Regulation of Cardiomyocyte Proliferation by microRNAs and Small Molecules

Understanding the molecular mechanisms regulating cardiac cell proliferation during the embryonic, fetal and adult life holds a paramount importance in view of developing innovative strategies aimed at inducing myocardial regeneration after cardiac damage. Previous high throughput screening studies in our laboratory identified a series of microRNAs able to trigger cardiomyocyte proliferation and stimulate cardiac regeneration after myocardial infarction. In the first part of this project, we investigated the mechanism of action of the top ten most effective of these miRNAs, revealing an involvement of the Hippo-YAP pathway in their action. We found that all the investigated miRNAs activated YAP-mediated transcription, nuclear localization of active YAP and increased expression of YAP responsive genes. Of notice, miR-199a-3p, one of the most effective miRNAs exerted its direct effect on two mRNA targets impinging on the Hippo pathway, the inhibitory kinase TAOK1 and the E3 ubiquitin ligase, β−TrCP. Most of the miRNAs inducing proliferation (including miR-199a-3p) also modulated the dynamics of the actin cytoskeleton in the treated cardiomyocytes, which displayed a rounded shape and gross bundles of actin fibers at the cytoplasm periphery. Consistent with these observations, we found that the Cofilin2 mRNA was a direct target of four of the investigated miRNAs and that downregulation of Cofilin2 itself was sufficient to promote cardiomyocyte proliferation, activate nuclear translocation of YAP and stimulate transcription of TEAD-responsive genes. The second part of the project was aimed at identifying small molecules exerting a mitogenic effect on neonatal cardiomyocytes through an unbiased high-throughput screening (HTS) of a library of 780 FDA-registered drugs. The neuroactive alkaloid harmine was identified as the most powerful molecule at inducing cardiomyocyte proliferation in vitro and heart regeneration after myocardial infarction in vivo. Harmine exerted its activity through the inhibition of the dual specificity phosphorylation-regulated tyrosine kinase, Dyrk1a and, again, the activation of YAP nuclear translocation. Collectively, these results identify both YAP activation and actin cytoskeleton remodelling as major determinants of cardiomyocyte proliferation and establish the molecular basis for the development of pharmacological therapies to promote heart regeneration through the stimulation of the endogenous capacity of cardiomyocytes to proliferate

Profit Share and Returns on Capital Stock in Italy: the Role of Privatisations behind the Rise of the 1990s

Profit share in Italy has been growing between the mid-1970s and the mid-1990s, remaining stable at historically high levels since than. After dropping in the first half of the 1070s, owing to an unprecedented rapid rise in wages, profit share started to recover. The rise during the 1980s involved the entire business sector and was part of this recovery process. During the 1990s profit share continued to grow on average, but with large cross-sector differences. Profit share in manufacturing, which is more exposed to international competition, declined, together with the returns on capital stock, but increased in the rest of the business sector. We show that the better performance of the non-manufacturing business sector is mainly due to the industries most affected by the large-scale privatisations and restructuring of State-owned companies that began in the first half of the 1990s. They led to a rapid growth in total factor productivity and a deceleration in wages, without a major impact on the market power of privatised companies, even those previously in the position of incumbent monopolists. Our evidence for Italy thus strongly supports the hypothesis that profit share growth during the 1990s, which was also observed in other countries, was mainly due to a redistribution of rents rather than to biased technological change.factor shares, returns on capital, privatisations

Firm Size Distribution and EPL in Italy

We study the role of employment protection legislation (EPL) in explaining the relative small average size of Italian firms. We construct a simple model that shows that the smooth relation between size and growth probability is disturbed in proximity of the thresholds at which EPL applies di.erentially. We use a comprehensive dataset of all Italian firms between 1986 and 1998 to estimate the e.ects of EPL in terms of discouraging small firms from growing. We then construct a stochastic transition matrix for firm size that, together with the estimates, allows for a quantitative evaluation of the e.ects of EPL in the long run. Our results show that EPL does influence firm size distribution, but that its e.ects are quantitatively modest: average firm size would increase by less than 1% when removing the threshold e.ect. In terms of policy, these findings suggest that changes in EPL are not likely to have a large impact on the propensity of small firms to growhttp://deepblue.lib.umich.edu/bitstream/2027.42/39999/3/wp613.pd

Reasoning about modular datatypes with Mendler induction

In functional programming, datatypes a la carte provide a convenient modular representation of recursive datatypes, based on their initial algebra semantics. Unfortunately it is highly challenging to implement this technique in proof assistants that are based on type theory, like Coq. The reason is that it involves type definitions, such as those of type-level fixpoint operators, that are not strictly positive. The known work-around of impredicative encodings is problematic, insofar as it impedes conventional inductive reasoning. Weak induction principles can be used instead, but they considerably complicate proofs. This paper proposes a novel and simpler technique to reason inductively about impredicative encodings, based on Mendler-style induction. This technique involves dispensing with dependent induction, ensuring that datatypes can be lifted to predicates and relying on relational formulations. A case study on proving subject reduction for structural operational semantics illustrates that the approach enables modular proofs, and that these proofs are essentially similar to conventional ones.Comment: In Proceedings FICS 2015, arXiv:1509.0282

Threshold effects and firm size: The case of firing costs

We study the role of employment protection legislation (EPL) in determining firm size distribution. In many countries the provisions of EPL are more stringent for firms above certain size thresholds. We construct a simple model that shows that the smooth relation between size and growth probability is broken in proximity of the thresholds at which EPL applies differentially. We use a comprehensive longitudinal dataset of all Italian firms, a country with an important threshold at 15 employees, to estimate the effects of EPL in terms of discouraging small firms from growing. We find that the probability of growing of firms in the proximity of the threshold is reduced by around 2%. We then construct a stochastic transition matrix for firm size that, together with the estimates, allows for a quantitative evaluation of the effects of EPL in the long run. Our results show that EPL does influence firm size distribution, but that its effects are quantitatively modest: average firm size would increase by less than 1% when removing the threshold effect. Our results suggest that EPL is unlikely to be a major determinant of cross-country differences in firm size.Firm size distribution, Employment protection, Firing costs.

Firm Size Distribution and EPL in Italy

We study the role of employment protection legislation (EPL) in explaining the relative small average size of Italian firms. We construct a simple model that shows that the smooth relation between size and growth probability is disturbed in proximity of the thresholds at which EPL applies di.erentially. We use a comprehensive dataset of all Italian firms between 1986 and 1998 to estimate the e.ects of EPL in terms of discouraging small firms from growing. We then construct a stochastic transition matrix for firm size that, together with the estimates, allows for a quantitative evaluation of the e.ects of EPL in the long run. Our results show that EPL does influence firm size distribution, but that its e.ects are quantitatively modest: average firm size would increase by less than 1% when removing the threshold e.ect. In terms of policy, these findings suggest that changes in EPL are not likely to have a large impact on the propensity of small firms to growFirm size distribution, Employment protection, Firing costs

Changing Institutions in the European Market: the Impact on Mark-ups and Rents Allocation

In this paper, we investigate whether the completion of the Single Market Programme has enhanced competition on the product markets across European countries, while taking into account the companion structural reforms undertaken by the member countries. In particular, since the Single Market Programme went hand in hand with major reforms in the labour market and in the institutional setting of important industries (i.e. network industries), we test for a break in both mark-ups and the division of rent between capital and labour. For this purpose we encompass efficient bargaining in the labour market in both our theoretical and empirical model. Using industry data for ten EU countries we find that, without controlling for changes in the rent sharing, mark-up estimates tend to increase in the 1990s. However, once we assume efficient bargaining in the labour market, mark-ups remain virtually unchanged or even decrease in some sectors or groups of countries; the result stems from the declining shares of rents accruing to workers owing to a decline in their bargaining power. Without controlling for this development, a rise in firms� profitability due to rent reallocation could be wrongly interpreted as an increase in market power. At the industry level the evidence is particularly strong for high and medium-tech manufacturing, for construction and for those activities that went through deep institutional changes and privatization programmes.Mark-ups, Rent Sharing, Bargaining

Changing institutions in the European market: the impact on mark-ups and rents allocation

We investigate whether the completion of the Single Market Programme has enhanced competition on the product markets across European countries, taking into account the companion structural reforms undertaken by the member countries, particularly in the labour market and the institutional setting of important industries (i.e. network industries). We test for a break in both mark-ups and the division of rent between capital and labour based on a statistical model incorporating efficient bargaining in the labour market. Using industry data for ten EU countries we find that, without controlling for changes in the rent sharing, mark-up estimates tend to increase in the 1990s. However, once we assume efficient bargaining in the labour market, mark-ups remain virtually unchanged or, in some sectors or groups of countries, even decrease; this reflects the declining shares of rents accruing to workers as a result of their diminished bargaining power. The evidence is particularly strong for high and medium-tech manufacturing, for construction and for those activities that went through deep institutional changes and privatization programmes.institutional changes, mark-up, rent-sharing

The distribution of employees’ labour earnings in the European Union: Data, concepts and first results

This paper studies the distribution of labour earnings among employees within the EU using data from Wave 2007-1 of the Community Statistics on Income and Living Conditions (EUSILC). The review of available information and the comparisons with external sources show that the EU-SILC data are not exempt from problems, particularly in some countries, yet can be fruitfully used to study the distribution of earnings in the EU; they also allow researchers to assess the sensitivity of results to various concepts of labour earnings. The ranking of countries by median full-time equivalent monthly gross earnings shows Eastern European nations at the bottom and Luxembourg at the top; earnings differences are sizeable, both across and within countries. Taking the euro area and the EU-25 (excluding Malta, for which data are unavailable) as a whole, inequality is higher when earnings are measured in euro at market rates rather than at purchasing power parities. The wage distribution is wider in the EU-25 than in the euro area, which is not surprising given that the former includes the poorer Eastern European countries that joined the Union in 2004. The higher inequality observed in the EU-25 is largely attributable to differences between countries, which are essentially due to the returns to individual attributes rather than to a different composition of the workforce with respect to these attributes.wage inequality, EU and euro area labour markets.