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Learning and memory are essential processes of both vertebrate and invertebrate nervous systems that allow animals to survive and reproduce. The neurotransmitter glutamate signals via ionotropic glutamate receptors (iGluRs) that have been linked to learning and memory formation; however, the signaling pathways that contribute to these behaviors are still not well understood. We therefore undertook a genetic and electrophysiological analysis of learning and memory in the nematode Caenorhabditis elegans. Here, we show that two genes, nmr-1 and nmr-2, are predicted to encode the subunits of an NMDA-type (NMDAR) iGluR that is necessary for memory retention in C. elegans. We cloned nmr-2, generated a deletion mutation in the gene, and showed that like nmr-1, nmr-2 is required for in vivo NMDA-gated currents. Using an associative-learning paradigm that pairs starvation with the attractant NaCl, we also showed that the memory of a learned avoidance response is dependent on NMR-1 and NMR-2 and that expression of NMDARs in a single pair of interneurons is sufficient for normal memory. Our results provide new insights into the molecular and cellular mechanisms underlying the memory of a learned event.

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The intertemporal current account approach predicts that the current account of a small open economy is independent of global shocks, and that responses of the current account to countryspecific shocks depend on the persistence of the shocks. The author shows that these predictions impose cross-equation restrictions (CERS) on a structural vector autoregression (SVAR). To test the CERs, the author develops identification schemes of the SVAR that exploit the orthogonality of the world real interest rate to country-specific shocks as well as the lack of a long-run response of net output to transitory shocks. Tests of the SVAR reveal two puzzling aspects of the Canadian and U.K. current account: (i) the response of the current account to a country-specific transitory shock is too large, and (ii) the fluctuations in the current account are dominated by countryspecific transitory shocks that explain almost none of the fluctuations in net output growth. JEL classification: F32, F41 Bank classification: Balance of payments and components RésuméSelon l'approche intertemporelle, la balance courante d'une petite économie ouverte n'est pas influencée par les chocs mondiaux et sa réaction aux chocs nationaux dépend de la persistance de ceux-ci. L'auteur montre que ces prédictions impliquent l'imposition de contraintes interéquations à un vecteur autorégressif structurel (VARS). Pour tester ces contraintes, il élabore des schémas d'identification qui présupposent l'orthogonalité du taux d'intérêt réel mondial aux chocs nationaux et l'absence d'une réaction à long terme de la production nette aux chocs passagers. L'auteur étudie l'évolution des balances courantes du Canada et du Royaume-Uni. Les tests qu'il effectue sur les VARS font ressortir deux illogismes : i) le solde de la balance courante de ces deux pays réagit de façon excessive aux chocs nationaux transitoires; ii) les fluctuations de ce solde sont principalement attribuables à des chocs nationaux transitoires qui n'expliquent à peu près aucune des variations de la croissance de la production nette.Classification JEL : F32, F41 Classification de la Banque : Agrégats monétaires 12 This sample period is close to those of related papers: it almost overlaps that of Bergin and Sheffrin (2000 and includes that of Nason and Rogers (2002.13 This paper constructs the demeaned series of the world real interest rate, the change in the log of net output, and the current account-net output ratio (i.e., rt, ∆ ln N Ot, and CAt/N Ot), and performs unit root tests for them based on the ADF τ -test. The ADF tests reject the unit-root null in all series at least at the 5 per cent significance level. From this evidence, the series rt, ∆ ln N Ot, and CAt/N Ot are considered to be stationary in the following analysis.

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ABSTRACT:Oseltamivir, an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), has been developed for the treatment of A and B strains of the influenza virus but has neuropsychiatric and other side effects. In this study, we characterized the transport across intestinal epithelial cells and the absorption of oseltamivir in rats. Uptake by Caco-2 cells (human carcinoma cell line) and HeLa cells transfected with peptide transporter 1 (HeLa/ PEPT1) was time-and temperature-dependent and was inhibited by typical PEPT1 inhibitors such as glycyl-sarcosine (Gly-Sar). The uptake by Caco-2 cells and HeLa/PEPT1 was saturable, with similar K m values. Oseltamivir absorption in adult rats was greatly reduced by simultaneous administration of milk, casein, or Gly-Sar. Furthermore, the plasma and brain concentrations of oseltamivir were higher in fasting than in nonfasting rats after oral administration. These results suggest that oseltamivir is a substrate of PEPT1 and that PEPT1 is involved in its intestinal absorption.Various transporters are expressed on apical and basolateral membranes of intestinal epithelial cells, serving to take up nutrients and to excrete xenobiotics into the lumen. Influx transporters are able to accept nutrients and also various drugs as substrates. In particular, peptide transporter 1 (PEPT1, SLC15A1), localized at brush-border membranes of human small intestine (Saito et al., 1995), plays important roles in the absorption of not only di-/tripeptides (Tamai et al., 1994) but also peptide-mimetic compounds, such as orally administered ␤-lactam antibiotics (Ganapathy et al., 1995;Sai et al., 1996) and the anticancer agent bestatin (Tomita et al., 1990;Inui et al., 1992). Several researchers recently found that intestinal PEPT1 can transport L-valine ester prodrugs, such as valacyclovir and valganciclovir (Balimane et al., 1998;Han et al., 1998;Sugawara et al., 2000). Therefore, such structural modification of drugs may result in increased intestinal absorption, mediated by PEPT1.Oseltamivir phosphate (oseltamivir), manufactured under the trade name Tamiflu as an ester-type prodrug of the neuraminidase inhibitor Ro 64-0802, has been developed for the treatment of A and B strains of the influenza virus. This drug has been reported to be associated with neuropsychiatric side effects (http://www.fda.gov/cder/drug/ infopage/tamiflu/QA20051117.htm and http://www.mhlw.go.jp/ english/index.html), which are likely to be caused by distribution of oseltamivir and/or its metabolite(s) to the central nervous system. We recently examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance (or resistant) 1 (MDR1) P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice (Morimoto et al., 2008). The permeability of oseltamivir in the basolateral-to-apical dire...

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