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The ability to detect toxic compounds in foods is essential for animal survival. However, the minimal subunit composition of gustatory receptors required for sensing aversive chemicals in Drosophila is unknown. Here we report that three gustatory receptors, GR8a, GR66a and GR98b function together in the detection of L-canavanine, a plant-derived insecticide. Ectopic co-expression of Gr8a and Gr98b in Gr66a-expressing, bitter-sensing gustatory receptor neurons (GRNs) confers responsiveness to L-canavanine. Furthermore, misexpression of all three Grs enables salt- or sweet-sensing GRNs to respond to L-canavanine. Introduction of these Grs in sweet-sensing GRNs switches L-canavanine from an aversive to an attractive compound. Co-expression of GR8a, GR66a and GR98b in Drosophila S2 cells induces an L-canavanine-activated nonselective cation conductance. We conclude that three GRs collaborate to produce a functional L-canavanine receptor. Thus, our results clarify the full set of GRs underlying the detection of a toxic tastant that drives avoidance behaviour in an insect.

Strychnine is a potent, naturally occurring neurotoxin that effectively protects plants from animal pests by deterring feeding behavior. In insects, such as the fruit fly, Drosophila melanogaster, bitter-tasting aversive compounds are detected primarily through a family of gustatory receptors (GRs), which are expressed in gustatory receptor neurons. We previously described multiple GRs that eliminate the behavioral avoidance to all bitter compounds tested, with the exception of strychnine. Here, we report the identity of a strychnine receptor, referred to as GR47a. We generated a mutation in Gr47a and found that it eliminated strychnine repulsion and strychnine-induced action potentials. GR47a was narrowly tuned, as the responses to other avoidance compounds were unaffected in the mutant animals. This analysis supports an emerging model that Drosophila GRs fall broadly into two specificity classes-one class is comprised of core receptors that are broadly required, whereas the other class, which includes GR47a, consists of narrowly tuned receptors that define chemical specificity.

Animals often must decide whether or not to consume a diet that contains competing attractive and aversive compounds. Here, using the fruit fly, Drosophila melanogaster, we describe a mechanism that influences this decision. Addition of bitter compounds to sucrose suppressed feeding behavior, and this inhibition depended on an odorant-binding protein (OBP) termed OBP49a. In wild-type flies, bitter compounds suppressed sucrose-induced action potentials, and the inhibition was impaired in Obp49a mutants. However, loss of OBP49a did not affect action potentials in sugar- or bitter-activated gustatory receptor neurons (GRNs) when the GRNs were presented with just one type of tastant. OBP49a was expressed in accessory cells and acted non-cell-autonomously to attenuate nerve firings in sugar-activated GRNs when bitter compounds were combined with sucrose. These findings demonstrate an unexpected role for an OBP in taste and identify a molecular player involved in the integration of opposing attractive and aversive gustatory inputs.

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-K[O.sup.SF-1]) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-K[O.sup.SF-1] and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis., Introduction Homeostatic regulation in the CNS is a complex process that is critical for systemic physiological balance. Therefore, identifying the brain systems integrating internal and external signals is paramount to [...]

Pipelines in critical engineered facilities, such as petrochemical and power plants, conduct important roles of fire extinguishing, cooling, and related essential tasks. Therefore, failure of a pipeline system can cause catastrophic disaster, which may include economic loss or even human casualty. Optimal sensor placement is required to detect and assess damage so that the optimal amount of resources is deployed and damage is minimized. This paper presents a novel methodology to determine the optimal location of sensors in a pipeline network for real-time monitoring. First, a lumped model of a small-scale pipeline network is built to simulate the behavior of working fluid. By propagating the inherent variability of hydraulic parameters in the simulation model, uncertainty in the behavior of the working fluid is evaluated. Sensor measurement error is also incorporated. Second, predefined damage scenarios are implemented in the simulation model and estimated through a damage classification algorithm using acquired data from the sensor network. Third, probabilistic detectability is measured as a performance metric of the sensor network. Finally, a detectability-based optimization problem is formulated as a mixed integer non-linear programming problem. An Adam-mutated genetic algorithm (AMGA) is proposed to solve the problem. The Adam-optimizer is incorporated as a mutation operator of the genetic algorithm to increase the capacity of the algorithm to escape from the local minimum. The performance of the AMGA is compared with that of the standard genetic algorithm. A case study using a pipeline system is presented to evaluate the performance of the proposed sensor network design methodology. [ABSTRACT FROM AUTHOR]

Chong, Seon Ah, Soo Young Hong, Seok Jun Moon, Jee Won Park, Jeong-Hee Hong, Jeong Mi An, Syng-III Lee, Dong Min Shin, and Jeong Taeg Seo. Partial inhibition of SERCA is responsible for extracellular [Ca.sup.2.sup.+] dependence of [Al[F.sup.-.sub.4]-induced [[Ca.sup.2.sup.+].sub.i] oscillations in rat pancreatic acinar cells. Am J Physiol Cell Physiol 285: C1142-C1149, 2003. First published July 23, 2003; 10.1152/ajpcell.00566.2002. --[Al[F.sup.-.sub.4] is known to generate oscillations in intracellular [Ca.sup.2.sup.+] concentration [([Ca.sup.2.sup.+].sub.i)] by activating G proteins in many cell types. However, in rat pancreatic acinar cells, [Al[F.sup.-.sub.4]evoked [[Ca.sup.2.sup.+].sub.i] oscillations were reported to be dependent on extracellular [Ca.sup.2.sup.+], which contrasts with the [[Ca.sup.2.sup.+].sub.i] oscillations induced by cholecystokinin (CCK). Therefore, we investigated the mechanisms by which [Al[F.sup.-.sub.4] generates extracellular [Ca.sup.2.sup.+]-dependent [[Ca.sup.2.sup.+].sub.i] oscillations in rat pancreatic acinar cells. [Al[F.sup.-.sub.4]-induced [[Ca.sup.2.sup.+].sub.i] oscillations were stopped rapidly by the removal of extracellular [Ca.sup.2.sup.+] and were abolished on the addition of 20 mM caffeine and 2[micro]M thapsigargin, indicating that [Ca.sup.2.sup.+] influx plays a crucial role in maintenance of the oscillations and that an inositol 1,4,5-trisphos-phate-sensitive [Ca.sup.2.sup.+] store is also required. The amount of [Ca.sup.2.sup.+] in the intracellular [Ca.sup.2.sup.+] store was decreased as the [Al[F.sup.-.sub.4]-induced [[Ca.sup.2.sup.+].sub.i] oscillations continued. Measurement of [sup.45][Ca.sup.2.sup.+] influx into isolated microsomes revealed that [Al[F.sup.-.sub.4] directly inhibited sarco/endoplasmic reticulum [Ca.sup.2.sup.+]-ATPase (SERCA). The activity of plasma membrane [Ca.sup.2.sup.+]-ATPase during [Al[F.sup.-.sub.4] stimulation was not significantly different from that during CCK stimulation. After partial inhibition of SERCA with 1 nM thapsigargin, 20 pM CCK-evoked [[Ca.sup.2.sup.+].sub.i] oscillations were dependent on extracellular [Ca.sup.2.sup.+]. This study shows that [Al[F.sup.-.sub.4] induces [[Ca.sup.2.sup.+].sub.i] oscillations, probably by inositol 1,4,5-trisphosphate production via G protein activation but that these oscillations are strongly dependent on extracellular [Ca.sup.2.sup.+] as a result of the partial inhibition of SERCA. cholecystokinin; plasma membrane adenosine 5'-triphosphatase; G proteins; caffeine