👤 Sathyamangla V Naga Prasad

Plasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorders. AngII (angiotensin II) infusion increases circulating 4EPS in mice, suggesting a potential mechanistic role. We hypothesized that 4EPS modulates AngII-regulated pathophysiology and disease progression by directly inhibiting AT1R (angiotensin II type 1 receptor). This hypothesis was tested by combining AT1R pharmacology, cell signaling assays, ex vivo vascular studies, an AngII-induced aortic aneurysm growth model, and plasma proteomics analysis. in vitro, 4EPS reduced the binding of both AngII and the antagonist candesartan to AT1R and suppressed AngII-induced calcium signaling. Ex vivo, 4EPS attenuated AngII-mediated vasoconstriction. In vivo, high-fat diet-fed ApoE-null mice coinfused with AngII and 4EPS showed significant blunting of blood pressure elevation and a marked reduction in aortic aneurysm-related mortality compared with mice infused with AngII alone. Analysis of aortic remodeling revealed increased elastin preservation and decreased thickening of the intimal and medial layers in 4EPS-treated animals. Plasma proteomics indicated alterations in actin-cytoskeletal signaling pathways consistent with reduced activation of ERK (extracellular-regulated kinase) 1/2, filamin-A, and proteins involved in vascular smooth muscle cell motility. These findings identify 4EPS as a benign, endogenous AT1R antagonist that diminishes AngII-mediated hemodynamic and vascular pathology. By suppressing cytoskeletal signaling associated with vascular remodeling, 4EPS provides significant protection against hypertension and aortic aneurysm progression in mice, revealing a previously unrecognized protective role for a gut microbial metabolite in modulating renin-angiotensin system activity. Show less

Bioinformatics is considered a powerful tool to investigate and deeply analyze large datasets. A significant quantity of data is generated by prostate cancer and dysregulation of microRNA (miRNA) in tissues and bodily fluids (serum, plasma, urine). Screening dysregulated miRNA is currently more accessible, more reliable, and more precise with the help of insilico approaches. Hence the objective of the study is to identify miRNAs and explore their mRNA interaction in prostate cancer development. Here in the present study, we analyzed the GEO dataset GSE112264 and performed GEO-2R analysis to segregate significantly upregulated and downregulated miRNAs. The targetome of each miRNA containing several target genes was analyzed and put in an interactive network form. Functional enrichment analysis using DAVID 6.8 and GSEA was carried out to get KEGG, Reactome, and GO-BP analysis. Our analysis revealed that out of 190 overlapped significant miRNAs, only 9 miRNAs (hsa-miRNA-185-5p, hsa-miRNA-211-5p, hsa-miRNA-330-3p, hsa-miRNA-342-3p, hsa-miRNA-3622b-5p, hsa-miRNA-486-5p, hsa-miRNA-520a-3p, hsa-miRNA-550a-3p, hsa-miRNA-574-3p) were found to target 20 unique target genes (AKT1, EP300, E2F1, KRAS, AR, CREB5, CCND1, CDKNA1, EGFR, ERBB2, FGFR1, FOXO1, IKBKG, IGF1R, MAPK1, PTEN, PIK3R1, and TP53) that were involved in Prostate cancer survival and proliferation. Out of 9 miRNAs, two miRNAs (miRNA-520a-3p and miRNA-550a-3p) are novel miRNAs that have yet to be explored in Prostate cancer pathogenesis. To conclude and for future research, 8 miRNAs are yet to be explored for non-invasive potential as diagnostic and prognostic biomarkers in Prostate cancer progression and development. The target genes of each miRNA could provide novel insights in developing therapeutics for better management of disease. Show less

Sepsis remains a leading cause of mortality in intensive care units (ICUs) worldwide, necessitating improved diagnostic and prognostic tools. This study aimed to estimate the novel sepsis biomarkers, including presepsin, interleukin (IL)-27, hepcidin, and plasma chitotriosidase in ICU patients with sepsis, evaluating their potential for enhancing early diagnosis and monitoring. This prospective study was conducted over 18 months at JSS Medical College and Hospital, Mysuru, India. The study included 73 ICU patients above 18 years diagnosed with bacterial sepsis based on Quick Sequential Organ Failure Assessment score and procalcitonin (PCT) levels. Blood samples were collected and analyzed using enzyme-linked immunosorbent assay with respective biomarker kits. Demographic data, clinical parameters, and laboratory values were recorded. Correlations between novel biomarkers and PCT were assessed using Pearson correlation analysis. The study population had a mean age of 55.7 years, with 60.3% male participants. Hypertension (56.16%) and type 2 diabetes mellitus (49.32%) were the most common comorbidities. Abnormal presepsin levels were observed in 53.4% of participants, showing a strong positive correlation with PCT ( r = 0.763, P < 0.001). Hepcidin levels were abnormal in 76.7% of participants, demonstrating a moderate positive correlation with PCT ( r = 0.522, P < 0.001). Only 11.0% of participants had abnormal IL-27 levels, with a weak, nonsignificant correlation with PCT ( r = 0.172, P = 0.540). All participants (100%) had abnormal chitotriosidase levels, showing a weak but significant positive correlation with PCT ( r = 0.234, P = 0.047). This study supports the potential of presepsin and hepcidin as novel biomarkers for sepsis in ICU patients. These markers showed strong correlations with PCT and high rates of abnormal levels in sepsis patients. IL-27 and chitotriosidase showed less promise in our study population. Integrating these novel biomarkers, particularly presepsin and hepcidin, into clinical practice could potentially improve early diagnosis and management of sepsis in critical care settings. Show less

Adipocytokines, including leptin, adiponectin, and resistin, are key mediators linking adiposity, insulin resistance, and inflammation. We present the first genome-wide association study (GWAS; N = 5258) and exome-wide association study (ExWAS; N = 4578) on leptin, adiponectin, and resistin in South Asian population. We identified novel associations in genes ZNF467, and LEPREL2 for leptin; ZNF467, LEPREL2, CRLF3, ZNF732, SOX30, XIRP1, ATP8B3, SPATA2L, TMCO4, TLN2, ABCA12, and SHB for adiponectin; and D2HGDH for resistin. Additionally, we confirmed known associations of FTO, MC4R, and HOXB3 with leptin and ADIPOQ with adiponectin. Notably, ADIPOQ variants were consistently significant across GWAS, ExWAS, and gene-based analyses, reinforcing their central role in regulating adiponectin levels. Most of these novel associations identified were population-specific, highlighting the importance of studying diverse populations to uncover unique genetic signals. After adjusting for BMI, the associations with adiponectin and resistin remained significant, whereas most associations for leptin weakened in both effect size and significance. Functional annotation revealed that the identified variants were enriched for expression in adipose tissue, the brain (cerebellar hemisphere and cerebral cortex), and the pituitary gland. These variants act as eQTLs and splice-QTLs in adipose, brain, and pancreas, suggesting cross-tissue regulatory mechanisms. ExWAS further implicated rare variant burden in genes such as LONP1, ZNF335, and TTC16 for adiponectin and resistin. These findings enhance our understanding of adipocytokine biology, emphasises the need for population-specific genetic research, and lays foundation for future functional studies. Show less

Childhood obesity (OB) is influenced by complex gene-environmental interaction. While genetics of adult OB have been extensively studied, polygenic childhood OB in non-European populations is still underexplored. Furthermore, in a developing nation such as India, how the environmental component strongly modulated by the socioeconomic status (SES) shapes the genetic susceptibility is crucial to understand. A two-staged genome-wide association study (GWAS; N = 5673) and an independent exome-wide association study (ExWAS; N = 4963) were performed using a generalized linear model assuming additive effect to identify the common and rare genetic variants respectively associated with childhood OB. Rare-variant burden testing was also performed. We used the gene expression profiles and regulatory data from public databases to explain the novel associations. The implications of SES as a potential modifier of genetic susceptibility were evaluated. GWAS identified novel associations in TCF7L2, IMMP2L, IPMK, CDC5L, SNTG1, and MX1, whereas ExWAS uncovered CNTN4, COQ4, TNFRSF10D, FLG-AS1, and BMP3. Both GWAS and ExWAS validated known associations in FTO and MC4R. Furthermore, rare-variant testing highlighted the role of 101 genes. We also observed that SES can modulate the inherent susceptibility to OB. Our study identified genetic variants associated with childhood OB and highlighted the gene-environmental interaction in childhood OB. Show less

Asparagus racemosus Willd, an Ayurvedic medicine, is known for its antioxidant, antiviral, immune-boosting, and neuro-nutraceutical benefits, particularly in female health. However, its metabolites, mechanisms of action, and target proteins are yet to be fully understood. The present study aimed to identify the metabolite constitution and metabolite-associated proteins in neuroprotective mechanisms in neurodegenerative disease. Mass spectrometry-based untargeted metabolomics and network pharmacology approaches were used to identify metabolites in A. racemosus root extract. In vitro studies, including oxidative stress regulation, neuronal apoptosis, and western blot analysis, were conducted to assess the plant's impact on Alzheimer's disease (AD). We identified 44,014 spectra in positive and negative modes, corresponding to 31,931 non-redundant metabolites at the MS1 level and 5,608 at the MS2 level, from A. racemosus root extract, which include metabolites belonging to phenols, lipids, flavonoids, isoprenoids, and fatty acyls. Novel and known compounds were identified, such as asparagine, sitosterol, arginine, muzanzagenin, pinene, flavone, and kaempferol. Network pharmacology predicted 44 potential human protein targets linked to Alzheimer's disease from these metabolites. These proteins belong to neuromodulator classes, including BACE1, CHRM3, APP, MAP2K1, GSK3B, and TNF, and some of the metabolites of A. racemosus including muzanzagenin interact with BACE1 protein. In vitro validation showed that A. racemosus regulates ROS levels, apoptosis pathways, and BACE1 expression in Alzheimer's disease (AD), highlighting its therapeutic potential. This study integrates network pharmacology and metabolomics, paving the way for clinical research into the neuropharmacological effects of A. racemosus on neurological disorders. Show less

Tinospora cordifolia has been used for thousands of years to treat various health conditions, including neurodegenerative diseases. The study aimed to elucidate the mechanism of action and protein targets of T. cordifolia in the context of Alzheimer's disease through untargeted metabolomics and network pharmacology. LC-MS/MS analysis resulted in 1186 metabolites, including known bioactive compounds such as liquiritin, Plastoquinone 3, and Shoyuflavone A, to name a few. The network pharmacology analysis highlighted the metabolite-protein interaction with the enrichment of 591 human proteins, including neurotransmitter receptors and other regulatory proteins. Pathway analysis highlighted the enrichment of cAMP, mTOR, MAPK, and PI3K-Akt signaling pathways along with cholinergic, dopaminergic, serotonergic, glutamatergic synapse, and apoptosis. The docking results suggest that T. cordifolia metabolites could interact with key Alzheimer's disease targets BACE1 and MAO-B, suggesting its role in neuroprotection. These findings provide insights into the biochemical pathways underlying T. cordifolia's therapeutic effects and provides a foundation for future exploration of T. cordifolia in the context of translational research. Show less

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management. Show less

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes. Show less

Cervical Cancer is the second most common gynecological malignancy affecting a large group of women worldwide. The molecular mechanism of cervical cancer progression is still not very clear. As a result, diagnosis of cervical cancer occurs at a very advanced stage when the disease has spread to its malignant stage, causing death in the majority of women. EMT is a major culprit associated with the malignant transformation of tumor cells during cancer progression and metastasis. Hence, identification of new biomarkers to detect cervical cancer at an early stage is essential to minimize incidence and mortality. The present study aims to identify Common Differentially Expressed Genes (DEGs) and early biomarkers associated with EMT in cervical cancer. The Datasets were downloaded from the Gene Expression Omnibus (GEO) database, with Accession numbers GSE26511, GSE67522, and GSE9750. Then, the Gene Ontology (GO), KEGG pathway enrichment analysis, and protein-protein interactions (PPI) were done. Further hub genes were identified by molecular interaction networks using Cytoscape from the constructed network of DEGs. Afterwards, survival analysis was performed to assess the prognostic significance of eight hub genes associated with EMT in cervical cancer. A total of 11,339 overlapping DEGs were identified from all three datasets, among all the total 61 DEGS, and 8 hub genes were linked to the EMT pathway. Our study suggests that these eight hub genes, CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2, may be critically associated with EMT progression. Among the eight identified EMT hub genes, CDH2 (N-cadherin) demonstrated a significant association with overall survival, while FN1 (fibronectin) was notably linked to disease-free survival, underscoring their prognostic value in cervical cancer. Based on these findings, our study suggests that CDH1, CDH2, MMP2, CD44, FN1, FGF2, SNAI1, and SNAI2 hold potential diagnostic and prognostic significance in the progression of cervical cancer. Show less

Prostate cancer is an adenocarcinoma that involves epithelial-mesenchymal transition (EMT) for metastasis. To uncover novel insights into the development of prostate tumors and to identify important genes and putative microRNAs (miRs) for patient care, this study performed an in-depth bioinformatics analysis using dbDEMC3.0 (Zhejiang University, Hangzhou, China), MIENTURNET (University of Rome Tor Vergata, Rome, Italy), and DIANA-miTED (University of Thessaly, Thessaly, Greece) to explore miRs regulating tumorigenesis, proliferation, and potential therapeutic targets. A total of 373 differently expressed miRs were examined in this study, of which 87 had significant upregulation and 85 had significant downregulation. Our results from the MIENTURNET software showed that miR-141-3p, miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-203a-3p, miR-429, miR-34a-5p, and miR-509-3-5p interact with the transcription factors CDH1, CDH2, SNAI1, ZEB1, and ZEB2, which play a significant role in the core EMT regulatory network. The Encyclopedia of RNA Interactomes (ENCORI) miR-target interaction co-expression analysis observed that miR-34a-5p had a strong interaction with CDH1 as compared to other genes. The results of DIANA-plasmiR analysis showed that miR-34a-5p is a useful prognostic and diagnostic biomarker. Our results suggest that this study advances our knowledge of the molecular mechanism underlying prostate adenocarcinoma and that the interaction between the EMT gene and differentially expressed miR (DEmiR) in prostate adenocarcinoma may represent a target for prostate cancer diagnosis and treatment. Show less

The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors. Show less

This work involved the preparation of pristine and iron nanoparticle-loaded biochar from a water chestnut shell to remove diclofenac sodium (DCF) containing effluent of pharmaceutical origin. To create suitable forecasting equations for the modelling of the DCF adsorption onto the adsorbent, response surface methodology (RSM) was used. The parameters, e.g. pH, adsorbent mass, DCF concentration and contact time, were used for the modeling of adsorption. The RSM model predicts that for 98.0% DCF removal, the ideal conditions are pH 6, an adsorbent dose of 0.5 g L Show less

Hemigraphis alternata (H. alternata), commonly known as Red Flame Ivy, is widely recognized for its wound healing capabilities. However, the pharmacologically active plant components and their mechanisms of action in wound healing are yet to be determined. This study presents the mass spectrometry-based global metabolite profiling of aqueous and ethanolic extract of H. alternata leaves. The analysis identified 2285 metabolites from 24,203 spectra obtained in both positive and negative polarities. The identified metabolites were classified under ketones, carboxylic acids, primary aliphatic amines, steroids and steroid derivatives. We performed network pharmacology analysis to explore metabolite-protein interactions and identified 124 human proteins as targets for H. alternata metabolites. Among these, several of them were implicated in wound healing including prothrombin (F2), alpha-2A adrenergic receptor (ADRA2A) and fibroblast growth factor receptor 1 (FGFR1). Gene ontology analysis of target proteins enriched cellular functions related to glucose metabolic process, platelet activation, membrane organization and response to wounding. Additionally, pathway enrichment analysis revealed potential molecular network involved in wound healing. Moreover, in-silico docking analysis showed strong binding energy between H. alternata metabolites with identified protein targets (F2 and PTPN11). Furthermore, the key metabolites involved in wound healing were further validated by multiple reaction monitoring-based targeted analysis. Show less

PP2A B55α, encoded by PPP2R2A, acts as a regulatory subunit of the serine/threonine phosphatase PP2A. Despite a frequent loss of heterozygosity of PPP2R2A in cases of non-small cell lung cancer (NSCLC), research on PP2A B55α's functions remains limited and controversial. To investigate the biological roles of PP2A B55α, we conducted bulk RNA-sequencing to assess the impact of PPP2R2A knockdown using two shRNAs in a NSCLC cell line. Gene set enrichment analysis (GSEA) of the RNA-sequencing data revealed significant enrichment of the epithelial-mesenchymal transition (EMT) pathway, with SNAI2 (the gene encoding Slug) emerging as one of the top candidates. Our findings demonstrate that PP2A B55α suppresses EMT, as PPP2R2A deficiency through knockdown or homozygous or hemizygous depletion promotes EMT and metastatic behavior in NSCLC cells, as evidenced by changes in EMT biomarkers, invasion and migration abilities, as well as metastasis in a tail vein assay. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 expression via the GSK3β-β-catenin pathway. Importantly, PPP2R2A deficiency also slows cell proliferation by disrupting DNA replication, particularly in PPP2R2A Show less

The placenta is a vital fetal organ that plays an important role in maintaining fetal sex hormone homeostasis. Xenobiotics can alter placental sex-steroidogenic enzymes and transporters, including enzymes such as aromatase (CYP19A1) and the hydroxysteroid dehydrogenases (HSDs) but studying how compounds disrupt in vivo placental metabolism is complex. Utilizing high-throughput in vitro models is critical to predict the disruption of placental sex-steroidogenic enzymes and transporters, particularly by drug candidates in the early stages of drug discovery. JAR and JEG-3 cells are the most common, simple, and cost-effective placental cell models that are capable of high-throughput screening, but how well they express the sex-steroidogenic enzymes and transporters is not well known. Here, we compared the proteomes of JAR and JEG-3 cells in the presence and absence of physiologically relevant concentrations of dehydroepiandrosterone (DHEA, 8 µM) and testosterone (15 nM) to aid the characterization of sex-steroidogenic enzymes and transporters in these cell models. Global proteomics analysis detected 2931 and 3449 proteins in JAR cells and JEG-3 cells, respectively. However, dramatic differences in sex-steroidogenic enzymes and transporters were observed between these cells. In particular, the basal expression of steroid sulfatase (STS), HSD17B1, and HSD17B7 were unique to JEG-3 cells. JEG-3 cells also showed significantly higher protein levels of aldo-keto reductase (AKR) 1A1 and AKR1B1, while JAR cells showed significantly higher levels of HSD17B4 and HSDB12. Aldehyde dehydrogenase (ALDH) 3A2 and HSD17B11 enzymes as well as the transporters sterol O-acyltransferase (SOAT) 1 and ATP binding cassette subfamily G2 (ABCG2) were comparable between the cell lines, whereas sulfotransferases (SULTs) were uniquely present within JAR cells. Androgen treatments significantly lowered HSD17B11, HSD17B4, HSD17B12, and ALDH3A2 levels in JAR cells. DHEA treatment significantly raised the level of HSD17B1 by 51 % in JEG-3 cells, whereas CYP19A1 was increased to significant levels in both JAR and JEG-3 cells after androgen treatments. The proteomics data were supported by a complementary targeted metabolomics analysis of culture media in the DHEA (8 µM) and testosterone (15 nM) treated groups. This study has indicated that untreated JEG-3 cells express more sex-steroidogenic enzymes and transporters. Nevertheless, JEG-3 and JAR cells are unique and their respective proteomics data can be used to select the best model depending on the hypothesis. Show less

The diagnostic performance of pleural fluid interleukins as potential biomarkers for tuberculous pleural effusion (TPE) remains unclear. We assessed the diagnostic accuracy of various interleukins in the pleural fluid for TPE and evaluated their ability to differentiate TPE from other effusions. We queried the PubMed and Embase databases for studies indexed till October 2021. We included studies that (a) provided information regarding sensitivity and specificity of pleural fluid interleukins for diagnosing TPE, or (b) compared pleural fluid interleukin levels between TPE and malignant or parapneumonic effusions. We used hierarchical summary receiver operating characteristic plots to model summary sensitivity and specificity. Random effects modeling was employed to pool standardized mean differences (SMD) across descriptive studies comparing TPE and other effusions. We included 80 publications in our review; most were small and of poor quality. All interleukins except interleukin-27 (interleukins 1-beta, 2, 4, 6, 8, 10, 12, 12p40, 13, 18, 33) showed poor diagnostic accuracy and inconsistent discrimination of TPE from other effusions. The summary estimates for sensitivity, specificity, and diagnostic odds ratio were 0.94 (95 % CI 0.85-0.98), 0.97 (95 % CI 0.93-0.99), and 507.13 (95 % CI 130.66-1968.34) respectively for pleural fluid interleukin-27. Mean pleural fluid interleukin-27 levels in TPE were significantly higher than malignant (summary SMD 3.72, 95 % CI 2.81-4.63) or parapneumonic (summary SMD 2.45, 95 % CI -1.80-3.09) effusions. Pleural fluid interleukins are poor diagnostic biomarkers for TPE. Only pleural fluid interleukin-27 exhibited good accuracy in diagnosing TPE and needs further evaluation. Show less

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects. Show less

Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the Show less

Many bacteria have the potential to use specific pesticides as a source of carbon, phosphorous, nitrogen and sulphur. Acephate degradation by microbes is considered to be a safe and effective method. The overall aim of the present study was to identify acephate biodegrading microorganisms and to investigate the degradation rates of acephate under the stress of humic acid and most common metal ions Fe(III) and copper Cu(II). Show less

Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10 In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se. Show less

Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6,617 MetS and 3,476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages-discovery phase ( Show less

Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation. Show less

Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the Six hundred and ninety three individuals underwent the direct Sanger sequencing of the In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis. Show less

Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. Five thousand one hundred pregnant women of gestational age 24-28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women. Show less

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less

The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1, and HOXD1 genes and studied the effect of these variants on mRNA expression in pancreatic islet and on metabolic phenotypes. Immunohistochemistry showed expression of GIPR, ABO, and HOXD1 in human enteroendocrine cells and expression of ABO in pancreatic islets, supporting a role in hormone secretion. This study thus provides candidate genes and insight into mechanisms by which secretion and breakdown of GIP and GLP-1 are regulated. Show less

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions. Show less

Mild ischaemic exposures before or after severe injurious ischaemia that elicit neuroprotective responses are referred to as preconditioning and post-conditioning. The corresponding molecular mechanisms of neuroprotection are not completely understood. Identification of the genes and associated pathways of corresponding neuroprotection would provide insight into neuronal survival, potential therapeutic approaches and assessments of therapies for stroke. The objectives of this study were to use global gene expression approach to infer the molecular mechanisms in pre- and post-conditioning-derived neuroprotection in cortical neurons following oxygen and glucose deprivation (OGD) in vitro and then to apply these findings to predict corresponding functional pathways. To this end, microarray analysis was applied to rat cortical neurons with or without the pre- and post-conditioning treatments at 3-h post-reperfusion, and differentially expressed transcripts were subjected to statistical, hierarchical clustering and pathway analyses. The expression patterns of 3,431 genes altered under all conditions of ischaemia (with and without pre- or post-conditioning). We identified 1,595 genes that were commonly regulated within both the pre- and post-conditioning treatments. Cluster analysis revealed that transcription profiles clustered tightly within controls, non-conditioned OGD and neuroprotected groups. Two clusters defining neuroprotective conditions associated with up- and downregulated genes were evident. The five most upregulated genes within the neuroprotective clusters were Tagln, Nes, Ptrf, Vim and Adamts9, and the five most downregulated genes were Slc7a3, Bex1, Brunol4, Nrxn3 and Cpne4. Pathway analysis revealed that the intracellular and second messenger signalling pathways in addition to cell death were predominantly associated with downregulated pre- and post-conditioning associated genes, suggesting that modulation of cell death and signal transduction pathways plays a role in the neuroprotection. A high degree of similarity in the pathways associated with the differentially expressed genes in the pre- and post-conditioning treatments suggests that similar molecular mechanisms may mediate their neuroprotective effects. Show less