👤 Sandosh Padmanabhan

Fuchs endothelial corneal dystrophy (FECD) results in the death of the nonproliferative endothelial cells of the posterior corneal surface, leading to corneal swelling, clouding, and potential blindness. Few studies have suggested the potential role of transcription factors in the endothelial to mesenchymal transition (EnMT) during disease progression. This study aimed to evaluate the expression of selected transcription factors in the corneal endothelium of FECD patients to understand their role in disease pathogenesis. This is a prospective, pilot, case-control study for studying the gene expression in patients with FECD. Transcription factors ZEB1, TCF4, smad proteins (SMAD3, SMAD4), zinc finger proteins SNAI1 and SNAI2, lymphoid enhancer binding factor 1 (LEF1), N-cadherin (CDH2), claudin 10 (CLDN10), and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2), which are involved in the EnMT, were selected for the study. Fourteen FECD endothelia were compared with 15 control endothelia for the gene expression analyses using quantitative real-time PCR. Significant differential expressions were seen in the levels of SMAD3 (P = 0.0251) in moderate cases compared to control tissues. Further, TCF4 and NFE2L2 showed significantly different expressions among the moderate and severe cases (P = 0.0262 and P = 0.0350, respectively), with expressions decreasing with severity, indicating their possible role in disease progression. Our pilot study on transcription factor gene expressions in FECD patients' tissue samples suggests NRF2 and TCF4 to play an important role in the disease pathogenesis and progression. Show less

The field of drug discovery has recognized the significance of computer-aided drug design. Recent advancements in structure identification and characterization, bio-computational science and molecular biology have significantly contributed to the development of novel treatments for various diseases. Alzheimer's disease is prevalent in over 50 million affected people, with the pathological condition of amyloidal plaque formation by the beta-amyloidal peptide that results in lesions of the patient's brain, thus making the target prediction and treatment a hurdle. In this study, we evaluated the potential of 54 bioactive compounds from Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less

Nek2 (NIMA-related kinase 2) is a serine/threonine-protein kinase that localizes to centrosomes and kinetochores, controlling centrosome separation, chromosome attachments to kinetochores, and the spindle assembly checkpoint. These processes prevent centrosome amplification (CA), mitotic dysfunction, and chromosome instability (CIN). Our group and others have suggested that Nek2 maintains high levels of CA/CIN, tumor growth, and drug resistance. We identified that Nek2 overexpression correlates with poor survival of breast cancer. However, the mechanisms driving these phenotypes are unknown. We now report that overexpression of Nek2 in MCF10A cells drives CA/CIN and aneuploidy. Besides, enhanced levels of Nek2 results in larger 3D acinar structures, but could not initiate tumors in a p53 Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. Show less

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10 Show less

Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to CDKN2A/CDKN2B/ANRIL, MTHFD1L, CELSR2, PSRC1 and SORT1 genes have been associated with CHD, and TMEM57, DOCK7, CELSR2, APOB, ABCG5, HMGCR, TRIB1, FADS2/S3, LDLR, NCAN and TOMM40-APOE with total cholesterol. Similarly, CELSR2-PSRC1-SORT1, PCSK9, APOB, HMGCR, NCAN-CILP2-PBX4, LDLR, TOMM40-APOE, and APOC1-APOE are associated with variations in low-density lipoprotein cholesterol levels. Altogether, forty, forty three and twenty loci have been associated with high-density lipoprotein cholesterol, triglycerides and BP phenotypes, respectively. Some of these identified loci are common for all the traits, some do not map to functional genes, and some are located in genes that encode for proteins not previously known to be involved in the biological pathway of the trait. GWAS have been successful at identifying new and unexpected genetic loci common to diseases and traits, thus rapidly providing key novel insights into disease biology. Since genotype information is fixed, with minimum biological variability, it is useful in early life risk prediction. However, these variants explain only a small proportion of the observed variance of these traits. Therefore, the utility of genetic determinants in assessing risk at later stages of life has limited immediate clinical impact. The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures. Show less

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically. Show less

CPEB is a sequence-specific RNA-binding protein that controls the polyadenylation-induced translation of mos and cyclin B1 mRNAs in maturing Xenopus oocytes. CPEB activity requires not only the phosphorylation of S174, but also the synthesis of a heretofore-unknown upstream effector molecule. We show that the synthesis of RINGO/Spy, an atypical activator of cyclin-dependent kinases (cdks), is necessary for CPEB-directed polyadenylation. Deletion analysis and mRNA reporter assays show that a cis element in the RINGO/Spy 3'UTR is necessary for translational repression in immature (G2-arrested) oocytes. The repression is mediated by 3'UTR Pumilio-Binding Elements (PBEs), and by its binding protein Pumilio 2 (Pum2). Pum2 also interacts with the Xenopus homolog of human Deleted for Azoospermia-like (DAZL) and the embryonic poly(A)-binding protein (ePAB). Following the induction of maturation, Pum2 dissociates not only from RINGO/Spy mRNA, but from XDAZL and ePAB as well; as a consequence, RINGO/Spy mRNA is translated. These results demonstrate that a reversible Pum2 interaction controls RINGO/Spy mRNA translation and, as a result, CPEB-mediated cytoplasmic polyadenylation. Show less