There are 64,000 living species of vertebrates on our planet and all of them have a heart. Comparative analyses devoted to understanding the regenerative potential of the myocardium have been performed in a dozen vertebrate species with the aim of developing regenerative therapies for human heart disease. Based on this relatively small selection of animal models, important insights into the evolutionary conservation of regenerative mechanisms have been gained. In this review, we survey cardiac regeneration studies in diverse species to provide an evolutionary context for the lack of regenerative capacity in the adult mammalian heart. Our analyses highlight the importance of cardiac adaptations that have occurred over hundreds of millions of years during the transition from aquatic to terrestrial life, as well as during the transition from the womb to an oxygen-rich environment at birth. We also discuss the evolution and ontogeny of cardiac morphological, physiological and metabolic adaptations in the context of heart regeneration. Taken together, our findings suggest that cardiac regenerative potential correlates with a low-metabolic state, the inability to regulate body temperature, low heart pressure, hypoxia, immature cardiomyocyte structure and an immature immune system. A more complete understanding of the evolutionary context and developmental mechanisms governing cardiac regenerative capacity would provide stronger scientific foundations for the translation of cardiac regeneration therapies into the clinic.

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Absolute total positive-ion electron ionization cross-sections from threshold to 220 eV are reported for a range of halogenated methanes and small perÑuorocarbons (2È4 carbon atoms). Correlations between the measured ionization cross-section and related molecular properties, in particular the vertical ionization potential (or vertical appearance energy) and molecular polarizability volume, are noted. Contributions to the total cross-section from individual bonds are also determined. Cross-sections predicted using these " bond contributions Ï are in agreement with experiment for a wide range of molecules to better than ^10% accuracy, and in most cases to better than ^5%. The experimental data are also compared with ionization efficiency curves calculated using the (DM) and binary encounter Bethe (BEB) models.

Measurements of electron impact ionization cross sections have been made for methane and the series methyl fluoride to methyl iodide. The results for methane and methyl fluoride to methyl bromide have been compared with ionization efficiency curves calculated using Deutsch-Märk (DM) and binary-encounter-Bethe (BEB) methods, and also with the results of an ab initio model which gives the maximum cross section as a function of molecular orientation. In addition, the ab initio and DM methods have been used to calculate the steric ratios for the electron impact ionization of methyl chloride which have been compared with experimental measurements made previously.

Timed exposure of pluripotent stem cell cultures to exogenous molecules is widely used to drive differentiation towards desired cell lineages. However, screening differentiation conditions in conventional static cultures can become impractical in large parameter spaces, and is intrinsically limited by poor spatiotemporal control of the microenvironment that also makes it impossible to determine whether exogenous factors act directly or through paracrine-dependent mechanisms. We detail here the development of a continuous flow microbioreactor array platform that combines full-factorial multiplexing of input factors with progressive accumulation of paracrine factors through serially-connected culture chambers, and further, the use of this system to explore the combinatorial parameter space of both exogenous and paracrine factors involved in human embryonic stem cell (hESC) differentiation to a MIXL1-GFP+ primitive streak-like population. We show that well known inducers of primitive streak (BMP, Activin and Wnt signals) do not simply act directly on hESC to induce MIXL1 expression, but that this requires accumulation of surplus, endogenous factors; and, that conditioned medium or FGF-2 supplementation is able to offset this. Our approach further reveals the presence of a paracrine, negative feedback loop to the MIXL1-GFP+ population, which can be overcome with GSK-3β inhibitors (BIO or CHIR99021), implicating secreted Wnt inhibitory signals such as DKKs and sFRPs as candidate effectors. Importantly, modulating paracrine effects identified in microbioreactor arrays by supplementing FGF-2 and CHIR in conventional static culture vessels resulted in improved differentiation outcomes. We therefore demonstrate that this microbioreactor array platform uniquely enables the identification and decoding of complex soluble factor signalling hierarchies, and that this not only challenges prevailing strategies for extrinsic control of hESC differentiation, but also is translatable to conventional culture systems.