Institute of Chartered Accountants of Nigeria

About: Institute of Chartered Accountants of Nigeria is a based out in . It is known for research contribution in the topics: Population & Adipose tissue. The organization has 528 authors who have published 579 publications receiving 18688 citations.

Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production

Abstract: Background —Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix (ECM) proteins, including osteopontin (OPN), conducing to progressive interstitial fibrosis. While OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. Methods —OPN deficient mice (OPN-/-) with their WT littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by RT-PCR, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of the visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor Agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). Results —Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and TGFβ levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. Conclusions —During aging VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN9s role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

Role of common and rare variants in SCN10A: Results from the Brugada syndrome QRS locus gene discovery collaborative study

Abstract: Aims Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. Methods and results A multi-centre study sequenced seven candidate genes ( SCN10A , HAND1 , PLN , CASQ2 , TKT , TBX3 , and TBX5 ) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A , were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A ) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35–3.87), P = 8.07 × 10–19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak I Na compared with ancestral allele A1073 (rs6795970). Conclusion Rare variants in the screened QRS-associated genes (including SCN10A ) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

The SOS-framework (Systems of Sedentary behaviours): An international transdisciplinary consensus framework for the study of determinants, research priorities and policy on sedentary behaviour across the life course: A DEDIPAC-study

Abstract: Background Ecological models are currently the most used approaches to classify and conceptualise determinants of sedentary behaviour, but these approaches are limited in their ability to capture the complexity of and interplay between determinants. The aim of the project described here was to develop a transdisciplinary dynamic framework, grounded in a system-based approach, for research on determinants of sedentary behaviour across the life span and intervention and policy planning and evaluation. Methods A comprehensive concept mapping approach was used to develop the Systems Of Sedentary behaviours (SOS) framework, involving four main phases: (1) preparation, (2) generation of statements, (3) structuring (sorting and ranking), and (4) analysis and interpretation. The first two phases were undertaken between December 2013 and February 2015 by the DEDIPAC KH team (DEterminants of DIet and Physical Activity Knowledge Hub). The last two phases were completed during a two-day consensus meeting in June 2015. Results During the first phase, 550 factors regarding sedentary behaviour were listed across three age groups (i.e., youths, adults and older adults), which were reduced to a final list of 190 life course factors in phase 2 used during the consensus meeting. In total, 69 international delegates, seven invited experts and one concept mapping consultant attended the consensus meeting. The final framework obtained during that meeting consisted of six clusters of determinants: Physical Health and Wellbeing (71 % consensus), Social and Cultural Context (59 % consensus), Built and Natural Environment (65 % consensus), Psychology and Behaviour (80 % consensus), Politics and Economics (78 % consensus), and Institutional and Home Settings (78 % consensus). Conducting studies on Institutional Settings was ranked as the first research priority. The view that this framework captures a system-based map of determinants of sedentary behaviour was expressed by 89 % of the participants. Conclusion Through an international transdisciplinary consensus process, the SOS framework was developed for the determinants of sedentary behaviour through the life course. Investigating the influence of Institutional and Home Settings was deemed to be the most important area of research to focus on at present and potentially the most modifiable. The SOS framework can be used as an important tool to prioritise future research and to develop policies to reduce sedentary time.

Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue.

Abstract: Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity Human primary adipose tissue cells, including pre-adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1β and IL-17) and pro-fibrotic (TGF-β1) factors rIL-1β and rIL-17 induced concordant pro-inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1β than IL-17 None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-β1-induced up-regulation of extracellular matrix components and pro-fibrotic factors In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release IL-1β and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-β1 occurred in face of an anti-inflammatory signature These data revealed that IL-1β and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1β

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Abstract: Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.