The development of moral reasoning in urban, high-social class families from Gujarat, India: A longitudinal study from middle childhood to late adolescence.

The aims of the present study were to quantitatively test hypotheses based on the cultural-developmental approach among children and adolescents in Vadodara, India, and to use qualitative analyses to examine the use of indigenous moral concepts. The study included 72 participants who were interviewed at two different age points, separated by approximately 4.5 years. At Time 1, participants were in middle childhood (Mage = 8.22 years) and in early adolescence (Mage = 11.54 years). At Time 2, the same participants were in early adolescence (Mage = 12.87 years) and late adolescence (Mage = 15.77 years). Three findings stood out: (1) As expected, the degree of use of Autonomy increased over the course of adolescence, as did the types of moral concepts. (2) The degree of use of Community significantly increased from middle childhood to adolescence. Duty, within Community was evoked prominently and consistently across all age points suggesting that aspects of social membership emerge early in Indian children's moral reasoning and remain important through adolescence. (3) The use of Divinity was prominent in middle childhood and its use decreased significantly through early adolescence; with a trend for a decrease in its use from early to late adolescence. While much of the reasoning in middle childhood was dominated by a concern for Punishment Avoidance from God, by adolescence Customary Traditional Authority and God's Authority gained prominence. Findings highlight aspects of adolescent moral reasoning that are largely missing in Western studies and point to the utility of emic, indigenous approaches to study moral development.

In silico assessment of natural products and approved drugs as potential inhibitory scaffolds targeting aminoacyl-tRNA synthetases from Plasmodium.

Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic interventions. Poor efficacy of the approved vaccine, and the rapid emergence of antimalarial drug resistance, warrants an urgent need to expedite the process of development of new lead molecules targeting malaria. Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes crucial for ribosomal protein synthesis and are valid antimalarial targets. This study explores the prospects of (re-)positioning the repertoire of approved drugs and natural products as potential malarial aaRS inhibitors. Molecular docking of these two sets of small-molecules to lysyl-, prolyl-, and tyrosyl- synthetases from Plasmodium followed by a comparison of the top-ranking docked compounds against human homologs facilitated identification of promising molecular scaffolds. Raltitrexed and Cefprozil, an anticancer drug and an antibiotic, respectively, showed stronger binding to Plasmodium aaRSs compared to human homologs with > 4 kcal/mol difference in the docking scores. Similarly, a difference of ~ 3 kcal/mol in Glide scores was observed for docked Calcipotriol, a drug used for psoriasis treatment, against the two lysyl-tRNA synthetases. Natural products such as Dihydroxanthohumol and Betmidin, having aromatic rings as a substructure, showed preferential docking to the purine binding pocket in Plasmodium tyrosyl-tRNA synthetase as evident from the calculated change in binding free energies. We present detailed analyses of the calculated intermolecular interaction for all top-scoring docked poses. Overall, this study provides a compelling foundation to design and develop specific antimalarials.

Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter.

To understand the molecular mechanisms underlying transcriptional activation of fatty-acid synthase (FAS), we examined the relationship between upstream stimulatory factor (USF) and SREBP-1c, two transcription factors that we have shown previously to be critical for FAS induction by feeding/insulin. Here, by using a combination of tandem affinity purification and coimmunoprecipitation, we demonstrate, for the first time, that USF and SREBP-1 interact in vitro and in vivo. Glutathione S-transferase pulldown experiments with various USF and sterol regulatory element-binding protein (SREBP) deletion constructs indicate that the basic helix-loop-helix domain of USF interacts directly with the basic helix-loop-helix and an N-terminal region of SREBP-1c. Furthermore, cotransfection of USF and SREBP-1c with an FAS promoter-luciferase reporter construct in Drosophila SL2 cells results in highly synergistic activation of the FAS promoter. We also show similar cooperative activation of the mitochondrial glycerol-3-phosphate acyltransferase promoter by USF and SREBP-1c. Chromatin immunoprecipitation analysis of mouse liver demonstrates that USF binds constitutively to the mitochondrial glycerol 3-phosphate acyltransferase promoter during fasting/refeeding in vivo, whereas binding of SREBP-1 is observed only during refeeding, in a manner identical to that of the FAS promoter. In addition, we show that the synergy we have observed depends on the activation domains of both proteins and that mutated USF or SREBP lacking the N-terminal activation domain could inhibit the transactivation of the other. Closely positioned E-boxes and sterol regulatory elements found in the promoters of several lipogenic genes suggest a common mechanism of induction by feeding/insulin.