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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.

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. 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. 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). 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). 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.

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.

Abstract 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.

The concept of topology has dramatically expanded the research landscape of magnetism, leading to the discovery of numerous magnetic textures with intriguing topological properties. A magnetic skyrmion is an emergent topological magnetic texture with a string-like structure in three dimensions and a disk-like structure in one and two dimensions. Skyrmions in zero dimensions have remained elusive due to challenges from many competing orders. Here, by combining electron holography and micromagnetic simulations, we uncover the real-space magnetic configurations of a skyrmionic vortex structure confined in a B20-type FeGe tetrahedral nanoparticle. An isolated skyrmionic vortex forms at the ground state and this texture shows excellent robustness against temperature without applying a magnetic field. Our findings shed light on zero-dimensional geometrical confinement as a route to engineer and manipulate individual skyrmionic metastructures. The real-space magnetic configurations of a zero-dimensional skyrmionic vortex structure is uncovered using electron holography and micromagnetic simulations.

Topology, a branch of mathematics that successfully describes several fundamental physical phenomena in the field of condensed matter physics. Understanding the role of topology plays in materials science has led to the development of several material platforms which come under the category of topological materials. The properties associated with the topological states in materials are robust against the continuous transformation and small perturbations that do not change topology. Hence, the research behind the exploration and utilization of topological materials in a goal specific application is currently advancing with a frantic pace.In magnetic materials, the marriage of topology and magnetism exists as a new form of magnetic ordering with whirlpool-like spin arrangements known as magnetic skyrmions. These topologically protected particle-like spin textures were first discovered a decade ago in non-centrosymmetric magnetic materials. Confining magnetic skyrmions in nanostructures leads to interesting fundamental insights on skyrmion stability and could provide convenient platforms for potential practical applications of skyrmions in information storage technology. In Chapter 1, I have introduced and summarized the recent advances on studying magnetic skyrmions in nanostructures of skyrmion hosting non-centrosymmetric materials (especially the cubic B20 materials) made via bottom-up synthesis or top-down fabrication methods. I further discussed various real space imaging (such as Lorentz transmission electron microscopy or electron holography) or physical property measurement (such as magneto-transport) techniques that have been used to observe and detect these exotic magnetic domains in both nanostructure and bulk samples, which have proven critical to fully understanding them. The morphology and dimensionality of skyrmion hosting materials in stabilizing isolated magnetic skyrmions in confined geometry and their benefits are critical for the implementation in magnetic memory applications. In Chapters 3 and 4, I have presented a comprehensive study of purely electrical detection methods corroborated with real space observation of magnetic skyrmions. This allows us to develop a complete toolkit to investigate stability, magnetic phase transformation and detection of magnetic skyrmion in confined geometries of nanostructures. With these investigations, we extend our understanding of the three-dimensional spin structure (known as skyrmion strings) in confined geometries of nanostructures. Magnetism mediated by symmetry breaking is ubiquitous in condensed matter systems as also depicted in case of non-centrosymmetric skyrmion hosts. Intrinsic crystal defects are often unavoidable during the growth processes of materials which break the local symmetry of the crystal in the vicinity of the defect site and could potentially influence the magnetic spin ordering. In Chapter 2, I have discussed the role of defects in controlling and manipulating the key fundamental properties in widely explored two-dimensional (2D) van der Waals (vdW) materials. Defect-tunable magnetism has not been studied in broad class of 2D magnetic van der Waals (vdW) materials. Furthermore, it might lead to an inaccurate interpretation of intrinsic magnetic ordering in 2D vdW magnets if the presence of crystal defects is not acknowledged with detailed structural characterization. In Chapter 5, I presented a study of defect-mediated ferromagnetism influenced by the presence of sulfur vacancy defects in strongly correlated 2D vdW antiferromagnet of NiPS3. These findings demonstrate the concept of tuning defect-mediated magnetic interactions to manipulate spin ordering in magnetic vdW materials. Interestingly, defects like dislocation in materials are distinguishable from other lattice imperfections as these are characterized by topological invariant known as Burgers vector and they fall under the category of topological defects. In Chapter 6, we have designed a first ever controlled vapor deposition method for the screw dislocation driven growth of layered vdW antiferromagnets, namely NiI2 and NiBr2. The presence of screw dislocation in magnetic vdW materials could allow the exploration of dislocation-spin interactions and magnetic spin structures that are governed by the principles of topology.

Introduction: Multiple Endocrine Neoplasia (MEN) type 2 is a rare familial endocrine syndrome. MEN 2B syndrome, the least common subtype of MEN 2 syndrome, is characterized by medullary carcinoma of thyroid (MTC), pheochromocytoma and absence of hyperparathyroidism. Identifying the responsible mutation have prognostic consequences. Majority of MEN2B cases occur due to de-novo mutation with 95% cases involving codon 918, and codon 883, 2-3% cases. Objective: Identification of the genetic mutation in patient presented with MTC, and bilateral adrenal pheochromocytoma. Methods: Whole Exome Analysis was performed to identify the genetic defect. The variants were prioritized using standard open-source computational pipelines. Results: Whole exome sequencing and computational analysis identified a non-synonymous single nucleotide polymorphism T1991C in the exon 13 of RET gene on chromosome 10, resulting in a missense mutation (p.M664T) in the protein responsible for phenotypic expression known as MEN 2B syndrome. Conclusion: MTC and bilateral pheochromocytoma are indications for detailed clinical and genetic examination of the proband. Bilateral adrenalectomy, followed by total thyroidectomy and prophylactic central neck dissection was done along with lifetime hormone supplementation. This is a rare mutation reported in MEN2B (A Rare Syndrome) which usually involve codon 918 and 883.

Introduction: Turner syndrome(TS) is defined by complete/partial monosomy of X chromosome in association with classic clinical manifestations. Conventional karyotyping is the gold standard test for diagnosis of TS. However it is labour intensive and inaccurate for detecting mosaicism, marker chromosomes and sub-microscopic deletions/duplications. TS is characterized by heterogeneous phenotypes despite identical karyotypes and precise genotype-phenotype correlations have not yet been deciphered. Presence of TS specific features in absence of X chromosome abnormality, evokes the hypothesis of possible autosomal involvement. Here, we report detailed Chromosomal microarray (CMA) analysis of 47 girls with clinically suspected TS, using Affymetrix CytoScan 750K array. Materials and Methods: The clinical diagnosis of TS was based on recommendations by clinical practice guidelines from 2016 Cincinnati International TS meeting. Peripheral venous sample was collected in EDTA tubes and DNA was extracted using Qiagen-DNAeasy Blood and Tissue kit (Cat No. 69504). DNA samples were then hybridized to the Affymetrix CytoScan 750K array as per manufacturer’s instructions. The data obtained was analysed using Chromosomal Analysis suite software and public genomic databases- ISCA, OMIM, DGV, DECIPHER. For bioinformatic analysis, all the genes (172) implicated in TS were retrieved from DisGeNET database. A TS-interactome of 4033 genes was then constructed from these genes and their first-degree neighbours from complete human interactome. Thereafter compilation was done based on CMA results and a protein-protein interaction network of 316 nodes was constructed. Results: Mean age of study cohort was 15.8 ± 3.64 years with short stature being the most common presenting phenotype (91.4%). CMA analysis detected copy number variations (CNVs) on chromosome 14 in 42 (89.3%) of 47 cases while X chromosome CNVs were present in only 28 (59.5%) cases, with all patients clinically qualifying as TS. Total 445 CNVs were discovered on X chromosome and 64 CNVs were found on Chromosome 14 exhibiting either CNV gain at 14q32.33 or CNV loss at 14q11.2 or both. The 30 cell karyotype was available for 27 patients and was found to be false negative in 7 (14.8%) patients. Also, 6 out of 47 cases had Y chromosome translocation detected on CMA that failed detection by karyotype. On enrichment analysis, thirty KEGG pathways were found to be enriched by the overlapping genes between TS-interactome and the interactome constructed by genes located within 14q11.2, and 14q32.33 67% of genes (212) in this network overlap with TS-interactome. Conclusions: CMA is a superior diagnostic modality for TS than karyotyping. Functional interactomes between Chromosome X and Chromosome 14 on enrichment analysis reveal novel pathways underlying phenotypic manifestations.

Background and Objectives: Congenital idiopathic growth hormone deficiency(GHD) is associated with various MRI abnormalities, including both sellar anomalies such as pituitary hypoplasia, ectopic pituitary, empty sella and abnormalities of the pituitary stalk and extrasellar abnormalities such as Arnold Chiari malformation, corpus callosum agenesis, arachnoid cyst, septum pellucidum agenesis, enlarged ventricles, vermis dysplasia, and sphenoid cyst. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity(severe or partial) and type(isolated GHD or multiple pituitary hormone deficiency MPHD). This study aimed to ascertain the abnormality that is the best predictor of severe GHD and type of GHD amongst the different MRI findings. Methods: This was an analytical cross-sectional study conducted from 2018-2020. During the study period, we included a total of 100 subjects diagnosed to have idiopathic GHD after the exclusion of syndromic causes, system illness, presence of pituitary mass, and those with h/o cranial irradiation. Patients were divided into severe GHD and partial GHD based on peak stimulated GH of <5 ng/dl and ≥ 5 ng/dl respectively and into groups based on isolated GHD and MPHD. Patients were further divided into groups based on the presence of pituitary hypoplasia,extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary and/or pituitary stalk abnormalities(EPP/PSA), respectively. Analyses were performed using SPSS version 24.0 software. Results: Amongst 100 subjects with idiopathic congenital GHD, 66 (66%) subjects had Isolated GHD while the remaining 34 (34%) had MPHD. 71 had severe GHD, and 29 had partial GHD. Amongst the MRI findings, pituitary hypoplasia was the most common finding observed in 53% of patients, while 23(23%) had EBA, and 25(25%) had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio(OR) of 10.8 (95% CI 3.38-29.6) followed by ectopic posterior pituitary /pituitary stalk abnormalities (OR =2.8, 95% CI 1.5-9.5) while the presence of extrasellar abnormalities was the weakest predictor (OR =1.8, 95% CI 1.05-3.2). Pituitary hypoplasia was the only finding to significantly predict MPHD (OR=9.2). On ROC analysis, a Pituitary height SDS of -2.03 had a 73.2 % sensitivity and specificity of 79.3%(AUC =0.787,95% CI 0.7-0.873) for severe GHD and a sensitivity of 88.2 % and specificity of 66.7% (AUC =0.745, 95% CI 0.68-0.877) for MPHD. Conclusion: We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.

Introduction: Insulin resistance (IR) is associated with abdominal obesity. Asian Indians have higher insulin resistance at lower abdominal obesity levels as compared to the western population. However, the relative association of various compartments of abdominal fat, i.e., Subcutaneous Fat (SCAT), Visceral fat (VAT), and ectopic Liver Fat, is not very clear. Our study’s objective was to look for the association of abdominal fat composition in Asian Indians with IR level and gender and diabetes status. Methodology: Our study is an analytical cross-sectional study conducted from 2018–2020 at SMS Hospital located in northwest India. 91 subjects were studied during the study period and underwent MRI for SCAT, VAT, and Liver fat estimation. We divided subjects into tertile groups, based on HOMA-IR levels, and statistical analysis for SCAT, VAT, and Lipid fat in each tertile and as a whole group carried out. Similarly, we analysed data in male and female and diabetic and non-diabetic groups, as tertiles and as a whole. Results: Of the recruited subjects 49 were diabetics (M: F=23:26) and 42 were non-diabetic (M: F=12:30). In the overall group, HOMA-IR has a weak positive association with VAT and Liver Fat and a weak negative association with SCAT (R=0.28,0.38 and -0.11, respectively). From tertile1 to tertile3, there was a consistent increase in VAT and Liver fat (119.3, 121.1, 156.6 cm2 and 8.18, 10.02, 10.89% respectively), so that R value increases from -0.24 to 0.21 for VAT and -0.195 to 0.58 for Liver Fat. On the other hand, the SCAT levels were not different and correlation with IR declined from -0.299 to -0.39. On Sex wise analysis negative correlation of SCAT with IR become substantial from tertile1 to tertile3 in both males and females but strong correlation was seen in females (-0.189 to -0.515) though amount of SCAT was not different among tertiles. Both VAT and Liver Fat increased with tertile1 to terrtile3; IR was very strongly correlated with Liver Fat in both the sexes at higher tertiles (0.91 for males and 0.71 for females). In the diabetic group, liver fat was significantly associated with IR at higher tertile (R=0.9). The SCAT was negatively associated with IR, and a further decline in correlation coefficient with each tertile, became significant at 3rd tertile (-0.41) with a weak correlation of IR with VAT. These relations have similar SCAT and Liver fat trends but a strong correlation not seen in the non-diabetic group. Conclusion: Insulin resistance strongly correlated with ectopic liver fat in Asian Indians including diabetics with no gender disparity which became significant at higher tertile. As compared to ectopic liver fat, VAT has only a minor role in development of IR. SCAT has a protective role against IR in both diabetics and non-diabetics.