Cdh23 and Prepulse Inhibition

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA

Distinct Metabolites for Photoreactive L-Phenylalanine Derivatives in Klebsiella sp. CK6 Isolated from Rhizosphere of a Wild Dipterocarp Sapling

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Incidence survey of acute otitis media in children in Sado Island, Japan--Sado Otitis Media Study (SADOMS).

BACKGROUND: Acute otitis media (AOM) is one of the most common forms of bacterial infection and cause for clinic visits in children. The incidence of AOM was 0.9-1.2 episodes per person-year during the first 2 years of life in previous reports conducted before 2000. The aim of this study was to 1) evaluate the latest AOM incidence in pediatric outpatients and 2) identify the bacterial pathogens from these patients and ascertain their serotypes and resistance. METHODS: The study was conducted in a closed population, involving all pediatricians and otolaryngologists in Sado Island allowing accurate determination of AOM incidence. In each month, one week was assigned as "surveillance week", and all outpatients with acute illness aged 0-18 years examined during the surveillance weeks were enrolled. AOM was diagnosed on the basis of otoscopic findings and clinical symptoms were recorded. Specimens were collected from the nasopharynx or middle ear cavity of AOM patients and examined for bacteria. Antimicrobial susceptibilities, serotypes, and molecular typing for resistance were determined among Streptococcus pneumoniae and Haemophilus influenzae. RESULTS: In total, 8,283 clinic visits were conducted, and 354 episodes (4.3%, 95% CI: 3.9-4.7%) among 312 children were diagnosed as AOM. The incidence of AOM was highest in children of 1 year of age (0.54 episodes/child/year, 95% CI: 0.44-0.64). Serotype coverage of 7- and 13-valent pneumococcal conjugate vaccines in this study were 38.0% (95% CI: 29.3-47.3) and 62.8% (95% CI: 53.6-71.4), respectively. Of 122 H.influenzae isolates available for typing, 120 were nontypeable and 2 were type b. A high proportion of S. pneumoniae isolates (46%) showed resistance to penicillin. Approximately half of H. influenzae isolates had genetic markers for beta-lactamase-negative ampicillin-resistance. CONCLUSIONS: Approximately 4-5% of pediatric outpatients, even without AOM-related symptoms, had AOM in our study. Pediatricians as well as otolaryngologists should check the tympanic membrane findings of all pediatric outpatients