sPIF promotes myoblast differentiation and utrophin expression while inhibiting fibrosis in Duchenne muscular dystrophy via the H19/miR-675/let-7 and miR-21 pathways

Duchenne muscular dystrophy (DMD) is a progressive, lethal, X-linked disease of skeletal and cardiac muscles caused by mutations in the dystrophin gene. Loss of dystrophin leads to muscle fiber damage and impairment of satellite cell asymmetric division, which are essential for muscle regeneration. These processes ultimately result in muscle wasting and the replacement of the degenerating muscles by fibrogenic cells, a process that leads to the generation of fibrotic tissues. Preimplantation factor (PIF) is an evolutionary conserved 15-amino acid peptide secreted by viable mammalian embryos. Synthetic PIF (sPIF) reproduces the protective/regenerative effects of the endogenous peptide in immune disorders and transplantation models. In this study, we demonstrated that sPIF treatment promoted mouse and human myoblast differentiation and inhibited the expression of collagen 1A1, collagen 1A2, and TGF-β in DMD patient-derived myoblasts. Additionally, sPIF increased the expression of utrophin, a homolog of dystrophin protein. sPIF effects were mediated via the upregulation of lncRNA H19 and miR-675 and downregulation of let-7. sPIF also inhibited the expression of miR-21, a major fibrosis regulator. The administration of sPIF in mdx mice significantly decreased serum creatine kinase and collagen I and collagen IV expression in the diaphragm, whereas it increased utrophin expression in the diaphragm, heart and quadriceps muscles. In conclusion, sPIF promoted the differentiation of DMD myoblasts, increased utrophin expression via the H19/miRNA-675/let-7 pathway, and reduced muscle fibrosis possibly via the upregulation of miR-675 and inhibition of miR-21 expression. These findings strongly support pursuing sPIF as a potential therapeutic agent for DMD. Moreover, the completion of an sPIF phase I safety trial will further promote the use of sPIF for the treatment of muscular dystrophies

Signatures of three-nucleon interactions in few-nucleon systems

Recent experimental results in three-body systems have unambiguously shown that calculations based only on nucleon-nucleon forces fail to accurately describe many experimental observables and one needs to include effects which are beyond the realm of the two-body potentials. This conclusion owes its significance to the fact that experiments and calculations can both be performed with a high accuracy. In this review, both theoretical and experimental achievements of the past decade will be underlined. Selected results will be presented. The discussion on the effects of the three-nucleon forces is, however, limited to the hadronic sector. It will be shown that despite the major successes in describing these seemingly simple systems, there are still clear discrepancies between data and the state-of-the-art calculations.Comment: accepted for publication in Rep. Prog. Phy

Essays on corporate social responsibility

Corporate Social Responsibility (CSR) is very high on corporations' agenda in recent years. CSR means different things to different stakeholders but generally refers to serving people, communities and the environment in a way that goes beyond what is legally required of a firm. In this paper-based dissertation we analyze some potential driving forces behind this corporate behavior. The first paper explores the role of Socially Responsible Investing (SRI) - making investment decisions according to both financial and ethical criteria. We analyze the effect of SRI on the investment decisions of firms that fail the screen ('polluting' firms) and on their decisions to adopt a CSR-approved technology. These issues are examined in an equilibrium setting with endogenous investment decisions. We find that the presence of socially responsible investors can lead to under-investment by polluting firms but their current proportion among all investors (11%) is not enough to induce polluting firms to change their technology. The second paper further explores the role of SRI in a richer theoretical framework. We model a capital market in which some investors get direct utility from owning firms that spend on CSR. We also assume different categories of firms: those with good CSR fundamentals and those with poor CSR fundamentals. In equilibrium, investors' CSR considerations shape their financial portfolio decisions, affect stock prices and influence corporate CSR spending decisions. We also examine optimal tax policy questions, looking to maximize total individual donations plus corporate CSR spending less the tax rebates given for such spending. The third paper argues that insiders (managers and large blockholders) who are affiliated with the firm may want to over-invest in CSR for their private benefit since it improves their reputation. We test this hypothesis by investigating the relation between firms' CSR ratings and their ownership and capital structure. We employ a unique dataset that sorts 3,000 US corporations according to their social record. We find that insiders' ownership and leverage are negatively related to the social rating of firms, while institutional ownership is uncorrelated with it. These results support the hypothesis that CSR is a source of a conflict between different shareholders.Business, Sauder School ofFinance, Division ofGraduat

Corporate Social Responsibility as a Conflict Between Shareholders

corporate social responsibility, ownership structure, corporate governance,

Nature or nurture: What determines investor behavior

Using data on identical and fraternal twins ’ complete financial portfolios, we decompose the crosssectional variation in investor behavior. We find that a genetic factor explains about one third of the variance in stock market participation and asset allocation. Family environment has an effect on the behavior of young individuals, but this effect is not long-lasting and disappears as an individual gains experiences. Frequent contact among twins results in similar investment behavior beyond a genetic factor. Twins who grew up in different environments still display similar investment behavior. Our interpretation of a genetic component of the decision to invest in the stock market is that there are innate differences in factors affecting effective stock market participation costs. We attribute the genetic component of asset allocation- the relative amount invested in equities and the portfolio volatility- to genetic variation in risk preferences