Type 2 diabetes (T2D) is a complex disease with an elusive link between its molecular aetiology and clinical presentation. Although, the role of visceral adipose tissue in insulin-resistance and T2D is known, limited information is available on the role of peripheral-subcutaneous adipose tissue especially in Asian Indians. In this microarray-based study of diabetic and normal glucose tolerant Asian Indians, we generated the transcriptome of their thigh adipose tissue and analyzed differentially expressed genes (DEGs) using weighted gene co-expression network analysis; further we identified perturbed pathways implicated by these DEGs in relevant co-expression modules. We also attempted to link these pathways with known aspects of T2D pathophysiology in terms of their association with some of their intermediate traits, namely; adipocyte size, HOMA-B, HOMA-R, Hb1Ac, insulin, glucose-level, TNF-α, IL-6, VLDLs, LDLs, HDLs, and NEFAs. It was observed that several modules of co-expressed genes show an association with diabetes and some of its intermediate phenotypic traits mentioned above. Therefore, these findings suggest a role of peripheral subcutaneous adipose tissue in the pathophsiology of T2D in Asian Indians. Additionally, our study indicated that the peripheral subcutaneous adipose tissue in diabetics shows pathologic changes characterized by adipocyte hypertrophy and up-regulation of inflammation-related pathways.

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Background: Mycobacterium ulcerans is the fundamental agent of the third most common Mycobacterial disease known as Buruli Ulcer (BU). It is an infection of the skin and soft tissue affecting the human population worldwide. Presently, the vaccine is not available against BU. Objective: This study aimed to investigate the vaccine potential of virulence proteins of M. ulcerans computationally. Methods: Chromosome encoded virulence proteins of Mycobacterium ulcerans strain Agy99 were selected, which were available at the VFDB database. These proteins were analyzed for their subcellular localization, antigenicity, and human non-homology analysis. Ten virulence factors were finally chosen and analyzed for further study. Three-dimensional structures for selected proteins were predicted using Phyre2. B cell and T cell epitope analysis was done using methods available at Immune Epitope Database and Analysis Resource. Antigenicity, allergenicity, and toxicity analysis were also done to predict epitopes. Molecular docking analysis was done for T cell epitopes, those showing overlap with B cell epitopes. Results: Selected virulence proteins were predicted with B cell and T cell epitopes. Some of the selected proteins were found to be already reported as antigenic in other mycobacteria. Some of the predicted epitopes also had similarities with experimentally identified epitopes of M. ulcerans and M. tuberculosis which further supported our predictions. Conclusion : In-silico approach used for the vaccine candidate identification predicted some virulence proteins that could be proved important in future vaccination strategies against this chronic disease. Predicted epitopes require further experimental validation for their potential use as peptide vaccines.

The prevalence of Type 2 Diabetes has reached an epidemic proportion particularly in south Asian countries. We have earlier shown that the anatomical fat distribution, termed ‘thin fat phenotype’ in this population indeed plays a major role for their T2D-predisposition it is indeed the sick fat or adiposopathy, which is the root cause of metabolic syndrome and diabetes and affects both—peripheral, as well as visceral adipose tissue compartments. In present study, we have attempted to unravel the altered regulatory mechanisms at the level of transcription factors, and miRNAs those may likely accounts to T2D pathophysiology in femoral subcutaneous adipose tissue. We prioritized transcription factors and protein kinases as likely upstream regulators of obtained differentially expressed genes in this RNA-seq study. An inferred network of these upstream regulators was then derived and the role of TFs and miRNAs in T2D pathophysiology was explored. In conclusions, this RNS-Seq study finds that peripheral subcutaneous adipose tissue among Asian Indians show pathology characterized by altered lipid, glucose and protein metabolism, adipogenesis defect and inflammation. A network of regulatory transcription factors, protein kinases and microRNAs have been imputed which converge on the process of adipogenesis. As the majority of these genes also showed altered expression in diabetics and some of them are also circulatory, therefore they deserve further investigation for potential clinical diagnostic and therapeutic applications.

We performed a systematic analysis of genes implicated in thigh subcutaneous adipose tissue of Asian Indian Type 2 Diabetes Mellitus (AIT2DM) and created a phenome-interactome network. This analysis was performed on 60 subjects specific to limb thigh fat by integrating phenotypic traits and similarity scores associated with AIT2DM. Using a phenotypic attribute, a contextual neighbor was identified across all the traits, viz. body mass index (BMI) statistics, adipocyte size, lipid parameters, homeostatic model assessment- insulin resistance (HOMA-IR), HOMA-ß. In this work, we have attempted to characterize transcription signatures using the phenome-interactome maps where each of the traits under study including the intermediary phenotypes has a distinct set of genes forming the hubs. Furthermore, we have identified various clinical, biochemical, and radiological parameters which show significant correlation with distinct hubs. We observed a number of novel pathways and genes including those that are non-coding RNAs implicated in AIT2DM.We showed that they appear to be associated with pathways, viz. tyrosine kinase JAK2, NOTCH thereby recruiting signaling molecules such as STAT5 and Src family kinases on the cell surface regulated them and our analyses comprising significant hubs suggest that thigh subcutaneous adipose tissue plays a role in pathophysiology of AIT2DM.

The roles of abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) in the molecular pathogenesis type-2 diabetics (T2D) among Asian Indians showing a “thin fat” phenotype largely remains obscure. In this study, we generated transcription profiles in biopsies of these adipose depots obtained during surgery in 19 diabetics (M: F ratio, 8:11) and 16 (M: F ratio 5:11) age- and BMI-matched non-diabetics. Gene set enrichment analysis (GSEA) was used for comparing transcription profile and showed that 19 gene sets, enriching inflammation and immune system-related pathways, were upregulated in diabetics with F.D.R. <25% and >25%, respectively, in VAT and SAT. Moreover, 13 out of the 19 significantly enriched pathways in VAT were among the top 20 pathways in SAT. On comparison of VAT vs. SAT among diabetics, none of the gene sets were found significant at F.D.R. <25%. The Weighted Gene Correlation Analysis (WGCNA) analysis of the correlation between measures of average gene expression and overall connectivity between VAT and SAT was significantly positive. Several modules of co-expressed genes in both the depots showed a bidirectional correlation with various diabetes-related intermediate phenotypic traits. They enriched several diabetes pathogenicity marker pathways, such as inflammation, adipogenesis, etc. It is concluded that, in Asian Indians, diabetes pathology inflicts similar molecular alternations in VAT and SAT, which are more intense in the former. Both adipose depots possibly play a role in the pathophysiology of T2D, and whether it is protective or pathogenic also depends on the nature of modules of co-expressed genes contained in them.

Background: Type 2 diabetes (T2D) is a common multi-factorial disease that is primarily ac-counted to ineffective insulin action in lowering blood glucose level and later escalates to impaired insu-lin secretion by pancreatic β cells. Deregulation in insulin signaling to its target organs is attributed to this disease phenotype. Various genome-wide microarray studies from multiple insulin responsive tis-sues have been conducted in past but due to inherent noise in microarray data and heterogeneity in dis-ease etiology; reproduction of prioritized pathways/genes is very low across various studies.Objective: In this study, we aim to identify consensus signaling and metabolic pathways through system level meta-analysis of multiple expression-sets to elucidate T2D pathobiology.Method: We used ‘R’, an open source statistical environment, which is routinely used for Microarray data analysis particularly using special sets of packages available at Bioconductor. We primarily focused on gene-set analysis methods to elucidate various aspects of T2D.Result: Literature-based evidences have shown the success of our approach in exploring various known aspects of diabetes pathophysiology.Conclusion: Our study stressed the need to develop novel bioinformatics workflows to advance our understanding further in insulin signaling

: Inborn errors of metabolism (IEM) are heterogeneous group of rare genetic disorders which are generally transmitted as autosomal or X-linked recessive ones. These defects arise due to mutations associated with specific gene(s) especially the ones associated with key metabolic enzymes. These enzymes or their product(s) are involved in various metabolic pathways- leading to accumulation of intermediary metabolite(s), which reflects their toxic effects upon mutations. The diagnosis of these metabolic disorders is based on the biochemical analysis of the clinical manifestations produced and its molecular mechanism. It is therefore imperative to devise diagnostic tests with high sensitivity, and specificity for early detection of IEM. Recent advances in biochemical and polymerase chain reaction based genetic analysis along with pedigree and prenatal diagnosis can be life saving in nature. Latest development in exome sequencing for rapid diagnosis and enzyme replacement therapy would be expected to facilitate the successful treatment of these metabolic disorders in future. Although the long-term clinical implications of these genetic manipulations are still a matter of debate among the intellectuals and is a matter of further research.