Changes in maxillofacial morphology due to improvement of nasal obstruction in rats.

OBJECTIVES: To investigate the effect of release of experimentally introduced nasal obstruction on maxillofacial morphology and percutaneous arterial oxygen saturation (SpO2 ) in rats. MATERIALS AND METHODS: Six-week-old male Wistar rats (n = 36) were divided into a control group (n = 6) and a nasal obstruction group (n = 30). In the nasal obstruction group, the right nostril was occluded with silicon, which was subsequently removed after a given experimental period (days 7, 21, 35, 49 and 63). These animals were then divided into groups D7, D21, D35, D49 and D63 (each n = 6), according to the day at which the obstruction was released. The SpO2 was measured in rats with nasal obstruction at five experimental points. The maxillofacial morphology in rats on the first day and 63 days after the start of the experiment was evaluated by microcomputed tomography. RESULTS: The SpO2 was still lower at 2 weeks after the improvement of the nasal obstruction in the D49 group than in the control group. In addition, the height of the nasal maxillary complex of the D35, D49 and D63 groups was significantly decreased compared with the control group. CONCLUSIONS: The results of this study suggest that long-term unilateral nasal obstruction in growing rats may affect the growth of the nasomaxillary complex and reduce the SpO2 permanently. Therefore, early improvement of nasal obstruction in rats during the growth period may improve the SpO2 and cranial development and promote normal growth and development.

Abnormal asymmetries in subcortical brain volume in schizophrenia.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Trends in psychological distress and alcoholism after The Great East Japan Earthquake of 2011.

AIMS: Many studies have shown that natural disasters affect mental health; however, longitudinal data on post-disaster mental health problems are scarce. The aims of our study were to investigate the trend in psychological distress and alcoholism after The Great East Japan Earthquake and tsunami in north eastern Japan, in March 2011. METHODS: A longitudinal study was conducted using annual health check data for the general population, in the city of Higashi-Matsushima, which was affected by the high impact of tsunami. In 2012 and 2013, the Kessler Psychological Distress Scale and the CAGE questionnaire (for screening for alcoholism) were used to assess psychological distress and prevalence of alcoholism. RESULTS: Of 11,855 total eligible residents, 2192 received the annual check in 2012 and 2013. The prevalence of mental illness and the mean score of alcoholism tendency increased during the follow-up period. The majority of respondents (43.8%) with baseline serious mental illness (SMI) continued to have SMI at follow-up; only 16.7% reported recovering. Older age, female sex, and severity of home damage predicted higher psychological distress, while male sex was a risk factor for alcoholism at follow-up. CONCLUSIONS: Psychological distress deteriorated 2 years after the huge natural disaster, compared with 1 year after the disaster. Long-term mental health care is needed for those affected by natural disasters, particularly those who have suffered loss.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, increases the number of circulating CD34⁺CXCR4⁺ cells in patients with type 2 diabetes.

We investigated the effects of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on the number of circulating CD34(+)CXCR4(+)cells, a candidate for endothelial progenitor cells (EPCs), plasma levels of stromal cell-derived factor (SDF)-1α, a ligand for CXCR4 receptor and a substrate for DPP-4, and plasma levels of interferon-inducible protein (IP)-10, for a substrate for DPP-4, in patients with type 2 diabetes. We studied 30 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea. Thirty diabetic patients were randomized in a 2:1 ratio into a sitagliptin (50 mg/day) treatment group or an active placebo group (glimepiride 1 mg/day) for 12 weeks. Both groups showed similar improvements in glycemic control. The number of circulating CD34(+)CXCR4(+) cells was increased from 30.5 (20.0, 47.0)/10(6) cells at baseline to 55.5 (31.5, 80.5)/10(6) cells at 12 weeks of treatment with 50 mg/day sitagliptin (P = 0.0014), while showing no significant changes in patients treated with glimepiride. Plasma levels of SDF-1α and IP-10, both physiological substrates of endogenous DPP-4 and chemokines, were significantly decreased at 12 weeks of sitagliptin treatment. In conclusion, treatment with sitagliptin increased the number of circulating CD34(+)CXCR4(+) cells by approximately 2-fold in patients with type 2 diabetes.

Does Internet-based cognitive behavioral therapy (iCBT) prevent major depressive episode for workers? A 12-month follow-up of a randomized controlled trial.

BACKGROUND: In this study we investigated whether an Internet-based computerized cognitive behavioral therapy (iCBT) program can decrease the risk of DSM-IV-TR major depressive episodes (MDE) during a 12-month follow-up of a randomized controlled trial of Japanese workers. METHOD: Participants were recruited from one company and three departments of another company. Those participants who did not experience MDE in the past month were randomly allocated to intervention or control groups (n = 381 for each). A 6-week, six-lesson iCBT program was provided to the intervention group. While the control group only received the usual preventive mental health service for the first 6 months, the control group was given a chance to undertake the iCBT program after a 6-month follow-up. The primary outcome was a new onset of DSM-IV-TR MDE during the 12-month follow-up, as assessed by means of the web version of the WHO Composite International Diagnostic Interview (CIDI), version 3.0 depression section. RESULTS: The intervention group had a significantly lower incidence of MDE at the 12-month follow-up than the control group (Log-rank χ2 = 7.04, p < 0.01). The hazard ratio for the intervention group was 0.22 (95% confidence interval 0.06-0.75), when estimated by the Cox proportional hazard model. CONCLUSIONS: The present study demonstrates that an iCBT program is effective in preventing MDE in the working population. However, it should be noted that MDE was measured by self-report, while the CIDI can measure the episodes more strictly following DSM-IV criteria.

Notch signaling induces root resorption via RANKL and IL-6 from hPDL cells.

In this study, we first investigated the expressions of Jagged1, Notch2, the receptor activator of nuclear factor-kappa B ligand (RANKL), and interleukin (IL)-6 in areas of root resorption during experimental tooth movement in rats in vivo. We then assessed the effects of compression force (CF) with or without GSI (an inhibitor of Notch signaling) on Jagged1, RANKL, and IL-6 release from human periodontal ligament (hPDL) cells. Twelve male 6-wk-old Wistar rats were subjected to an orthodontic force of 50 g to induce mesially tipping movement of the upper first molars for 7 d. The expression levels of tartrate-resistant acid phosphatase, Jagged1, Notch2, IL-6, and RANKL proteins in the dental root were determined using an immunohistochemical analysis. Furthermore, the effects of the CF on Jagged1, IL-6, and RANKL production were investigated using hPDL cells in vitro. The effects of the cell-conditioned medium obtained from the hPDL cells subjected to CF (CFM) and Jagged 1 on osteoclastogenesis of human osteoclast precursor cells (hOCPs) were also investigated. Under the conditions of experimental tooth movement in vivo, resorption lacunae with multinucleated cells were observed in the 50 g group. In addition, immunoreactivity for Jagged1, Notch2, IL-6, and RANKL was detected on day 7 in the PDL tissue subjected to the orthodontic force. In the in vitro study, the compression force increased the production of Jagged1, IL-6, and RANKL from the hPDL cells, whereas treatment with GSI inhibited the production of these factors in vitro. The osteoclastogenesis increased with the CFM and rhJagged1, and the increase in the osteoclastogenesis was almost inhibited by GSI. These results suggest that the Notch signaling response to excessive orthodontic forces stimulates the process of root resorption via RANKL and IL-6 production from hPDL cells.

Oxytocin's neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial.

The neuropeptide oxytocin may be an effective therapeutic strategy for the currently untreatable social and communication deficits associated with autism. Our recent paper reported that oxytocin mitigated autistic behavioral deficits through the restoration of activity in the ventromedial prefrontal cortex (vmPFC), as demonstrated with functional magnetic resonance imaging (fMRI) during a socio-communication task. However, it is unknown whether oxytocin exhibited effects at the neuronal level, which was outside of the specific task examined. In the same randomized, double-blind, placebo-controlled, within-subject cross-over clinical trial in which a single dose of intranasal oxytocin (24 IU) was administered to 40 men with high-functioning autism spectrum disorder (UMIN000002241/000004393), we measured N-acetylaspartate (NAA) levels, a marker for neuronal energy demand, in the vmPFC using (1)H-magnetic resonance spectroscopy ((1)H-MRS). The differences in the NAA levels between the oxytocin and placebo sessions were associated with oxytocin-induced fMRI signal changes in the vmPFC. The oxytocin-induced increases in the fMRI signal could be predicted by the NAA differences between the oxytocin and placebo sessions (P=0.002), an effect that remained after controlling for variability in the time between the fMRI and (1)H-MRS scans (P=0.006) and the order of administration of oxytocin and placebo (P=0.001). Furthermore, path analysis showed that the NAA differences in the vmPFC triggered increases in the task-dependent fMRI signals in the vmPFC, which consequently led to improvements in the socio-communication difficulties associated with autism. The present study suggests that the beneficial effects of oxytocin are not limited to the autistic behavior elicited by our psychological task, but may generalize to other autistic behavioral problems associated with the vmPFC.

Common variants at 1p36 are associated with superior frontal gyrus volume.

The superior frontal gyrus (SFG), an area of the brain frequently found to have reduced gray matter in patients with schizophrenia, is involved in self-awareness and emotion, which are impaired in schizophrenia. However, no genome-wide association studies of SFG volume have investigated in patients with schizophrenia. To identify single-nucleotide polymorphisms (SNPs) associated with SFG volumes, we demonstrated a genome-wide association study (GWAS) of gray matter volumes in the right or left SFG of 158 patients with schizophrenia and 378 healthy subjects. We attempted to bioinformatically ascertain the potential effects of the top hit polymorphism on the expression levels of genes at the genome-wide region. We found associations between five variants on 1p36.12 and the right SFG volume at a widely used benchmark for genome-wide significance (P<5.0 × 10(-8)). The strongest association was observed at rs4654899, an intronic SNP in the eukaryotic translation initiation factor 4 gamma, 3 (EIF4G3) gene on 1p36.12 (P=7.5 × 10(-9)). No SNP with genome-wide significance was found in the volume of the left SFG (P>5.0 × 10(-8)); however, the rs4654899 polymorphism was identified as the locus with the second strongest association with the volume of the left SFG (P=1.5 × 10(-6)). In silico analyses revealed a proxy SNP of rs4654899 had effect on gene expression of two genes, HP1BP3 lying 3' to EIF4G3 (P=7.8 × 10(-6)) and CAPN14 at 2p (P=6.3 × 10(-6)), which are expressed in moderate-to-high levels throughout the adult human SFG. These results contribute to understand genetic architecture of a brain structure possibly linked to the pathophysiology of schizophrenia.

A snapshot of plasma metabolites in first-episode schizophrenia: a capillary electrophoresis time-of-flight mass spectrometry study.

Few biomarkers have been known that can easily measure clinical conditions in mental illnesses such as schizophrenia. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) is a new method that can measure ionized and low-molecular-weight metabolites. To explore global metabolomic alterations that characterize the onset of schizophrenia and identify biomarkers, we profiled the relative and absolute concentrations of the plasma metabolites from 30 patients with first-episode schizophrenia (FESZ, four drug-naïve samples), 38 healthy controls and 15 individuals with autism spectrum disorders using CE-TOFMS. Five metabolites had robust changes (increased creatine and decreased betaine, nonanoic acid, benzoic acid and perillic acid) in two independent sample sets. Altered levels of these metabolites are consistent with well-known hypotheses regarding abnormalities of the homocysteine metabolism, creatine kinase-emia and oxidative stress. Although it should be considered that most patients with FESZ received medication, these metabolites are candidate biomarkers to improve the determination of diagnosis, severity and clinical stages, especially for FESZ.

Th17-cells in atopic dermatitis stimulate orthodontic root resorption.

OBJECTIVE: The aim of this study was to investigate how atopic dermatitis (AD) contributes to root resorption during orthodontic tooth movement. MATERIALS AND METHODS: Atopic dermatitis model mice and wild-type mice were subjected to an excessive orthodontic force (OF) to induce movement of the upper first molars. The expression levels of the tartrate-resistant acid phosphatase (TRAP), IL-17, IL-6, and RANKL proteins were determined in the periodontal ligament (PDL) by an immunohistochemical analysis. Furthermore, the effects of the compression force on co-cultures of CD4(+) cells from AD patients or healthy individuals and human PDL cells were investigated with regard to the levels of secretion and mRNA expression of IL-17, IL-6, RANKL, and osteoprotegerin. RESULTS: The immunoreactivities for TRAP, IL-17, IL-6, and RANKL in the AD group were found to be significantly increased. The double immunofluorescence analysis for IL-17/CD4 detected immunoreaction. The secretion of IL-17, IL-6, and RANKL, and the mRNA levels of IL-6 and RANKL in the AD patients were increased compared with those in healthy individuals. CONCLUSION: Th17 cells may therefore be associated with the deterioration of root resorption of AD mice, and may explain why AD patients are more susceptible to root resorption than healthy individuals when an excessive OF is applied.

Meta-analysis of genome-wide association studies for panic disorder in the Japanese population.

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10(-5), odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10(-4)). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

Absence of age-related prefrontal NAA change in adults with autism spectrum disorders.

Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy ((1)H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental-socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=-0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher's r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=-3.23, P=0.001), which indicated that the age-NAA relationship was significantly specific to people with TD. The current (1)H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood.

Age-related change in brain metabolite abnormalities in autism: a meta-analysis of proton magnetic resonance spectroscopy studies.

Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of (1)H-magnetic resonance spectroscopy ((1)H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of (1)H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation.

T-helper 17 cells mediate the osteo/odontoclastogenesis induced by excessive orthodontic forces.

OBJECTIVE: The aim of this study was to investigate how T-helper 17 cells (Th17 cells), interleukin (IL)-17, and interleukin-6 contribute to root resorption during orthodontic tooth movement. MATERIALS AND METHODS: Fifteen male 6-week-old Wistar rats were subjected to orthodontic force of 10 or 50 g to induce a mesially tipping movement of the upper first molars for 7 days. The expression levels of TRAP, IL-17, the IL-17 receptor (IL-17R), and IL-6 proteins were determined in periodontal ligament (PDL) by immunohistochemical analysis. Moreover, the fluorescent localization immunoassay was performed to detect Th17 cells. Furthermore, the effects of IL-17 on IL-6 release were investigated using human PDL cells in vitro. The effect of IL-17 on osteoclastogenesis was evaluated by TRAP staining, actin ring staining, and the pit formation assay. RESULTS: The immunoreactivity for Th17, IL-17, IL-17R, and IL-6 was detected in PDL tissue subjected to the orthodontic force on day 7. IL-17 increased the release of IL-6 from human periodontal ligament cells in a time-dependent manner. Moreover, IL-17 stimulated osteoclastogenesis from human osteoclast precursor cells, and these effects were partially suppressed by an anti-IL-6 antibody. CONCLUSION: These results suggest that Th17 cells may aggravate the process of orthodontically induced inflammatory root resorption.

Properties of L-type bovine spongiform encephalopathy in intraspecies passages.

The origin and transmission routes of atypical bovine spongiform encephalopathy (BSE) remain unclear. To assess whether the biological and biochemical characteristics of atypical L-type BSE detected in Japanese cattle (BSE/JP24) are conserved during serial passages within a single host, 3 calves were inoculated intracerebrally with a brain homogenate prepared from first-passaged BSE/JP24-affected cattle. Detailed immunohistochemical and neuropathologic analysis of the brains of second-passaged animals, which had developed the disease and survived for an average of 16 months after inoculation, revealed distribution of spongiform changes and disease-associated prion protein (PrP(Sc)) throughout the brain. Although immunolabeled PrP(Sc) obtained from brain tissue was characterized by the presence of PrP plaques and diffuse synaptic granular accumulations, no stellate-type deposits were detected. Western blot analysis suggested no obvious differences in PrP(Sc) molecular mass or glycoform pattern in the brains of first- and second-passaged cattle. These findings suggest failures to identify differences in mean incubation period and biochemical and neuropathologic properties of the BSE/JP24 prion between the first and second passages in cattle.

Measuring RNA editing of serotonin 2C receptor.

Pre-mRNA of serotonin 2C receptor (HTR2C, 5-hydroxytryptamine (serotonin) receptor 2C) undergoes A-to-I type RNA editing, which is a post-transcriptional event leading to the change of genomically encoded information. RNA editing generates various HTR2C isoforms, each of which has distinctive receptor activity. Postmortem, animal, and pharmacological studies have suggested that the altered RNA editing of HTR2C is involved in the pathophysiology of mental disorders, although results remain inconsistent. Here we review the techniques used for estimation of RNA editing of HTR2C. Among the techniques reported so far, a high-throughput sequencing-based method would be the most powerful method of choice for the large-scale experiments. Several different methods that were previously developed, such as pyrosequencing and capillary electrophoresis, should be suitable for validation as well as for rapid screening or exploratory purposes.

IL-8 and MCP-1 induced by excessive orthodontic force mediates odontoclastogenesis in periodontal tissues.

OBJECTIVE: The aim of this study was to investigate how interleukin (IL)-8 (cytokine-induced neutrophil chemoattractant; CINC-1) and monocyte chemotactic protein (MCP)-1/CCL2 contribute to root resorption during orthodontic tooth movement. MATERIALS AND METHODS: Forty 6-week-old male Wistar rats were subjected to orthodontic force of 10 or 50 g to induce a mesially tipping movement of the upper first molars for 7 days. We determined the expressions of CINC-1, CXCR2, and MCP-1 proteins in root resorption area using immunohistochemistry. Furthermore, we investigated the effects of compression forces (CF) on IL-8 and MCP-1 production by human periodontal ligament (hPDL) cells. We observed an effect of chemokine treatment on rat odonto/osteoclasts in dentin slices that recapitulated root resorption. RESULTS: The immunoreactivity for CINC-1/CXCR2 and MCP-1 was detected in odontoclasts and PDL fibroblasts by the orthodontic force of 50 g on day 7. CF increased the secretion and the expression of mRNA of IL-8 and MCP-1 from PDL cells in a magnitude-dependent manner. Moreover, CINC-1 and MCP-1 stimulated osteoclastogenesis from rat osteoclast precursor cells. CONCLUSION: IL-8 (CINC-1) and MCP-1 may therefore facilitate the process of root resorption because of excessive orthodontic force.

The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism.

OBJECTIVE: Autism appears to have a strong genetic component. The product of the NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene is included in the mitochondrial electron transport chain. METHOD: We performed a case-control study of 235 patients with autism and 214 controls and examined three single-nucleotide polymorphisms (SNPs) within this gene in a Japanese population. We then conducted a transmission disequilibrium test (TDT) analysis in 148 autistic trios. RESULTS: In the case-control study, two SNPs (rs12666974 and rs3779262) showed a significant association with autism (P=0.00064 and 0.00046 respectively). Furthermore, a haplotype containing these two SNPs showed a significant association (P-global=0.0013, individual haplotype A-A: P=0.010). In TDT analysis, the global and A-A haplotype P-values also indicated significant associations. Minor allele and genotype frequencies were decreased in the autistic subjects. CONCLUSION: We found significant association between the NDFA5 gene and autism.

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin.

The Krüppel-like zinc-finger protein GLI1 functions as a downstream transcription factor of Hedgehog signaling and plays a pivotal role in the cellular proliferation of many types of tumors, including pancreatic ductal adenocarcinoma (PDA). PDA develops from dysplastic lesions called pancreatic intraepithelial neoplasia (PanIN) through a multistep carcinogenesis process that changes its cellular characteristics, including a mucin expression profile. Increased expression of a gel-forming mucin, MUC5AC, was previously revealed as a major biomarker for the poor prognosis of PDA patients, but the molecular mechanisms responsible for its expression and correlation with poor prognosis are not fully understood. Here we show that MUC5AC is a direct transcriptional target of GLI1 in PDA cells. Overexpression of GLI1 enhanced MUC5AC expression, and a double knockdown of GLI1 and GLI2 suppressed endogenous MUC5AC expression in PDA cells. Luciferase reporter assays revealed that GLI1 and GLI2 can activate the MUC5AC promoter through its conserved CACCC-box-like cis-regulatory elements. We also found that GLI1-upregulated MUC5AC was expressed in the intercellular junction between cultured PDA cells and interfered with the membrane localization of E-cadherin, leading to decreased E-cadherin-dependent cell-cell adhesion and promoting the migration and invasion of PDA cells. Consistently, GLI1 induced the nuclear accumulation and target gene expression of ß-catenin in a MUC5AC-dependent manner. Finally, immunohistochemical analysis revealed that GLI1 expression statistically correlated with MUC5AC expression and also with altered subcellular localization of E-cadherin and ß-catenin in PanIN lesions and PDA. This evidence revealed a new aspect of GLI1 function in modulating E-cadherin/ß-catenin-regulated cancer cell properties through the expression of a gel-forming mucin.