Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

On the accumulation of deleterious mutations during range expansions

We investigate the effect of spatial range expansions on the evolution of fitness when beneficial and deleterious mutations co-segregate. We perform individual-based simulations of a uniform linear habitat and complement them with analytical approximations for the evolution of mean fitness at the edge of the expansion. We find that deleterious mutations accumulate steadily on the wave front during range expansions, thus creating an expansion load. Reduced fitness due to the expansion load is not restricted to the wave front but occurs over a large proportion of newly colonized habitats. The expansion load can persist and represent a major fraction of the total mutation load thousands of generations after the expansion. Our results extend qualitatively and quantitatively to two-dimensional expansions. The phenomenon of expansion load may explain growing evidence that populations that have recently expanded, including humans, show an excess of deleterious mutations. To test the predictions of our model, we analyze patterns of neutral and non-neutral genetic diversity in humans and find an excellent fit between theory and data

A Careers Perspective on Entrepreneurship

[Excerpt] What if being an entrepreneur were treated like any other occupation—teacher, nurse, manager? What if the decision to found a new venture were thought of as one of many options that individuals consider as they try to structure a meaningful and rewarding career? How would the field of entrepreneurship research be different? In our view, there is much to be learned by conceiving of entrepreneurship not solely as a final destination, but as a step along a career trajectory. Doing so opens the study of entrepreneurship to a wider range of scholarly insights, and promises important insights for entrepreneurial practice, training, and policy. This special issue takes an important step in this direction

Afterlife: Who Takes Heart for Restart?

The performance of young and newly founded firms depends largely to the human capital of the firm owner. The entrepreneur is therefore one of the main success factors for the firm. Yet entrepreneurs differ considerably in their background and characteristics. Particularly, founders? individual entrepreneurial experience is a property that might be crucial for firm development, though it is part of the firm?s human capital, too. Business failures, namely bankruptcies, may trigger the transition from being a novice entrepreneur to becoming an entrepreneur who is entrepreneurially experienced. About 3 percent of novice entrepreneurs who file for bankruptcy reestablish afterwards. On average, slightly more than 15 months will elapse until such ?fallen? entrepreneurs venture out anew. They differ from entrepreneurs not willing or able to take a second chance in several respects. --Bankruptcy,Business Failure,Restart,Second Chance

Ventured: The Burton D. Morgan Foundation 2012 Annual Report

This annual report gives examples of entrepreneurial activities the foundation has funded, as well as a list of grants and financial statements for the year 2012. It also includes a letter from the president and lists of the board and staff members. Ventured captures a year of experimentation in support of the Northeast Ohio entrepreneurial ecosystem. Throughout, we focus directly on the perspectives of entrepreneurs as they navigate startup hurles and utilize the resources of the region to network, pitch, pivot, and grow. In addition to the lively observations shared in the body of this report, you will find QR codes that lead you to videos of the entrepreneurs providing first-hand insights into their entrepreneurial journeys

Should I Stay or Should I go? Founder Power and Exit via Initial Public Offering

Founders can voluntarily exit their ventures via initial public offerings (IPOs). In this study, we build on power theory to develop and test a model of founder exit using a dataset of 313 founders from 177 entrepreneurial IPOs between 2002 and 2010. We largely find support for the model—a negative relationship between founder power and full exit. To capture the underlying mechanism of the power-exit relationship, we conducted two experiments in which we randomly assigned decision makers to either a high- or low-power condition. We find that decision makers in the low-power condition are more likely to use a full exit via IPO than those in the high-power condition and that frustration mediates this relationship. However, founders can also engage in partial exits, including a managerial partial exit in which the founder leaves management but keeps ownership and a financial partial exit in which the founder divests ownership but remains in management. We find that the negative relationship between founder power and exit is more negative for full exits than partial exits. With this paper, we contribute to the literature on exit by identifying a novel mechanism—frustration—underlying power’s influence on the likelihood and type of founder exit

Turning scientific and technological human capital into economic capital: the experience of biotech start-ups in France

This paper examines how scientific and technological (S&T) human capital is transformed into financial capital through the creation of firms by scientists. The analysis is based on a database describing the positions held by 132 founders from 62 French biotech SMEs. It shows that star scientists engage in highly risky but also valuable firms. Less famous scientists must develop their human capital rather than valorising a stock. The paper concludes by pointing to three paradoxes concerning the commitment and compensation scheme of star scientists and the managerial position of less known scientists.Biotechnology; SMEs; Scientist; Founder; Technological transfer; Human capital

Assessing the effectiveness of business support services in England: evidence from a theory based evaluation

In England, publicly supported advisory services for small firms are organised primarily through the Business Link (BL) network. Based on the programme theory underlying this business support services we develop four propositions and test these empirically using data from a new survey of over 3,000 English small firms. Our empirical results provide a broad validation of the programme theory underlying BL assistance for small firms in England during 2003, and more limited support for its effectiveness. More specifically, we find strong support for the value of BL operators maintaining a high profile as a way of boosting take-up. We also find some support for the approach to market segmentation adopted by BL allowing more intensive assistance to be targeted on younger firms and those with limited liability status. In terms of the outcomes of BL support, and allowing for issues of sample selection, we find no significant effects on growth from ‘other’ assistance but do find positive and significant employment growth effects from intensive assistance. This provides partial support for the programme theory assertion that BL support will lead to improvements in business growth performance and stronger support for the proposition that there would be differential outcomes from intensive and other assistance. The positive employment growth outcomes identified here from intensive assistance, even allowing for sample selection, suggest something of an improvement in the effectiveness of the BL network since the late 1990s

ROLE OF REGIONAL HEAD OF STATE’S ATTITUDES IN IMPLEMENTATION OF FINANCE POLICY ABOUT THE GOVERNMENT ACCOUNTING STANDARDS IN INDONESIA

ndonesian state financial policies have undergone major changes since the release the Law on State Finance package in 2003 and 2004 as well as the Law on Local Government Package of 2004. The legislation has been set up clearly financial management with a transparent and accountable as well as the financial management in the region from President to the Regional Head. This implies a stronger role of the Regional Head in implementing the financial policy in the local government. The financial policy communication to local governments are often disruption whereby the policy is not communicated clearly and consistently. This study is a single case study for examining the phenomenon in which the object of research is the Semarang City Government as the only one that has been implemented government accounting standards accrual-based policy. In adequately of the financial policy’s communication about implementation of government accounting standards accrual-based policy from the central government to the local government can be overcome by the attitude of the Regional Head avoiding uncertainty (uncertainty avoidance) and has a vision for the future (confucian dynamism) so to encourage the attitude of the staff at the local government and also encourage the emergence of support from external parties to support the implementation of the financial policy of the country