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We report in situ structural measurements of shock‐compressed single crystal orthoenstatite up to 337 ± 55 GPa on the Hugoniot, obtained by coupling ultrafast X‐ray diffraction to laser‐driven shock compression. Shock compression induces a disordering of the crystalline structure evidenced by the appearance of a diffuse X‐ray diffraction signal at nanosecond timescales at 80 ± 13 GPa on the Hugoniot, well below the equilibrium melting pressure (>170 GPa). The formation of bridgmanite and post‐perovskite have been indirectly reported in microsecond‐scale plate‐impact experiments. Therefore, we interpret the high‐pressure disordered state we observed at nanosecond scale as an intermediate structure from which bridgmanite and post‐perovskite crystallize at longer timescales. This evidence of a disordered structure of MgSiO3 on the Hugoniot indicates that the degree of polymerization of silicates is a key parameter to constrain the actual thermodynamics of shocks in natural environments. Plain Language Summary: The study of silicate materials at extreme pressures and temperatures provides insight on the evolution of planetary bodies evolution during solar system formation. During their accretion, rocky bodies have undergone several collisions and possibly planetary impacts that have transformed their minerals. The microscopic processes occurring during such events are not fully understood. In this study, we used high‐power lasers to generate shock waves into MgSiO3 enstatite crystals, creating conditions comparable to the deepest part of the early Earth mantle and large planetary impacts. During the shock wave transit, within few nanoseconds, we probed the structure of shocked enstatite between 14 ± 3 and 337 ± 55 GPa using intense X‐ray pulses from Linac Coherent Light Source X‐ray free electron laser facility. We found that, when shocked between 80 ± 13 GPa and the conditions of equilibrium melting (above 170 GPa), enstatite transforms into a disordered structure instead of forming bridgmanite or post‐perovskite—the expected equilibrium phases. This disordered structure is similar to MgSiO3 glass or liquid and is observed up to 337 ± 55 GPa. This study provides the first direct measurement of shocked enstatite structure and suggests that the observed disordered state is an intermediate phase on the transformation pathway of bridgmanite in natural impacts. Key Points: We performed ultrafast X‐ray diffraction of orthoenstatite crystals shock compressed up to 337 ± 55 GPa on the HugoniotA disordered structure was observed from 80 ± 13 GPa along the Hugoniot, well below the melting temperatureThe degree of polymerization strongly influences the kinetics of recrystallization in shocked silicates [ABSTRACT FROM AUTHOR]

Direct metrology of coherent short-wavelength beamlines is important for obtaining operational beam characteristics at the experimental site. However, since beam-time limitation imposes fast metrology procedures, a multi-parametric metrology from as low as a single shot is desirable. Here a two-dimensional (2D) procedure based on high-resolution Fresnel diffraction analysis is discussed and applied, which allowed an efficient and detailed beamline characterization at the SACLA XFEL. So far, the potential of Fresnel diffraction for beamline metrology has not been fully exploited because its high-frequency fringes could be only partly resolved with ordinary pixel-limited detectors. Using the high-spatial-frequency imaging capability of an irradiated LiF crystal, 2D information of the coherence degree, beam divergence and beam quality factor M2 were retrieved from simple diffraction patterns. The developed beam metrology was validated with a laboratory reference laser, and then successfully applied at a beamline facility, in agreement with the source specifications. [ABSTRACT FROM AUTHOR]

Sphincter of Oddi dysfunction is one of the most important symptoms in post-cholecystectomy syndrome. Using either electrical or mechanical stimulation and retrogradely transported neuronal dyes, it has been demonstrated that there are direct neural pathways connecting gall bladder and the sphincter of Oddi in the Australian opossum and the golden hamster. In the present study, we employed whole-mount immunohistochemistry staining to observe and verify that there are two different plexuses of the extrahepatic biliary tract in Suncus murinus. One, named Pathway One, showed a fine, irregular but dense network plexus that ran adhesively and resided on/in the extrahepatic biliary tract wall, and the plexus extended into the intrahepatic area. On the other hand, named Pathway Two, exhibiting simple, thicker and straight neural bundles, ran parallel to the surface of the extrahepatic biliary tract and passed between the gall bladder and duodenum, but did not give off any branches to the liver. Pathway Two was considered to involve direct bidirectional neural connections between the duodenum and the biliary tract system. For the first time, morphologically, we demonstrated direct neural connections between gall bladder and duodenum in S. murinus. Malfunction of the sphincter of Oddi may be caused by injury of the direct neural pathways between gall bladder and duodenum by cholecystectomy. From the viewpoint of preserving the function of the major duodenal papilla and common bile duct, we emphasize the importance of avoiding kocherization of the common bile duct so as to preserve the direct neural connections between gall bladder and sphincter of Oddi. [ABSTRACT FROM AUTHOR]

Background and Objective The periodontal ligament ( PDL) is vital to maintaining the homeostasis of the tooth and periodontal tissue. The influence of iron levels on the cytodifferentiation of PDL cells has not been studied, despite evidence that iron overload or deficiency can have adverse effects on alveolar bone density. The purpose of this study was to examine the effects of altered iron levels on cytodifferentiation in human PDL cells. Material and Methods Human PDL cells were incubated with culture media supplemented with 10-50 μ m ammonium ferric citrate or 5 μ m deferoxamine (an iron chelator) during differentiation. Intracellular iron status was assessed by measuring changes in the expression of ferritin RNA and protein. PDL cell differentiation and function were evaluated by measuring osteoblast differentiation gene markers and the capacity of cultures to form mineralized nodules. Results Iron accumulation resulted in upregulation of light and heavy chain ferritin proteins. Concurrently, osteoblast differentiation gene markers and mineralized nodule formation were suppressed. Iron deficiency resulted in downregulation of light and heavy chain ferritin proteins, suppression of alkaline phosphatase activity and formation of mineralized nodules during PDL cell differentiation. Conclusion We conclude that iron is critical for normal cell differentiation of human PDL cells. [ABSTRACT FROM AUTHOR]

ABSTRACT Recently, Rajapaksa et al. (2010) showed that the rate of uptake of potential vaccine delivery nanoparticles in the mucosal layer is a function of the electrostatic properties of the corresponding solvent. This fundamentally implies that the dominant driving forces that may be capitalized on for mucosal vaccine strategies are electrostatic in nature. We hypothesize that the driving force normal to the cell (in the direction from apical to basolateral across the cell) is of particular importance. In addition, it has been theoretically shown that the electrostatic properties of mucosal cells are directly related to their development of brush border. Here we correlate the development of brush border on a human mucosal epithelial model (Caco-2) cultured in DMEM on 3.0 µm pore sized polycarbonate membranes to their corresponding electrostatic properties characterized by measuring their normal zeta potential. Properties of normal streaming potential, hydraulic permeability, and brush border development (as determined by size and number) were monitored for 2, 6, and 16 days (after cells were confluent). Human endothelial cells (HECs), which lack brush border, were used as the control. Our results demonstrate that normal zeta potential of Caco-2 cells significantly changed from −5.7 ± 0.11 mV to −3.4 ± 0.11 mV for a period between 2 and 16 days, respectively. The zeta potential of the control cell line, HECs, stayed constant (statistically not different, P > 0.05) for the duration of the experiments. Our results show that the calculated increase in surface area of the Caco-2 cells with microvilli from 6 to 16 days was directly proportional to the corresponding measured zeta potential difference. These results imply that microvilli alter the electrostatic local environment around Caco-2 cells and, hence, enhance the normal electrostatic selective transport of solute across the mucosal barrier. Biotechnol. Bioeng. 2013;110: 2742-2748. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

To clarify the mechanism of tenderness after bone injury, we investigated changes in the withdrawal threshold to mechanical stimuli, nerve distribution and nerve growth factor ( NGF)-expression in a rat model of bone injury without immobilization for bone injury healing. Rats were divided into three groups as follows: (1) rats incised in the skin and periosteum, followed by drilling a hole in the tibia [bone lesion group ( BLG)]; (2) those incised in the skin and periosteum without bone drilling [periosteum lesion group ( PLG)]; and (3) those incised in the skin [skin lesion group ( SLG)]. Mechanical hyperalgesia continued for 28 days at a lesion in the BLG, 21 days in PLG and 5 days in SLG after treatments, respectively. Endochondral ossification was observed on days 5-28 in BLG and on days 5-21 in PLG. Nerve growth appeared in deep connective tissue ( DCT) at day 28 in BLG. Nerve fibres increased in both cutaneous tissue and DCT at day 7 in PLG, but they were not found at day 28. Mechanical hyperalgesia accompanied with endochondral ossification and nerve fibres increasing at the lesion in both BLG and PLG. NGF was expressed in bone-regenerating cells during the bone injury healing. Anti- NGF and trk inhibitor K252a inhibited hyperalgesia in the different time course. This study shows that localized tenderness coincides with the bone healing and involves NGF expression and nerve sprouting after bone injury. The findings present underlying mechanisms and provide pathophysiological relevance of local tenderness to determination of bone fracture and its healing. [ABSTRACT FROM AUTHOR]

The bile acid-binding ability of a highly polymerized tannin (kaki-tannin) extracted from dried-young fruits of persimmon (Diospyros kaki) was examined. The kaki-tannin was composed mainly of epicatechin, epigallocatechin, epicatechin-3-O-gallate and epigallocatechin-3-O-gallate. Bile acid-binding ability of kaki-tannin was examined against cholic acid, glycocholic acid, taurocholic acid and deoxycholic acid in vitro, and its effect on fecal bile acid excretion in mice was also examined. Although the bile acid-binding ability of kaki-tannin was weaker than that of cholestyramine, kaki-tannin adsorbed all the bile acids tested and significantly promoted fecal bile acid excretion in mice when supplied at 1% (w/w) in the diet. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Several lines of evidence from animal and genetic analyses showed that the calcineurin A gamma subunit gene (PPP3CC) plays an important role in the pathogenesis of schizophrenia. Moreover, a recent large Japanese case-control study confirmed the genetic association of PPP3CC with schizophrenia. The symptoms of methamphetamine (MAP)-induced psychosis are similar to those of schizophrenia, suggesting that PPP3CC is an attractive candidate gene not only for schizophrenia, but also for METH-related disorders. In this study, we carried out a genetic association study of PPP3CC with MAP-use disorder in a Japanese population. We selected five haplotype-tagging SNPs from the aforementioned replication study and genotyped 393 samples (MAP abuse, 128; control, 265). We could not detect a significant association of all tagging SNPs with each condition. In conclusion, our data suggest that PPP3CC does not elevate the risk of MAP-use disorder in the Japanese population. [ABSTRACT FROM AUTHOR]

Casein kinase 1 epsilon (CKIℇ) is a component of the DARPP-32 in second-messenger pathway. CKIℇ phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. A recent clinical study showed that rs135745, a noncoding single nucleotide polymorphism of the 3′-untranslated region of the CSNK1E gene, was associated with the intensity of the subjective response to an oral amphetamine dose in normal volunteers. Differences in sensitivity to the drug should affect development of dependence to it. Hence, we genotyped rs135745 of the CSNK1E (MIM 600863) gene in 215 patients with methamphetamine dependence and 274 age- and gender-matched normal controls. No significant differences in genotype and allele frequencies were observed between the patients with methamphetamine dependence and controls. There was also no significant association between rs135745 and the clinical characteristics of methamphetamine dependence and co-morbid methamphetamine psychosis (e.g., age of first consumption, latency of psychosis, prognosis of psychosis after therapy, spontaneous relapse of psychotic symptoms, and poly-substance abuse status). The present findings suggest that having a genetic variant of the CSNK1E gene did not affect susceptibility to methamphetamine dependence or psychosis, at least in a Japanese population. [ABSTRACT FROM AUTHOR]

Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is β-arrestin 2 (ARRB2). We therefore conducted a genetic case–control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of ‘tag single nucleotide polymorphisms (SNPs)’ was found in METH use disorder (rs1045280: Pgenotype = 0.0118, Pallele = 0.00351; rs2036657: Pallele = 0.0431; rs4790694: Pgenotype = 0.0167, Pallele = 0.0202), but no association was found with schizophrenia. We also evaluated the gene–gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder. [ABSTRACT FROM AUTHOR]

Dihydropyrimidinase-related protein 2 (DRP-2 or DPYSL-2)mediates the intracellular response to collapsin, a repulsive extracellular guidance cue or axonal outgrowth. DRP-2 is also referred to as collapsin response mediator protein 2 (CRMP-2). We have previously demonstrated that the DRP-2 gene is associated with susceptibility to schizophrenia, but not to bipolar disorders. In addition, a genetic association was observed with paranoid-type schizophrenia, but not with hebephrenic-type schizophrenia. It has been well documented that repeated abuse of methamphetamine (METH) for a long period frequently produces psychotic symptoms, such as auditory hallucinations and delusions that are hardly distinguishable from those of paranoid-type schizophrenia. Therefore, we hypothesized that a certain genetic variant of the DRP-2 gene may affect individual vulnerability to the development of METH-induced psychosis. We examined the genetic association by a case–control method. The polymorphism *2236T>C in the 3′ untranslated region of the DRP-2 gene, which has been shown to be a negative genetic risk factor for paranoid-type schizophrenia, was analyzed in 198 patients with METH psychosis and 221 corresponding healthy controls in a Japanese population. No significant association of the DRP-2 gene with METH psychosis was found. Neither did we find an association with the clinical phenotype of METH psychosis, such as the age of first consumption of METH, latency to development of psychosis after METH abuse, prognosis of psychosis after detoxification from METH use, complication of spontaneous relapse of psychosis without reconsumption of the drug, or multisubstance abuse status. These findings indicate that a genetic variant of the DRP-2 gene may not affect the risk of METH psychosis or any clinical phenotype of the disorder. [ABSTRACT FROM AUTHOR]

Recent preclinical findings that repeated treatment with methamphetamine (METH) induced an increase in tumor necrosis factor-α (TNF-α) mRNA in some brain regions and that TNF-α blocked METH neurotoxicity and rewarding effects suggest TNF-α, a multifunctional pro-inflammatory cytokine, may be involved in METH dependence. We hypothesized that genetic polymorphisms of the TNF-α gene and its receptor genes may be associated with vulnerability to METH dependence. Genetic association of -308G>A and -857C>T in the promotor region of the TNF-α gene, and 36A>G in exon 1 of the TNF receptor 1A gene (TNFR-SF1A), were analyzed in patients with METH dependence ( n= 185) and healthy controls ( n= 221) in a Japanese population. No significant association of alleles or haplotypes of the TNF-α or TNFR-SF1A genes with METH dependence was found. Neither was any significant association of clinical phenotype with METH dependence found. These results suggest that genetic variations in the TNF-α gene and its receptor genes may not be involved in individual vulnerability to METH dependence. [ABSTRACT FROM AUTHOR]

Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, −156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that metabolic changes in the kynurenic acid (KYNA) pathway are related to the etiology of schizophrenia. The inhibitor of kynurenine 3-monooxygenase (KMO) is known to increase KYNA levels, and the KMO gene is located in the chromosome region associated with schizophrenia, 1q42-q44. Single-marker and haplotype analyses for 6-tag single nucleotide polymorphisms (SNPs) of KMO were performed (cases = 465, controls = 440). Significant association of rs2275163 with schizophrenia was observed by single-marker comparisons ( P = 0.032) and haplotype analysis including this SNP ( P = 0.0049). Significant association of rs2275163 and haplotype was not replicated using a second, independent set of samples (cases = 480, controls = 448) ( P = 0.706 and P = 0.689, respectively). These results suggest that the KMO is unlikely to be related to the development of schizophrenia in Japanese. [ABSTRACT FROM AUTHOR]

Objective: Worldwide use of the Hamilton Rating Scale for Depression (HRSD) presupposes that depression symptomatology can be measured the same way across countries but no empirical study has yet examined this issue. We therefore examined cross-cultural consistency of factor structure of HRSD. Method: A 17-item HRSD data were sought for 5185 individuals diagnosed with major depression in Japan, Europe and North America. Candidate factor structures were obtained with simultaneous component analysis (SCA) across the three cultures. They were then submitted to multiple-group confirmatory factor analysis (CFA). Results: According to SCA, 3-, 4- or 5-factor solutions were found to optimally and adequately summarize the variables for all the three populations. When submitted to CFA, the 5-factor solution was the best fitting and the most parsimonious: they were ‘anhedonia/retardation,’‘guilt/agitation,’‘bodily symptoms,’‘insomnia’ and ‘appetite.’ Conclusion: Common underlying factors exist for HRSD among Japanese, European and American patients with major depression. [ABSTRACT FROM AUTHOR]

Our group, Ujike et al., recently reported that the A1 allele of TaqI A polymorphism of the dopamine receptor D2 (DRD2) gene, associated with transient psychosis, significantly differs from that of patients with prolonged psychosis in methamphetamine psychosis. Therefore, we examined the association between the TaqI A polymorphism of the DRD2 gene and the brain MRI view for patients with methamphetamine psychosis. The subjects underwent brain MRI scans using the FLAIR method. Genotyping was performed by PCR-RFLP methods using genomic DNA extracted from peripheral blood by the phenol method. Ten subjects had the A1/A2 genotype, eleven subjects had the A2/A2 genotype, and no subject had the A1/A1 genotype. The domain size, including the thalamus and basal ganglia that were inside each side of the putamens, did not differ between the three groups (the A1/A2-group, the A2/A2- group, and the young healthy person group). In the comparison based on this domain, the temporal lobe tended to narrow in the A2/A2-group compared to the A1/A2-group (P = .06). The other domain (cerebrum, corpus callosum, etc.) showed no difference between the A1/A2-group and the A2/A2-group. It is suggested that in methamphetamine psychosis the TaqI A polymorphism not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe. [ABSTRACT FROM AUTHOR]

In the central nervous system, tissue-plasminogen activator (t-PA)/ plasmin system is involved in long-term synaptic plasticity and remodeling, and participates in rewarding effects of methamphetamine (MAP), by acutely regulating MAP-induced dopamine release in the nucleus accumbens. The aim of this study was to examine the relationships between the patients with MAP abusers/psychosis and the t-PA/plasminogen system genes. Subjects comprised 185 MAP abusers and 288 healthy controls. Four polymorphisms in the t-PA, plasminogen activator inhibitor, and plasminogen genes were examined in the present study. No significant differences were observed in each polymorphism between healthy controls and MAP abusers/psychosis. This study suggests that t-PA/plasminogen system is unlikely to be a major contributor to the substance abuse liability and/or the development of MAP psychosis. [ABSTRACT FROM AUTHOR]

It has been suggested that individual genetic factors are involved in susceptibility to drug dependence and the manifestation of drug-induced psychosis. The aim of this study was to examine the relation between methamphetamine abusers/psychosis and the type 1 sigma receptor gene polymorphisms. Subjects comprised 143 MAP abusers and 181 healthy controls. Two polymorphisms in the type 1 sigma receptor gene, GC-241-240TT and A61C (Gln2Pro), were examined in the present study. No significant differences were observed in either polymorphism between healthy controls and MAP abusers/psychosis. In the subgroup analyses, the rate of CC genotype of A61C tended to be higher in MAP patients who had experienced spontaneous relapse without MAP use than in those who had not (P = .06, OR = 3.02 95%CI = 0.92-9.92). However, the level of this significant trend did not remain after the Bonferroni's multiple correction. This study suggests that type 1 sigma receptor gene is unlikely to play a major role in substance abuse liability and/or the development of MAP psychosis. [ABSTRACT FROM AUTHOR]

Human serotonin 5A (5-HT[SUB5A]) receptors were stably expressed in undifferentiated C6 glioma. In 5-HT[SUB5A] receptors-expressing cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously. Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed, indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger mediating ryanodine-sensitive Ca[SUP2+] mobilization. On the other hand, 5-HT-induced outward currents were observed using the patch-clamp technique in whole-cell configuration. The 5-HT-induced outward current was observed in 84% of the patched 5-HT[SUB5A] receptor-expressing cells and was concentration-dependent. The 5-HT-induced current was inhibited when intracellular K[SUP+] was replaced with Cs[SUP+] but was not significantly inhibited by typical K[SUP+] channel blockers. The 5-HT-induced current was significantly attenuated by 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) in the patch pipette. Depleting intracellular Ca[SUP2+] stores by application of caffeine or thapsigargin also blocked the 5-HT-induced current. Blocking G protein, the inositol tri-phosphate (IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced current. IP3 showed a transient (increase after application of 5-HT in 5-HT[SUB5A] (receptor-expressing cells. It was concluded that in addition to the inhibition of (cAMP accumulation and ADP-ribosyl cyclase activity, 5-HT[SUB5A] receptors regulate intracellular Ca[SUP2+] mobilization which is probably a result of the IP3-sensitive Ca[SUP2+] store. These multiple signal transduction systems may induce complex changes in the serotonergic system in brain function. [ABSTRACT FROM AUTHOR]

Objective: To make a direct comparison of patients with obsessive-compulsive disorder (OCD) and major depression (MD) and a normal control group in terms of the Temperament and Character Inventory (TCI) personality dimensions. Method: Additionally to 43 patients with primary OCD, 43 MD patients and 43 normal subjects who were matched against the OCD patients for sex and age filled out the TCI. Results: Compared to the controls, the OCD and MD patients scored significantly higher on harm avoidance and significantly lower on self-directedness and co-operativeness. The OCD patients scored significantly lower on novelty-seeking than the MD patients and the controls. Conclusion: Whereas OCD and MD share similar personality deviations on harm avoidance, self-directedness and co-operativeness, OCD is distinguishable from MD in terms of low novelty-seeking. Low novelty-seeking may have a profound relationship to the specific aetiology of OCD. [ABSTRACT FROM AUTHOR]

In order to forecast the effects of global warming on the water environment, the relationship between meteorological conditions and lake water quality was investigated statistically using 17 years of monitoring data obtained from a shallow eutrophic lake, Lake Kasumigaura. The usefulness of the DPY (difference from the previous year) method was confirmed for removing the watershed change (e.g. land cover, population, etc.). From the analysis of the relationships between air temperature and water temperature on a monthly basis, the delay of time was seen to be negligible, but the gain was reduced due to the high frequency of change. As the amount of precipitation affected their relationship on a yearly basis, the slopes of 170-172 deg. C water temperature/ deg. C air temperature were determined with the DPY method by excluding the combinations of the years having large difference inannual precipitation. The deterioration of lake water quality, such as increases in COD (chemical oxygen demand) and decreases in transparency, was quantitatively assessed as corresponding to an increase inair temperature. In addition, we found that higher precipitation ledto high nitrogen concentrations on a monthly basis, as well as on a yearly basis, probably induced by both the runoff of soilwater havinghigh concentrations and the lowering of residence times of lake water. [ABSTRACT FROM AUTHOR]

Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2)  = 8.327, P = 0.0039), CNV6 (χ(2)  = 19.66, P = 0.00005), and CNV8 (χ(2)  = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia., (© 2016 Wiley Periodicals, Inc.)

Recent genome-wide association studies (GWASs) of schizophrenia (SCZ) identified several susceptibility genes and suggested shared genetic components between SCZ and bipolar disorder (BD). We conducted a genetic association study of single nucleotide polymorphisms (SNPs) selected according to previous SCZ GWAS targeting psychotic disorders (SCZ and BD) in the Japanese population. Fifty-one SNPs were analyzed in a two-stage design using first-set screening samples (all SNPs: 1,032 SCZ, 1,012 BD, and 993 controls) and second-set replication samples ("significant" SNPs in the first-set screening analysis: 1,808 SCZ, 821 BD, and 2,321 controls). We assessed allelic associations between the selected SNPs and the three phenotypes (SCZ, BD, and "psychosis" [SCZ + BD]). Nine SNPs revealed nominal association signals for all comparisons (P(uncorrected) < 0.05), of which two SNPs located in the major histocompatibility complex region (rs7759855 in zinc finger and SCAN domain containing 31 [ZSCAN31] and rs1736913 in HLA-F antisense RNA1 [HLA-F-AS1]) were further assessed in the second-set replication samples. The associations were confirmed for rs7759855 (P(corrected) = 0.026 for psychosis; P(corrected) = 0.032 for SCZ), although the direction of effect was opposite to that in the original GWAS of the Chinese population. Finally, a meta-analysis was conducted using our two samples and using our data and data from Psychiatric GWAS Consortium (PGC), which have shown the same direction of effect. SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes (best P = 6.8 × 10(-5) for psychosis: present plus PGC results). These data support shared risk SNPs between SCZ and BD in the Japanese population and association between MHC and psychosis., (© 2014 Wiley Periodicals, Inc.)

Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia., (Copyright © 2012 Wiley Periodicals, Inc.)

Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia., (Copyright © 2012 Wiley Periodicals, Inc.)

Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia., (Copyright © 2011 Wiley Periodicals, Inc.)

As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population., (Copyright © 2011 Wiley-Liss, Inc.)

The polymeric title compound, {[Mn(II) (2)W(IV)(CN)(8)(C(10)H(8)N(2))(2)(H(2)O)(4)]·6H(2)O}(n), has a one-dimensional cyanide-bridged Mn(II)-W(IV) bimetallic assembly. The coordination geometry of the W(IV) atom is eight-coordinate square-anti-prismatic and that of each of the Mn(II) atoms is six-coordinate distorted octa-hedral. Two pairs of CN ligands of W(CN)(8) are bridged to two Mn(II) atoms, the remaining CN ligands being terminal. Each Mn(II) atom is additionally coordinated by a bidentate 2,2'-bipyridyl ligand and two water mol-ecules. The crystal structure is stabilized by O-H⋯O and O-H⋯N hydrogen bonds.

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case-control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities., (Copyright © 2011 Wiley-Liss, Inc.)

Chromosome 22q13 region has been implicated in schizophrenia in several linkage studies. Genes within this locus are therefore promising genetic and biologic candidate genes for schizophrenia if they are expressed in the brain or predicted to have some role in brain development. A recent study reported that bromodomain-containing 1 gene (BRD1), located in 22q13, showed an association with schizophrenia in a Scottish population. Except for being a putative regulator of transcription, the precise function of BRD1 is not clear; however, expression analysis of BRD1 mRNA revealed widespread expression in mammalian brains. In our study, we explored the association of BRD1 with schizophrenia in a Japanese population (626 cases and 770 controls). In this association analysis, we first examined 10 directly genotyped single-nucleotide polymorphisms (SNPs) and 20 imputed SNPs. Second, we compared the BRD1 mRNA levels between cases and controls using lymphoblastoid cell lines (LCLs) derived from 29 cases and 30 controls. Although the SNP (rs138880) that previously has been associated with schizophrenia showed the same trend in the Japanese population, no significant association was detected between BRD1 and schizophrenia in our study. Similarly, no significant differences in BRD1 mRNA levels in LCLs were detected. Taken together, we could not strongly show that common SNPs in the BRD1 gene account for a substantial proportion of the genetic risk for schizophrenia in the Japanese population.

Deficits in prepulse inhibition (PPI) are a biological marker for psychiatric illnesses such as schizophrenia and bipolar disorder. To unravel PPI-controlling mechanisms, we previously performed quantitative trait loci (QTL) analysis in mice, and identified Fabp7, that encodes a brain-type fatty acid binding protein (Fabp), as a causative gene. In that study, human FABP7 showed genetic association with schizophrenia. FABPs constitute a gene family, of which members FABP5 and FABP3 are also expressed in the brain. These FABP proteins are molecular chaperons for polyunsaturated fatty acids (PUFAs) such as arachidonic and docosahexaenoic acids. Additionally, the involvement of PUFAs has been documented in the pathophysiology of schizophrenia and mood disorders. Therefore in this study, we examined the genetic roles of FABP5 and 3 in schizophrenia (N = 1,900 in combination with controls) and FABP7, 5, and 3 in bipolar disorder (N = 1,762 in the case-control set). Three single nucleotide polymorphisms (SNPs) from FABP7 showed nominal association with bipolar disorder, and haplotypes of the same gene showed empirical associations with bipolar disorder even after correction of multiple testing. We could not perform association studies on FABP5, due to the lack of informative SNPs. FABP3 displayed no association with either disease. Each FABP is relatively small and it is assumed that there are multiple regulatory elements that control gene expression. Therefore, future identification of unknown regulatory elements will be necessary to make a more detailed analysis of their genetic contribution to mental illnesses., ((c) 2009 Wiley-Liss, Inc.)

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary., (2009 Wiley-Liss, Inc.)

Accumulating evidence suggests that phosphatidylinositol (PI) pathways have been involved in the secretion of dopamine (DA) and the regulation of DA transporter, which is a target of methamphetamine (METH). A recent large-scale gene-association study in a Dutch population demonstrated that the PIK4CA gene was closely linked to schizophrenia [Jungerius et al. (2007); Mol Psychiatry]. Here, we conducted a case (N = 232)-control (N = 233) study of the PIK4CA gene on Japanese METH abusers, which can manifest severe psychosis similar to schizophrenia. The genotype and allelic distributions of all four single nucleotide polymorphisms (SNPs) did not differ significantly between the METH abusers and the controls. The comparisons based on the classification of the psychosis as transient or prolonged and on the presence or absence of spontaneous relapse revealed no significant distribution of the four SNPs compared to the controls. Furthermore, haplotype analyses showed almost the same frequencies between the METH abusers and the controls. The present study suggests that the PIK4CA gene does not play a significant role in the vulnerability to METH use disorder in the Japanese population., (2008 Wiley-Liss, Inc.)

NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population.

Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)-related enzymes; glutathione S-transferases (GSTs) such as GSTT1 (Non-deletion/Null), GSTT2 (Met139Ile), GSTA1 (-69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate-cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03-2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged-type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13-5.23) than that (44.4%) of transient-type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population.