105 results found
Behmoaras J, Petretto E, 2018, Cell function in disease: there are more than two parties at play., Ann Rheum Dis
Moreno-Moral A, Bagnati M, Koturan S, et al., 2018, Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk, ANNALS OF THE RHEUMATIC DISEASES, Vol: 77, Pages: 596-601, ISSN: 0003-4967
Olona A, Terra X, Ko J-H, et al., 2018, Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis., Mol Metab, Vol: 11, Pages: 18-32
OBJECTIVE: When molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis. The role of arachidonic acid (AA) and its downstream enzymatic cascades, such as cyclooxygenase, in adipogenesis is well established. The exact contribution of the P450 epoxygenase pathway, however, remains to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus which shows extensive allelic expansion in mice. Here we aimed to establish the role of endogenous epoxygenase during adipogenesis under homeostatic and metabolic stress conditions. METHODS: We took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and used a Cyp2j4 (orthologue of human CYP2J2) knockout rat in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4-/- rats under CAF was integrated with proteomics (LC-MS/MS) and lipidomics (LC-MS) analyses in the liver and the adipose tissue. RESULTS: We report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterized by (i) down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, (ii) adipocyte hypertrophy, (iii) extracellular matrix remodeling, and (iv) alternative usage of AA pathway. Specifically, in Cyp2j4-/- rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid accumulation, and dysregulated gluconeogenesis. CONCLUSION: These results suggest that AA epoxygenases are essential regulators of healthy adipogenesis. Our results uncover their synergistic role in fine-tuning AA pathway in obesity-mediated hepatic steatosis.
Pereira M, Petretto E, Gordon S, et al., 2018, Common signalling pathways in macrophage and osteoclast multinucleation., J Cell Sci, Vol: 131
Macrophage cell fusion and multinucleation are fundamental processes in the formation of multinucleated giant cells (MGCs) in chronic inflammatory disease and osteoclasts in the regulation of bone mass. However, this basic cell phenomenon is poorly understood despite its pathophysiological relevance. Granulomas containing multinucleated giant cells are seen in a wide variety of complex inflammatory disorders, as well as in infectious diseases. Dysregulation of osteoclastic bone resorption underlies the pathogenesis of osteoporosis and malignant osteolytic bone disease. Recent reports have shown that the formation of multinucleated giant cells and osteoclast fusion display a common molecular signature, suggesting shared genetic determinants. In this Review, we describe the background of cell-cell fusion and the similar origin of macrophages and osteoclasts. We specifically focus on the common pathways involved in osteoclast and MGC fusion. We also highlight potential approaches that could help to unravel the core mechanisms underlying bone and granulomatous disorders in humans.
Rodriguez-Martinez A, Posma JM, Ayala R, et al., 2018, MWASTools: an R/bioconductor package for metabolome-wide association studies, BIOINFORMATICS, Vol: 34, Pages: 890-892, ISSN: 1367-4803
Sigmundsson K, Ojala JRM, Öhman MK, et al., 2018, Culturing functional pancreatic islets on α5-laminins and curative transplantation to diabetic mice., Matrix Biol
The efficacy of islet transplantation for diabetes treatment suffers from lack of cadaver-derived islets, islet necrosis and long transfer times prior to transplantation. Here, we developed a method for culturing mouse and human islets in vitro on α5-laminins, which are natural components of islet basement membranes. Adhering islets spread to form layers of 1-3 cells in thickness and remained normoxic and functional for at least 7 days in culture. In contrast, spherical islets kept in suspension developed hypoxia and central necrosis within 16 h. Transplantation of 110-150 mouse islets cultured on α5-laminin-coated polydimethylsiloxane membranes for 3-7 days normalized blood glucose already within 3 days in mice with streptozotocin-induced diabetes. RNA-sequencing of isolated and cultured mouse islets provided further evidence for the adhesion and spreading achieved with α5-laminin. Our results suggest that use of such in vitro expanded islets may significantly enhance the efficacy of islet transplantation treatment for diabetes.
Solimena M, Schulte AM, Marselli L, et al., 2018, Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes, DIABETOLOGIA, Vol: 61, Pages: 641-657, ISSN: 0012-186X
Beltrami C, Besnier M, Shantikumar S, et al., 2017, Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis, MOLECULAR THERAPY, Vol: 25, Pages: 679-693, ISSN: 1525-0016
Chen T-D, Rotival M, Chiu L-Y, et al., 2017, Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function, GENETICS, Vol: 206, Pages: 1139-1151, ISSN: 0016-6731
Coan PM, Hummel O, Diaz AG, et al., 2017, Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat, DISEASE MODELS & MECHANISMS, Vol: 10, Pages: 297-306, ISSN: 1754-8403
Heinig M, Adriaens ME, Schafer S, et al., 2017, Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
Imprialou M, Petretto E, Bottolo L, 2017, Expression QTLs Mapping and Analysis: A Bayesian Perspective., Pages: 189-215
The aim of expression Quantitative Trait Locus (eQTL) mapping is the identification of DNA sequence variants that explain variation in gene expression. Given the recent yield of trait-associated genetic variants identified by large-scale genome-wide association analyses (GWAS), eQTL mapping has become a useful tool to understand the functional context where these variants operate and eventually narrow down functional gene targets for disease. Despite its extensive application to complex (polygenic) traits and disease, the majority of eQTL studies still rely on univariate data modeling strategies, i.e., testing for association of all transcript-marker pairs. However these "one at-a-time" strategies are (1) unable to control the number of false-positives when an intricate Linkage Disequilibrium structure is present and (2) are often underpowered to detect the full spectrum of trans-acting regulatory effects. Here we present our viewpoint on the most recent advances on eQTL mapping approaches, with a focus on Bayesian methodology. We review the advantages of the Bayesian approach over frequentist methods and provide an empirical example of polygenic eQTL mapping to illustrate the different properties of frequentist and Bayesian methods. Finally, we discuss how multivariate eQTL mapping approaches have distinctive features with respect to detection of polygenic effects, accuracy, and interpretability of the results.
Krishnan ML, Van Steenwinckel J, Schang A-L, et al., 2017, Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
McDermott-Roe C, Leleu M, Rowe GC, et al., 2017, Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function, PLOS ONE, Vol: 12, ISSN: 1932-6203
Moreno-Moral A, Pesce F, Behmoaras J, et al., 2017, Systems Genetics as a Tool to Identify Master Genetic Regulators in Complex Disease., Pages: 337-362
Systems genetics stems from systems biology and similarly employs integrative modeling approaches to describe the perturbations and phenotypic effects observed in a complex system. However, in the case of systems genetics the main source of perturbation is naturally occurring genetic variation, which can be analyzed at the systems-level to explain the observed variation in phenotypic traits. In contrast with conventional single-variant association approaches, the success of systems genetics has been in the identification of gene networks and molecular pathways that underlie complex disease. In addition, systems genetics has proven useful in the discovery of master trans-acting genetic regulators of functional networks and pathways, which in many cases revealed unexpected gene targets for disease. Here we detail the central components of a fully integrated systems genetics approach to complex disease, starting from assessment of genetic and gene expression variation, linking DNA sequence variation to mRNA (expression QTL mapping), gene regulatory network analysis and mapping the genetic control of regulatory networks. By summarizing a few illustrative (and successful) examples, we highlight how different data-modeling strategies can be effectively integrated in a systems genetics study.
Nefzger CM, Rossello FJ, Chen J, et al., 2017, Cell Type of Origin Dictates the Route to Pluripotency, CELL REPORTS, Vol: 21, Pages: 2649-2660, ISSN: 2211-1247
Petretto E, 2017, Genetics of Neurodevelopmental Disorders: Connecting The Dots in The Brain, 18th International Congress of Developmental Biology, Publisher: ELSEVIER SCIENCE BV, Pages: S4-S4, ISSN: 0925-4773
Rackham OJL, Langley SR, Oates T, et al., 2017, A Bayesian Approach for Analysis of Whole-Genome Bisulfite Sequencing Data Identifies Disease-Associated Changes in DNA Methylation, GENETICS, Vol: 205, Pages: 1443-1458, ISSN: 0016-6731
Schafer S, Viswanathan S, Widjaja AA, et al., 2017, IL-11 is a crucial determinant of cardiovascular fibrosis, NATURE, Vol: 552, Pages: 110-+, ISSN: 0028-0836
Srivastava PK, Bagnati M, Delahaye-Duriez A, et al., 2017, Genome-wide analysis of differential RNA editing in epilepsy, GENOME RESEARCH, Vol: 27, Pages: 440-450, ISSN: 1088-9051
Srivastava PK, Roncon P, Lukasiuk K, et al., 2017, Meta-Analysis of MicroRNAs Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy, ENEURO, Vol: 4, ISSN: 2373-2822
Suresh J, Harmston N, Lim KK, et al., 2017, An embryonic system to assess direct and indirect Wnt transcriptional targets, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Delahaye-Duriez A, Srivastava P, Shkura K, et al., 2016, Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery, GENOME BIOLOGY, Vol: 17, ISSN: 1474-760X
Diaz-Montana JJ, Rackham OJL, Diaz-Diaz N, et al., 2016, Web-based Gene Pathogenicity Analysis (WGPA): a web platform to interpret gene pathogenicity from personal genome data, BIOINFORMATICS, Vol: 32, Pages: 635-637, ISSN: 1367-4803
Johnson MR, Shkura K, Langley SR, et al., 2016, Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease, NATURE NEUROSCIENCE, Vol: 19, Pages: 223-+, ISSN: 1097-6256
Lewin A, Saadi H, Peters JE, et al., 2016, MT-HESS: an efficient Bayesian approach for simultaneous association detection in OMICS datasets, with application to eQTL mapping in multiple tissues, BIOINFORMATICS, Vol: 32, Pages: 523-532, ISSN: 1367-4803
Madan B, Ke Z, Harmston N, et al., 2016, Wnt addiction of genetically defined cancers reversed by PORCN inhibition, ONCOGENE, Vol: 35, Pages: 2197-2207, ISSN: 0950-9232
Martinez-Micaelo N, Gonzalez-Abuin N, Ardevol A, et al., 2016, Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 56, Pages: 1-10, ISSN: 0952-5041
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