Temporal dissection of p53 function in vitro and in vivo

To investigate the functions of the p53 tumor suppressor, we created a new knock-in gene replacement mouse model in which the endogenous Trp53 gene is substituted by one encoding p53ER(TAM), a p53 fusion protein whose function is completely dependent on ectopic provision of 4-hydroxytamoxifen. We show here that both tissues in vivo and cells in vitro derived from such mice can be rapidly toggled between wild-type and p53 knockout states. Using this rapid perturbation model, we define the kinetics, dependence, persistence and reversibility of p53-mediated responses to DNA damage in tissues in vivo and to activation of the Ras oncoprotein and stress in vitro. This is the first example to our knowledge of a new class of genetic model that allows the specific, rapid and reversible perturbation of the function of a single endogenous gene in vivo.     

Rainfall and drought in equatorial east Africa during the past 1,100 years

Knowledge of natural long-term rainfall variability is essential for water-resource and land-use management in sub-humid regions of the world. In tropical Africa, data relevant to determining this variability are scarce because of the lack of long instrumental climate records and the limited potential of standard high-resolution proxy records such as tree rings and ice cores. Here we present a decade-scale reconstruction of rainfall and drought in equatorial east Africa over the past 1,100 years, based on lake-level and salinity fluctuations of Lake Naivasha (Kenya) inferred from three different palaeolimnological proxies: sediment stratigraphy and the species compositions of fossil diatom and midge assemblages. Our data indicate that, over the past millennium, equatorial east Africa has alternated between contrasting climate conditions, with significantly drier climate than today during the 'Medieval Warm Period' (approximately AD 1000-1270) and a relatively wet climate during the 'Little Ice Age' (approximately AD 1270-1850) which was interrupted by three prolonged dry episodes. We also find strong chronological links between the reconstructed history of natural long-term rainfall variation and the pre-colonial cultural history of east Africa, highlighting the importance of a detailed knowledge of natural long-term rainfall fluctuations for sustainable socio-economic development.