| 1. |
- Murugesan, Vignesh
(författare)
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Challenging the mystique Connection. Deciphering cell-matrix interactions role in atherosclerosis and restenosis.
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is the underlying cause for myocardal infarction, stroke and peripheral arterial disease, collectively referred to as cardiovascular diseases. These represent the major cause of death globally. Phenotypic modulationof vascular smooth muscle cells form a contractile to a synthetic state and subsequent migration into the intima, isone of the prime events that marks the genesis of atherosclerosis. To effectuate, cells are required to weaken the connection with their own basment membrane, a network of extracellular matrix molecules. This thesis exploresthe importance of Cell-ECM connections in atherosclerotic and restenostic settings using mice as a model. In detail, this thesis discusses the role of dystrophin and beta-sarcoglycan, two important components of theDystrophin-glycoprotein complex — one important way cells use to communicate with basement membranes.In paper I & II, we investigated whether beta-sarcoglycan has a role in the development of atherosclerotic plaquesand vascular injury induced neointima formation. Much to our surprise, we found that the absence of betasarcoglycanreduced advanced atherosclerotic plaque development, and in contrast, stimulated neo-intimalhyperplasia under conditions involving the presence or absence of an ApoE-deficient background, respectively.Under an atherosclerotic setting, the relative area of differentiated smooth muscle cells in the plaques wasincreased in beta-sarcoglycan deficient mice. Further, deficiency of beta-sarcoglycan decreased the weight ofvisceral adipose tissue and reduced the size of both brown and white adipocytes.In paper III, we utilized mdx mice to determine if there is also a role for dystrophin in the process of atheroscleroticplaque development. We obtained similar results as in the study with sarcoglycan deficient mice; the mdx miceexhibited a significant attenuation of advanced atherosclerotic plaque growth with an increase in the relative areaof differentiated smooth muscle cells in their plaques. A reduction in T-cell content in these plaques and an overallreduction in systemic inflammation was also observed.In paper IV, we observed that actin dynamics influence genes important for regulation of VSMC phenotypes andfound dystrophin to be significantly increased and decreased by actin polymerization and depolymerization,respectively. A significant downregulation of dystrophin was observed under the influence of vascular injury.To summarize, this thesis uncovers the important influence of a functional CELL-ECM linkage mediated bydystrophin and beta-sarcoglycan on vascular lesion development.
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| 2. |
- Murugesan, Vignesh, et al.
(författare)
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β-Sarcoglycan Deficiency Reduces Atherosclerotic Plaque Development in ApoE-Null Mice
- 2017
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 54, s. 235-245
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smooth muscle cells are important for atheroscleroticplaque stability. Their proper ability to communicatewith the extracellular matrix is crucial for maintainingthe correct tissue integrity. In this study, we have investigatedthe role of β-sarcoglycan within the matrix-binding dystrophin-glycoproteincomplex in the development of atherosclerosis.Results: Atherosclerotic plaque developmentwas significantly reduced in ApoE-deficient mice lackingβ-sarcoglycan, and their plaques contained an increase indifferentiated smooth muscle cells. ApoE-deficient micelacking β-sarcoglycan showed a reduction in ovarian adiposetissue and adipocyte size, while the total weight of theanimals was not significantly different. Western blot analysisof adipose tissues showed a decreased activation of proteinkinase B, while that of AMP-activated kinase was increasedin mice lacking β-sarcoglycan. Analysis of plasma in β-sarcoglycan-deficientmice revealed reduced levels of leptin,adiponectin, insulin, cholesterol, and triglycerides but in-creased levels of IL-6, IL-17, and TNF-α. Conclusions: Our resultsindicate that the dystrophin-glycoprotein complex andβ-sarcoglycan can affect the atherosclerotic process. Furthermore,the results show the effects of β-sarcoglycan deficiencyon adipose tissue and lipid metabolism, which mayalso have contributed to the atherosclerotic plaque reduction.
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| 3. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Clinical characteristics and novel mutations of omicron subvariant XBB in Tamil Nadu, India - a cohort study
- 2023
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Ingår i: The Lancet Regional Health - Southeast Asia. - : ELSEVIER. - 2772-3682. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite the continued vaccination efforts, there had been a surge in breakthrough infections, and the emergence of the B.1.1.529 omicron variant of SARS-CoV-2 in India. There is a paucity of information globally on the role of newer XBB variants in community transmission. Here, we investigated the mutational patterns among hospitalised patients infected with the XBB omicron sub-variant, and checked if there was any association between the rise in the number of COVID-19 cases and the observed novel mutations in Tamil Nadu, India. Methods Nasopharyngeal and oropharyngeal swabs, collected from symptomatic and asymptomatic COVID-19 patients were subjected to real-time PCR followed by Next Generation Sequencing (NGS) to rule out the ambiguity of mutations in viruses isolated from the patients (n = 98). Using the phylogenetic association, the mutational patterns were used to corroborate clinico-demographic characteristics and disease severity among the patients. Findings Overall, we identified 43 mutations in the S gene across 98 sequences, of which two were novel mutations (A27S and T747I) that have not been reported previously with XBB sub-variants in the available literature. Additionally, the XBB sequences from our cohort had more mutations than omicron B.1.1.529. The phylogenetic analysis comprising six major branches clearly showed convergent evolution of XBB. Our data suggests that age, and underlying conditions (e.g., diabetes, hypertension, and cardiovascular disease) or secondary complications confers increased susceptibility to infection rather than vaccination status or prior exposure. Many vaccinated individuals showed evidence of a breakthrough infection, with XBB.3 being the predominant variant identified in the study population. Interpretation Our study indicates that the XBB variant is highly evasive from available vaccines and may be more transmissible, and potentially could emerge as the 'next' predominant variant, which likely could overwhelm the existing variants of SARS-CoV-2 omicron variants.Funding National Health Mission (India), SIDA SARC, VINNMER (Sweden), ORIP/NIH (USA).Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 4. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Evolution of the Omicron B.1.1.529 Sars-Cov-2 and its Variants in Tamil Nadu, India – a State-Wide Prospective Longitudinal Genomic Surveillance
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The emergence of the omicron SARS-CoV-2 variant beholding many mutations, especially in the spike (S) protein severely threatens global health. With an aim to understand the mutational pattern of the variant and its genetic interrelationship in the Indian population, here we prospectively followed the viral evolution and transmission between December 2021 and March 2023 in Tamil Nadu.Methods: A total of 11526 nasopharyngeal and oropharyngeal swabs (6431 males, 5095 females including 603 children) collected from across the 38 districts of Tamil Nadu were subjected to WGS. Of the 10663 samples (92.5%) positive for omicron variants, 1688 were sequenced at the State Public Health Laboratory. We longitudinally studied the evolutionary dynamics of the different omicron variants, starting from the first detected case (B.1.1.529) to the recently reported recombinant XBB variants by sequencing the S gene and by performing phylo-geographic and molecular modeling analyses.Findings: Administration of a booster dose was associated with reduced risk of hospitalization and death. BA.1 sub-variants and BA.2.75 were associated with increased risk of severe disease, whereas BA.1 and BA.2 were associated with increased risk of death. High quality WGS data from 150 samples revealed six major omicron clusters and several other sub-clusters. Seven variants in the same BA lineages with different divergences in the S protein were noticed. Of the 5009 mutations detected, the highest was seen in the receptor-binding domain (RBD) followed by the N-terminal domain (NTD) in varying proportions among the different omicron lineages. Importantly, the mutations were observed in the sub-domain (SD1/2) furin cleavage site, fusion peptide (FP), and the heptapeptide repeat sequence (HR1) regions. Notably, unique mutations Y473I, P479F, C480F, V483T, E484C, G485T, P491G, L492K, S494M, Y495C, and G496Q were detected in BA.2.43 whereas A475Q and T478S occurred in the RBD domain of the BA.2.43 variant. The XBB variant showed 41 different mutations between the HR1 and HR2 domains of the S2 subunit. Molecular modeling using BA.2 lineage as a template for seven divergent proteins showed that BA.2.12.1, BA.4 and BA.5 exhibited strong binding affinity towards ACE2.Interpretation: The high frequency of mutations in the RBD highlights the wider distribution of vaccine escape-variants that would impact the structural and functional attributes of the omicron variant in the population. Further, our work provides key insights on the evolutionary pattern leading to the identification of seven divergent variants of omicron in Tamil Nadu, India.
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| 5. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Genomic surveillance of omicron B.1.1.529 SARS‐CoV‐2 and its variants between December 2021 and March 2023 in Tamil Nadu, India—A state‐wide prospective longitudinal study
- 2024
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Ingår i: Journal of Medical Virology. - : John Wiley & Sons. - 0146-6615 .- 1096-9071. ; 96:2
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Tidskriftsartikel (refereegranskat)abstract
- A state-wide prospective longitudinal investigation of the genomic surveillance of the omicron B.1.1.529 SARS-CoV-2 variant and its sublineages in Tamil Nadu, India, was conducted between December 2021 and March 2023. The study aimed to elucidate their mutational patterns and their genetic interrelationship in the Indian population. The study identified several unique mutations at different time-points, which likely could attribute to the changing disease characteristics, transmission, and pathogenicity attributes of omicron variants. The study found that the omicron variant is highly competent in its mutating potentials, and that it continues to evolve in the general population, likely escaping from natural as well as vaccine-induced immune responses. Our findings suggest that continuous surveillance of viral variants at the global scenario is warranted to undertake intervention measures against potentially precarious SARS-CoV-2 variants and their evolution.
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| 6. |
- Selvavinayagam, Sivaprakasam T, et al.
(författare)
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Plasma CXCL8 and MCP-1 as biomarkers of latent tuberculosis infection
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundEarly detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy.Methods We investigated whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. We also measured the plasma cytokines using a commercial Bio-Plex Pro Human Cytokine 17-plex assay.ResultsIncreased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold.ConclusionsWe postulated that CXCL8 and MCP-1 could be the surrogate biomarkers of LTBI, especially in resource-limited settings.
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| 7. |
- Selvavinayagam, Sivaprakasam T, et al.
(författare)
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Plasma CXCL8 and MCP-1 as surrogate plasma biomarkers of latent tuberculosis infection among household contacts-A cross-sectional study
- 2023
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Ingår i: PLOS Global Public Health. - : Public Library of Science (PLoS). - 2767-3375. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. The study investigates whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. The plasma cytokines were measured using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Increased plasma CXCL8 and decreased MCP-1, TNF-a, and IFN-? were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Our study suggests that CXCL-8 and MCP-1 could serve as the surrogate biomarkers of LTBI, particularly in resource-limited settings. Further laboratory investigations are warranted before extrapolating CXCL8 and MCP-1 for their usefulness as surrogate biomarkers of LTBI in resource-limited settings.
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| 8. |
- Shami, Annelie, et al.
(författare)
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Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.
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| 9. |
- Turczynska, Karolina, et al.
(författare)
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Regulation of Smooth Muscle Dystrophin and Synaptopodin 2 Expression by Actin Polymerization and Vascular Injury.
- 2015
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 35:6, s. 1489-1497
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Tidskriftsartikel (refereegranskat)abstract
- Actin dynamics in vascular smooth muscle is known to regulate contractile differentiation and may play a role in the pathogenesis of vascular disease. However, the list of genes regulated by actin polymerization in smooth muscle remains incomprehensive. Thus, the objective of this study was to identify actin-regulated genes in smooth muscle and to demonstrate the role of these genes in the regulation of vascular smooth muscle phenotype.
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| 10. |
- Yong, Yean K., et al.
(författare)
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Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161(++)TCR iV alpha 7.2(+) Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection
- 2018
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells, defined as CD161(++) TCR iV alpha 7.2(+) T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3(+)CD161(++)TCR iV alpha 7.2(+) MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVa7.2+ CD161(+) MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4(+) T cells and MAIT cells and with CD57 on CD8(+) T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iV alpha 7.2(+) MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.
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