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Rising cases of type 2 diabetes (T2D) in India, especially in metropolitan cities is an increasing concern. The individuals that were most affected are young professionals working in the corporate sector. However, the corporate sector has remained the least explored for T2D risk predisposition. Considering corporate employees’ lifestyles and the role of gene-environment interaction in T2D susceptibility, the study aims to find genetic variants associated with T2D predisposition. In this first kind of study, 680 young professionals (284 T2D cases, and 396 controls) were diagnosed and screened for 2658 variants on an array designed explicitly for the CoGsI study. The variant filtering was done at Bonferroni p-value of 0.000028. The genetic data was analysed using PLINK v1.09, SPSS, R programming, VEP tool, and FUMA GWAS tool. Interestingly, 42 variants were associated with the T2D risk. Out of 42, three missense variants (rs1402467, rs6050, and rs713598) in Sulfotransferase family 1 C member 4 ( SULT1C4 ), Fibrinogen Alpha Chain ( FGA ), and Taste 2 Receptor Member 38 ( TAS2R38 ) and two untranslated region (UTR) variants (rs1063320 and rs6296) in Major Histocompatibility Complex, Class I, G ( HLA-G ) and 5-Hydroxytryptamine Receptor 1B ( HTR1B ) were associated with the T2D risk. CoGsI identified potential genomic markers increasing susceptibility to the early onset of T2D. Present findings provide insights into mechanisms underlying T2D manifestation in corporate professionals due to genetics interacting with occupational stress and urban lifestyles.

Background Varicose veins (VV) are spectrum of common vascular diseases having complex genetic etiology. The Castor Zinc Finger 1 ( CASZ1 ) gene has been involved in vascular development and its variant has shown association with VV in various ethnicities, but CASZ1 susceptibility to VV risk is unexplored in the South Asian Indian population. The objective of this study was to estimate the association of the CASZ1 gene variations and VV susceptibility in the South Asian Indians, and to examine the evolutionary patterns of these variants compared to other populations. Methodology Population based case control analysis was conducted on all CASZ1 variants present in the Global Screening Array, including the established VV variant rs11121615 with a focus on validating and identification of both novel and established genetic markers to capture a full spectrum of population-specific genetic markers unique to studied population group. Linkage disequilibrium patterns and cumulative variant effects were also analyzed, followed by selection pressure assessment using neutrality tests. Results Three CASZ1 variants rs72860191 (OR 1.58, 95% CI 1.07–2.32, p  = 0.01), rs7519604 (OR 1.43, 95% CI 1.05–1.94, p  = 0.01), and rs11121615 (OR 0.69, 95% CI 0.50–0.95, p  = 0.02) were observed to be significantly associated with VV. Haplotype analysis identified unique haplotype structure of South Asian Indians compared to other global populations. Moreover, the cumulative OR was observed to be higher than the independently estimated values (OR = 2.41, 95% CI 1.48–3.94), indicating genotypic epistasis of VV associated variants. The neutrality tests revealed balancing selection within CASZ1 in the studied population compared to other populations, Conclusion The present study identified CASZ1 variants and their epistatic interactions is associated with VV susceptibility supported with evidence of balancing selection, provides crucial insights into the genetic architecture of VV in studied group, highlighting the impact of evolutionary forces on disease susceptibility.

Background Varicose vein is a chronic condition that affects the lower extremities of the human body. Several factors have been implicated in the development of this disease, viz age, gender, weight, height and prolonged standing. Recently, genome-wide studies have identified genetic biomarkers that are associated with varicose veins in different ethnic groups. Such genetic studies are lacking in South Asians specifically in Indians where the prevalence of varicose veins is high, and it is important to replicate these variants in the stated population. The study aimed to replicate the association of genetic variants associated with varicose veins in this target population, which were found to be associated with the other ethnic groups. Methodology The studied cohort is of the Indian population comprising unrelated 104 varicose veins cases and 448 non-varicose vein controls. The samples were genotyped using the Illumina Global Screening Array. Using the genomic data from UK BioBank and 23andMe studied cohorts; eight genetic variants were selected to replicate in our dataset. The allelic association was performed to identify the effective allele and risk was estimated using odds ratio and p -value as level of significance. Multifactor Dimensionality Reduction was used to estimate the cumulative effect of variants in Indians. Result Variant rs3791679 of EFEMP1 was found to be associated with varicose veins in Indians. After observing the association of the EFEMP 1 with varicose veins, we further ensued to identify all genetic variants within EFEMP1 to uncover the additional variants associated with this trait. Interestingly, we identified six new variants of EFEMP1 gene that have shown association. Moreover, the cumulative effect of all associated variations was estimated and the risk was 2.7 times higher in cases than controls whereas independently their effect ranges from 0.37–1.58. Conclusion This study identifies EFEMP1 as a potential gene related to the risk of varicose veins in Indians. It also highlights that evaluating the maximum number of variants of a gene rather than focusing solely on replicating single variations offers a more comprehensive and nuanced understanding of the genetic factors contributing to a complex trait like varicose veins.

Introduction: Increased Vascular Endothelial Growth Factor A (VEGF-A) levels are associated with Severe Acute Respiratory (SARS) infection. The aim was to investigate in vivo VEGF-A and VEGF-B (VEGF-A/B) gene expression (GE) in severe pulmonary disease pathogenesis. Method: Twelve temporal Mus musculus Wildtype (WT) C57BL/6 SARS-CoV MA15 lung studies were selected from the NCBI GEO database for GE profiling. Results: In murine dataset (GSE68820) Day 2 was compared to Day 7 demonstrating a downregulation trend in VEGF-A GE, with an opposite effect on VEGF-B GE (p=4.147e-03, p=7.580e-07, respectively). A v-shaped VEGF-B gene expression trajectory was noteworthy across certain datasets and after dORF6 stimulation. In addition, MA15 dose stimulation studies showed that a higher antigenic load caused more profound effects on VEGF-A resulting in a steeper fall in GE compared to other antigens. Conclusions: Distinct temporal trajectory patterns of VEGF-A and VEGF-B gene expression were associated with SARS-CoV MA15 stimulation. Unraveling the importance of VEG-A/B dynamics offers exciting prospects for improved bio-marking and therapeutic precision.Competing Interest StatementThe authors have declared no competing interest.

This study examines temporal gene expression (GE) patterns in a murine model of SARS-CoV infection. We focused on a Temporal Gene Set (TGS) comprising pro-inflammatory genes (TNF, NFKB1, VEGF-A) and VEGF-B. A systematic search of the NCBI Geo database for MA15 (SARS-CoV) pulmonary studies using C57BL Wild (WT) mice and filtering according to TGS GE patterns eluded seven datasets for further analysis. Encompassing the GE profiles from these datasets alluded to a rising and falling pattern in TNF and NFKB1 GE. Also, our findings reveal a temporal decrease in VEGF-A GE coinciding with an increase in VEGF-B GE post-immunogenic stimulation. Notably, differential responses were observed with the MA15 dosage and in comparison, to other antigens (dORF6 and NSP16). Further, the human SARS-CoV-2 gene enrichment in this murine study confirms the MA15 murine model’s relevance for SARS research. Our study also suggests potential interactions between SARS-CoV-2 Spike protein and VEGF-related receptors, hinting at other pathophysiological mechanisms. Our results indicate severe inflammation may lead to a flattened VEGF-B GE response, influencing VEGF-B’s cell survival role. We underline the significance of considering VEGF-A/B interactions, particularly temporal differences, in manipulating angiogenic processes. Future research needs to consider temporal changes in VEGF-A and VEGF-B GE, in terms of time-associated gene-switching, in line with changing host inflammation.

A 3-year field experiment was setup to address the threat of underground water depletion and sustainability of agrifood systems. Subsurface drip irrigation (SDI) system combined with nitrogen management under conservation agriculture-based (CA) maize-wheat system (MWS) effects on crop yields, irrigation water productivity (WPi), nitrogen use efficiency (NUE) and profitability. Grain yields of maize, wheat, and MWS in the SDI with 100% recommended N were significantly higher by 15.8%, 5.2% and 11.2%, respectively, than conventional furrow/flood irrigation (CT-FI) system. System irrigation water savings (~ 55%) and the mean WPi were higher in maize, wheat, and MWS under the SDI than CT-FI system. There was saving of 25% of fertilizer N in maize and MWS whereas no saving of N was observed in wheat. Net returns from MWS were significantly higher (USD 265) under SDI with 100% N (with no subsidy) than CT-FI system despite with higher cost of production. The net returns were increased by 47% when considering a subsidy of 80% on laying SDI system. Our results showed a great potential of complementing CA with SDI and N management to maximize productivity, NUE, and WPi, which may be economically beneficial and environmentally sound in MWS in Trans-IGP of South Asia.

Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in stromal tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and function. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through a collagen receptor. Discoidin domain receptor tyrosine kinase 1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells via Notch signaling to differentiate and form lobules. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that lead to formation of a complex ductal-lobular network. Mammary morphogenesis is a complex process. Here the authors describe how stem cells build a three-dimensional self-organizing multi-lineage tissue by showing that positional signals from the extracellular matrix through the collagen receptor DDR1 lead stem cells to differentiate into multi-lineage committed multi-layered progeny.

Background Aiming to improve treatment options for BRAF wild-type melanoma, we previously conducted the DOC-MEK study of docetaxel with MEK inhibitor (MEKi) selumetinib or placebo, revealing trends to prolongation of progression-free survival (hazard ratio 0.75, P  = 0.130), and improved response rates (32% vs 14%, P  = 0.059) with docetaxel plus selumetinib. NRAS status did not associate with outcome. Here, the aim was to identify novel biomarkers of response to MEKi. Methods A MEK 6 gene signature was quantified using NanoString and correlated with clinical outcomes. Two components of the gene signature were investigated by gene silencing in BRAF/NRAS wild-type melanoma cells. Results In melanomas of patients on the selumetinib but not the placebo arm, two gene signature components, dual-specificity protein phosphatase 4 (DUSP4) and ETS translocation variant 4 (ETV4), were expressed more highly in responders than non-responders. In vitro, ETV4 depletion inhibited cell survival but did not influence sensitivity to MEKi selumetinib or trametinib. In contrast, DUSP4-depleted cells showed enhanced cell survival and increased resistance to both selumetinib and trametinib. Conclusions ETV4 and DUSP4 associated with clinical response to docetaxel plus selumetinib. DUSP4 depletion induced MEKi resistance, suggesting that DUSP4 is not only a biomarker but also a mediator of MEKi sensitivity. Clinical Trial Registration DOC-MEK (EudraCT no: 2009-018153-23).

OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is a strong risk factor for end-stage liver disease. Trigonelline (TG) is a plant alkaloid with anti-oxidant, anti-dyslipidemic, and anti-insulin resistance activities. Everolimus (EV), a conventional drug and an mTOR inhibitor, has been demonstrated to improve metabolic outcomes. The synergistic effect of the co-treatment of TG and EV against NASH conditions remains unknown. MATERIALS AND METHODS: We have developed a fast food (FF)-diet and thioacetamide-induced chronic steatohepatitis in a C57BL/6J mice model of 24 weeks duration. We have evaluated the synergistic protective effect of TG and EV at reduced doses to avoid any undesired toxic manifestations of the FF and thioacetamide. The study was demonstrated by comparative analysis across different groups after 24 weeks. RESULTS: Co-exposure to FF diet and thioacetamide resulted in chronic steatohepatitis, evident by focal necrosis, bridging fibrosis, loss of liver architecture, and excessive collagen deposition. Protein and gene analysis revealed enhanced de novo lipogenesis (SREBP-1, PPAR-Ƴ, CD36), inflammation (interleukin-6, tumor necrosis factor, CYP2E1), fibrosis (transforming growth factor beta, alpha-smooth muscle actin, tissue inhibitors of metalloproteinases-1), and extracellular matrix deposition (MMP-1, Col1A1). TG + EV at reduced doses showed marked synergistic effects in preventing inflammation, fibrosis, and lipogenesis markers. CONCLUSION: This study provides a novel 24-week FF diet and thioacetamide-induced murine NASH model for possible preclinical drug discovery studies. Furthermore, our treatment regimen discovered the synergistic effect of TG and EV at reduced doses in preventing chronic steatohepatitis.