The Return Trip Is Felt Shorter Only Postdictively: A Psychophysiological Study of the Return Trip Effect

The return trip often seems shorter than the outward trip even when the distance and actual time are identical. To date, studies on the return trip effect have failed to confirm its existence in a situation that is ecologically valid in terms of environment and duration. In addition, physiological influences as part of fundamental timing mechanisms in daily activities have not been investigated in the time perception literature. The present study compared round-trip and non-round-trip conditions in an ecological situation. Time estimation in real time and postdictive estimation were used to clarify the situations where the return trip effect occurs. Autonomic nervous system activity was evaluated from the electrocardiogram using the Lorenz plot to demonstrate the relationship between time perception and physiological indices. The results suggest that the return trip effect is caused only postdictively. Electrocardiographic analysis revealed that the two experimental conditions induced different responses in the autonomic nervous system, particularly in sympathetic nervous function, and that parasympathetic function correlated with postdictive timing. To account for the main findings, the discrepancy between the two time estimates is discussed in the light of timing strategies, i.e., prospective and retrospective timing, which reflect different emphasis on attention and memory processes. Also each timing method, i.e., the verbal estimation, production or comparative judgment, has different characteristics such as the quantification of duration in time units or knowledge of the target duration, which may be responsible for the discrepancy. The relationship between postdictive time estimation and the parasympathetic nervous system is also discussed.     

Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors

We have discovered and reported potent p53–MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.     

Isolation and partial characterization of proteoglycans from rice bran

Extraction of rice bran with hot water, followed by removal of protein and starch, yielded a proteoglycan. Successive fractionation of this proteoglycan by salting out with ammonium sulfate and by DEAE-Sephadex column chromatography yielded several fractions shown to be homogeneous by disc electrophoresis. Treatment of the fractions with alkali and a proteolytic enzyme has shown that the polysaccharide and protein of the proteoglycan are most probably linked through an O-glycosyl linkage through hydroxyproline.     

Competitive solubilization of cholesterol and six species of sterol/stanol in bile salt micelles

Slight differences in the molecular structures of a category of sterol/stanol species affect the solubility of cholesterol in a bile salt solution. We systematically studied the preferential solubilization of cholesterol and sterol/stanol in sodium taurodeoxycholate solutions using relatively minor plant species of sterol/stanol (brassicasterol and stigmasterol) and a non-plant sterol (cholestanol). As relatively major sterol/stanol species (β-sitosterol, β-sitostanol, and campesterol) have already been examined using nearly identical procedures to that used in our system, we were able to sufficiently discuss the cholesterol-lowering effects resulting from the molecular structures of six sterol/stanol species. The results of competitive solubilization revealed that cholestanol has the largest cholesterol-lowering effect, decreasing cholesterol solubility to 33% of that in a single solubilizate system. The molecular structure of cholestanol is also most similar to that of cholesterol. In contrast, brassicasterol and stigmasterol have little ability to decrease cholesterol solubility in a mixed binary system. Both have an unsaturated double bond at the side chain of the steroid ring. By applying thermodynamic analyses to these results, we found that the Gibbs energy changes (ΔG°) of solubilization for sterol/stanol species with cholesterol-lowering effects show larger negative values than that for cholesterol.     

Enhanced extrinsic innervation of nasal and oral chemosensory mucosae in keratin 14-NGF transgenic mice

The role of nerve growth factor (NGF) in neurotrophic support for the extrinsic innervation of the nasal and oral mucosae was investigated in keratin 14 (K14)-NGF transgenic mice in which NGF was over-expressed in K14-synthesizing cells. K14 immunoreactivity was localized in the epithelial basal cells of the whisker pad skin, the hard palate, the floor of the ventral meatus, and the anterior tongue that are stratified squamous epithelia, and also in basal cells of the vomeronasal, olfactory, and respiratory epithelia that are non-stratified epithelia. In transgenic mice, NGF expression was identified and confined primarily to the basal cells of stratified epithelia. The nasal mucosae including the vomeronasal, olfactory, and respiratory mucosae, and the glands associated with the vomeronasal organ received a greater innervation of protein gene product 9.5-immunoreactive extrinsic fibers in transgenic animals than nontransgenic controls. An increased density of calcitonin gene-related peptide-immunoreactive extrinsic fibers was observed in the nonsensory epithelia of the vomeronasal organ, the olfactory sensory and respiratory epithelia in transgenic animals. Our results indicated that the hyperinnervation of the nasal and oral mucosae by extrinsic neurons is due at least partially to target-derived NGF synthesis and release by K14-expressing basal cells.This work was supported by NIH grants NIDCD-00159 (T.V.G.), NIDCO-01715 (M.L.G.), and NINDS-31826 (K.M.A.).     

Proteolytic activation can produce a phosphatidylinositol phosphodiesterase highly sensitive to Ca2+

The phosphatidylinositol phosphodiesterase of rat brain shows little activity under conditions likely to pertain in vivo (neutral pH and micromolar Ca(2+) concentrations). A short incubation of a brain supernatant with trypsin, or a longer pre-incubation of the supernatant alone, produce new forms of the enzyme, which are active under such conditions. A possible role of receptor-linked proteinases in initiating phosphatidylinositol catabolism is discussed.     

Involvement of peptidyl-prolyl isomerase Pin1 in the inhibitory effect of fluvastatin on endothelin-1-induced cardiomyocyte hypertrophy

Aims

Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of their common intracellular pathways is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions.

Main methods

We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [³H]-leucine incorporation.

Key findings

Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [³H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it reached basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin.

Significance

This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation.