms, Psychiatry
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Background: Smartphone-based monitoring constitutes a cost-effective instrument to assess and predict affective symptom trajectories. Large-scale transdiagnostic studies utilizing this methodology are yet lacking in psychiatric research. Thus, we introduce the Remote Monitoring Application in Psychiatry (ReMAP) and evaluate its feasibility and adherence in a large transdiagnostic sample., Methods: The ReMAP app was distributed among n = 997 healthy control participants and psychiatric patients, including affective, anxiety, and psychotic disorders. Passive sensor data (acceleration, geolocation, walking distance, steps), optional standardized self-reports on mood and sleep, and voice samples were assessed. Feasibility and adherence were evaluated based on frequency of transferred data, and participation duration. Preliminary results are presented while data collection is ongoing., Results: Retention rates of 90.25% for the minimum study duration of two weeks and 33.09% for one year were achieved (median participation 135 days, IQR=111). Participants transferred an average of 51.83 passive events per day. An average of 34.59 self-report events were transferred per user, with a considerable range across participants (0-552 events). Clinical and non-clinical subgroups did not differ in participation duration or rate of data transfer. The mean rate of days with passive data was higher and less heterogeneous in iOS (91.85%, SD=21.25) as compared to Android users (63.04%, SD=35.09)., Limitations: Subjective user experience was not assessed limiting conclusions about app acceptance., Conclusions: ReMAP is a technically feasible tool to assess affective symptoms with high temporal resolution in large-scale transdiagnostic samples with good adherence. Future studies should account for differences between operating systems., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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37. Molecular determinants of health and disease.
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Ludwig S, Blass-Kampmann S, and Müller FU
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- Humans, Health, Disease
- Published
- 2021
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38. Shooting at a Moving Target-Effectiveness and Emerging Challenges for SARS-CoV-2 Vaccine Development.
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Günl F, Mecate-Zambrano A, Rehländer S, Hinse S, Ludwig S, and Brunotte L
- Abstract
Since late 2019 the newly emerged pandemic SARS-CoV-2, the causative agent of COVID-19, has hit the world with recurring waves of infections necessitating the global implementation of non-pharmaceutical interventions, including strict social distancing rules, the wearing of masks and the isolation of infected individuals in order to restrict virus transmissions and prevent the breakdown of our healthcare systems. These measures are not only challenging on an economic level but also have a strong impact on social lifestyles. Using traditional and novel technologies, highly efficient vaccines against SARS-CoV-2 were developed and underwent rapid clinical evaluation and approval to accelerate the immunization of the world population, aiming to end the pandemic and return to normality. However, the emergence of virus variants with improved transmission, enhanced fitness and partial immune escape from the first generation of vaccines poses new challenges, which are currently being addressed by scientists and pharmaceutical companies all over the world. In this ongoing pandemic, the evaluation of SARS-CoV-2 vaccines underlies diverse unpredictable dynamics, posed by the first broad application of the mRNA vaccine technology and their compliance, the occurrence of unexpected side effects and the rapid emergence of variations in the viral antigen. However, despite these hurdles, we conclude that the available SARS-CoV-2 vaccines are very safe and efficiently protect from severe COVID-19 and are thereby the most powerful tools to prevent further harm to our healthcare systems, economics and individual lives. This review summarizes the unprecedented pathways of vaccine development and approval during the ongoing SARS-CoV-2 pandemic. We focus on the real-world effectiveness and unexpected positive and negative side effects of the available vaccines and summarize the timeline of the applied adaptations to the recommended vaccination strategies in the light of emerging virus variants. Finally, we highlight upcoming strategies to improve the next generations of SARS-CoV-2 vaccines.
- Published
- 2021
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39. Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.
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Opel N, Thalamuthu A, Milaneschi Y, Grotegerd D, Flint C, Leenings R, Goltermann J, Richter M, Hahn T, Woditsch G, Berger K, Hermesdorf M, McIntosh A, Whalley HC, Harris MA, MacMaster FP, Walter H, Veer IM, Frodl T, Carballedo A, Krug A, Nenadic I, Kircher T, Aleman A, Groenewold NA, Stein DJ, Soares JC, Zunta-Soares GB, Mwangi B, Wu MJ, Walter M, Li M, Harrison BJ, Davey CG, Cullen KR, Klimes-Dougan B, Mueller BA, Sämann PG, Penninx B, Nawijn L, Veltman DJ, Aftanas L, Brak IV, Filimonova EA, Osipov EA, Reneman L, Schrantee A, Grabe HJ, Van der Auwera S, Wittfeld K, Hosten N, Völzke H, Sim K, Gotlib IH, Sacchet MD, Lagopoulos J, Hatton SN, Hickie I, Pozzi E, Thompson PM, Jahanshad N, Schmaal L, Baune BT, and Dannlowski U
- Subjects
- Aged, Brain diagnostic imaging, Cerebral Cortex, Humans, Magnetic Resonance Imaging, Obesity genetics, Risk Factors, Depressive Disorder, Major genetics
- Abstract
Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions., (© 2020. The Author(s).)
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- 2021
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40. PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology.
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Sundararaman SS, Döring Y, and van der Vorst EPC
- Abstract
Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is secreted mostly by hepatocytes and to a lesser extent by the intestine, pancreas, kidney, adipose tissue, and vascular cells. PCSK9 has been known to interact with the low-density lipoprotein receptor (LDLR) and chaperones the receptor to its degradation. In this manner, targeting PCSK9 is a novel attractive approach to reduce hyperlipidaemia and the risk for cardiovascular diseases. Recently, it has been recognised that the effects of PCSK9 in relation to cardiovascular complications are not only LDLR related, but that various LDLR-independent pathways and processes are also influenced. In this review, the various LDLR dependent and especially independent effects of PCSK9 on the cardiovascular system are discussed, followed by an overview of related PCSK9-polymorphisms and currently available and future therapeutic approaches to manipulate PCSK9 expression.
- Published
- 2021
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41. Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2.
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Kuscuoglu D, Bewersdorf L, Wenzel K, Gross A, Kobazi Ensari G, Luo Y, Kilic K, Hittatiya K, Golob-Schwarzl N, Leube RE, Preisinger C, George J, Metwally M, Eslam M, Lampertico P, Petta S, Mangia A, Berg T, Boonstra A, Brouwer WP, Abate ML, Loglio A, Sutton A, Nahon P, Schaefer B, Zoller H, Aigner E, Trautwein C, Haybaeck J, and Strnad P
- Subjects
- Animals, Hepatitis B Surface Antigens toxicity, Humans, Liver Diseases pathology, Mice, Stress, Physiological physiology, alpha 1-Antitrypsin toxicity, Hepatitis B Surface Antigens metabolism, Liver Diseases metabolism, NF-E2-Related Factor 2 metabolism, Sequestosome-1 Protein metabolism, alpha 1-Antitrypsin metabolism
- Abstract
Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2021
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42. Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health.
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Sundararaman SS and van der Vorst EPC
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- Animals, Cardiovascular Diseases metabolism, Humans, Inflammation metabolism, Signal Transduction, Calcium metabolism, Cardiovascular Diseases physiopathology, Inflammation physiopathology, Receptors, Calcium-Sensing metabolism
- Abstract
The calcium Sensing Receptor (CaSR) is a cell surface receptor belonging to the family of G-protein coupled receptors. CaSR is mainly expressed by parathyroid glands, kidneys, bone, skin, adipose tissue, the gut, the nervous system, and the cardiovascular system. The receptor, as its name implies is involved in sensing calcium fluctuations in the extracellular matrix of cells, thereby having a major impact on the mineral homeostasis in humans. Besides calcium ions, the receptor is also activated by other di- and tri-valent cations, polypeptides, polyamines, antibiotics, calcilytics and calcimimetics, which upon binding induce intracellular signaling pathways. Recent studies have demonstrated that CaSR influences a wide variety of cells and processes that are involved in inflammation, the cardiovascular system, such as vascular calcification, atherosclerosis, myocardial infarction, hypertension, and obesity. Therefore, in this review, the current understanding of the role that CaSR plays in inflammation and its consequences on the cardiovascular system will be highlighted.
- Published
- 2021
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43. The first versatile human iPSC-based model of ectopic virus induction allows new insights in RNA-virus disease.
- Author
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Peischard S, Ho HT, Piccini I, Strutz-Seebohm N, Röpke A, Liashkovich I, Gosain H, Rieger B, Klingel K, Eggers B, Marcus K, Linke WA, Müller FU, Ludwig S, Greber B, Busch K, and Seebohm G
- Subjects
- Cell Line, Doxycycline pharmacology, Humans, Models, Biological, Myocytes, Cardiac virology, Virus Activation drug effects, Induced Pluripotent Stem Cells virology, RNA Virus Infections virology, RNA Viruses physiology
- Abstract
A detailed description of pathophysiological effects that viruses exert on their host is still challenging. For the first time, we report a highly controllable viral expression model based on an iPS-cell line from a healthy human donor. The established viral model system enables a dose-dependent and highly localized RNA-virus expression in a fully controllable environment, giving rise for new applications for the scientific community.
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- 2020
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44. Replication of a hippocampus specific effect of the tescalcin regulating variant rs7294919 on gray matter structure.
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Goltermann J, Opel N, Redlich R, Repple J, Kaehler C, Grotegerd D, Dohm K, Leehr EJ, Böhnlein J, Förster K, Meinert S, Enneking V, Emden D, Leenings R, Winter NR, Hahn T, Mikhail S, Jansen A, Krug A, Nenadić I, Rietschel M, Witt SH, Heilmann-Heimbach S, Hoffmann P, Forstner AJ, Nöthen MM, Baune BT, Kircher T, and Dannlowski U
- Subjects
- Adult, Cohort Studies, Cross-Sectional Studies, Depressive Disorder, Major diagnostic imaging, Depressive Disorder, Major genetics, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Young Adult, Calcium-Binding Proteins genetics, Genetic Variation genetics, Gray Matter diagnostic imaging, Hippocampus diagnostic imaging, Polymorphism, Single Nucleotide genetics
- Abstract
While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association., Competing Interests: Conflict of interest Tilo Kircher received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. Markus Wöhr is scientific advisor of Avisoft Bioacoustics. No further conflicts of interest are declared., (Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.)
- Published
- 2020
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45. Brain Changes Induced by Electroconvulsive Therapy Are Broadly Distributed.
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Ousdal OT, Argyelan M, Narr KL, Abbott C, Wade B, Vandenbulcke M, Urretavizcaya M, Tendolkar I, Takamiya A, Stek ML, Soriano-Mas C, Redlich R, Paulson OB, Oudega ML, Opel N, Nordanskog P, Kishimoto T, Kampe R, Jorgensen A, Hanson LG, Hamilton JP, Espinoza R, Emsell L, van Eijndhoven P, Dols A, Dannlowski U, Cardoner N, Bouckaert F, Anand A, Bartsch H, Kessler U, Oedegaard KJ, Dale AM, and Oltedal L
- Subjects
- Brain diagnostic imaging, Gray Matter diagnostic imaging, Humans, Magnetic Resonance Imaging, Depressive Disorder, Major therapy, Electroconvulsive Therapy
- Abstract
Background: Electroconvulsive therapy (ECT) is associated with volumetric enlargements of corticolimbic brain regions. However, the pattern of whole-brain structural alterations following ECT remains unresolved. Here, we examined the longitudinal effects of ECT on global and local variations in gray matter, white matter, and ventricle volumes in patients with major depressive disorder as well as predictors of ECT-related clinical response., Methods: Longitudinal magnetic resonance imaging and clinical data from the Global ECT-MRI Research Collaboration (GEMRIC) were used to investigate changes in white matter, gray matter, and ventricle volumes before and after ECT in 328 patients experiencing a major depressive episode. In addition, 95 nondepressed control subjects were scanned twice. We performed a mega-analysis of single subject data from 14 independent GEMRIC sites., Results: Volumetric increases occurred in 79 of 84 gray matter regions of interest. In total, the cortical volume increased by mean ± SD of 1.04 ± 1.03% (Cohen's d = 1.01, p < .001) and the subcortical gray matter volume increased by 1.47 ± 1.05% (d = 1.40, p < .001) in patients. The subcortical gray matter increase was negatively associated with total ventricle volume (Spearman's rank correlation ρ = -.44, p < .001), while total white matter volume remained unchanged (d = -0.05, p = .41). The changes were modulated by number of ECTs and mode of electrode placements. However, the gray matter volumetric enlargements were not associated with clinical outcome., Conclusions: The findings suggest that ECT induces gray matter volumetric increases that are broadly distributed. However, gross volumetric increases of specific anatomically defined regions may not serve as feasible biomarkers of clinical response., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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46. Predicting rehospitalization within 2 years of initial patient admission for a major depressive episode: a multimodal machine learning approach.
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Cearns M, Opel N, Clark S, Kaehler C, Thalamuthu A, Heindel W, Winter T, Teismann H, Minnerup H, Dannlowski U, Berger K, and Baune BT
- Subjects
- Adult, Aged, Antidepressive Agents therapeutic use, Area Under Curve, Biomarkers, Brain diagnostic imaging, Brain pathology, Depressive Disorder, Major diagnostic imaging, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Predictive Value of Tests, Treatment Outcome, Depressive Disorder, Major physiopathology, Depressive Disorder, Major therapy, Machine Learning, Patient Readmission
- Abstract
Machine learning methods show promise to translate univariate biomarker findings into clinically useful multivariate decision support systems. At current, works in major depressive disorder have predominantly focused on neuroimaging and clinical predictor modalities, with genetic, blood-biomarker, and cardiovascular modalities lacking. In addition, the prediction of rehospitalization after an initial inpatient major depressive episode is yet to be explored, despite its clinical importance. To address this gap in the literature, we have used baseline clinical, structural imaging, blood-biomarker, genetic (polygenic risk scores), bioelectrical impedance and electrocardiography predictors to predict rehospitalization within 2 years of an initial inpatient episode of major depression. Three hundred and eighty patients from the ongoing 12-year Bidirect study were included in the analysis (rehospitalized: yes = 102, no = 278). Inclusion criteria was age ≥35 and <66 years, a current or recent hospitalisation for a major depressive episode and complete structural imaging and genetic data. Optimal performance was achieved with a multimodal panel containing structural imaging, blood-biomarker, clinical, medication type, and sleep quality predictors, attaining a test AUC of 67.74 (p = 9.99
-05 ). This multimodal solution outperformed models based on clinical variables alone, combined biomarkers, and individual data modality prognostication for rehospitalization prediction. This finding points to the potential of predictive models that combine multimodal clinical and biomarker data in the development of clinical decision support systems.- Published
- 2019
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47. Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study
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Opel N, Cearns M, Clark S, Toben C, Grotegerd D, Heindel W, Kugel H, Teuber A, Minnerup H, Berger K, Dannlowski U, and Baune BT
- Subjects
- Adult, Brain diagnostic imaging, Brain pathology, Case-Control Studies, Cerebral Cortex diagnostic imaging, Cerebral Cortex pathology, Cross-Sectional Studies, Female, Gray Matter pathology, Humans, Male, Middle Aged, Organ Size, Prefrontal Cortex diagnostic imaging, Prefrontal Cortex pathology, C-Reactive Protein metabolism, Depressive Disorder, Major diagnostic imaging, Depressive Disorder, Major metabolism, Gray Matter diagnostic imaging, Inflammation metabolism
- Abstract
Background: Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations in the brain; as well as with low-grade peripheral inflammation. However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research, well-powered studies to confirm this hypothesis in patients with MDD have been lacking. We aimed to investigate the potential association between structural brain alterations and low-grade inflammation as interrelated biological correlates of MDD., Methods: In this cross-sectional study, 514 patients with MDD and 359 healthy controls underwent structural MRI. We used voxel-based morphometry to study local differences in grey matter volume. We also assessed serum levels of high-sensitivity C-reactive protein (hsCRP) in each participant., Results: Compared with healthy controls (age [mean ± standard deviation] 52.57 ± 7.94 yr; 50% male), patients with MDD (49.14 ± 7.28 yr, 39% male) exhibited significantly increased hsCRP levels (Z = −5.562, p < 0.001) and significantly decreased grey matter volume in the prefrontal cortex and the insula. Prefrontal grey matter volume reductions were significantly associated with higher hsCRP levels in patients with MDD (x = 50, y = 50, z = 8; t1,501 = 5.15; k = 92; pFWE < 0.001). In the MDD sample, the significant negative association between hsCRP and grey matter appeared independent of age, sex, body mass index, current smoking status, antidepressant load, hospitalization and medical comorbidities., Limitations: This study had a cross-sectional design., Conclusion: The present study highlights the role of reduced grey matter volume and low-grade peripheral inflammation as interrelated biological correlates of MDD. The reported inverse association between peripheral low-grade inflammation and brain structural integrity in patients with MDD translates current knowledge from experimental studies to the bedside., Competing Interests: B. Baune is member of advisory boards, received funding and/or gave presentations for AstraZeneca, Lundbeck, Janssen, Pfizer, Servier, and Wyeth, outside the submitted work. No other competing interests declared., (© 2019 Joule Inc. or its licensors)
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- 2019
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48. Reduced fractional anisotropy in depressed patients due to childhood maltreatment rather than diagnosis.
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Meinert S, Repple J, Nenadic I, Krug A, Jansen A, Grotegerd D, Förster K, Enneking V, Dohm K, Schmitt S, Stein F, Brosch K, Meller T, Redlich R, Böhnlein J, Sindermann L, Goltermann J, Leehr EJ, Opel N, Aldermann L, Reuter A, Schubotz RI, Hahn T, Kircher T, and Dannlowski U
- Subjects
- Adult, Animals, Anisotropy, Brain diagnostic imaging, Cohort Studies, Depressive Disorder, Major complications, Diffusion Tensor Imaging, Female, Humans, Male, White Matter diagnostic imaging, Adult Survivors of Child Abuse psychology, Brain pathology, Depressive Disorder, Major diagnosis, Depressive Disorder, Major pathology, White Matter pathology
- Abstract
Reduced fractional anisotropy (FA) associated with Major Depressive Disorder (MDD) overlaps anatomically with effects of childhood maltreatment experiences. The aim of this study was, therefore, to replicate the negative effect of childhood maltreatment on white matter fiber structure and to demonstrate, that alterations in MDD might be partially attributed to the higher occurrence of childhood maltreatment in MDD. Two independent cohorts (total N = 1 256) were investigated in a diffusion tensor imaging study: The Münster Neuroimaging Cohort (MNC, N = 186 MDD, N = 210 healthy controls, HC) as discovery sample and the Marburg-Münster Affective Disorders Cohort Study (MACS, N = 397 MDD, N = 462 HC) as replication sample. The effects of diagnosis (HC vs. MDD) and Childhood Trauma Questionnaire (CTQ) scores on FA were analyzed. A main effect of diagnosis with higher FA in MDD patients compared with HC was found in the MNC (p
FWE = 0.021), but not in the MACS (pFWE = 0.52) before correcting for CTQ. A significant negative correlation of FA with CTQ emerged in both cohorts (MNC: pFWE = 0.006, MACS: pFWE = 0.012) in several tracts previously described in the literature. No CTQ × diagnosis interaction could be detected. Any main effect of diagnosis was abolished after correcting for CTQ (MNC: pFWE = 0.562, MACS: pFWE = 0.115). No differences in FA between MDD and HC could be found after correcting for childhood maltreatment, suggesting that previously reported group differences might be attributed partially to higher levels of maltreatment experiences in MDD rather than diagnosis itself. Furthermore, a well-established finding of reduced FA following childhood maltreatment experiences was replicated.- Published
- 2019
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49. Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis.
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Puelles VG, Fleck D, Ortz L, Papadouri S, Strieder T, Böhner AMC, van der Wolde JW, Vogt M, Saritas T, Kuppe C, Fuss A, Menzel S, Klinkhammer BM, Müller-Newen G, Heymann F, Decker L, Braun F, Kretz O, Huber TB, Susaki EA, Ueda HR, Boor P, Floege J, Kramann R, Kurts C, Bertram JF, Spehr M, Nikolic-Paterson DJ, and Moeller MJ
- Subjects
- Animals, Capillaries, Disease Models, Animal, Disease Progression, Fluorescence, Fluorescent Dyes chemistry, Genes, Reporter genetics, Glomerulonephritis immunology, Green Fluorescent Proteins chemistry, Green Fluorescent Proteins genetics, Humans, Male, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Podocytes ultrastructure, Glomerulonephritis pathology, Histocytological Preparation Techniques methods, Imaging, Three-Dimensional, Podocytes physiology, Single-Cell Analysis methods
- Abstract
Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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50. Topographic protein profiling of the age-related proteome in the retinal pigment epithelium of Callithrix jacchus with respect to macular degeneration.
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König S, Hadrian K, Schlatt S, Wistuba J, Thanos S, and Böhm MRR
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- Angiostatic Proteins, Animals, Basement Membrane chemistry, Callithrix, Inflammation, Mass Spectrometry methods, Molecular Chaperones, Oxidative Stress, Proteins analysis, Proteins physiology, Proteome metabolism, Proteomics methods, Retinal Pigment Epithelium chemistry, Aging physiology, Macular Degeneration pathology, Proteome analysis, Retinal Pigment Epithelium metabolism
- Abstract
In the retinal pigment epithelium (RPE) several factors within the macular compared to peripheral regions cause differences in physiological aging. The molecular mechanisms during aging in the context of topography are not well known. The proteome of RPE of different aged macular-bearing primates Callithrix jacchus was thus analysed with ion mobility mass spectrometry. Macular and periphery of neonate RPE were well differentiated from aged tissues as demonstrated by principal component analysis. This finding was mainly due to proteins involved in major developmental processes and the visual cycle. The distinction of adult from senile tissue and macular from periphery was more subtle. The hypotheses of inflammation increasing with age was supported. High expression levels of proteins related to oxidative stress (e.g., cathepsin B) and chaperones (e.g., HSP90) were detected in aged RPE as confirmed by Western blot and immunohistochemical analysis. Decreased levels of proteins participating in angiostatic properties (e.g., thrombospondin 1) and the integrity of tissue basement membranes with age (e.g., nidogen 1) were in agreement with neovascularization. This study presents targets for further investigations of the mechanisms of the aging process with the aim to elucidate predictive factors for the conversion of physiological aging into pathological conditions. SIGNIFICANCE: The current study characterized the different protein profiles of the retinal pigment epithelium (RPE) of the macula-bearing, non-human primate Callithrix jacchus during life-time. In addition, the subproteomes of macular and peripheral RPE were investigated. Differently expressed proteins described developmental processes in neonate tissue and destructive mechanisms in aged samples. Insights into the physiological aging process of the RPE and its conversion into pathophysiological conditions were gained. They assist in designing therapeutical approaches to counteract age-related diseases of the retina., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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