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The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.

Drought, the most prominent threat to agricultural production worldwide, accelerates leaf senescence, leading to a decrease in canopy size, loss in photosynthesis and reduced yields. On the basis of the assumption that senescence is a type of cell death program that could be inappropriately activated during drought, we hypothesized that it may be possible to enhance drought tolerance by delaying droughtinduced leaf senescence. We generated transgenic plants expressing an isopentenyltransferase gene driven by a stress-and maturationinduced promoter. Remarkably, the suppression of drought-induced leaf senescence resulted in outstanding drought tolerance as shown by, among other responses, vigorous growth after a long drought period that killed the control plants. The transgenic plants maintained high water contents and retained photosynthetic activity (albeit at a reduced level) during the drought. Moreover, the transgenic plants displayed minimal yield loss when watered with only 30% of the amount of water used under control conditions. The production of drought-tolerant crops able to grow under restricted water regimes without diminution of yield would minimize drought-related losses and ensure food production in water-limited lands.cytokinins ͉ isopentenyltransferase ͉ water stress ͉ water use efficiency ͉ oxidative stress D rought is the most serious environmental factor limiting the productivity of agricultural crops worldwide, with devastating economical and sociological impact. Climate models have indicated that drought episodes will become more frequent because of the long-term effects of global warming (1, 2), emphasizing the urgent need to develop adaptive agricultural strategies for a changing environment. These range from changes in traditional management and agronomic practices to the use of marker-assisted selection for the improvement of drought-related traits and the development of transgenic crops with enhanced tolerance of drought and improved water use efficiency that would minimize drought-related losses and ensure food production for a growing population.Plants can use a combination of different strategies to avoid or tolerate drought stress (3, 4). In arid regions, for example, winter annuals combine a relatively short life cycle with a high growth rate during the wet season to avoid drought altogether. Other types of avoidance include closing of stomata to minimize water loss, adjusting sink/source allocation by increasing root growth, and decreasing canopy by reducing growth and shedding of older leaves (5). Accelerated leaf senescence and leaf abscission are associated with drought in nature as a means to decrease canopy size. In perennial plants, this strategy contributes to the survival of the plant and the completion of the plant life cycle under drought stress. In contrast, this strategy reduces the yields of annual crops, with concomitant economical loss to farmers. We hypothesized that it is possible to enhance the tolerance of plants of drought stress by delaying the drought-induced...

Cell therapy is emerging as a promising strategy for myocardial repair. This approach is hampered, however, by the lack of sources for human cardiac tissue and by the absence of direct evidence for functional integration of donor cells into host tissues. Here we investigate whether cells derived from human embryonic stem (hES) cells can restore myocardial electromechanical properties. Cardiomyocyte cell grafts were generated from hES cells in vitro using the embryoid body differentiating system. This tissue formed structural and electromechanical connections with cultured rat cardiomyocytes. In vivo integration was shown in a large-animal model of slow heart rate. The transplanted hES cell-derived cardiomyocytes paced the hearts of swine with complete atrioventricular block, as assessed by detailed three-dimensional electrophysiological mapping and histopathological examination. These results demonstrate the potential of hES-cell cardiomyocytes to act as a rate-responsive biological pacemaker and for future myocardial regeneration strategies.