Faculty Profiles - ALEKSIC Branko

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/acn3.51093

Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia. Reviewed International journal

Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 74 ( 5 ) page： 318 - 327 2020.5

Language：English Publishing type：Research paper (scientific journal)

AIM: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. METHODS: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. RESULTS: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. CONCLUSION: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.

DOI： 10.1111/pcn.12993

Characterization of a schizophrenia patient with a rare RELN deletion by combining genomic and patient-derived cell analyses. Reviewed International journal

Yuko Arioka, Akihiro Hirata, Itaru Kushima, Branko Aleksic, Daisuke Mori, Norio Ozaki

Schizophrenia research Vol. 216 page： 511 - 515 2020.2

Publishing type：Research paper (scientific journal)

Genetic studies have identified rare RELN variants as risk factors for psychiatric disorders. However, additional genetic factors appear to be necessary for disease onset. Detailed genetic information and the use of patient-derived neuronal cells may thus enable to discover these disease-related additional factors. Here, we performed whole-genome sequencing of a schizophrenia patient with a rare RELN deletion and his healthy mother, and examined the phenotypes of 3D-cultured neuronal cells derived from induced pluripotent stem cells of this patient. Our results revealed that, along with the RELN deletion, neuronal death was promoted in this patient; thus, neuronal death may be a vulnerable factor for schizophrenia.

DOI： 10.1016/j.schres.2019.10.038

Drug-Induced Extrapyramidal Symptoms Scale of the Norwegian version: inter-rater and test-retest reliability. Reviewed International journal

Bernhard Weidle, Ashmita Chaulagain, Kenneth Stensen, Branko Aleksic, Norbert Skokauskas, Toshiya Inada

Nordic journal of psychiatry Vol. 73 ( 8 ) page： 546 - 550 2019.11

Publishing type：Research paper (scientific journal)

Background: The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) is a multidimensional rating scale designed for the fast, easy and reliable assessment of extrapyramidal symptoms (EPSs) induced by antipsychotics. Aim: The aim of this study was to validate the level of inter-rater and test-retest reliability of the Norwegian translation of this scale. Methods: A total of 125 video clips showing a variety of or no signs of EPSs were used in the present study. The participants recorded were Japanese psychiatric patients receiving first- and/or second-generation antipsychotics. A total of 103 patients (47 males and 56 females), diagnosed with schizophrenia (n = 68) or mood disorders (n = 35) appeared in the video clips. Their mean age was 48.7 ± 16.3 years (range 18-80) at the time of video recording. Inter-rater agreement was assessed with five raters and test-retest reliability with three. Results: Inter-rater reliability analyses showed interclass correlation coefficients (ICCs) ranging from 0.74 to 0.93 for each individual item. Test-retest reliability analysed independently for each rater ranged from 0.71 to 0.96. Conclusions: Inter-rater and test-retest agreement exhibited satisfactory ICC levels above 0.70. The Norwegian version of the DIEPSS is a reliable instrument for the assessment of drug-induced EPSs.

DOI： 10.1080/08039488.2019.1665708

INVESTIGATION OF RARE SINGLE-NUCLEOTIDE DAB1 VARIANTS AND ITS CONTRIBUTION TO SCHIZOPHRENIA AND AUTISM SPECTRUM DISORDER SUSCEPTIBILITY Reviewed International journal

Nawa Yoshihiro, Kimura Hiroki, Ishizuka Kanako, Kushima Iraru, Aleksic Branko, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S164 - S165 2019.10

Relation Between Perinatal Depressive Symptoms, Harm Avoidance, and a History of Major Depressive Disorder: A Cohort Study of Pregnant Women in Japan. Reviewed International journal

Chika Kubota, Toshiya Inada, Tomoko Shiino, Masahiko Ando, Branko Aleksic, Aya Yamauchi, Maya Sato, Masako Ohara, Satomi Murase, Mako Morikawa, Yukako Nakamura, Takashi Okada, Setsuko Goto, Atsuko Kanai, Norio Ozaki

Frontiers in psychiatry Vol. 10 page： 515 - 515 2019.7

Publishing type：Research paper (scientific journal)

Introduction: The relationship between perinatal depressive symptoms, harm avoidance (HA), and a history of major depressive disorder (MDD) was examined in a prospective cohort study. Methods: This study was conducted from May 1, 2011, to December 31, 2016. A history of MDD was evaluated using the Inventory to Diagnose Depression, Lifetime version during pregnancy. Depressive state and HA were evaluated during pregnancy and at 1 month postnatal using the Edinburgh Postnatal Depression Scale (EPDS) and Temperament and Character Inventory, respectively. The relationship between these variances was examined using structural equation modeling. Results: A total of 338 participants with complete data were included in the present study. Pregnant women with compared with those without a history of MDD were observed to have a significantly higher intensity of HA and more severe depressive symptoms in both the prenatal and postnatal periods. A history of MDD affected the severity of depressive symptoms [standardized path coefficient (SPC) = 0.25, p < 0.001] and the intensity of HA during pregnancy (SPC = 0.36, p < 0.001). The intensity of HA during pregnancy affected that at 1 month postnatal (SPC = 0.78, p < 0.001), while the severity of depressive symptoms as assessed by the EPDS during pregnancy affected that at 1 month postnatal (SPC = 0.41, p < 0.001). The SPC for perinatal HA to postnatal depressive symptoms (SPC = 0.13, p = 0.014) was significant and higher than that for perinatal depressive symptoms to postnatal HA (SPC = 0.06, p = 0.087). Conclusion: The present results suggest that early intervention in pregnant women with a history of MDD or a high intensity of HA is important to prevent postnatal depressive symptoms.

DOI： 10.3389/fpsyt.2019.00515

Web of Science

Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect. Reviewed International journal

Masashi Ikeda, Atsushi Takahashi, Yoichiro Kamatani, Yukihide Momozawa, Takeo Saito, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Takaya Sakusabe, Yoshimi Iwayama, Tomoko Toyota, Tomoyasu Wakuda, Mitsuru Kikuchi, Nobuhisa Kanahara, Hidenaga Yamamori, Yuka Yasuda, Yuichiro Watanabe, Satoshi Hoya, Branko Aleksic, Itaru Kushima, Heii Arai, Manabu Takaki, Kotaro Hattori, Hiroshi Kunugi, Yuko Okahisa, Tohru Ohnuma, Norio Ozaki, Toshiyuki Someya, Ryota Hashimoto, Takeo Yoshikawa, Michiaki Kubo, Nakao Iwata

Schizophrenia bulletin Vol. 45 ( 4 ) page： 824 - 834 2019.7

Publishing type：Research paper (scientific journal)

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

DOI： 10.1093/schbul/sby140

Methylation analysis for postpartum depression: a case control study. Reviewed International journal

Yukako Nakamura, Masahiro Nakatochi, Shohko Kunimoto, Takashi Okada, Branko Aleksic, Miho Toyama, Tomoko Shiino, Mako Morikawa, Aya Yamauchi, Akira Yoshimi, Yoko Furukawa-Hibi, Taku Nagai, Masako Ohara, Chika Kubota, Kiyofumi Yamada, Masahiko Ando, Norio Ozaki

BMC psychiatry Vol. 19 ( 1 ) page： 190 - 190 2019.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Postpartum depression (PPD) is a major depressive disorder that occurs after childbirth. Objective diagnostic and predictive methods for PPD are important for early detection and appropriate intervention. DNA methylation has been recognized as a potential biomarker for major depressive disorder. In this study, we used methylation analysis and peripheral blood to search for biomarkers that could to lead to the development a predictive method for PPD. METHODS: Study participants included 36 pregnant women (18 cases and 18 controls determined after childbirth). Genome-wide DNA methylation profiles were obtained by analysis with an Infinium Human Methylation 450BeadChip. The association of DNA methylation status at each DNA methylation site with PPD was assessed using linear regression analysis. We also conducted functional enrichment analysis of PPD using The Database for Annotation, Visualization and Integrated Discovery 6.8 to explore enriched functional-related gene groups for PPD. RESULTS: In the analysis with postpartum depressed state as an independent variable, the difference in methylation frequency between the postpartum non-depressed group and the postpartum depressed group was small, and sites with genome-wide significant differences were not confirmed. After analysis by The Database for Annotation, Visualization and Integrated Discovery 6.8, we revealed four gene ontology terms, including axon guidance, related to postpartum depression. CONCLUSIONS: These findings may help with the development of an objective predictive method for PPD.

DOI： 10.1186/s12888-019-2172-x

Effects of Snoezelen-Multisensory environment on CARS scale in adolescents and adults with autism spectrum disorder. Reviewed International journal

Neda Novakovic, Milica Pejovic Milovancevic, Slavica Djukic Dejanovic, Branko Aleksic

Research in developmental disabilities Vol. 89 page： 51 - 58 2019.6

Publishing type：Research paper (scientific journal)

BACKGROUND: New classification system Diagnostic and statistical manual of mental disorders. 5th ed.(DSM - 5) includes sensory problems as one of the symptoms in diagnostic profile of Autism Spectrum Disorder (ASD). Researching the effects of sensory integration treatment may improve new approaches to the individuals with ASD. The objective of this study is to determine the effects of Snoezelen, multisensory environment on the severity of ASD and stereotyped/repetitive behaviours in adolescents and adults using CARS scale. METHOD: The study involved 40 subjects with ASD associated with intellectual difficulties of both sexes, aged 15-35. The subjects were randomly divided into two groups: a control one (without treatment) and an experimental one (with treatment). The assessments were rated by CARS (Childhood Autism Rating Scale) before and after the three-month treatment. RESULTS: In the experimental group, there was a statistically significant difference of the total CARS score before and after the treatment (p < 0.0005). Comparing the results of both experimental and control groups, a statistically significant difference was found on total CARS score (p < 0.0005). Conslusion: The results in the present study indicate that the continual sessions in Snoezelen room had effects on reducing severity of ASD and repetitive and stereotyped behaviours on CARS scale.

DOI： 10.1016/j.ridd.2019.03.007

Author Correction: Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients. Reviewed International journal

Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki

Translational psychiatry Vol. 9 ( 1 ) page： 146 - 146 2019.5

Language：English Publishing type：Research paper (scientific journal)

The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.

DOI： 10.1038/s41398-019-0479-5

Joint Degree Program for Graduate Students at the Nagoya University Graduate School of Medicine. Reviewed

Hideki Kasuya, Branko Aleksic, Seiji Sumigama, Itzel Bustos, Hitoki Hasegawa, Mika P Kasai, Miho Kobayashi, Yumiko Samizo

Nagoya journal of medical science Vol. 81 ( 2 ) page： 183 - 192 2019.5

Publishing type：Research paper (scientific journal)

In a world of increasing academic mobility, most universities seek to give their students opportunities to experience education in different countries, which is especially true for senior research students. The Nagoya University Graduate School of Medicine started a joint degree program (JDP) for PhD students with the University of Adelaide, Faculty of Health Science (Australia) in 2015 and with Lund University Faculty of Medicine (Sweden) in 2017. Furthermore, we have started a new JDP with the University of Freiburg, Faculty of Medicine (Germany) in 2018. This article reports the issues specific to counterpart medical schools, including student's recruitment, the curriculum, and the general differences between each schools. JDPs are not only important for educational collaboration, but also as a strategy to encourage international research collaboration, which is a core criterion to a university's world-ranking reputation. Acquiring knowledge about educational strategies that are implemented in different foreign medical schools represents a unique opportunity to improve our own curriculum.

DOI： 10.18999/nagjms.81.2.183

Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients. Reviewed International journal

Translational psychiatry Vol. 9 ( 1 ) page： 126 - 126 2019.4

Language：English Publishing type：Research paper (scientific journal)

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

DOI： 10.1038/s41398-019-0461-2

A NOVEL RARE VARIANT R292H IN RTN4R AFFECTS GROWTH CONE FORMATION AND POSSIBLY CONTRIBUTES TO SCHIZOPHRENIA SUSCEPTIBILITY

Kimura Hiroki, Ishizuka Kanako, Wang Chenyao, Kushima Itaru, Morikawa Mako, Uno Yota, Okada Takashi, Inanda Toshiya, Aleksic Branko, Mori Daisuke, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S1014 - S1014 2019

INVESTIGATION OF NOVEL RARE VARIANTS IN NRXN1 CONTRIBUTES TO THE INCREASED RISK OF AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA Reviewed International journal

Ishizuka Kanako, Aleksic Branko, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S829 - S829 2019

TARGET SEQUENCING OF GENES INVOLVED IN NEURODEVELOPMENT FROM WHOLE GENOME COPY NUMBER VARIATION ANALYSIS OF JAPANESE SCHIZOPHRENIA Reviewed International journal

Kimura Hiroki, Aleksic Branko, Ishizuka Kanako, Wang Chenyao, Kushima Itaru, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： 1334 - 1334 2019

Stable factor structure of the Edinburgh Postnatal Depression Scale during the whole peripartum period: Results from a Japanese prospective cohort study. Reviewed International journal

Chika Kubota, Toshiya Inada, Yukako Nakamura, Tomoko Shiino, Masahiko Ando, Branko Aleksic, Aya Yamauchi, Mako Morikawa, Takashi Okada, Masako Ohara, Maya Sato, Satomi Murase, Setsuko Goto, Atsuko Kanai, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 17659 - 17659 2018.12

Language：English Publishing type：Research paper (scientific journal)

Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach's alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclusion, the EPDS is a useful rating scale, and its factor structure is consistently stable during the whole peripartum period.

DOI： 10.1038/s41598-018-36101-z

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. Reviewed International journal

Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Branko Aleksic, Daisuke Mori, Yasuyuki Osanai, Kenta Kobayashi, Anna M Taylor, Manzoor A Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki, Kazuhiro Ikenaka

Journal of neurochemistry Vol. 147 ( 3 ) page： 395 - 408 2018.11

Publishing type：Research paper (scientific journal)

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

DOI： 10.1111/jnc.14553

Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. Reviewed International journal

Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki

Psychiatric genetics Vol. 28 ( 5 ) page： 90 - 93 2018.10

Publishing type：Research paper (scientific journal)

Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

DOI： 10.1097/YPG.0000000000000204

Impact of perceived rearing and social support on bonding failure and depression among mothers: A longitudinal study of pregnant women. Reviewed International journal

Masako Ohara, Masahiro Nakatochi, Takashi Okada, Branko Aleksic, Yukako Nakamura, Tomoko Shiino, Aya Yamauchi, Chika Kubota, Mako Morikawa, Satomi Murase, Setsuko Goto, Atsuko Kanai, Ryuji Kato, Masahiko Ando, Norio Ozaki

Journal of psychiatric research Vol. 105 page： 71 - 77 2018.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although previous studies have reported associations between bonding failure, depression, social support among mothers, and perceived rearing, the causal relationships remain unclear. METHODS: A total of 855 women (mean age, 32.4 ± 4.4 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), the Japanese version of the Social Support Questionnaire, and the Parental Bonding Instrument in early pregnancy before week 25 (T1) and at 1 month after delivery (T2). We created a path model to clarify the causal relationships between perinatal bonding failure, depression, social support, and perceived rearing during pregnancy and at 1 month after delivery. The model was tested using structural equation modeling. RESULTS: Our recursive model showed acceptable fit (chi-squared statistic/degree of freedom = 2.1, comparative fit index = 0.98, root mean square error of approximation = 0.04). It was revealed that: (1) at T1, higher overprotection significantly predicted MIBQ scores; (2) at T1, poorer social support significantly predicted both MIBQ and EPDS scores; and (3) at T1, both MIBQ and EPDS scores significantly predicted respective scores at T2. CONCLUSIONS: These results showed that bonding failure in the postpartum period was significantly influenced by mothers' own perceived rearing and social support during pregnancy. In addition, depression in the postpartum period was strongly influenced by social support during pregnancy. These findings suggest that psychosocial interventions that focus on both mothers' recollections of their own upbringing and social support during pregnancy are effective for preventing bonding failure and depression in the postpartum period.

DOI： 10.1016/j.jpsychires.2018.09.001

The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Reviewed International journal

Ibrahim Ragab Eissa, Itzel Bustos-Villalobos, Toru Ichinose, Shigeru Matsumura, Yoshinori Naoe, Noriyuki Miyajima, Daishi Morimoto, Nobuaki Mukoyama, Wu Zhiwen, Maki Tanaka, Hitoki Hasegawa, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya

Cancers Vol. 10 ( 10 ) 2018.10

Publishing type：Research paper (scientific journal)

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

DOI： 10.3390/cancers10100356

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Reviewed International journal

Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

Cell reports Vol. 24 ( 11 ) page： 2838 - 2856 2018.9

Language：English Publishing type：Research paper (scientific journal)

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

DOI： 10.1016/j.celrep.2018.08.022

Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia

Yamamoto Maeri, Kushima Itaru, Suzuki Ryohei, Branko Aleksic, Kawano Naoko, Inada Toshiya, Iidaka Tetsuya, Ozaki Norio

PSYCHIATRY RESEARCH-NEUROIMAGING Vol. 278 page： 35 - 41 2018.8

Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. Reviewed International journal

Akira Sobue, Itaru Kushima, Taku Nagai, Wei Shan, Takao Kohno, Branko Aleksic, Yuki Aoyama, Daisuke Mori, Yuko Arioka, Naoko Kawano, Maeri Yamamoto, Mitsuharu Hattori, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 13046 - 13046 2018.8

Language：English Publishing type：Research paper (scientific journal)

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

DOI： 10.1038/s41598-018-31390-w

Postpartum depression among women in Nagoya indirectly exposed to the Great East Japan Earthquake. Reviewed International journal

Chika Kubota, Takashi Okada, Mako Morikawa, Yukako Nakamura, Aya Yamauchi, Masahiko Ando, Tomoko Shiino, Masako Ohara, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Branko Aleksic, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 11624 - 11624 2018.8

Language：English Publishing type：Research paper (scientific journal)

This study aimed to assess the situation of postpartum depression and maternal bonding in Nagoya, a city distant from the epicenter of the Great East Japan Earthquake that occurred on March 11, 2011. Among the participants at 1 month after childbirth between March 11, 2010 and March 10, 2013 (n = 188), 152 fully responded to the Edinburgh Postnatal Depression Scale (EPDS) and Mother-Infant Bonding Questionnaire (MIBQ). They were divided into pre-quake (n = 58), and 0-6, 6-12, 12-18, and 18-24 months after the earthquake groups (n = 20, 26, 29, and 19, respectively). The rate of mothers who scored above the cutoff point for the EPDS increased from 12.1% in the pre-quake to 35.0% in the 0-6 months group (p = 0.022). The EPDS total and anxiety subscale scores (mean ± standard error) were also significantly different between the pre-quake and 0-6 months after the earthquake groups (4.45 ± 0.50 vs. 7.95 ± 1.47, p = 0.024; 2.16 ± 0.26 vs. 3.65 ± 0.57, p = 0.021, respectively). The EPDS total and anxiety scores were the highest for the 0-6 months group, followed by the 6-12, 12-18, 18-24 months groups (p = 0.019, p = 0.022). MIBQ scores did not differ between the pre-quake and 0-6 months groups. Depressive symptoms, mainly explained by anxiety, increased after the earthquake with no changes in maternal bonding.

DOI： 10.1038/s41598-018-30065-w

Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. Reviewed International journal

Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki

Translational psychiatry Vol. 8 ( 1 ) page： 129 - 129 2018.7

Language：English Publishing type：Research paper (scientific journal)

Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

DOI： 10.1038/s41398-018-0177-8

Driving performance of stable outpatients with depression undergoing real-world treatment. Reviewed International journal

Akemi Miyata, Kunihiro Iwamoto, Naoko Kawano, Branko Aleksic, Masahiko Ando, Kazutoshi Ebe, Kiyoshi Fujita, Motonori Yokoyama, Tsuyoshi Akiyama, Yoshio Igarashi, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 72 ( 6 ) page： 399 - 408 2018.6

Publishing type：Research paper (scientific journal)

AIM: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily-practice psychopharmacologic treatment. METHODS: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed. RESULTS: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II. CONCLUSION: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study.

DOI： 10.1111/pcn.12648

Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders. Reviewed International journal

Kanako Ishizuka, Hidenori Tabata, Hidenori Ito, Itaru Kushima, Mariko Noda, Akira Yoshimi, Masahide Usami, Kyota Watanabe, Mako Morikawa, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki, Koh-Ichi Nagata

Journal of neuroscience research Vol. 96 ( 5 ) page： 789 - 802 2018.5

Language：English Publishing type：Research paper (scientific journal)

Migfilin, encoded by FBLIM1 at the 1p36 locus, is a multi-domain adaptor protein essential for various cellular processes such as cell morphology and migration. Small deletions and duplications at the 1p36 locus, monosomy of which results in neurodevelopmental disorders and multiple congenital anomalies, have also been identified in patients with autism spectrum disorder (ASD). However, the impact of FBLIM1, the gene within 1p36, on the pathogenesis of ASD is unknown. In this study, we performed morphological analyses of migfilin to elucidate its role in brain development. Migfilin was detected specifically in the embryonic and perinatal stages of the mouse brain. Either silencing or overexpression of migfilin in embryos following in utero electroporation disrupted Neocortical neuronal migration. Additionally, neurite elongation was impaired when migfilin was silenced in cultured mouse hippocampal neurons. We then screened FBLIM1 for rare exonic deletions/duplications in 549 Japanese ASD patients and 824 controls, detecting one case of ASD and intellectual delay that harbored a 26-kb deletion at 1p36.21 that solely included the C-terminal exon of FBLIM1. The FBLIM1 mRNA expression level in this case was reduced compared to levels in individuals without FBLIM1 deletion. Our findings indicate that tightly regulated expression of migfilin is essential for neuronal development and that FBLIM1 disruption may be related to the phenotypes associated with ASD and related neurodevelopmental disorders.

DOI： 10.1002/jnr.24194

Assessment of a GLO1 frameshift variant, c.365delC, in Japanese cases of schizophrenia and controls Reviewed International journal

Ishizuka Kanako, Aleksic Branko, Ozaki Norio

HUMAN GENOMICS Vol. 12 2018.3

Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed International journal

Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

HUMAN GENOMICS Vol. 12 2018.3

Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed International journal

Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

HUMAN GENOMICS Vol. 12 2018.3

Issues on the diagnosis and etiopathogenesis of mood disorders: reconsidering DSM-5 Reviewed International journal

Kazuyoshi Ogasawara, Yukako Nakamura, Hiroyuki Kimura, Branko Aleksic, Norio Ozaki

Journal of Neural Transmission Vol. 125 ( 2 ) page： 211 - 222 2018.2

Publishing type：Research paper (scientific journal) Publisher：Springer-Verlag Wien

The authors present a narrative review from the diagnostic and nosologic viewpoints of mood disorders (bipolar and depressive ones) by revisiting the revision from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision to DSM-5, including the following: the separation of the bipolar and depressive sections
the addition of increased energy and continuation of symptoms to the hypo/manic criteria
the elimination of mixed episodes
the creation of new categories and specifiers (“other specified bipolar and related disorder”, “disruptive mood dysregulation disorder”, “with anxious distress”, “with mixed features”, “with peripartum onset”)
the categorization of hypo/manic episodes during antidepressant treatment into bipolar disorder
the elimination of the “bereavement exclusion”
the ambiguous separation between bipolar I and II
the insufficient distinction between “other specified bipolar and related disorders” and major depressive disorder
the differentiation regarding borderline personality disorder
agitation
premenstrual dysphoric disorder
and society and psychiatry. Through this analysis, we point out both the achievements and limitations of DSM-5. In addition, to examine the future direction of psychiatry, we introduce our cohort study regarding maternal depression and an outline of the National Institute of Mental Health’s Research Domain Criteria project in the US. Finally, we advocate the importance of elucidating etiopathogeneses by starting from or going beyond the DSM operational diagnostic system, which has shown great efficacy.

DOI： 10.1007/s00702-017-1828-2

Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. Reviewed International journal

Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki

Translational psychiatry Vol. 8 ( 1 ) page： 12 - 12 2018.1

Language：English Publishing type：Research paper (scientific journal)

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

DOI： 10.1038/s41398-017-0061-y

Genetics in pediatric consultation-liaison psychiatry and multidisciplinary management of complex conditions Reviewed International journal

Aleksic B.

Pediatric Consultation-Liaison Psychiatry: A Global, Healthcare Systems-Focused, and Problem-Based Approach page： 251 - 264 2018.1

CLINICALLY RELEVANT GENETIC VARIANTS: MODELS FOR UNDERSTANDING SCHIZOPHRENIA AND OTHER NEUROPSYCHIATRIC DISORDERS DUPLICATIONS AT 15Q11-Q13 IN SCHIZOPHRENIA AND NEURODEVELOPMENTAL DISORDERS Reviewed International journal

Kirov George, Isles Anthony, Ingason Andres, Lowther Chelsea, Walters James, Bassett Anne, Costain Gregory, Levinson Douglas, Gawlick Micha, Degenhardt Franziska, Aleksic Branko, Ahn JooWook, Ogilvie Caroline, Stefansson Kari, Owen Michael

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S277 - S277 2017.10

Relationship between maternal depression and bonding failure: A prospective cohort study of pregnant women Reviewed International journal

Masako Ohara, Takashi Okada, Chika Kubota, Yukako Nakamura, Tomoko Shiino, Branko Aleksic, Mako Morikawa, Aya Yamauchi, Yota Uno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Masahiko Ando, Norio Ozaki

PSYCHIATRY AND CLINICAL NEUROSCIENCES Vol. 71 ( 10 ) page： 733 - 741 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Aim: Although the association between maternal depression and bonding failure during pregnancy and after delivery has been investigated, the causal relationships remain unclear.
Methods: A total of 751 women (mean [SD] age, 32.1 [4.4] years) completed the Mother-Infant Bonding Questionnaire and the Edinburgh Postnatal Depression Scale during early pregnancy before week 25 (T1), during late pregnancy around week 36 (T2), and at 5 days after delivery (T3). We created a structural regression model to clarify the relationships between depressive mood and bonding failure during pregnancy and at 5 days after delivery. The model was tested with structural equation modeling.
Results: Our non-recursive model fit the data well, and we found that: (i) during T2, bonding failure predicted depressive mood (P < 0.01, r = 0.23); (ii) at T3, bonding failure predicted depressive mood (P < 0.05, r = 0.31); (iii) during T1, depressive mood was correlated with bonding failure (P < 0.01, r = 0.45); (iv) depressive mood during T1 predicted depressive mood during T2 (P < 0.01, r = 0.58); (v) depressive mood during T2 predicted depressive mood at T3 (P < 0.01, r = 0.45); (vi) bonding failure during T1 predicted bonding failure during T2 (P < 0.01, r = 0.84); and (vii) bonding failure during T2 predicted bonding failure at T3 (P < 0.01, r = 0.44). The determinant coefficients of depressive mood and bonding failure at T3 were 0.41 and 0.28, respectively.
Conclusion: Our large-scale cohort study indicates that bonding failure predicts depressive mood during pregnancy and 5 days after delivery. These findings suggest that protection and support for pregnant women with depressive mood and bonding failure may prevent both issues during pregnancy and the early stage after delivery.

DOI： 10.1111/pcn.12541

MUTATION SCREENING OF THE PCDH15 GENE IN PATIENTS SUFFERING FROM AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA Reviewed International journal

Ishizuka Kanako, Wang Chenyao, Kimura Hiroki, Xing Jingrui, Kushima Itaru, Arioka Yuko, Yoshimi Akira, Nakamura Yukako, Oya-Ito Tomoko, Takasaki Yuto, Uno Yota, Okada Takashi, Mori Daisuke, Aleksic Branko, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S162 - S163 2017.10

IDENTIFICATION OF RARE DISRUPTIVE VARIANTS IN VOLTAGE-GATED CHANNEL GENES (CACNA1C, CACNA1D, CACNA1S, CACNA1I) IN JAPANESE SAMPLES OF SCHIZOPHRENIA AND AUTISM SPECTRUM DISORDER USING ION TORRENT PGM PLATFORM Reviewed International journal

Wang Chenyao, Kimura Hiroki, Xing Jingrui, Ishizuka Kanoko, Kushima Itaru, Arioka Yuko, Yoshimi Akira, Nakamura Yukako, Shiino Yomoko, Oya Yuko, Takasaki Yuto, Aleksic Branko, Mori Daisuke, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 27 page： S341 - S342 2017.10

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Reviewed International journal

Elaine T. Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S. Kamumbu, Xiaochang Zhang, Alissa M. D'Gama, Sonia N. Kim, Robert Sean Hill, Arthur P. Goldberg, Christopher Poultney, Nancy J. Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J. Penzol, Angel Carracedo, Alexander Kolevzon, Christina M. Hultman, Lauren A. Weiss, Menachem Fromer, Andreas G. Chiocchetti, Christine M. Freitag, George M. Church, Stephen W. Scherer, Joseph D. Buxbaum, Christopher A. Walsh

NATURE NEUROSCIENCE Vol. 20 ( 9 ) page： 1217 - + 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 x 10(-6)), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 x 10(-3)). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

DOI： 10.1038/nn.4598

A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility

Kimura H., Fujita Y., Kawabata T., Ishizuka K., Wang C., Iwayama Y., Okahisa Y., Kushima I., Morikawa M., Uno Y., Okada T., Ikeda M., Inada T., Branko A., Mori D., Yoshikawa T., Iwata N., Nakamura H., Yamashita T., Ozaki N.

TRANSLATIONAL PSYCHIATRY Vol. 7 2017.8

Social support helps protect against perinatal bonding failure and depression among mothers: a prospective cohort study Reviewed International journal

Masako Ohara, Takashi Okada, Branko Aleksic, Mako Morikawa, Chika Kubota, Yukako Nakamura, Tomoko Shiino, Aya Yamauchi, Yota Uno, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Masahiro Nakatochi, Masahiko Ando, Norio Ozaki

SCIENTIFIC REPORTS Vol. 7 ( 1 ) page： 9546 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Causal relationships between perinatal bonding failure, depression, and social support among mothers remain unclear. A total of 494 women (mean age 32.4 +/- 4.5 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), and the Japanese version of the Social Support Questionnaire in early pregnancy before week 25 (T1) and 1 month after delivery (T2). Our model of recursive structured equation modeling (SEM) showed acceptable fit (CMIN/df = 2.2, CFI = 0.97, and RMSEA = 0.05). It was revealed that: (1) a lower number of supportive persons at T1 significantly predicted both MIBQ and EPDS scores at T1 and T2; (2) at T1, poorer satisfaction with the social support received significantly predicted EPDS scores; (3) both MIBQ and EPDS scores at T1 significantly predicted their respective scores at T2. Out cohort study indicates that the number of individuals who are available to provide social support and the degree of satisfaction with the level of social support received during pregnancy have a great influence on bonding failure and depression in the postpartum period. These findings suggest that psychosocial interventions that focus on these two aspects of social support during pregnancy are effective in preventing bonding failure and depression in the postpartum period.

DOI： 10.1038/s41598-017-08768-3

Genomic signature of the natural oncolytic herpes simplex virus HF10 and its therapeutic role in preclinical and clinical trials Reviewed International journal

Ibrahim Ragab Eissa, Yoshinori Naoe, Itzel Bustos-Villalobos, Toru Ichinose, Maki Tanaka, Wu Zhiwen, Nobuaki Mukoyama, Taishi Morimoto, Noriyuki Miyajima, Hasegawa Hitoki, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya

Frontiers in Oncology Vol. 7 ( JUL ) page： 149 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media S.A.

Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

DOI： 10.3389/fonc.2017.00149

Effect of Adjunctive Aripiprazole on Sexual Dysfunction in Schizophrenia: A Preliminary Open-Label Study Reviewed International journal

Junko Fujioi, Kunihiro Iwamoto, Masahiro Banno, Tsutomu Kikuchi, Branko Aleksic, Norio Ozaki

PHARMACOPSYCHIATRY Vol. 50 ( 2 ) page： 74 - 78 2017.3

Publishing type：Research paper (scientific journal) Publisher：GEORG THIEME VERLAG KG

Introduction Although adjunctive aripiprazole improves hyperprolactinemia, sufficient evidence for its effects on sexual dysfunction has not been obtained. We assessed the usefulness of adjunctive aripiprazole for schizophrenia with sexual dysfunction.
Methods 22 Japanese schizophrenia patients with antipsychotic-induced hyperprolactinemia and sexual dysfunction were enrolled, and 19 of them completed the study. Aripiprazole was administrated in a flexible titration schedule to participants according to the judgment of each doctor, and patients were followed for 24 weeks. Serum prolactin, Clinical Global Impression Scales-Severity (CGI-S), and Nagoya Sexual Function Questionnaire (NSFQ) were measured at baseline and at 4, 8, 12, and 24 weeks.
Results Prolactin at week 4 and later was significantly lower than that at baseline. Compared to baseline, we observed a significant improvement in total sexual dysfunction as measured by NSFQ at week 8 and later. In males, erectile dysfunction was significantly reduced at week 24. In females, menstrual irregularity and galactorrhea were significantly reduced at week 24. CGI-S did not significantly change.
Discussion Although the small sample size is a limitation in this study, adjunctive aripiprazole may be useful treatment for sexual dysfunction including hyperprolactinemia in schizophrenia.

DOI： 10.1055/s-0042-116323

Web of Science

Other Link： http://orcid.org/0000-0002-2539-1031

Schizophrenia polygenic risk score and prepubertal developmental impairments Reviewed International journal

Branko Aleksic, Norio Ozaki

The Lancet Psychiatry Vol. 4 ( 1 ) page： 7 - 8 2017.1

Serbian Language version of the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up: Cross-Cultural Adaptation and Assessment of Reliability Reviewed International journal

Mia Carakovac, Jelena Jovanovic, Marko Kalanj, Nenad Rudic, Olivera Aleksic-Hil, Branko Aleksic, Itzel Bustos Villalobos, Hideki Kasuya, Norio Ozaki, Dusica Lecic-Tosevski, Milica Pejovic-Milovancevic

SCIENTIFIC REPORTS Vol. 6 page： 38222 2016.12

Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Early detection of Autism Spectrum Disorder (ASD) has proven to be of high significance, however there is a limited availability of ASD screening tools in Serbian language. In this study we aim to translate, assess reliability and, in part, test the applicability of Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT R/F) in Serbian Healthcare environment. We screened 128 children in three primary healthcare centres and 20 children in a tertiary psychiatric center, using M-CHAT R/F translated into Serbian language, between December 2014 and October 2015. At the end of the screening process 80% of participants in the risk group screened positive for ASD, while in the control group 4 (3.1%) participants screened positive, with a mean total scores of 8.25 and 0.66 respectively. The Cronbach's a coefficient was 0.91 and Guttman's.6 was 0.93. Test-retest reliability was deemed as acceptable, and no significant correlation was found between M-CHAT-R/F scores and Epworth Sleepiness Scale for children scores. The Serbian version of the M-CHAT-R/F has shown satisfactory reliability. We can therefore assert that it is a reliable tool for identifying ASD and it can be used in clinical practice to improve early detection, assessment and treatment.

DOI： 10.1038/srep38222

Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes Reviewed

Kanako Ishizuka, Hiroki Kimura, Akira Yoshimi, Masahiro Banno, Itaru Kushima, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki

Nagoya Journal of Medical Science Vol. 78 ( 4 ) page： 465 - 474 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of <= 1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.

DOI： 10.18999/nagjms.78.4.465

Web of Science