Heart automaticity is a fundamental physiological function in animals. In the adult heart of higher vertebrates, automaticity is generated in the sino-atrial node by specialized “pacemaker” cells having low contractility and generating a periodic electrical oscillation. The readout of cardiac automaticity is heart rate, which is a primary determinant of the capability of the organism to fulfill the physiological demand of the environment. Heart rate is also positively correlated with cardiovascular mortality and constitutes an important epidemiological parameter. However, despite of its importance, the signalling pathways involved in the genesis of pacemaking and heart rate regulation are not completely understood and some essential aspects of the cardiac pacemaker mechanism are still hotly debated. Development of therapeutically active molecules, able to control heart rate, is thus of outstanding interest. The clinical development of ivabradine (©Procoralan) for stable angina pectoris is a striking example of the potential importance of heart rate control in cardiac pathologies. However, the lack of knowledge on the importance of some mechanisms underlying pacemaking is a major obstacle in the development of heart rate controlling drugs and cellular therapy of heart diseases. The Beat-Genesis consortium proposes a cutting edge research program to reach two main objectives. First, we aim to define the role of critical ion channels and protein involved in intracellular Ca2+ signalling in cardiac automaticity and in the determination of heart rate and secondly, we will explore the potential cardioprotective effect of gene inactivation or pharmacological inhibition of critical ion channels (L-type Cav1.3, T-type Cav3.1 and HCN) against cardiac ischemia. The Beat-Genesis research program is based on recent advances in the understanding of heart rate regulation obtained by already established and fruitful collaborations between partners. The project is based on a unique collection of genetically-modified mouse strains which is the outcome of an eight years long strategic investment to target key points of the complex cellular pathway underlying cardiac automaticity. This mouse line collection will allow definition of the respective functional roles of Cav1.3 and HCN channels in cardiac automaticity and heart rate control of adult hearts. Furthermore, we propose to investigate the minimal or predominant mechanism required for generating viable automaticity during the adulthood and to study how the loss of Cav1.3 and HCN channels influences automaticity and cellular differentiation of pacemaker cells differentiated from skeletal muscle derived stem cells. Finally, we propose to investigate the potential cardioprotective role of genetic inactivation or pharmacological inhibition of Cav1.3 and Cav3.1 channels.

Miletus on the western coast of Turkey has been an important megapolis of the ancient Mediterranean. It is now a central place for research on ancient urbanisation, as it offers an ideal case for the study of the genesis of a big city perfectly integrated into Mediterranean networks. Field research however has until now concentrated on particular parts of the settlement from the Bronze age to Archaic times, and on the monumental centre of the post-classical city. The aim of the present project is, on the reverse, to provide a thorough study of the dynamics of settlement development beyond the central public places, in a long-term perspective, from the Late Bronze age to the end of the Roman Empire (from circa 1400 BC to circa 400 AD). In the framework of a cooperation between the ENS Paris and Hamburg University, the specific forms of life in a big city will be explored on three different scales : the houses and their immediate environment, the global structure of the settlement, and the relations between the megapolis and the neighbouring region. The absence of a modern occupation on the site enables us to plan a whole series of interdisciplinary archaeological investigations, which will converge into an appropriate study of each context according to its peculiarities. We notably plan, basing on the results of geophysical prospections which took place in the last years, precise soundings in different parts of the site to reconstruct the spatial and temporal dynamics of settlement history, as well as excavations providing case studies on spaces lying outside, or far from, the centre. Study of the material will shed light on domestic equipment but also on vegetal and animal remains. Precious information will be gained through the exploitation of data from contexts from earlier excavations. A GIS will integrate all existing data sets, which can be complemented by a reconstruction of the coastal line based on recent geomorphological investigation and by a Digital elevation model currently being build. All data will be placed on a GeoServer with differentiated access for participants to the project, for interested colleagues and for the wider audience. The results will be the subject of a vast monography. This project, generally, aims at a contribution to our knowledge oft he forms of life in a bug city in Ancient times through the example of Miletus..