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Metabolic programming determines the lineage-differentiation fate of murine bone marrow stromal progenitor cells

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Bone research 2019年第4期7卷 410-423页

作者： Michaela Tencerova Elizabeth Rendina-Ruedy Ditte Neess Nils Faergeman Florence Figeac Dalia Ali Morten Danielsen Anders Haakonsson Clifford J.Rosen Moustapha Kassem Department of Molecular Endocrinology University of Southern Denmark and Odense University Hospital5000 OdenseDenmark center for Molecular Medicine Maine Medical Center Research InstituteScarboroughME 04074USA Villum center for Analytical Biosciences Department of Biochemistry and Molecular BiologyUniversity of Southern Denmark5230 OdenseDenmark MSOmics 2950 CopenhagenDenmark Department of Cellular and Molecular Medicine Novo Nordisk Foundation Center for Stem Cell Biology(DanStem)University of Copenhagen2200 CopenhagenDenmark

Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation *** determine the molecular mechanisms,we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors(BMSCs^adipo and BMSC^sosteo,respectively)under basal and adipogenic culture *** baseline,BMSCs^adipo,and BMSCs^osteo exhibit a distinct metabolic program evidenced by the presence of specific global gene expression,cellular bioenergetics,and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs^osteo versus oxidative phosphorylation in BMSCs^*** test the flexibility of the metabolic program,we treated BMSCsadipo with parathyroid hormone,S961(an inhibitor of insulin signaling)and oligomycin(an inhibitor of oxidative phosphorylation).The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic ***,12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors,enhanced adipocyte differentiation and insulin signaling in cultured *** data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.

关键词： progenitor impaired programming

CRISPy-web: An online resource to design sgRNAs for CRISPR applications

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Synthetic and Systems Biotechnology 2016年第2期1卷 118-121页

作者： Kai Blin Lasse Ebdrup Pedersen TilmannWeber Sang Yup Lee The novo nordisk Foundation center for Biosustainability Technical University of DenmarkKogle Alle 62970 HosholmDenmark Metabolic and Biomolecular Engineering National research Laboratory Department of Chemical and Biomolecular Engineering(BK21 Plus Program)Center for Systems and Synthetic BiotechnologyInstitute for the BioCenturyKorea Advanced Institute of Science and Technology(KAIST)Daejeon 305-701Republic of Korea

CRISPR/Cas9-based genome editing has been one of the major achievements of molecular biology,allowing the targeted engineering of a wide range of *** system originally evolved in prokaryotes as an adaptive immune system against bacteriophage *** now sees widespread application in genome engineering workflows,especially using the Streptococcus pyogenes endonuclease *** utilize Cas9,so-called single guide RNAs(sgRNAs)need to be designed for each target *** there are many tools available to design sgRNAs for the popular model organisms,only few tools that allow designing sgRNAs for non-model organisms ***,we present CRISPy-web(http://***/),an easy to use web tool based on CRISPy to design sgRNAs for any userprovided microbial ***-web allows researchers to interactively select a region of their genome of interest to scan for possible *** checks for potential off-target matches,the resulting sgRNA sequences are displayed graphically and can be exported to text *** steps and information are accessible from a web browser without the requirement to install and use command line scripts.

关键词： CRISPR Cas9 sgRNA Guide RNA Genome editing Genome engineering

Identification and heterologous expression of the globomycin biosynthetic gene cluster

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Synthetic and Systems Biotechnology 2023年第2期8卷 206-212页

作者： Daniel Oves-Costales Tetiana Gren Eva Baggesgaard Sterndorff Jesús Martín Francisco Javier Ortiz-Lopez Tue S.Jørgensen Xinglin Jiang Fernando Roman-Hurtado Fernando Reyes Olga Genilloud Tilmann Weber Fundacion MEDINA Centro de Excelencia en Investigaci´on de Medicamentos Innovadores en AndalucíaAvda del Conocimiento 3418016ArmillaGranadaSpain The novo nordisk Foundation center for Biosustainability Technical University of DenmarkKemitorvetbuilding 2202800 Kgs.LyngbyDenmark

Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative *** mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II(LspA),which is absent in eukaryotes and considered an attractive target for the development of new *** its interesting biological properties,the gene cluster encoding its biosynthesis has not yet been *** this study we employed a genome-mining approach in the globomycin-producing Streptomyces ***-278952 to identify a candidate gene cluster responsible for its biosynthesis.A null mutant was constructed using CRISPR base editing where production was abolished,strongly suggesting its involvement in the *** putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146,therefore unambigu-ously linking globomycin and its biosynthetic gene *** work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties.

关键词： Globomycin Signal peptidase II Cyclic lipodepsipeptide Genome mining CRISPR-cBEST Heterologous expression

Spatial separation of phosphatase and kinase activity within the Bub complex is required for proper mitosis

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Journal of Molecular Cell Biology 2022年第11期14卷 24-35页

作者： Lei Wang Thomas Kruse Blanca López-Méndez Yuqing Zhang Chunlin Song Lei Zhu Bing Li Jing Fang Zhimin Lu Jakob Nilsson Gang Zhang The Cancer Institute The Affiliated Hospital of Qingdao UniversityQingdao UniversityQingdao 266061China novo nordisk Foundation center for Protein research Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark The Department of Genetics and Cell Biology Basic Medical CollegeQingdao UniversityQingdao 266061China Institute of Translational Medicine Zhejiang University School of MedicineHangzhou 310029China

The Bub1 and BubR1 kinetochore proteins support proper chromosome segregation and mitotic checkpoint activity. Bub1 and BubR1 are paralogs with Bub1 being a kinase, while BubR1 localizes the PP2A-B56 protein phosphatase to kinetochores in humans. Whether this spatial separation of kinase and phosphatase activity is important is unclear as some organisms integrate both activities into one Bub protein. Here, we engineer human Bub1 and BubR1 proteins integrating kinase and phosphatase activities into one protein and show that these do not support normal mitotic progression. A Bub1–PP2A-B56 complex can support chromosome alignment but results in impairment of the checkpoint due to dephosphorylation of the Mad1 binding site in Bub1. Furthermore, a chimeric BubR1 protein containing the Bub1 kinase domain induces delocalized H2ApT120 phosphorylation, resulting in the reduction of centromeric hSgo2 and chromosome segregation errors. Collectively, these results argue that the spatial separation of kinase and phosphatase activities within the Bub complex is required for balancing its functions in the checkpoint and chromosome alignment.

关键词： mitosis spindle assembly checkpoint kinetochores Bub1 BubR1 PP2A/B56

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3063-3072页

作者： Yi Zhu Na Li Mingyang Huang Xi Chen Yu AAn Jianping Li Shangang Zhao Jan-Bernd Funck Jianhong Cao Zhenyan He Qingzhang Zhu Zhuzhen Zhang Zhao VWang Lin Xu Kevin W.Williams Chien Li Kevin Grove Philipp E.Scherer Touchstone Diabetes center Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Cardiology Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Hypothalamic research Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Quantitative Biomedical research center Department of Population and Data Sciencesthe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Department of Pediatrics the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA novo nordisk research center SeattleWA 98109USA Children’s Nutrition research center Department of PediatricsBaylor College of MedicineHoustonTX 77030USA Department of Cell Biology the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA

Adipose tissue is a promising target for treating obesity and metabolic ***,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese *** have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple *** reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose *** an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and ***,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced *** light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage ***,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

关键词： GJA1 Adipose tissue Gap junction Connexin43 FGF21 β3-Adrenergic receptor agonist Obesity Type 2 diabetes

Comparison of Two Chemically-Induced Colitis-Models in Adult Zebrafish, Using Optical Projection Tomography and Novel Transcriptional Markers

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Open Journal of Immunology 2016年第4期6卷 154-180页

作者： Simon Haarder Per W. Kania Thomas Lindebo Holm Maki Ohtani Kurt Buchmann novo nordisk-LIFE In Vivo Pharmacology Centre Frederiksberg Denmark Laboratory of Aquatic Pathobiology Department of Veterinary Disease Biology Faculty of Health and Medical Sciences University of Copenhagen Frederiksberg Denmark Global research Novo Nordisk A/S Malov Denmark

Crohn’s disease and ulcerative colitis—inflammatory bowel diseases (IBD)—are chronic conditions with an inadequately understood pathogenesis. Employing a set of novel molecular markers in a gene expression assay (qPCR), we have used adult zebrafish to investigate two acute inflammatory models, induced by the haptenizing agents oxazolone and TNBS. In addition, goblet cell dynamics in the scales and intestine and 5-HT (serotonin) in intestinal tissues were investigated through optical projection tomography. Gene expression studies revealed a distinct and significant upregulation of proinflammatory cytokines, acute-phase reactants and metalloprotease 9 in both chemical models, primarily after 72 hours. In comparison, transcription factors and cytokines associated with Th1 and Th17 (Crohn’s) and Th2 (ulcerative colitis) were mainly not affected in this acute setting. However, elevated transcript levels were detected in Foxp3, IL-10 and T-bet, which are linked with tolerance and Tregs in mammals. Goblet cells in scales were depleted in both chemical models and in the intestine of oxazolone-treated fish. A marked 5-HT signal was noted in intestinal tissue of some chemically treated zebrafish. In conclusion, a distinct acute inflammatory reaction was induced in both chemical models. Further, oxazolone and TNBS did not result in clear-cut Th2 and Th1/Th17 pathway signaling at this early timepoint, but the applied molecular tools may provide further insight to the IBD pathogenesis and translational value of the IBD zebrafish model.

关键词： IBD Zebrafish qPCR Disease Model OPT

Discovery of gargantulides B and C,new 52-membered macrolactones from Amycolatopsis *** absolute stereochemistry of the gargantulide family

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Organic Chemistry Frontiers 2022年第2期9卷 462-470页

作者： Daniel Carretero-Molina Francisco Javier Ortiz-López Tetiana Gren Daniel Oves-Costales Jesús Martín Fernando Román-Hurtado Tue Sparholt Jorgensen Mercedes de la Cruz Caridad Díaz Francisca Vicente Kai Blin Fernando Reyes Tilmann Weber Olga Genilloud Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en AndalucíaAvda.del Conocimiento 3418016 ArmillaGranadaSpain The novo nordisk Foundation center for Biosustainability Technical University of DenmarkKemitorvetbuilding 2202800 Kgs.LyngbyDenmark

Gargantulides B and C,two new and highly complex 52-membered glycosylated macrolactones,were isolated from Amycolatopsis *** CA-230715 during an antibacterial screening *** structures of these giant macrolides were elucidated by 2D NMR spectroscopy and shown to be related to gargantulide A,although containing additional β-glucopyranose and/orα-arabinofuranose monosaccharides separately attached to their *** sequencing allowed the identification of a strikingly large 216 kbp biosynthetic gene cluster,among the largest type Ⅰ PKS clusters described so far,and the proposal of a previously unreported biosynthetic pathway for gargantulides *** absolute configurations of gargantulides B and C were assigned based on a combination of NMR and bioinformatics analysis of ketoreductase and enoylreductase domains within the multimodular type Ⅰ *** addition,the absolute stereochemistry of gargantulide A has now been revised and *** B and C display potent antibacterial activity against a set of drug-resistant Gram-positive bacteria and moderate activity against the clinically relevant Gram-negative pathogen Acinetobacter baumannii.

关键词： absolute membered backbone

THE EFFECT OF COUPLED FEEDBACK ON NOISE FILTERING IN SIGNAL TRANSDUCTION NETWORKS

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Journal of Systems Science & Complexity 2010年第5期23卷 942-950页

作者： Dengyu LIU Xiao CHANG Zengrong LIU Luonan CHEN Ruiqi WANG Institute of Systems Biology Shanghai University Shanghai 200444 China College of Physics and Mathematics Jinggangshan University Ji'an 343009 China Institute of Systems Biology Shanghai University Shanghai 200444 China Key Laboratory of Systems Biology SIBS-Novo Nordisk Translational Research Centre for PreDiabetes Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China

Many interacting biomolecular components in cells form different positive or negative feedback loops. When biological signals transduce through cascades consisting of various loops they will be affected or even distorted. Especially, how to process various signals buried in various intrinsic and extrinsic noises is an important issue. This paper analyzes how the response time influences noise filtering ability and how to enhance the ability by coupling different feedback loops. A parameter to measure the response time of the signal transduction, i.e., τ0.9, and its relationship between the response time and noise filtering will be discussed. The authors show clearly that the longer the response time is, the better the ability to filter noises will be. Therefore, to enhance the ability to filter noises, the authors can prolong the response time by coupling different positive or negative feedback loops. The results provide a possible approach to enhance the ability to filter noises in larger biomolecular networks.

关键词： Coupled feedback filtering noises response time signal cycle.

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2018年第2期24卷 179-194页

作者： Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh Gubra Aps Horsholm DK-2970Denmark Department of Biomedical Sciences Faculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Section for Metabolic Imaging and Liver Metabolism The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Department of Chemistry Faculty of ScienceUniversity of CopenhagenCopenhagen DK-2200Denmark

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of *** Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 *** Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid *** DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical d

关键词： Nonalcoholic steatohepatitis Disease models Pathology Fibrosis Liver biopsy Transcriptomics Pharmacodynamics Glucagon-like peptide-1 receptor Peroxisome proliferator-activated receptor Farnesoid X receptor