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Background and Hypothesis: Problematic internet use (PIU) is prevalent among adolescents. Past research suggested cross-sectional associations between PIU and psychotic experiences, but little information is available on the longitudinal association. We hypothesized that PIU in adolescence may be longitudinally associated with psychotic experiences, adjusting for confounders., Study Design: We analyzed a random sample of adolescents in the Tokyo Teen Cohort to examine how PIU at ages 10 (2012-2015), 12 (2014-2017), and 16 (2019-2021) was associated with mental health issues at age 16. PIU was evaluated by the modified Compulsive Internet Use Scale, psychotic experiences by the Adolescent Psychotic-like Symptom Screener, and depression by the Short Mood and Feelings Questionnaire. We also examined the mediating role of social withdrawal., Study Results: We analyzed 3171 adolescents; 151 reported psychotic experiences and 327 reported depression at age 16. Compared with the lowest tertile PIU group, the highest tertile PIU group at age 12 showed an increased adjusted risk of psychotic experiences (RD 3.3%, 95% CI 2.9%-3.7%; RR 1.65, 95% CI 1.55-1.73) and depression (RD 5.9%, 95% CI 5.5%-6.3%; RR 1.61, 95% CI 1.55-1.68) at age 16. PIU at age 16 showed analogous results, while PIU at age 10 suggested a smaller impact. Social withdrawal mediated 9.4%-29.0% of the association between PIU and psychotic experiences., Conclusions: PIU is longitudinally associated with psychotic experiences and depression in adolescents. Further longitudinal and intervention studies are warranted to provide robust public health implications and foster a safer digital future., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Discrepancies in self-rated and observer-rated depression severity may underlie the basis for biological heterogeneity in depressive disorders and be an important predictor of outcomes and indicators to optimize intervention strategies. However, the neural mechanisms underlying this discrepancy have been understudied. This study aimed to examine the brain networks that represent the neural basis of the discrepancy between self-rated and observer-rated depression severity using resting-state functional MRI. To examine the discrepancy between self-rated and observer-rated depression severity, self- and observer-ratings discrepancy (SOD) was defined, and the higher and lower SOD groups were selected from depressed patients as participants showing extreme deviation. Resting-state functional MRI analysis was performed to examine regions with significant differences in functional connectivity in the two groups. The results showed that, in the higher SOD group compared to the lower SOD group, there was increased functional connectivity between the frontal pole and precuneus, both of which are subregions of the default mode network that have been reported to be associated with ruminative and self-referential thinking. These results provide insight into the association of brain circuitry with discrepancies between self- and observer-rated depression severity and may lead to more treatment-oriented diagnostic reclassification in the future., (© The Author(s) 2024. Published by Oxford University Press.)

In the event of exposure to high doses of radiation, prompt dose estimation is crucial for selecting appropriate treatment modalities, such as cytokine therapy or stem cell transplantation. The chemical-induced premature chromosome condensation (PCC) method offers a simple approach for such dose estimation with significant radiation exposure, but its 48-h incubation time poses challenges for early dose assessment. In this study, we optimized the chemical-induced PCC assay for more rapid dose assessment. A sufficient number of PCC and G2/M-PCC cells were obtained after 40 h of culture for irradiated human peripheral blood up to 20 Gy. By adding caffeine (final concentration of 1 mM) at 34 h from the start of culture, G2/M-PCC index increased by 1.4-fold in 10 Gy cultures. There was also no significant difference in the G2/M-PCC ring frequency induced for doses 0 to 15 Gy between our 40-h caffeine-supplemented chemical-induced PCC method and the conventional 48-h PCC assay., (© Published by Oxford University Press 2024.)

Sound frequency and duration are essential auditory components. The brain perceives deviations from the preceding sound context as prediction errors, allowing efficient reactions to the environment. Additionally, prediction error response to duration change is reduced in the initial stages of psychotic disorders. To compare the spatiotemporal profiles of responses to prediction errors, we conducted a human electrocorticography study with special attention to high gamma power in 13 participants who completed both frequency and duration oddball tasks. Remarkable activation in the bilateral superior temporal gyri in both the frequency and duration oddball tasks were observed, suggesting their association with prediction errors. However, the response to deviant stimuli in duration oddball task exhibited a second peak, which resulted in a bimodal response. Furthermore, deviant stimuli in frequency oddball task elicited a significant response in the inferior frontal gyrus that was not observed in duration oddball task. These spatiotemporal differences within the Parasylvian cortical network could account for our efficient reactions to changes in sound properties. The findings of this study may contribute to unveiling auditory processing and elucidating the pathophysiology of psychiatric disorders., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Auditory sensory processing is assumed to occur in a hierarchical structure including the primary auditory cortex (A1), superior temporal gyrus, and frontal areas. These areas are postulated to generate predictions for incoming stimuli, creating an internal model of the surrounding environment. Previous studies on mismatch negativity have indicated the involvement of the superior temporal gyrus in this processing, whereas reports have been mixed regarding the contribution of the frontal cortex. We designed a novel auditory paradigm, the "cascade roving" paradigm, which incorporated complex structures (cascade sequences) into a roving paradigm. We analyzed electrocorticography data from six patients with refractory epilepsy who passively listened to this novel auditory paradigm and detected responses to deviants mainly in the superior temporal gyrus and inferior frontal gyrus. Notably, the inferior frontal gyrus exhibited broader distribution and sustained duration of deviant-elicited responses, seemingly differing in spatio-temporal characteristics from the prediction error responses observed in the superior temporal gyrus, compared with conventional oddball paradigms performed on the same participants. Moreover, we observed that the deviant responses were enhanced through stimulus repetition in the high-gamma range mainly in the superior temporal gyrus. These features of the novel paradigm may aid in our understanding of auditory predictive coding., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adolescence is a critical period for psychological difficulties. Auditory mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are representative electrophysiological indices that mature during adolescence. However, the longitudinal association between MMN/ASSR and psychological difficulties among adolescents remains unclear. We measured MMN amplitude for duration and frequency changes and ASSR twice in a subsample (n = 67, mean age 13.4 and 16.1 years, respectively) from a large-scale population-based cohort. No significant longitudinal changes were observed in any of the electroencephalography indices. Changes in SDQ-TD were significantly associated with changes in duration MMN, but not frequency MMN and ASSR. Furthermore, the subgroup with higher SDQ-TD at follow-up showed a significant duration MMN decrease over time, whereas the subgroup with lower SDQ-TD did not. The results of our population neuroscience study suggest that insufficient changes in electroencephalography indices may have been because of the short follow-up period or non-monotonic change during adolescence, and indicated that the longitudinal association with psychological difficulties was specific to the duration MMN. These findings provide new insights that electrophysiological change may underlie the development of psychosocial difficulties emerging in adolescence., (© The Author(s) 2023. Published by Oxford University Press.)

Background and Hypothesis: Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders., Study Design: We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network., Study Results: DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively., Conclusions: DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Multiple epidemiological studies have shown that obesity is a serious risk factor for cancer development. While the underlying mechanisms between obesity and cancer are still unknown, obesity disrupts the role of adipocytes in energy homeostasis, and the alteration of adipokine, insulin and sex steroid signaling. Recently, it has been identified that adipose tissue-derived exosome-like vesicles (ELVs) regulate metabolic homeostasis. In this study, we collected ELVs from adipose tissue of an obese mouse (ob/ob) strain and control mouse (C57BL/6) strain, and checked whether adipose ELVs influence radiation-induced cell death on mouse fibroblast cells (m5S). Furthermore, we analyzed the micronucleus (MN) frequency in survived cells after radiation exposure to investigate the effect of ELVs on radiation-induced genomic instability. We first observed that ELVs from control and obese mice showed enhanced colony forming ability in un-irradiated m5S cells. However, enhanced survival was observed only in 3 Gy-irradiated m5S cells with obese ELV treatment. Despite no ELV effect on colony size, interestingly, the frequency of MN in survived m5S cells after 3 Gy irradiation was elevated when treated obese ELVs compared to control ELVs. These results suggested that obese mouse adipose ELVs could enhance the survival of irradiated cells harboring increased radiation-induced genomic instability., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Hypotheses: A wealth of evidence suggests that adolescent psychotic experiences (PEs), and especially auditory hallucinations (AHs), are associated with an increased risk for self-injurious behavior (SIB). However, the directionality and specificity of this association are not well understood, and there are no published studies investigating within-person effects over time. The present study aimed to test whether AHs and SIB prospectively increase reciprocal risk at the individual level during early-to-middle adolescence., Study Design: Three waves (12y, 14y, and 16y) of self-reported AHs and SIB data from a large Tokyo-based adolescent birth cohort (N = 2825) were used. Random Intercept Cross-Lagged Panel Model (RI-CLPM) analysis was conducted to test the within-person prospective associations between AHs and SIB., Study Results: At the within-person level, AHs were associated with subsequent SIB over the observation period (12y-14y: β = .118, P < .001; 14-16y: β = .086, P = .012). The reverse SIB->AHs relationship was non-significant at 12-14y (β = .047, P = .112) but emerged from 14y to 16y as the primary direction of influence (β = .243, P < .001). Incorporating depression as a time-varying covariate did not meaningfully alter model estimates., Conclusions: A complex bi-directional pattern of relationships was observed between AHs and SIB over the measurement period, and these relationships were independent of depressive symptoms. Adolescent AHs may be both a predictor of later SIB and also a manifestation of SIB-induced psychological distress., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background and Hypothesis: Machine learning approaches using structural magnetic resonance imaging (MRI) can be informative for disease classification; however, their applicability to earlier clinical stages of psychosis and other disease spectra is unknown. We evaluated whether a model differentiating patients with chronic schizophrenia (ChSZ) from healthy controls (HCs) could be applied to earlier clinical stages such as first-episode psychosis (FEP), ultra-high risk for psychosis (UHR), and autism spectrum disorders (ASDs)., Study Design: Total 359 T1-weighted MRI scans, including 154 individuals with schizophrenia spectrum (UHR, n = 37; FEP, n = 24; and ChSZ, n = 93), 64 with ASD, and 141 HCs, were obtained using three acquisition protocols. Of these, data regarding ChSZ (n = 75) and HC (n = 101) from two protocols were used to build a classifier (training dataset). The remainder was used to evaluate the classifier (test, independent confirmatory, and independent group datasets). Scanner and protocol effects were diminished using ComBat., Study Results: The accuracy of the classifier for the test and independent confirmatory datasets were 75% and 76%, respectively. The bilateral pallidum and inferior frontal gyrus pars triangularis strongly contributed to classifying ChSZ. Schizophrenia spectrum individuals were more likely to be classified as ChSZ compared to ASD (classification rate to ChSZ: UHR, 41%; FEP, 54%; ChSZ, 70%; ASD, 19%; HC, 21%)., Conclusion: We built a classifier from multiple protocol structural brain images applicable to independent samples from different clinical stages and spectra. The predictive information of the classifier could be useful for applying neuroimaging techniques to clinical differential diagnosis and predicting disease onset earlier., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Alopecia is one of the common symptoms after high-dose radiation exposure. In our experiments, neonatal mice that received 7 Gy X-ray exhibited defects in overall hair growth, except for their cheeks. This phenomenon might suggest that some substances were secreted and prevented hair follicle loss in the infant tissues around their cheeks after radiation damage. In this study, we focused on exosome-like vesicles (ELV) secreted from cheek skin tissues and back skin tissues, as control, and examined their radiation protective effects on mouse fibroblast cell lines. We observed that ELV from irradiated cheek skin showed protective effects from radiation. Our results suggest that ELV from radiation-exposed cheek skin tissue is one of the secreted factors that prevent hair follicle loss after high-dose radiation., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although the relationship between schizophrenia spectrum disorder (SSD) and autism spectrum disorder (ASD) has long been debated, it has not yet been fully elucidated. The authors quantified and visualized the relationship between ASD and SSD using dual classifiers that discriminate patients from healthy controls (HCs) based on resting-state functional connectivity magnetic resonance imaging. To develop a reliable SSD classifier, sophisticated machine-learning algorithms that automatically selected SSD-specific functional connections were applied to Japanese datasets from Kyoto University Hospital (N = 170) including patients with chronic-stage SSD. The generalizability of the SSD classifier was tested by 2 independent validation cohorts, and 1 cohort including first-episode schizophrenia. The specificity of the SSD classifier was tested by 2 Japanese cohorts of ASD and major depressive disorder. The weighted linear summation of the classifier's functional connections constituted the biological dimensions representing neural classification certainty for the disorders. Our previously developed ASD classifier was used as ASD dimension. Distributions of individuals with SSD, ASD, and HCs s were examined on the SSD and ASD biological dimensions. We found that the SSD and ASD populations exhibited overlapping but asymmetrical patterns in the 2 biological dimensions. That is, the SSD population showed increased classification certainty for the ASD dimension but not vice versa. Furthermore, the 2 dimensions were correlated within the ASD population but not the SSD population. In conclusion, using the 2 biological dimensions based on resting-state functional connectivity enabled us to discover the quantified relationships between SSD and ASD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Disruptions in the dopamine system have been observed in psychiatric disorders. Since dopamine is mainly produced in the ventral tegmental area (VTA), elucidating the differences in the VTA neural network across psychiatric disorders would facilitate a greater understanding of the pathophysiological mechanisms underlying these disorders. However, no study has compared VTA-seed-based functional connectivity across psychiatric disorders. Therefore, we conducted a resting-state functional magnetic resonance imaging (rs-fMRI) study to perform a seed-based fMRI analysis, using the VTA as a seed., Methods: We included participants with major depressive disorder (MDD; n = 45), schizophrenia (n = 32), and bipolar disorder (BPD; n = 30), along with healthy control participants (n = 46) who were matched for age, gender, and handedness., Results: The results showed that patients with MDD and BPD had altered VTA-related connectivity in the superior frontal gyrus, frontal pole regions, hippocampus, cerebellum, and posterior cingulate cortex. Some of these differences in connectivity were also found between affective disorders and schizophrenia; however, there were no differences between the schizophrenia and control groups. Connectivity between the VTA and the hippocampus was correlated with positive symptoms in the schizophrenia group. The connectivity was not associated with medication dose, and the results remained significant after controlling for dose., Conclusions: The results suggest that altered brain functional connectivity related to VTA networks could be associated with the distinctive pathophysiologies of psychiatric disorders, especially affective disorders., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The auditory mismatch negativity (MMN) is a translatable electroencephalographic biomarker automatically evoked in response to unattended sounds that is robustly associated with cognitive and psychosocial disability in patients with schizophrenia. Although recent animal studies have tried to clarify the neural substrates of the MMN, the nature of schizophrenia-related deficits is unknown. In this study, we applied a novel paradigm developed from translational animal model studies to carefully deconstruct the constituent neurophysiological processes underlying MMN generation. Patients with schizophrenia (N = 25) and healthy comparison subjects (HCS; N = 27) underwent MMN testing using both a conventional auditory oddball paradigm and a "many-standards paradigm" that was specifically developed to deconstruct the subcomponent adaptation and deviance detection processes that are presumed to underlie the MMN. Using a conventional oddball paradigm, patients with schizophrenia exhibited large effect size deficits of both duration and frequency MMN, consistent with many previous studies. Furthermore, patients with schizophrenia showed selective impairments in deviance detection but no impairment in adaptation to repeated tones. These findings support the use of the many-standards paradigm for deconstructing the constituent processes underlying the MMN, with implications for the use of these translational measures to accelerate the development of new treatments that target perceptual and cognitive impairments in schizophrenia and related disorders., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57; 95% CI, -1.27 to 0.13; P = 0.023) and confirmatory trials (-0.41; -0.62 to -0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen's d = -0.78; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen's d = -0.46; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen's d = -0.35; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen's d = -1.24; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals' facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Although advanced paternal and maternal age at birth (PA/MA) increases the risk of autism spectrum disorder (ASD), the underlying neurobiological mechanisms are not fully understood. To explore the neuroanatomical correlates of advanced PA/MA, the current study conducted brain morphometric analyses in 39 high-functioning adult males with ASD and 39 age-, intellectual level-, and parental socioeconomic background-matched, typically developed (TD) males. Whole-brain analysis revealed that the regional gray matter volume (GMV) in bilateral posterior cingulate cortex (PCC) and precuneus (PCU) were significantly smaller in the individuals with ASD than in TD subjects (false discovery rate-corrected P = 0.014). Additional analyses of the constituents of GMV reduction in these brain regions revealed that the cortical thickness of the right ventral PCC was significantly thinner (P = 0.014) and the surface area of bilateral PCU was significantly smaller (left: P = 0.001; right: P = 0.049) in the adults with ASD, compared with TD subjects. Although the analyses were exploratory, the thinner cortical thickness of right ventral PCC was significantly correlated with older PA in the ASD individuals (P = 0.028). The current findings shed new light on the neurobiological mechanisms underlying the link between advanced PA and ASD., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Both plants and animals must contend with changes in their environment. The ability to respond appropriately to these changes often underlies the ability of the individual to survive. In plants, an early response to environmental stress is an alteration in plasmodesmatal permeability with accompanying changes in cell to cell signaling. However, the ways in which plasmodesmata are modified, the molecular players involved in this regulation, and the biological significance of these responses are not well understood. Here, we examine the effects of nutrient scarcity and excess on plasmodesmata-mediated transport in the Arabidopsis thaliana root and identify two CALLOSE SYNTHASES and two β-1,3-GLUCANASES as key regulators of these processes. Our results suggest that modification of plasmodesmata-mediated signaling underlies the ability of the plant to maintain root growth and properly partition nutrients when grown under conditions of excess nutrients.

Background: Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation., Methods: The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry., Results: GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation., Conclusions: Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: The clinical features and laboratory parameters of patients with Kawasaki disease (KD) and systemic juvenile idiopathic arthritis (s-JIA) tend to overlap. Furthermore, there have been no definitive biomarkers for these diseases, making clinical diagnosis difficult. The purpose of this study was to investigate the diagnostic value of serum ferritin levels for differentiating KD from s-JIA and predicting the disease severity of KD., Methods: We analyzed 228 patients with KD and 81 patients with s-JIA. Serum ferritin levels were compared between patients with s-JIA and KD. Furthermore, serum ferritin levels in patients with KD were compared with respect to clinical features such as responsiveness to intravenous immunoglobulin (IVIG) therapy., Results: Serum ferritin levels in KD patients with no response to IVIG therapy were significantly higher than those in KD patients with a good response to IVIG therapy. Serum ferritin levels in patients with KD needing plasma exchange (PE) were significantly higher than those in patients not needing PE. However, serum ferritin levels overlapped between severe KD patients with nonresponsiveness to IVIG therapy or needing PE and other patients with mild KD. Furthermore, patients with s-JIA showed a distinct elevation of serum ferritin levels compared with KD patients. The cutoff value of serum ferritin levels for differentiating KD from s-JIA was 369.6 ng/ml., Conclusions: Serum ferritin levels were significantly elevated in s-JIA patients compared with KD patients. Measurement of serum ferritin levels can be useful for differentiating s-JIA from KD.

Macrophage activation syndrome (MAS) is a severe and potential life-threatening complication of childhood systemic inflammatory disorders. Corticosteroids are commonly used as the first-line therapy for MAS. We report four patients with MAS who were successfully treated with dexamethasone palmitate (DexP), a liposome-incorporated dexamethasone, much more efficient than free corticosteroids. DexP effectively inhibited inflammation in MAS patients in whom the response to pulse methylprednisolone was not sufficient to manage their diseases. DexP was also effective as the first-line therapy for MAS. Based on these findings, DexP is an effective therapy in treating MAS patients.

Alterations in gamma-band auditory steady-state response (ASSR) are the most robust finding of abnormal neural oscillations in patients with first-episode (FES) and chronic schizophrenia. Gamma-band ASSRs may indicate GABAergic interneuron dysfunction. Nevertheless, it is unknown whether abnormal gamma-band ASSRs are present before the onset of psychosis. Subjects were 15 ultra-high-risk (UHR) individuals, 13 FES patients, and 21 healthy control (HC) subjects. We performed electroencephalogram recordings and measured ASSRs in each group as they were presented with click trains at 20, 30, and 40 Hz. We then conducted time-frequency analyses and calculated intertrial phase coherence and event-related spectral perturbation. The time course of gamma-band ASSRs showed significantly different features among groups. Compared with the HC group, the UHR group was characterized by intact early-latency (0-100 ms) and reduced late-latency (300-500 ms) ASSRs. In contrast, both early- and late-latency ASSRs were significantly reduced in the FES group. Gamma-band ASSRs were correlated with clinical symptoms and attentional functioning in FES (|rs| > 0.70). These results suggest differential alterations of gamma-band ASSRs between UHR and FES groups. The late-latency ASSR alteration may represent a biomarker for early detection of psychosis, while the early-latency ASSR abnormality may develop through the onset of psychosis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Autism spectrum disorder is a prevalent neurodevelopmental disorder with no established pharmacological treatment for its core symptoms. Although previous literature has shown that single-dose administration of oxytocin temporally mitigates autistic social behaviours in experimental settings, it remains in dispute whether such potentially beneficial responses in laboratories can result in clinically positive effects in daily life situations, which are measurable only in long-term observations of individuals with the developmental disorder undergoing continual oxytocin administration. Here, to address this issue, we performed an exploratory, randomized, double-blind, placebo-controlled, crossover trial including 20 high-functional adult males with autism spectrum disorder. Data obtained from 18 participants who completed the trial showed that 6-week intranasal administration of oxytocin significantly reduced autism core symptoms specific to social reciprocity, which was clinically evaluated by Autism Diagnostic Observation Scale (P = 0.034, PFDR < 0.05, Cohen's d = 0.78). Critically, the improvement of this clinical score was accompanied by oxytocin-induced enhancement of task-independent resting-state functional connectivity between anterior cingulate cortex and dorso-medial prefrontal cortex (rho = -0.60, P = 0.011), which was measured by functional magnetic resonance imaging. Moreover, using the same social-judgement task as used in our previous single-dose oxytocin trial, we confirmed that the current continual administration also significantly mitigated behavioural and neural responses during the task, both of which were originally impaired in autistic individuals (judgement tendency: P = 0.019, d = 0.62; eye-gaze effect: P = 0.03, d = 0.56; anterior cingulate activity: P = 0.00069, d = 0.97; dorso-medial prefrontal activity: P = 0.0014, d = 0.92; all, PFDR < 0.05). Furthermore, despite its longer administration, these effect sizes of the 6-week intervention were not larger than those seen in our previous single-dose intervention. These findings not only provide the evidence for clinically beneficial effects of continual oxytocin administration on the core social symptoms of autism spectrum disorder with suggesting its underlying biological mechanisms, but also highlight the necessity to seek optimal regimens of continual oxytocin treatment in future studies., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Schizophrenia is a disabling clinical syndrome found across the world. While the incidence and clinical expression of this illness are strongly influenced by ethnic factors, it is unclear whether patients from different ethnicities show distinct brain deficits. In this multicentre study, we used structural Magnetic Resonance Imaging to investigate neuroanatomy in 126 patients with first episode schizophrenia who came from 4 ethnically distinct cohorts (White Caucasians, African-Caribbeans, Japanese, and Chinese). Each patient was individually matched with a healthy control of the same ethnicity, gender, and age (±1 year). We report a reduction in the gray matter volume of the right anterior insula in patients relative to controls (P < .05 corrected); this reduction was detected in all 4 ethnic groups despite differences in psychopathology, exposure to antipsychotic medication and image acquisition sequence. This finding provides evidence for a neuroanatomical signature of schizophrenia expressed above and beyond ethnic variations in incidence and clinical expression. In light of the existing literature, implicating the right anterior insula in bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety, we speculate that the neuroanatomical deficit reported here may represent a transdiagnostic feature of Axis I disorders., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objectives: Although recent studies have demonstrated that patients with schizophrenia and healthy controls did not differ in the speed of age-related decline in cortical thickness and performances on cognitive tests, hemodynamic changes assessed by functional neuroimaging remain unclear. This study investigated age effects on regional brain cortical activity to determine whether there is similar age-related decline in cortical activity as those observed in cortical thickness and cognitive test performance., Method: A total of 109 patients with schizophrenia (age range: 16-59 y) and 106 healthy controls (age range: 16-59 y) underwent near-infrared spectroscopy (NIRS) while performing a verbal fluency test (VFT). Group comparison of cortical activity was examined using 2-tailed t tests, adopting the false discovery rate method. The relationship between age and cortical activity was investigated using correlational and multiple regression analyses, adjusting for potential confounding variables. A 2-way ANOVA was conducted to investigate differences in the age effects between diagnostic groups., Results: The patient group exhibited significantly decreased cortical activity in several regions of the frontotemporal cortices. However, slopes of age-dependent decreases in cortical activity were similar between patients and healthy individuals at the bilateral frontotemporal regions., Conclusions: Our study showed no significant between-group differences in the age-related decline in cortical activity, as measured by NIRS, over the frontotemporal regions during a VFT. The results of our study may indicate a decrease in cortical activity in a relatively limited period around illness onset rather than continuously progressing over the course of the illness., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Recent studies have suggested oxytocin's therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others' social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person's social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others' social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others' social emotions (P = 0.018) but not in inferring others' beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others' social emotions, and in the dorsomedial prefrontal cortex during inferring others' beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others' social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others' social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others' beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others' social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Changes in brain pathology as schizophrenia progresses have been repeatedly suggested by previous studies. Meta-analyses of previous proton magnetic resonance spectroscopy ((1)H MRS) studies at each clinical stage of schizophrenia indicate that the abnormalities of N-acetylaspartate (NAA) and glutamatergic metabolites change progressively. However, to our knowledge, no single study has addressed the possible differences in (1)H MRS abnormalities in subjects at 3 different stages of disease, including those at ultrahigh risk for psychosis (UHR), with first-episode schizophrenia (FES), and with chronic schizophrenia (ChSz). In the current study, 24 patients with UHR, 19 FES, 25 ChSz, and their demographically matched 3 independent control groups (n = 26/19/28 for the UHR, FES, and ChSz control groups, respectively) underwent (1)H MRS in a 3-Tesla scanner to examine metabolites in medial prefrontal cortex. The analysis revealed significant decreases in the medial prefrontal NAA and glutamate + glutamine (Glx) levels, specifically in the ChSz group as indexed by a significant interaction between stage (UHR/FES/ChSz) and clinical status (patients/controls) (P = .008). Furthermore, the specificity of NAA and Glx reductions compared with the other metabolites in the patients with ChSz was also supported by a significant interaction between the clinical status and types of metabolites that only occurred at the ChSz stage (P = .001 for NAA, P = .004 for Glx). The present study demonstrates significant differences in (1)H MRS abnormalities at different stages of schizophrenia, which potentially correspond to changes in glutamatergic neurotransmission, plasticity, and/or excitotoxicity and regional neuronal integrity with relevance for the progression of schizophrenia., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN)., Methods: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria., Results: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission., Conclusions: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.)

Despite increasing interest in anxiety and psychological stress in daily life, little is known about neural correlates that underlie maintained psychological stress and their relationship with anxiety. In particular, the activation characteristics of lateral prefrontal subregions and their relationship with anxiety and cognitive performance under maintained psychological stress remain unknown. This study used near-infrared spectroscopy (NIRS), a noninvasive and "real-world" functional neuroimaging method, to investigate the hemodynamic responses in wide areas of the prefrontal cortex (PFC) and the influence of anxiety under conditions of maintained stress induced by a continuous arithmetic task (2 sets, 15 min each) performed in a natural sitting posture. Although anxiety and performance are not directly correlated, the hemodynamic response in the medial portion of the lateral PFC (dorsolateral and frontopolar PFC) was significantly associated with anxiety, while hemodynamic responses in the ventrolateral PFC were associated with performance. Additionally, in the same medial region of the lateral PFC, trait and state anxieties were related to changes in deoxy- and oxy-hemoglobin concentrations, respectively. This NIRS finding suggests disparate roles for prefrontal subregions in anxiety and performance under psychological stress and may lead to a better understanding of neural correlates for anxiety in everyday life., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The calyculin A-induced premature chromosome condensation (PCC) assay is a simple and useful method for assessing the cell-cycle distribution in cells, since calyculin A induces chromosome condensation in various phases of the cell cycle. In this study, a novel parameter, the cell-cycle progression index (CPI), in the PCC assay was validated as a novel biomarker for biodosimetry. Peripheral blood was drawn from healthy donors after informed consent was obtained. CPI was investigated using a human peripheral blood lymphocyte (PBL) ex vivo irradiation ((60)Co-gamma rays: ∼0.6 Gy min(-1), or X ray: 1.0 Gy min(-1); 0-10 Gy) model. The calyculin A-induced PCC assay was performed for chromosome preparation. PCC cells were divided into the following five categories according to cell-cycle stage: non-PCC, G1-PCC, S-PCC, G2/M-PCC and M/A-PCC cells. CPI was calculated as the ratio of G2/M-PCC cells to G1-PCC cells. The PCC-stage distribution varied markedly with irradiation doses. The G1-PCC cell fraction was significantly reduced, and the G2/M-PCC cell fraction increased, in 10-Gy-irradiated PBL after 48 h of culture. CPI levels were fitted to an exponential dose-response curve with gamma-ray irradiation [y = 0.6729 + 0.3934 exp(0.5685D), r = 1.0000, p < 0.0001] and X-ray irradiation [y = -0.3743 + 0.9744 exp(0.3321D), r = 0.9999, p < 0.0001]. There were no significant individual (p = 0.853) or gender effects (p = 0.951) on the CPI in the human peripheral blood ex vivo irradiation model. Furthermore, CPI measurements are rapid (< 15 min per case). These results suggest that the CPI is a useful screening tool for the assessment of radiation doses received ranging from 0 to 10 Gy in radiation exposure early after a radiation event, especially after a mass-casualty radiological incident., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Arabidopsis thaliana BOR1 was the first boron (B) transporter identified in living systems. There are four AtBOR1-like genes, OsBOR1, 2, 3 and 4, present in the rice genome. We characterized the activity, expression and physiological function of OsBOR4. OsBOR4 is an active efflux transporter of B. Quantitative PCR analysis and OsBOR4 promoter-green fluorescent protein (GFP) fusion revealed that OsBOR4 was both highly and specifically expressed in pollen. We obtained five Tos17 insertion mutants of osbor4. The pollen grains were viable and development of floral organs was normal in the homozygous osbor4 mutants. We observed that in all Tos17 insertion lines tested, the frequency of osbor4 homozygous plants was lower than expected in the progeny of self-fertilized heterozygous plants. These results establish that OsBOR4 is essential for normal reproductive processes. Pollen from osbor4 homozygous plants elongated fewer tubes on wild-type stigmas, and tube elongation of mutant pollen was less efficient compared with the wild-type pollen, suggesting reduced competence of osbor4 mutant pollen. The reduced competence of mutant pollen was further supported by the crosses of independent Tos17-inserted alleles of OsBOR4. Our results suggest that OsBOR4, a boron efflux transporter, is required for normal pollen germination and/or tube elongation.

Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers.

LEC-1 is a major galectin in Caenorhabditis elegans and contains two carbohydrate recognition domains (CRDs), N-CRD and C-CRD. To determine the role of LEC-1, we examined the phenotypes of a mutant C. elegans strain lacking lec-1. We observed negligible differences in embryogenesis, morphogenesis and egg laying at 20 °C between the mutant and the wild-type. Furthermore, the life spans of the mutant and the wild-type were equivalent at either 20 °C or 25 °C. However, the lec-1 mutant showed a greater susceptibility to H2O2 and paraquat than the wild-type. This result suggests an increased susceptibility to oxidative stress, with the phenotypes being similar to those of lec-10 deletion mutants as previously described. To understand the molecular mechanism underlying this phenotype, C. elegans proteins bound by either the LEC-1 N-CRD or C-CRD were isolated and identified using a nano liquid chromatography-tandem mass spectrometry technique. MIG-6 was identified as a major binding partner of LEC-1 with both N- and C-CRD. From these results and previous reports, we speculate that interaction of LEC-1 and MIG-6 in the pharynx may affect susceptibility to paraquat and that LEC-10 has different functions from LEC-1 in regulating H2O2 and paraquat resistance in the intestine.

The effects of prenatal low-dose irradiation with heavy ions on embryonic development in mice and on melanocyte differentiation are not well understood. We performed whole-body irradiation of pregnant C57BL/10J mice at embryonic Day 9 (E9) with a single dose of γ-rays, silicon, argon or iron ions. The number of living embryos and embryonic body weight at E18 decreased after exposure to heavy ions at high doses. Malformations such as small eyes and limb anomalies were observed in heavy-ion-treated embryos, but not in γ-ray-treated embryos. The frequency of abnormally curved tails was increased by exposure to γ-rays and argon and iron ions even at a dose of 0.1 Gy (P < 0.05). In contrast, a dose-dependent decrease in the number of epidermal melanoblasts/melanocytes and hair bulb melanocytes was observed after 0.1 Gy irradiation with γ-rays or heavy ions (P < 0.01). The decrease in the number of dorsal hair bulb melanocytes, dorsal and ventral epidermal melanoblasts/melanocytes and ventral hair bulb melanocytes was not necessarily correlated with the linear energy transfer of the radiation tested. Moreover, the effects of heavy ions were larger on the ventral skin than on the dorsal skin, indicating that the sensitivity of melanocytes to heavy ions differs between the dorsal and ventral skin. Taken together, these results suggest that the effects of the low-dose heavy ions differ between cell types and tissues, and the effects on the prenatal development of mice and melanocyte development are not necessarily greater than those of γ-rays.

Finnish-type familial amyloidosis (FAF) is a rare hereditary systemic amyloidosis that mainly exhibits cranial neuropathy. We describe a Japanese family with FAF manifested predominantly as renal amyloidosis. The proband was a 42-year-old woman with a 21-year history of proteinuria due to renal amyloidosis. Her mother was subsequently diagnosed with a similar disorder. After the first renal biopsy, both patients were followed up routinely for a period of 14 years. Genetic analysis of DNA samples revealed a heterozygous G654A gelsolin mutation. Severe renal involvement has not been reported previously in patients with FAF bearing a heterozygous gelsolin mutation.

Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model ('Yonezawa Effect') was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo.

Boron (B) is an essential micronutrient for normal development of roots, shoots and reproductive tissues in plants. Due to its role in the structure of rhamnogalacturonan II, a polysaccharide required for pollen tube growth, B deficiency has been associated with the occurrence of parthenocarpic seedless grapes in some varieties of Vitis vinifera L. Despite that, it is unclear how B is mobilized and accumulated in reproductive tissues. Here we describe the characterization of an efflux B transporter, VvBOR1, homolog to AtBOR1, which is involved in B xylem loading in Arabidopsis thaliana roots. VvBOR1-green fluorescent protein (GFP) fusion protein expressed in A. thaliana localizes in the proximal plasma membrane domain in root pericycle cells, and VvBOR1 overexpression restores the wild-type phenotype in A. thaliana bor1-3 mutant plants exposed to B deficiency. Complementation of a mutant yeast strain indicates that VvBOR1 corresponds to a B efflux transporter. Transcriptional analyses during grapevine reproductive development show that the VvBOR1 gene is preferentially expressed in flowers at anthesis and a direct correlation between the expression pattern and B content in grapes was established, suggesting the involvement of this transporter in B accumulation in grapevine berries.

The differentiation and functions of osteoclasts are regulated by receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) system that stimulates osteoclasts formation. Macrophage colony-stimulating factor (M-CSF) is also essential for osteoclastogenesis. A recent immunocytochemical study reported that RANKL/RANK and M-CSF/c-fms were localized in the periodontal ligament of rat molars during experimental orthodontic tooth movement. The present study focused on the expressions of RANKL/RANK and M-CSF/c-fms in root resorption area during experimental tooth movement in rats. Forty 6-week-old male Wistar rats were subjected to an orthodontic force of 10 or 50 g with a closed coil spring (wire size: 0.005 inch, diameter: 1/12 inch) ligated to the maxillary first molar cleat by a 0.008 inch stainless steel ligature wire to induce a mesial tipping movement of the upper first molars. Experimental tooth movement was undertaken for 10 days. Each sample was sliced into 6 μm continuous sections in a horizontal direction and prepared for haematoxylin and eosin (H and E) and immunohistochemistry staining for tartrate-resistant acid phosphatase (TRAP), RANK, RANKL M-CSF, and c-fms in root resorption area. Statistical analysis was carried out using a Mann-Whitney U-test with a significance level of P<0.01. On days 7 and 10, immunoreactivity for RANKL/RANK and M-CSF/c-fms was detected in odontoclasts with an orthodontic force of 50 g, but not 10 g. Therefore, RANKL/RANK and M-CSF/c-fms systems may be involved in the process of root resorption by heavy orthodontic force.

Effects of prenatal low-dose irradiations of heavy ions on the postnatal development of mice and of melanocytes have not been well studied. Pregnant females of C57BL/10J mice were irradiated whole-body at 9 days of gestation with a single acute dose of γ-rays, silicon (Si, 57 keV/µm), argon (Ar, 100 keV/µm) and iron (Fe, 220 keV/µm) ions. The effects were studied by scoring changes in the postnatal development of mice as well as in the pigmentation of cutaneous coats and tail-tips of their offspring 22 days after birth. The survival to day 22 decreased from the offspring exposed to 0.4 Gy of argon and iron ions and to 0.75 Gy of silicon ions. White spots were found in the mid-ventrum and tail-tips of irradiated offspring. The frequency and size of the white spots in the mid-ventrum in mice exposed to silicon, argon and iron ions were greater than those of γ-rays. Even in the low dose (0.1 Gy), γ-rays and heavy ions increased the frequency of the ventral spots. The RBE estimated by the frequency of the ventral spots was 2.3 (Si), 3.1 (Ar) and 4.5 (Fe). These results suggest that prenatal exposure to heavy ions possesses a greater effect on the postnatal development of mice as well as melanocyte development than does exposure to γ-rays.

Autism is a severe neurodevelopmental disorder with a complex genetic aetiology. The wingless-type MMTV integration site family member 2 (WNT2) gene has been considered as a candidate gene for autism. We conducted a case-control study and followed up with a transmission disequilibrium test (TDT) analysis to confirm replication of the significant results for the first time. We conducted a case-control study of nine single nucleotide polymorphisms (SNPs) within the WNT2 gene in 170 patients with autism and 214 normal controls in a Japanese population. We then conducted a TDT analysis in 98 autistic families (trios) to replicate the results of the case-control study. In the case-control study, three SNPs (rs3779547, rs4727847 and rs3729629), two major individual haplotypes (A-T-C and G-G-G, consisting of rs3779547, rs4727847, and rs3729629), and global probability values of the haplotype distributions in the same region (global p=0.0091) showed significant associations with autism. Furthermore, all of these significant associations were also observed in the TDT analysis. Our findings provide evidence for a significant association between WNT2 and autism. Considering the important role of the WNT2 gene in brain development, our results therefore indicate that the WNT2 gene is one of the strong candidate genes for autism.

It has previously been reported that low-energy laser irradiation stimulated the velocity of tooth movement via the receptor activator of nuclear factor kappa B (RANK)/RANK ligand and the macrophage colony-stimulating factor/its receptor (c-Fms) systems. Matrix metalloproteinase (MMP)-9, cathepsin K, and alpha(v) beta(3) [alpha(v)beta3] integrin are essential for osteoclastogenesis; therefore, the present study was designed to examine the effects of low-energy laser irradiation on the expression of MMP-9, cathepsin K, and alpha(v)beta3 integrin during experimental tooth movement. Fifty male, 6-week-old Wistar strain rats were used in the experiment. A total force of 10g was applied to the rat molars to induce tooth movement. A Ga-Al-As diode laser was used to irradiate the area around the moving tooth and, after 7 days, the amount of tooth movement was measured. To determine the amount of tooth movement, plaster models of the maxillae were made using a silicone impression material before (day 0) and after tooth movement (days 1, 2, 3, 4, and 7). The models were scanned using a contact-type three-dimensional (3-D) measurement apparatus. Immunohistochemical staining for MMP-9, cathepsin K, and integrin subunits of alpha(v)beta3 was performed. Intergroup comparisons of the average values were conducted with a Mann-Whitney U-test for tooth movement and the number of tartrate-resistant acid phosphatase (TRAP), MMP-9, cathepsin K, and integrin subunits of alpha(v)beta3-positive cells. In the laser-irradiated group, the amount of tooth movement was significantly greater than that in the non-irradiated group at the end of the experiment (P < 0.05). Cells positively stained with TRAP, MMP-9, cathepsin K, and integrin subunits of alpha(v)beta3 were found to be significantly increased in the irradiated group on days 2-7 compared with those in the non-irradiated group (P < 0.05). These findings suggest that low-energy laser irradiation facilitates the velocity of tooth movement and MMP-9, cathepsin K, and integrin subunits of alpha(v)beta3 expression in rats.

To study mechanisms which could be involved in the reverse dose rate effect observed during mutation induction after exposure to high LET radiation, synchronized mouse L5178Y cells were exposed to carbon 290 MeV/n beams with different LET values at the G2/M, G1, G1/S or S phases in the cell cycle. The frequency of Hprt-deficient (6-thioguanine-resistant) mutant induction was subsequently determined. The results showed that after exposure to high LET value radiation (50.8 and 76.5 keV/microm), maximum mutation frequencies were seen at the G2/M phase, but after exposure to lower LET radiation (13.3 keV/microm), the highest mutation frequencies were observed at the G1 phase. The higher LET beam always produced higher mutation frequencies in the G2/M phase than in the G1 phase, regardless of radiation dose. These results suggest that cells in the G2/M phase is hyper-sensitive for mutation induction from high LET radiation, but not to mutation induction from low LET radiation. Molecular analysis of mutation spectra showed that large deletions (which could include almost entire exons) of the mouse Hprt gene were most efficiently induced in G2/M cells irradiated with high LET radiation. These entire exon deletions were not as frequent in cells exposed to lower LET radiation. This suggests that inappropriate recombination repair might have occurred in response to condensed damage in condensed chromatin in the G2/M phase. In addition, by using a hyper-sensitive mutation detection system (GM06318-10 cells), a reverse dose-rate effect was clearly observed after exposure to carbon beams with higher LET values (66 keV/microm), but not after exposure to beams with lower LET values (13.3 keV/microm). Thus, G2/M sensitivity towards mutation induction, and the dependence on radiation LET values could both be major factors involved in the reverse dose rate effect produced by high LET radiation.

Autism is a severe neurodevelopmental disorder of early childhood. Genetic factors play an important role in the aetiology of the disorder. In this study, we considered the NRCAM gene as a candidate gene of autism. This gene is expressed in the central nervous system and located in the 7q region, a susceptibility locus of autism. We conducted a case-control study of 18 single nucleotide polymorphisms (SNPs) within the NRCAM gene for possible association with autism in 170 autistic patients and 214 normal controls in a Japanese population. Seven SNPs in the NRCAM gene were significantly associated with autism, among which rs2300045 indicated the most prominent result (p=0.0009 uncorrected, p=0.017 corrected). In haplotype analyses, several individual haplotypes, including a common NRCAM haplotype C-T-T-C-T-T-G-C for rs3763463, rs1859767, rs1034825, rs2300045, rs2300043, rs2300039, rs722519, and rs2216259, showed a significant association after Bonferroni correction (p=0.0035 uncorrected, p=0.028 corrected). These haplotypes were located in the 5' intron-2 region of the gene. In addition, we also assessed the above mentioned SNPs and haplotypes using the transmission disequilibrium test with 148 trios of autistic families. Haplotype G-T-T-T-T-C-G-C in the same eight SNPs was also associated with autism. In summary, our findings provide evidence for a significant association of NRCAM with autism. Considering the important role of the NRCAM gene in brain development, our results therefore indicated that the NRCAM gene is one of the strong candidate genes for autism.

Human altruistic cooperativeness, one of the most important components of our highly organized society, is along with a greatly enlarged brain relative to body size a spectacular outlier in the animal world. The "social-brain hypothesis" suggests that human brain expansion reflects an increased necessity for information processing to create social reciprocity and cooperation in our complex society. The present study showed that the young adult females (n = 66) showed greater Cooperativeness as well as larger relative global and regional gray matter volumes (GMVs) than the matched males (n = 89), particularly in the social-brain regions including bilateral posterior inferior frontal and left anterior medial prefrontal cortices. Moreover, in females, higher cooperativeness was tightly coupled with the larger relative total GMV and more specifically with the regional GMV in most of the regions revealing larger in female sex-dimorphism. The global and most of regional correlations between GMV and Cooperativeness were significantly specific to female. These results suggest that sexually dimorphic factors may affect the neurodevelopment of these "social-brain" regions, leading to higher cooperativeness in females. The present findings may also have an implication for the pathophysiology of autism; characterized by severe dysfunction in social reciprocity, abnormalities in social-brain, and disproportionately low probability in females.

To evaluate whether the continuous treatment of two cytokine combinations is effective in megakaryocytopoiesis and thrombopoiesis in hematopoietic stem/progenitor cells exposed to heavy ion beams, the effects of a 2-step culture by a combination of recombinant human interleukin-3 (IL-3) + stem cell factor (SCF) + thrombopoietin (TPO), which just slightly protected against carbon-ion beam-induced damages, and a combination of IL-3 + TPO, which selectively stimulated the differentiation of the hematopoietic stem/progenitor cells to megakaryocytes and platelets, were examined. CD34(+)-hematopoietic stem/progenitor cells isolated from the human placental and umbilical cord blood were exposed to carbon-ion beams (LET = 50 keV/microm) at 2 Gy. These cells were cultured under three cytokine conditions. The number of megakaryocytes, platelets and hematopoietic progenitors were assessed using a flow cytometer and a clonogenic assay at 14 and 21 days after irradiation, respectively. However, the efficacy of each 2-step culture was equal or lower than that of using the IL-3 + SCF + TPO combination alone and the 2-step culture could not induce megakaryocytes and platelets from hematopoietic stem/progenitor cells exposed to high LET-radiation such as carbon-ion beams. Therefore, additional cytokines and/or hematopoietic promoting compounds might be required to overcome damage to hematopoietic cells by high LET radiation.

Two distinct biosynthetic pathways for Phe in plants have been proposed: conversion of prephenate to Phe via phenylpyruvate or arogenate. The reactions catalyzed by prephenate dehydratase (PDT) and arogenate dehydratase (ADT) contribute to these respective pathways. The Mtr1 mutant of rice (Oryza sativa) manifests accumulation of Phe, Trp, and several phenylpropanoids, suggesting a link between the synthesis of Phe and Trp. Here, we show that the Mtr1 mutant gene (mtr1-D) encodes a form of rice PDT with a point mutation in the putative allosteric regulatory region of the protein. Transformed callus lines expressing mtr1-D exhibited all the characteristics of Mtr1 callus tissue. Biochemical analysis revealed that rice PDT possesses both PDT and ADT activities, with a preference for arogenate as substrate, suggesting that it functions primarily as an ADT. The wild-type enzyme is feedback regulated by Phe, whereas the mutant enzyme showed a reduced feedback sensitivity, resulting in Phe accumulation. In addition, these observations indicate that rice PDT is critical for regulating the size of the Phe pool in plant cells. Feeding external Phe to wild-type callus tissue and seedlings resulted in Trp accumulation, demonstrating a connection between Phe accumulation and Trp pool size.

The aim of this investigation was to examine the effects of experimental occlusal hypofunction, and recovery, on mandibular bone mineral density (BMD) using peripheral quantitative computed tomography. A metal cap was inserted between the upper and lower incisors of 40 male Wistar rats (aged 6 weeks) to prevent the molars from biting. The rats were divided into two equal groups: 'hypofunction' and 'recovery' animals. In addition, there was a third group comprising 20 control animals. The recovery animals were anaesthetized at 4 weeks in order to remove the metal cap using pliers. The rats were killed under deep anaesthesia, after which the mandibles were immediately removed and fixed in 10 per cent neutral formalin. After 2, 4, 6, and 8 weeks, BMD was measured in the cancellous and cortical bone in the first molar region. Data were analysed using one-way analysis of variance. At 6 and 8 weeks, in the hypofunction group, cancellous bone density decreased on the buccal and lingual sides, at the bifurcation of the root and at the root apex. In the recovery group, the density on the buccal and lingual sides had recovered to the normal levels, compared with the control group. However, density of the bifurcation of the root and the root apex recovered by only 30 and 50 per cent, respectively. At 6 and 8 weeks, cortical bone density in the hypofunction group had reduced in the lingual basal and lingual middle cortical bone areas. Cortical bone density in the lingual basal and lingual areas recovered to control group levels at 6 weeks. Recovery of occlusal hypofunction may restore decreased BMD of both cancellous and cortical bone.