Blonanserin ameliorates social deficit through dopamine-D3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia.

Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D3 receptor agonist, and SCH23390, a dopamine-D1 receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI, a serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D3 receptor antagonist and SKF38393, a dopamine-D1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser897 by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of NMDA receptors due to Ser897-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D1 receptor-PKA signaling through dopamine-D3 receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D3 receptors may be useful as a novel treatment strategy and that the dopamine-D3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.

Usefulness of Interprofessional Education (Tsurumai-Meijo IPE) in Program Collaborating with Simulated Patients.

Collaboration with multiple healthcare professionals is important to provide safer and higher quality care. Interprofessional education (IPE) promotes the practice of team-based care. The establishment of Tsurumai-Meijo IPE, including interprofessional education and practice (IPEP) and video-teaching materials, was conducted in collaboration with school of medicine/nursing in Nagoya University and Fujita Health University, because Meijo University does not have its own clinical settings and faculties except for pharmacy. In the established Tsurumai-Meijo IPE, pharmacy, medicine, and nursing students interviewed simulated patients (SP) together or separately and practiced team-based care through Tsurumai-Meijo IPEP. Students could learn in advance and on their own about each professional's knowledge related to patient care by using video-teaching materials from the Meijo IPE homepage. Using a questionnaire survey at the end of program, this study was examined whether Tsurumai-Meijo IPEP, and video-teaching materials were useful for understanding importance of team-based care. More than 83% of students indicated that Tsurumai-Meijo IPE is useful on future clinical practice. This suggests that the program and materials are beneficial to the medical student education. In the optional survey of some clinical pharmacists, who had participated in Tsurumai-Meijo IPE before graduation, they utilized it in their work and it facilitated their work related to team-based care. Tsurumai-Meijo IPE collaborating with SP is likely to contribute to provide high quality and safe team-based care by taking advantage of specialized professional ability of healthcare professionals.

Fluorescent reporter analysis revealed the timing and localization of AVR-Pia expression, an avirulence effector of Magnaporthe oryzae.

In order to facilitate infection, the rice blast pathogen Magnaporthe oryzae secretes an abundance of proteins, including avirulence effectors, to diminish its host's defences. Avirulence effectors are recognized by host resistance proteins and trigger the host's hypersensitive response, which is a rapid and effective form of innate plant immunity. An understanding of the underlying molecular mechanisms of such interactions is crucial for the development of strategies to control disease. However, the expression and secretion of certain effector proteins, such as AVR-Pia, have yet to be reported. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that AVR-Pia was only expressed during infection. Fluorescently labelled AVR-Pia indicated that AVR-Pia expression was induced during appressorial differentiation in the cells of both rice and onion, as well as in a penetration-deficient (Δpls1) mutant capable of developing melanized appressoria, but unable to penetrate host cells, suggesting that AVR-Pia expression is independent of fungal penetration. Using live-cell imaging, we also documented the co-localization of green fluorescent protein (GFP)-labelled AVR-Pia and monomeric red fluorescent protein (mRFP)-labelled PWL2, which indicates that AVR-Pia accumulates in biotrophic interfacial complexes before being delivered to the plant cytosol. Together, these results suggest that AVR-Pia is a cytoplasmic effector that is expressed at the onset of appressorial differentiation and is translocated to the biotrophic interfacial complex, and then into the host's cytoplasm.

Spatiotemporal Organization and Cross-Frequency Coupling of Sleep Spindles in Primate Cerebral Cortex.

STUDY OBJECTIVES: The sleep spindle has been implicated in thalamic sensory gating, cortical development, and memory consolidation. These multiple functions may depend on specific spatiotemporal emergence and interactions with other spindles and other forms of brain activity. Therefore, we measured sleep spindle cortical distribution, regional heterogeneity, synchronization, and phase relationships with other electroencephalographic components in freely moving primates. METHODS: Transcortical field potentials were recorded from Japanese monkeys via telemetry and were analyzed using the Hilbert-Huang transform. RESULTS: Spindle (12-20 Hz) current sources were identified over a wide region of the frontoparietal cortex. Most spindles occurred independently in their own frequency, but some appeared concordant between cortical areas with frequency interdependence, particularly in nearby regions and bilaterally symmetrical regions. Spindles in the dorsolateral prefrontal cortex appeared around the surface-positive and depth-negative phase of transcortically recorded slow oscillations (< 1 Hz), whereas centroparietal spindles emerged around the opposite phase. The slow-oscillation phase reversed between the prefrontal and central regions. Gamma activities increased before spindle onset. Several regional heterogeneities in properties of human spindles were replicated in the monkeys, including frequency, density, and inter-cortical time lags, although their topographic patterns were different from those of humans. The phase-amplitude coupling between spindle and gamma activity was also replicated. CONCLUSIONS: Spindles in widespread cortical regions are possibly driven by independent rhythm generators, but are temporally associated to spindles in other regions and to slow and gamma oscillations by corticocortical and thalamocortical pathways.

Gamma Oscillations and Their Cross-frequency Coupling in the Primate Hippocampus during Sleep.

STUDY OBJECTIVES: The mechanism by which sleep consolidates memory is unclear. Based on the two-stage model of memory consolidation, different functions for slow wave sleep (SWS) and rapid eye movement (REM) sleep have been proposed; thus, state-dependent changes of neural oscillations in the hippocampus might clarify this fundamental question. METHODS: We recorded hippocampal local field potentials from freely behaving monkeys via telemetry and analyzed their nonstationary oscillations using Hilbert-Huang transform. RESULTS: By applying a recently developed empirical mode decomposition analysis, we found strong cross-frequency coupling between high-frequency and slow wave oscillations during SWS and a prominent increase of gamma band activity in short bursts during REM sleep in unanesthetized primates' hippocampus. CONCLUSION: Spatiotemporal integration through coupled oscillations during slow wave sleep might be a physiological basis of system consolidation, whereas gamma bursts during rapid eye movement sleep might be related to synaptic consolidation in the local hippocampal neural circuit.

Homologous recombination causes the spontaneous deletion of AVR-Pia in Magnaporthe oryzae.

AVR-Pia, an avirulence gene in the genome of the rice blast fungus Magnaporthe oryzae, triggers a hypersensitive reaction in rice cultivars harbouring the resistance gene Pia. The copy number of AVR-Pia was revealed to vary from one to three among M. oryzae isolates avirulent to Pia rice, and three copies of the gene were located on a single chromosome in strain Ina168, from which the gene was originally cloned. The spontaneous avr-Pia mutant originated from Ina168, named Ina168m95-1, which lacks the AVR-Pia gene, and was therefore used to elucidate the molecular mechanism of the deletion of all three copies of AVR-Pia. Screening and analysis of cosmid clones indicated that two copies of the DNA-type transposon Occan (Occan(9E12) and Occan(3A3) ) were located on the same chromosome, and three copies of AVR-Pia were located in between the two Occan elements. Ina168m95-1 contains a conserved Occan element, named Occan(m95-1) , between sequences homologous to the 5'-flanking region of Occan(3A3) and the 3'-flanking region of Occan(9E12) . In addition, sequence polymorphisms indicated a homologous recombination between Occan(3A3) and Occan(9E12) , which resulted in Occan(m95-1) . Based on these observations, we propose the hypothesis that homologous recombination in the two Occan elements leads to the deletion of AVR-Pia in Ina168m95-1.