Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. The molecular basis for these two properties is not well understood. Herein we report the crystal structures of glucokinase in its active and inactive forms, which demonstrate that global conformational change, including domain reorganization, is induced by glucose binding. This suggests that the positive cooperativity of monomeric glucokinase obeys the "mnemonical mechanism" rather than the well-known concerted model. These structures also revealed an allosteric site through which small molecules may modulate the kinetic properties of the enzyme. This finding provided the mechanistic basis for activation of glucokinase as a potential therapeutic approach for treating type 2 diabetes mellitus.

As one effort to estimate the global soil moisture distribution, the Global Soil Wetness Project (GSWP) was conceived. Under the GSWP, the global soil moisture distribution on 1x1 mesh for 1987 and 1988 was simulated in an offline mode by 11 land surface models (LSMs). Even though the forcing conditions are mostly based on observations, validation studies are necessary because LSMs may not simulate accurately the partitioning of water at the surface of the earth between runoff, evaporation, and changes in soil moisture. A gridded 1x1 global river channel network, named Total Runoff Integrating Pathways (TRIP) is used to calculate mean runoff estimated by the LSMs for drainage areas upstream of 250 operational gauging stations. Runoff observations from these stations in 150 major river basins of the world have been collected for 1987 and 1988, and were compared with the LSM products. It was found that LSMs estimated annual runoff fairly well, with a relative root mean square error of 40% for drainage areas with a fairly high density of raingauge observations (>30/106km2), which was used to prepare the forcing precipitation. The error corresponds to approximately 18% of annual evapotranspiration. LSMs are also found to have a tendency to underestimate the annual runoff. This may be caused by underestimation of raingauges under strong wind conditions, especially for snow, because all of the LSMs underestimated the runoff for most of the drainage areas located in higher latitudes. A linear river routing model was applied for the global runoff products from the LSMs and analyzed at 250 gauging stations. The correlations between observed and simulated monthly runoff were improved for most of the LSMs by introducing the routing. River runoff information was found to be effective for the validation of water cycles on the continental scale.

To test the hypothesis that glucokinase is a critical regulator of neuronal glucosensing, glucokinase activity was increased, using a glucokinase activator drug, or decreased, using RNA interference combined with calcium imaging in freshly dissociated ventromedial hypothalamic nucleus (VMN) neurons or primary ventromedial hypothalamus (VMH; VMN plus arcuate nucleus) cultures. To assess the validity of our approach, we first showed that glucoseinduced (0.5-2.5 mmol/l) changes in intracellular Ca U nlike most neurons in the brain that utilize glucose to fuel their metabolic needs (1), a select group of neurons use glucose as a signaling molecule to alter their firing rate as a means of glucosensing (2,3). Glucose-excited neurons increase, whereas glucose-inhibited neurons decrease, their firing rate as ambient glucose levels rise (2-7). During situations of low glucose availability, glucose-inhibited neurons are activated and glucose-excited neurons inactivated (4 -8).The ventromedial hypothalamus (VMH) area contains both the ventromedial hypothalamic nucleus (VMN) and arcuate nucleus. Both contain glucosensing neurons that respond to differing levels of glucose and are linked to pathways involved in the regulation of glucose homeostasis (3-11) and the counterregulatory responses to hypoglycemia (12-19). Our work (6,7) and that of others (8) strongly support a role for glucokinase (hexokinase IV) as a key regulator of neuronal glucosensing, which is similar to its purported role in pancreatic ␤-cell glucosensing (20,21). We previously demonstrated that inhibition of glucokinase activity reduced glucose-excited and increased glucose-inhibited neuronal activity at 2.5 mmol/l glucose, the concentration at which they are normally active and inactive, respectively (6,7).Recurrent hypoglycemia is common in patients with type 1 diabetes, especially in children (22)(23)(24)(25). This leads to hypoglycemia-associated autonomic failure, in which counterregulatory responses to subsequent bouts of hypoglycemia are severely blunted (26 -28). Our previous studies suggested that the development of hypoglycemiaassociated autonomic failure might be associated with changes in the ability of VMH neurons to sense and respond to glucose (6,28). Furthermore, its development is associated with upregulation of glucokinase mRNA in the VMH (6,28,29). This upregulation might be a compensatory response that makes glucosensing neurons more sensitive to glucose by shifting their concentration-response to the left. If so, this could underlie the development of hypoglycemia-associated autonomic failure because it would require lower levels of glucose to be reached before counterregulatory responses were initiated. This would predict that increasing glucokinase activity would produce a leftward shift in glucose sensitivity in VMH glucosensing neurons such as it does in pancreatic ␤-cells, using a drug that increases glucokinase activity (30). It would also predict that reducing glucokinase activity would inhibit the response to glucose. Here, we ...

A new high-resolution atmosphere-ocean coupled general circulation model named MIROC4h has been developed, and its performance in a 120-year control experiment (including a 50-year spin-up) Compared with MIROC3h and MIROC3m, many improvements have been achieved; for example, errors in the surface air temperature and sea surface temperature are smaller, there is less drift of the ocean water temperature in the subsurface-deep ocean, and the frequency of heavy rain is comparable to observations. The fine horizontal resolution in the atmosphere makes orographic wind and its effects on the ocean more realistic than those of the former models, and the treatment of coastal upwelling motion in the ocean has been improved. Phenomena in the atmosphere and ocean related to the El Niño and southern oscillation are now closer to observations than was obtained by MIROC3h and MIROC3m. The effective climate sensitivity for CO 2 doubling is calculated to be about 5.7 K, which is much larger than the value obtained using the IPCC AR4 models, and is mainly due to a decrease in the low-level clouds at low latitudes.

Using a high‐resolution atmosphere–ocean coupled climate model, responses of the Kuroshio and the Kuroshio Extension (KE) to global warming are investigated. In a climate change experiment with atmospheric CO2 concentration ideally increased by 1% year−1, the current velocity of the Kuroshio and KE increases, while the latitude of the Kuroshio separation to the east of Japan does not change significantly. The increase of the current velocity is up to 0.3 m s−1 at 150°E. This acceleration of the Kuroshio and KE is due to changes in wind stress over the North Pacific and consequent spin‐up of the Kuroshio recirculation gyre. The acceleration of the currents may affect sea level along the southern coast of Japan and northward heat transport under global warming.