Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa, Jaculus jaculus.

Vertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most or all distal limb muscle. We previously showed that nascent muscles are present in the jerboa hindfoot at birth and that these myofibers are rapidly and completely lost soon after by a process that shares features with pathological skeletal muscle atrophy. Here, we apply an intra- and interspecies differential RNA-Seq approach, comparing jerboa and mouse muscles, to identify gene expression differences associated with the initiation and progression of jerboa hindfoot muscle loss. We show evidence for reduced hepatocyte growth factor and fibroblast growth factor signaling and an imbalance in nitric oxide signaling; all are pathways that are necessary for skeletal muscle development and regeneration. We also find evidence for phagosome formation, which hints at how myofibers may be removed by autophagy or by nonprofessional phagocytes without evidence for cell death or immune cell activation. Last, we show significant overlap between genes associated with jerboa hindfoot muscle loss and genes that are differentially expressed in a variety of human muscle pathologies and rodent models of muscle loss disorders. All together, these data provide molecular insight into the process of evolutionary and developmental muscle loss in jerboa hindfeet.

Characterization of Human Shoulder Joint Stiffness Across 3D Arm Postures and Its Sex Differences.

Understanding the characteristics of shoulder joint stiffness can offer insights into how the shoulder joint contributes to arm stability and assists in various arm postures and movements. This study aims to characterize posture-dependent shoulder stiffness in a three-dimensional (3D) space and investigate its potential sex differences. A multi-degree-of-freedom, parallel-actuated shoulder exoskeleton robot was used' to perturb the participant's shoulder joint and measure the resulting torque responses while participants relaxed their shoulder muscles. The group average results of 40 healthy individuals (20 males and 20 females) revealed that arm postures significantly affect shoulder stiffness, particularly in postures involving shoulder flexion/extension and horizontal flexion/extension. Shoulder stiffness consistently increased as the shoulder flexion angle decreased and the shoulder horizontal flexion/extension approached the limit of its range of motion. The comparative group results between males and females indicated that shoulder stiffness in males was greater than that in females across all 15 arm postures measured in this study. Even after normalizing the data by subject body mass, the female group showed significantly lower stiffness than the male group in 12 out of the 15 arm postures. The results highlight that 3D arm postures and sex significantly affect shoulder stiffness even under relaxed muscles. This study provides valuable foundations for future studies aimed at characterizing shoulder stiffness in the context of active muscles and dynamic movement tasks, evaluating changes in shoulder stiffness following neuromuscular injuries, and formulating rehabilitative training protocols for individuals suffering from shoulder problems.

Abdominal fat depots and their association with insulin resistance in patients with type 2 diabetes.

BACKGROUND: Asian-Indians show thin fat phenotype, characterized by predominantly central deposition of excess fat. The roles of abdominal subcutaneous fat (SAT), intra-peritoneal adipose tissue, and fat depots surrounding the vital organs (IPAT-SV) and liver fat in insulin resistance (IR), type-2 diabetes (T2D) and metabolic syndrome (MetS) in this population are sparsely investigated. AIMS AND OBJECTIVES: Assessment of liver fat, SAT and IPAT-SV by MRI in subjects with T2D and MetS; and to investigate its correlation with IR, specifically according to different quartiles of HOMA-IR. METHODS: Eighty T2D and the equal number of age sex-matched normal glucose tolerant controls participated in this study. Abdominal SAT, IPAT-SV and liver fat were measured using MRI. IR was estimated by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: T2D and MetS subjects have higher quantity liver fat and IPAT-SV fat than controls (P = 9 x 10-4 and 4 x 10-4 for T2D and 10-4 and 9 x 10-3 for MetS subjects respectively). MetS subjects also have higher SAT fat mass (P = 0.012), but not the BMI adjusted SAT fat mass (P = 0.48). Higher quartiles of HOMA-IR were associated with higher BMI, W:H ratio, waist circumference, and higher liver fat mass (ANOVA Test P = 0.020, 0.030, 2 x 10-6 and 3 x 10-3 respectively with F-values 3.35, 3.04, 8.82, 4.47 respectively). In T2D and MetS subjects, HOMA-IR showed a moderately strong correlation with liver fat (r = 0.467, P < 3 x 10-5 and r = 0.493, P < 10-7), but not with SAT fat and IPAT-SV. However, in MetS subjects IPAT-SV fat mass showed borderline correlation with IR (r = 0.241, P < 0.05), but not with the BMI adjusted IPAT-SV fat mass (r = 0.13, P = 0.26). In non-T2D and non-MetS subjects, no such correlation was seen. On analyzing the correlation between the three abdominal adipose compartment fat masses and IR according to its severity, the correlation with liver fat mass becomes stronger with increasing quartiles of HOMA-IR, and the strongest correlation is seen in the highest quartile (r = 0.59, P < 10-3). On the other hand, SAT fat mass tended to show an inverse relation with IR with borderline negative correlation in the highest quartile (r = -0.284, P < 0.05). IPAT-SV fat mass did not show any statistically significant correlation with HOMA-IR, but in the highest quartile it showed borderline, but statistically insignificant positive correlation (P = 0.07). CONCLUSION: In individuals suffering from T2D and MetS, IR shows a trend towards positive and borderline negative correlation with liver fat and SAT fat masses respectively. The positive trend with liver fat tends to become stronger with increasing quartile of IR. Therefore, these findings support the theory that possibly exhaustion of protective compartment's capacity to store excess fat results in its pathological deposition in liver as ectopic fat.

Effect of 38% Silver Diamine Fluoride on Salivary Matrix Metalloproteinase-9 Levels in Children with Early Childhood Caries: A Clinical Study.

Background: Early childhood caries is a major oral health problem in most industrialized countries, affecting the overall quality of life of children. It is caused by the action of bacterial acids on the enamel surface thereby demineralizing it and progressively destroying the tooth. It presents initially as smooth-surface carious lesions affecting the primary maxillary incisors. With the advancement of the lesion, decay progresses further to involve other primary teeth as well and if not treated early, the caries may involve the pulp leading to irreversible pulpitis. Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade almost all the proteins of the extracellular matrix (ECM). Among the different types of MMP, MMP-9 (gelatinase B) is one of the chief MMPs responsible for the breakdown of the organic matrix. Traces of MMP-9 can be found in the human carious lesions, saliva, and gingival crevicular fluid. They are activated by the release of acids by cariogenic bacteria and once activated they are able to digest demineralized dentin matrix. Thus, host-derived MMPs, which are activated by bacterial acids have a crucial role in the destruction of dentine by caries. Thus, this study was undertaken to investigate the effect of 38% silver diamine fluoride (SDF) solution on MMP-9 levels. Aim: This clinical trial investigated the MMP-9 levels before and after the application of 38% SDF in children with early childhood caries. Materials and methods: About 15 children were selected and were subjected to clinical and radiographic assessment before the commencement of the procedure. After the collection of saliva, the teeth with carious lesions were isolated and SDF was applied. Saliva samples were again collected after 1, 3, and 6 months postapplication of SDF. The collected saliva samples were then analyzed for their MMP-9 levels using a human salivary enzyme-linked immunosorbent assay (ELISA) kit. Finally, the data obtained were subjected to statistical analysis by repeated measures of analysis of variance (ANOVA). Conclusion: The MMP-9 levels were found to be gradually increasing postapplication of 38% SDF and were significantly higher after 6 months and the highest mean difference in the MMP-9 levels was observed between baseline and 6th-month follow-up. Also, no new carious lesion appeared in the teeth during the experimental time period of 6 months and the decayed, extraction needed, filled teeth (deft) scores remained the same. How to cite this article: Bora P, Saxena A, Goswami M. Effect of 38% Silver Diamine Fluoride on Salivary Matrix Metalloproteinase-9 Levels in Children with Early Childhood Caries: A Clinical Study. Int J Clin Pediatr Dent 2023;16(S-1):S51-S56.

Machine Learning Model Based on Insulin Resistance Metagenes Underpins Genetic Basis of Type 2 Diabetes.

Insulin resistance (IR) is considered the precursor and the key pathophysiological mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS). However, the pathways that IR shares with T2D are not clearly understood. Meta-analysis of multiple DNA microarray datasets could provide a robust set of metagenes identified across multiple studies. These metagenes would likely include a subset of genes (key metagenes) shared by both IR and T2D, and possibly responsible for the transition between them. In this study, we attempted to find these key metagenes using a feature selection method, LASSO, and then used the expression profiles of these genes to train five machine learning models: LASSO, SVM, XGBoost, Random Forest, and ANN. Among them, ANN performed well, with an area under the curve (AUC) > 95%. It also demonstrated fairly good performance in differentiating diabetics from normal glucose tolerant (NGT) persons in the test dataset, with 73% accuracy across 64 human adipose tissue samples. Furthermore, these core metagenes were also enriched in diabetes-associated terms and were found in previous genome-wide association studies of T2D and its associated glycemic traits HOMA-IR and HOMA-B. Therefore, this metagenome deserves further investigation with regard to the cardinal molecular pathological defects/pathways underlying both IR and T2D.

Computational Analysis to Predict Drug Targets for the Therapeutic Management of Mycobacterium avium sub. Paratuberculosis.

BACKGROUND: Mycobacterium avium sp. paratuberculosis (MAP) is a pathogen, which causes paratuberculosis in animals; it has also been found to be associated with a number of autoimmune disorders in humans. The emergence of drug resistance has also been found in this bacillus during disease management. OBJECTIVE: The present study's focus was to identify potential therapeutic targets for the therapeutic management of Mycobacterium avium sp. paratuberculosis infection by in silico analysis. METHODS: Differentially-expressed genes (DEGs) can be good drug targets, which can be identified from microarray studies. We used gene expression profile GSE43645 to identify differentiallyexpressed genes. An integrated network of upregulated DEGs was constructed with the STRING database and the constructed network was analyzed and visualized by Cytoscape. Clusters in the proteinprotein interaction (PPI) network were identified by the Cytoscape app ClusterViz. MAP proteins predicted in clusters were analyzed for their non-homology with the human proteins, and homologous proteins were excluded. Essential proteins and cellular localization analysis and the physicochemical characteristics prediction were also done. Finally, the druggability of the target proteins and drugs that can block the targets was predicted using the DrugBank database and confirmed by molecular docking. Structural prediction and verification of drug target proteins were also carried out. RESULTS: Two drug targets, MAP_1210 (inhA) and MAP_3961 (aceA), encoding enoyl acyl carrier protein reductase and isocitrate lyase enzymes, respectively, were finally predicted as potential drug targets. CONCLUSION: Both of these proteins have been predicted as drug targets in other mycobacterial species also, supporting our results. However, further experiments are required to confirm these results.

Clustering pedestrians' perceptions towards road infrastructure and traffic characteristics.

In India, over 25,000 pedestrian fatalities occur due to road crashes every year. While several studies have identified possible causative factors that contribute to these fatalities, little is known about how pedestrians perceive their surrounding environment. This study attempts to bridge this gap by analysing the pedestrian perception of the built environment and traffic-related aspects considering urban roads (arterial and sub-arterial). Fourteen parameters were selected to assess pedestrian perception, and four factors were derived through factor analysis. The obtained factor scores were then subjected to two-step cluster analysis to determine whether pedestrian perception is different for people from different socio-economic demographics with varying travel behaviour. Based on the results obtained from the descriptive analysis, the respondents were most satisfied with the 'quality of streetlights at sidewalks' and 'visibility/sight distances', while they were most dissatisfied with 'pedestrian volume at sidewalks' and 'lighting facilities at crossings'. From the cluster analysis, it can be summarized that female pedestrians walk less frequently than males and perceive a higher probability of collision or near-collision incidents against male pedestrians. The study findings can aid the policymakers in the assessment of the pedestrian perception of the existing road infrastructure and suggest improvements to ensure pedestrian safety.

Quantum ghost imaging of a transparent polarisation sensitive phase pattern.

A transparent polarisation sensitive phase pattern exhibits a position and polarisation dependent phase shift of transmitted light and it represents a unitary transformation. A quantum ghost image of this pattern is produced with hyper-entangled photons consisting of Einstein-Podolsky-Rosen (EPR) and polarisation entanglement. In quantum ghost imaging, a single photon interacts with the pattern and is detected by a stationary detector and a non-interacting photon is imaged on a coincidence camera. EPR entanglement manifests spatial correlations between an object plane and a ghost image plane, whereas a polarisation dependent phase shift exhibited by the pattern is detected with polarisation entanglement. In this quantum ghost imaging, the which-position-polarisation information of a photon interacting with the pattern is not present in the experiment. A quantum ghost image is constructed by measuring correlations of the polarisation-momentum of an interacting photon with polarisation-position of a non-interacting photon. The experiment is performed with a coincidence single photon detection camera, where a non-interacting photon travels a long optical path length of 17.83 m from source to camera and a pattern is positioned at an optical distance of 19.16 m from the camera.

Interspecies transcriptomics identify genes that underlie disproportionate foot growth in jerboas.

Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has "mouse-like" arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as "nodes" for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.

Higher CNV Frequencies in Chromosome 14 of Girls With Turner Syndrome Phenotype.

CONTEXT: Precise genotype-phenotype correlations in Turner syndrome (TS) have not yet been deciphered. The chromosomal basis of the clinical TS phenotype in the absence of X chromosome aberrations on conventional karyotyping remains more and less unexplored. OBJECTIVE: To elucidate the high-resolution chromosomal picture and analyze the genotype-phenotype associations in girls with clinical phenotype of TS by chromosomal microarray. DESIGN AND PATIENTS: Cross sectional observational study conducted between October 2018 and January 2020 on 47 girls presenting the clinical TS phenotype and fulfilling the criteria for chromosomal analysis. SETTING: Outpatient department at Department of Endocrinology and the Molecular Research Lab at tertiary care teaching institution. RESULTS: The copy number variation (CNV) polymorphs were more frequent on autosomes than X chromosomes, and they were detected in 89.3%, 61.7%, and 92.8% of patients, respectively, on chromosome 14 or X or both. A total 445 and 64 CNV polymorphs were discovered on chromosome X and 14, respectively. The latter exhibited either gain at 14q32.33, loss at 14q11.2, or both. Karyotype was available for 27 patients; 55.6% of cases displayed X chromosome abnormalities while 44.4% cases had a normal karyotype. Functional interactomes of the genes that were present in chromosome 14 CNVs and those known to be associated with TS showed an overlap of 67% and enriched various development-related cellular pathways underlying TS phenotype. CONCLUSIONS: On high-resolution karyotype analysis, clinical phenotype of TS can be associated with CNV defects in autosomes, specifically chromosome 14 or X chromosome or both. The syndrome of chromosome 14 CNV defects with and without X-chromosomal defects clinically mimics TS and shares a common genomic network that deserves further investigations.

Whole transcriptome RNA-seq reveals key regulatory factors involved in type 2 diabetes pathology in peripheral fat of Asian Indians.

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.

Diversification of the vertebrate limb: sequencing the events.

Naturalists leading up to the early 20th century were captivated by the diversity of limb form and function and described its development in a variety of species. The advent of discoveries in genetics followed by molecular biology led to focused efforts in few 'model' species, namely mouse and chicken, to understand conserved mechanisms of limb axis specification and development of the musculoskeletal system. 'Non-traditional' species largely fell by the wayside until their recent resurgence into the spotlight with advances in next-generation sequencing technologies (NGS). In this review, we focus on how the use of NGS has provided insights into the development, loss, and diversification of amniote limbs. Coupled with advances in chromatin interrogation techniques and functional tests in vivo, NGS is opening possibilities to understand the genetic mechanisms that govern the remarkable radiation of vertebrate limb form and function.

Analyzing brain structural differences among undergraduates with different grades of self-esteem using multiple anatomical brain network.

BACKGROUND: Self-esteem is the individual evaluation of oneself. People with high self-esteem grade have mental health and can bravely cope with the threats from the environment. With the development of neuroimaging techniques, researches on cognitive neural mechanisms of self-esteem are increased. Existing methods based on brain morphometry and single-layer brain network cannot characterize the subtle structural differences related to self-esteem. METHOD: To solve this issue, we proposed a multiple anatomical brain network based on multi-resolution region of interest (ROI) template to study the brain structural connections of self-esteem. The multiple anatomical brain network consists of ROI features and hierarchal brain network features that are extracted from structural MRI. For each layer, we calculated the correlation relationship between pairs of ROIs. In order to solve the high-dimensional problem caused by the large amount of network features, feature selection methods (t-test, mRMR, and SVM-RFE) are adopted to reduce the number of features while retaining discriminative information to the maximum extent. Multi-kernel SVM is employed to integrate the various types of features by appropriate weight coefficient. RESULT: The experimental results show that the proposed method can improve classification accuracy to 97.26% compared with single-layer brain network. CONCLUSIONS: The proposed method provides a new perspective for the analysis of brain structural differences of self-esteem, which also has potential guiding significance in other researches involved brain cognitive activity and brain disease diagnosis.

Occurrence of Inborn Errors of Metabolism in Newborns, Diagnosis and Prophylaxis.

Inborn errors of metabolism (IEM) are a heterogeneous group of rare genetic disorders that are generally transmitted as autosomal or X-linked recessive disorders. 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 the accumulation of intermediary metabolite(s), reflecting their toxic effects upon mutations. The diagnosis of these metabolic disorders is based on the biochemical analysis of the clinical manifestations produced and their molecular mechanism. Therefore, it is 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. The latest development in exome sequencing for rapid diagnosis and enzyme replacement therapy would facilitate the successful treatment of these metabolic disorders in the future. However, the longterm clinical implications of these genetic manipulations is still a matter of debate among intellectuals and requires further research.

In Silico Prediction of Epitopes in Virulence Proteins of Mycobacterium ulcerans for Vaccine Designing.

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.

Haematopoietic stem cell-dependent Notch transcription is mediated by p53 through the Histone chaperone Supt16h.

Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.

Secondary ossification center induces and protects growth plate structure.

Growth plate and articular cartilage constitute a single anatomical entity early in development but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land - amniotes. Analysis of the ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modeling revealed that SOC reduces mechanical stress within the growth plate. Functional experiments revealed the high vulnerability of hypertrophic chondrocytes to mechanical stress and showed that SOC protects these cells from apoptosis caused by extensive loading. Atomic force microscopy showed that hypertrophic chondrocytes are the least mechanically stiff cells within the growth plate. Altogether, these findings suggest that SOC has evolved to protect the hypertrophic chondrocytes from the high mechanical stress encountered in the terrestrial environment.

The Transcriptomic Evidence on the Role of Abdominal Visceral vs. Subcutaneous Adipose Tissue in the Pathophysiology of Diabetes in Asian Indians Indicates the Involvement of Both.

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.

The common pathophysiologic threads between Asian Indian diabetic's 'Thin Fat Phenotype' and partial lipodystrophy: the peripheral adipose tissue transcriptomic evidences.

T2D is a complex disease with poorly understood mechanisms. In Asian Indians, it is associated with "thin fat" phenotype which resembles with partial lipodystrophy. We hypothesized that disturbed expression of lipodystrophy genes might play a role in T2D pathogenesis. Therefore, we attempted to establish a link between these two diseases by studying the overlap between the network of lipodystrophy genes and the differentially expressed genes (DEGs) in the peripheral subcutaneous adipose tissue of Asian Indians diabetics. We found that 16, out of 138 lipodystrophy genes were differentially regulated in diabetics and around 18% overlap between their network and the DEGs; the expression level of lipodystrophy genes showed an association with disease-related intermediate phenotypic traits among diabetics but not in the control group. We also attempted to individualize the diabetic patients based on ±2 fold altered expression of lipodystrophy genes as compared to their average expression in the control group. In conclusion, significant overlap exists between some of the lipodystrophy genes and their network with DEGs in the peripheral adipose tissue in diabetics. They possibly play a role in the pathogenesis of diabetes and individualization of diabetics is possible based on their altered expression in their peripheral adipose tissue.

Functional Interactomes of Genes Showing Association with Type-2 Diabetes and Its Intermediate Phenotypic Traits Point towards Adipo-Centric Mechanisms in Its Pathophysiology.

The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein-protein interaction subnetworks of glycemic traits-HOMA-ß and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-ß subnetwork, suggesting a role of these tissues in ß-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-ß subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.