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The productivity decline in drug discovery and development is mainly caused by two factors; higher regulatory hurdles and low-hanging fruits being all picked. In addition, the recent target-based approach is thought to be increasing the price of innovation. Although target-based approach had many successes, a postreductionism method, which is systems biology, is on the rise. In this review, we discuss the foundations of two distinct approaches in finding a new drug.

Sasang constitutional medicine (SCM) is a traditional form of medicine that is widely used in Korea to clinically diagnose and treat disease. The main characteristic of SCM is its classification of people according to physical constitution. The theory asserts that four different types of physical constitution exist: Taeyang, Soyang, Taeeum, and Soeum. One noticeable clinical observation in SCM is that Taeeum-type people are prone to obesity. Although extensive clinical investigations have shown this tendency in SCM, no scientific hypothesis has been proposed to delineate its mechanism. According to SCM theory, Taeeum-type people have a hypoactive lung system and a hyperactive liver system. In this paper, we propose a new hypothesis explaining this finding from a physiological viewpoint. A functional weakness in the lung system indicates intrinsic hypoactivity in the consumption of metabolic energy, therefore we deduced that the tendency can easily induce body weight gain via an increase in anabolism.

Riparian areas can be highly biodiverse and provide critical ecosystem services. However, they are frequently subject to anthropogenic impacts such as land clearing, agricultural use, and urban development. Restoration of riparian areas via revegetation commonly improves the health of waterways and surrounding areas, but vegetation outcomes are rarely assessed. Our study compared 10 to 14‐year‐old revegetation to remnant vegetation in riparian areas of south‐eastern Australia to determine if species composition, vegetation structure, and ecosystem function (plant recruitment) differed. We also assessed if the amount of surrounding native vegetation, browsers (including deer, rabbits, and macropods), or soil characteristics influenced native woody plant recruitment at revegetated sites. While native and exotic woody species richness did not differ, native woody plants were less abundant and exotic woody plants twice as abundant at revegetated sites. The ground layer of revegetated sites was dominated by weeds, whereas remnant sites largely comprised native herbaceous plants and leaf litter. Tree heights and tree canopy cover were similar in revegetated and remnant areas, although shrubs and ferns were lacking in revegetation. Native woody plant recruitment was lower at revegetated sites and was negatively associated with browser presence. Our results suggest that while revegetation may have similar species richness and tree cover as remnant areas, weeds often dominate and important structural components such as shrubs and ferns, and ecological processes such as plant recruitment, are lacking. Better consideration of all vegetation strata, reduced browsing pressure and weed control are likely to achieve better revegetation outcomes. [ABSTRACT FROM AUTHOR]

Mouse B cells and their cell line (WEHI-231) express large-conductance background [K.sup.+] channels ([LK.sub.bg]) that are activated by arachidonic acids, characteristics similar to TREK-2. However, there is no evidence to identify the molecular nature of [LK.sub.bg]; some properties of [LK.sub.bg] were partly different from the reported results of TREK type channels. In this study, we compared the properties of cloned TREK-2 and [LK.sub.bg] in terms of their sensitivities to ATP, phosphatidylinositol 4,5-bisphosphate ([PIP.sub.2]), intracellular pH ([pH.sub.i], and membrane stretch. Similar to the previous findings of [LK.sub.bg], TREK-2 showed spontaneous activation after membrane excision (i-o patch) and were inhibited by MgATP or by [PIP.sub.2]. The inhibition by MgATP was prevented by wortmannin, suggesting membrane-delimited regulation of TREKs by phosphoinositide (PI) kinase. The same was observed with the property of [LK.sub.bg]; the activation of TREK-2 by membrane stretch was suppressed by U73122 (PLC inhibitor). As with the known properties of TREK-2, [LK.sub.bg] were activated by acidic [pH.sub.i] and inhibited by PKC activator. Finally, we confirmed the expression of TREK-2 in WEHI-231 by using RT-PCR and immunoblot analyses. The amplitude of background [K.sup.+] current and the TREK-2 expression in WEHI-231 were commonly decreased by genetic knockdown of TREK-2 using small interfering RNA. The downregulation of TREK-2 attenuated [Ca.sup.2+]-influx induced by arachidonic acid in WEHI-231. As a whole, these results strongly indicate that TREK-2 encodes [LK.sub.bg] in mouse B cells. We also newly suggest that the low activity of TREK-2 in intact cells is due to the inhibition by intrinsic [PIP.sub.2]. K2P channel; arachidonic acid; PI kinase; membrane stretch; immune cells

We examined the effects of acute hypoxia on [Ba.sup.2+]-sensitive inward rectifier [K.sup.+] ([K.sub.IR]) current in rabbit coronary arterial smooth muscle cells. The amplitudes of [K.sub.IR] current was definitely higher in the cells from small-diameter (< 100 [micro]m) coronary arterial smooth muscle cells (SCASMC, -12.8 [+ or -] 1.3 pA/pF at -140 mV) than those in large-diameter coronary arterial smooth muscle cells (>200 [micro]m, LCASMC, -1.5 [+ or -] 0.1 pA p[F.sup.-1]). Western blot analysis confirmed that Kir2.1 protein was expressed in SCASMC but not LCASMC. Hypoxia activated much more [K.sub.IR] currents in symmetrical 140 [K.sup.+]. This effect was blocked by the adenylyl cyclase inhibitor SQ-22536 (10 [micro]M) and mimicked by forskolin (10 [micro]M) and dibutyryl-cAMP (500 [micro]M). The production of cAMP in SCASMC increased 5.7-fold after 6 min of hypoxia. Hypoxia-induced increase in Kin currents was abolished by the PKA inhibitors, Rp-8- (4-chlorophenylthio)-cAMPs (10 [micro]M) and KT-5720 (1[micro]M). The inhibition of G protein with GDP[beta]S (1 mM) partially reduced (~50%) the hypoxia-induced increase in [K.sub.IR] currents. In Langendorff-perfused rabbit hearts, hypoxia increased coronary blood flow, an effect that was inhibited by [Ba.sup.2+]. In summary, hypoxia augments the [K.sub.IR] currents in SCASMC via cAMP- and PKA-dependent signaling cascades, which might, at least partly, explain the hypoxia-induced coronary vasodilation. inwardly rectifying [K.sup.+] current: coronary vasodilation; protein kinase A; Kit2.1

In freshly isolated rabbit pulmonary artery smooth muscle cells, endothelin (ET)-1 induced a transient increase in intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) followed by a return to the initial [[[Ca.sup.2+]].sub.i]. This response was not abolished by the voltage-dependent [Ca.sup.2+] channel blocker nicardipine or removal of [Ca.sup.2+] from the bath solution but was inhibited by ryanodine and thapsigargin. This finding suggested that the increase in [[[Ca.sup.2+]].sub.i] induced by ET-1 was attributable to release of [Ca.sup.2+] from ryanodine-and inositol 1,4,5-trisphosphate-sensitive intracellular [Ca.sup.2+] stores. The transient increase in [[[Ca.sup.2+]]sub.i]; induced by ET-1 was also inhibited by pretreatment with antagonists of ET type A and B (E[T.sub.A] and E[T.sub.B]) receptors (BQ-123 and BQ-788, respectively). Furthermore, the E[T.sub.B] receptor agonist IRL-1620 induced an increase in [[[Ca.sup.2+]].sub.i] that was followed by a sustained increase in [Ca2+]i; the sustained increase in [[[Ca.sup.2+]].sub.i] was blocked by nicardipine. Using the nystatin-perforated patch-clamp technique, we found that IRL-1620 caused an increase in [Ca.sup.2+] current that was inhibited by addition of ET-1. ET-1 did not inhibit [Ca.sup.2+] current when cells were pretreated with BQ-123. These results suggested that when both receptor types are activated, the opposing responses lead to abolition of the sustained [[[Ca.sup.2+].sub.i] increases induced by E[T.sub.B] receptor activation. Western blot analysis confirmed expression of E[T.sub.A] and E[T.sub.B] receptors. Finally, U-73122 inhibited the ET-1-induced [[[Ca.sup.2+]].sub.i] increase, indicating that phospholipase C was involved in modulation of the ET-1-induced [[[Ca.sup.2+]].sub.i] increase in rabbit pulmonary artery smooth muscle cells. endothelin receptors; voltage-dependent [Ca.sup.2+] channel

Taurine increases glucose sensitivity of UCP2-overexpressing [beta]-cells by ameliorating mitochondrial metabolism. Am J Physiol Endocrinol Metab 287: E1008-E1018, 2004. First published July 20, 2004; doi:10.1152/ajpendo.00008.2004.--A low-taurine diet during fetal or early postnatal life causes abnormal pancreatic [beta]-cell development. Tissue and plasma taurine concentrations can also be low in diabetic patients. We examined the effect of taurine on impaired glucose responses in diabetic rat [beta]-cells adenovirally overexpressing uncoupling protein (UCP)2, which is upregulated in obesity-related type 2 diabetes. We found that taurine pretreatment restored the ATP-to-ADP (ATP/ADP) ratio and glucose-stimulated insulin secretion in UCP2-infected islets. ATP-sensitive [K.sup.+] channel sensitivity to dihydroxyacetone, another insulin secretagogue, was similar in both UCP2-infected and control [beta]-cells. In freshly isolated mitochondria from UCP2-overexpressing insulin-secreting (INS)-1 [beta]-cells, methyl pyruvate-mediated mitochondrial [Ca.sup.2+] increase was significantly ameliorated by taurine. A mitochondrial [Ca.sup.2+] uniporter blocker. ruthenium red. inhibited the action of taurine. This study suggests that taurine enhances the glucose sensitivity of UCP2-overexpressing [beta]-cells, probably by increasing mitochondrial [Ca.sup.2+] influx through the [Ca.sup.2+] uniporter, thereby enhancing mitochondrial metabolic function and increasing the ATP/ADP ratio. insulin; ATP-sensitive K+ channel; mitochondrial [Ca.sup.2+]; ATP-to-ADP ratio; pancreatic islets; uncoupling protein 2

The present investigation tested the hypothesis that nitric oxide (NO) potentiates ATP-sensitive [K.sup.+] ([K.sub.ATP]) channels by protein kinase G (PKG)-dependent phosphorylation in rabbit ventricular myocytes with the use of patch-clamp techniques. Sodium nitroprusside (SNP; 1 mM) potentiated [K.sub.ATP] channel activity in cell-attached patches but failed to enhance the channel activity in either inside-out or outside-out patches. The 8-(4-chlorophenylthio)-cGMP Rp isomer (Rp-CPT-cGMP, 100 [micro]M) suppressed the potentiating effect of SNP. 8-(4-Chlorophenylthio)-cGMP (8-pCPT-cGMP, 100 [micro]M) increased [K.sub.ATP] channel activity in cell-attached patches. PKG (5 U/[micro]l) added together with ATP and cGMP (100 [micro]M each) directly to the intracellular surface increased the channel activity. Activation of [K.sub.ATP] channels was abolished by the replacement of ATP with ATP[gamma]S. Rp-pCPT-cGMP (100 [micro]M) inhibited the effect of PKG. The heat-inactivated PKG had little effect on the [K.sub.ATP] channels. Protein phosphatase 2A (PP2A, 1 U/ml) reversed the PKG-mediated [K.sub.ATP] channel activation. With the use of 5 nM okadaic acid (a PP2A inhibitor), PP2A had no effect on the channel activity. These results suggest that the NO-cGMP-PKG pathway contributes to phosphorylation of [K.sub.ATP] channels in rabbit ventricular myocytes. phosphorylation