p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G1 phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state

ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis

ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis

From a utilitarian universal health coverage to an inclusive health coverage

This is one of the topics covered by the Encyclopedia of the Sustainable Development Goals, dedicated to goal 3, Health and Well-Being. It discusses the use of utilitarianism as philosophical approach to justify the purpose of most existing health care systems and delves on the evolution and current trends on the implementation and development of health care systems, required to achieve sustainable development patterns.Healthcare systems vary across countries but the access to health is considered fundamental both individually and collectively. Individually, good health is one of the main contributors to well-being, and collectively it has an important effect on countries’ productivity. From a utilitarian perspective, governmental intervention in health coverage has the purpose to maximise the total ‘utility’, in this case the total welfare, of all the members of society. Health services must therefore be produced and allocated efficiently, and distributed in accordance to equity. This approach gave origin to the so-called ‘universal’ healthcare systems, in trying to provide healthcare for as many members of a community as possible. Such systems can be considered inclusive insofar to try not to leave anyone out of coverage, but their implementation is not free of criticism. One of the limitations is that they tend to provide the same level of coverage for everyone, regardless of their differing characteristics, circumstances, and needs. This also means that some health issues will not be covered by the public health system, and if patients need specialised attention they will need to use private health provision, with the subsequent exclusion of those without enough resources. It is for this reason that healthcare systems are evolving to become ‘inclusive’ in a different manner, away from the ‘one size fits all’ approach covering only basic minimum health services, and aiming to provide different services to people with different needs, including giving access to health to the poorest of society

Accounting choices in Brazil: identifying the characteristics of publicly traded companies that opted to maintain versus derecognise deferred assets

The issuance of Brazilian Law 11.638/2007 is a critical step in the convergence of the Brazilian Generally Accepted Accounting Principles (GAAPs) towards International Financial Reporting Standards. After the law was implemented and later modified by Provisional Executive Order 449/2008 (converted into Law 11.941/2009), certain accounting choices were allowed during the transition period. The Brazilian GAAPs allowed for restructuring costs and costs related to opening a new facility to be recognised as assets. As a transitional provision, companies were allowed to choose between maintaining or eliminating these values. In this paper, we attempted to identify which company characteristics were associated with this accounting choice. The final sample consisted of Brazilian companies listed on the BM & FBOVESPA, and a logistic regression identified two characteristics. Participation in one of the three different corporate governance levels of the BM & FBOVESPA was associated with the choice to derecognise the deferred assets, while companies decided to maintain the deferred asset if it was relatively large. The empirical evidence reported here contributes to the literature by explaining the manner in which a set of firm characteristics is related to a firm's accounting choices