Alternative polyadenylation determines the functional landscape of inverted Alu repeats.

Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' untranslated regions (UTRs). Yet, the biological significance of IRAlus embedded in 3' UTRs remains largely unknown. Here, we find that 3' UTR IRAlus silences genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, including amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3' UTR IRAlus and its role in human pathophysiology.

Aberrant Neural Activation Underlying Idiom Comprehension in Korean Children with High Functioning Autism Spectrum Disorder.

PURPOSE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and repetitive behaviors or restricted interests. Impaired pragmatic language comprehension is a universal feature in individuals with ASD. However, the underlying neural basis of pragmatic language is poorly understood. In the present study, we examined neural activation patterns associated with impaired pragmatic language comprehension in ASD, compared to typically developing children (TDC). MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) was applied to 15 children with ASD and 18 TDC using the Korean pragmatic language task. RESULTS: Children with ASD were less accurate than TDC at comprehending idioms, particularly when they were required to interpret idioms with mismatched images (mismatched condition). Children with ASD also showed different patterns of neural activity than TDC in all three conditions (neutral, matched, and mismatched). Specifically, children with ASD showed decreased activation in the right inferior frontal gyrus (IFG) (Brodmann area 47) in the mismatched condition, compared with TDC (IFG; t(31)=3.17, p<0.001). CONCLUSION: These results suggest that children with ASD face difficulties in comprehending pragmatic expressions and apply different pragmatic language processes at the neural level.

The Relationship between the SNAP-25 Polymorphism and Omission Errors in Korean Children with Attention Deficit Hyperactivity Disorder.

OBJECTIVE: This study aimed to investigate the association between the synaptosomal-associated protein 25 kDa (SNAP-25) genotype and performance on the continuous performance test (CPT) in Korean children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Eighty-seven children with ADHD (mean age, 9.23±1.99 years) participated in this study. Omission errors, commission errors, reaction time, and reaction time variability on the CPT were analyzed. The single-nucleotide polymorphism (SNP) rs3746544 (1065 T＞G) of SNAP-25 was genotyped to examine the association with CPT performance. RESULTS: We found significantly more omission errors on the CPT among children with the TT genotype of SNAP-25 (t=2.56, p=0.012) after correcting for multiple testing. CONCLUSION: Our results suggest the possible involvement of the SNAP-25 1065 T＞G polymorphism in the inattention phenotype in children with ADHD. Further studies with more refined neuropsychological measures and much larger sample sizes are needed to confirm our findings.

The effect of epilepsy on autistic symptom severity assessed by the social responsiveness scale in children with autism spectrum disorder.

BACKGROUND: As the prevalence of autism spectrum disorders in people with epilepsy ranges from 15 to 47 % (Clarke et al. in Epilepsia 46:1970-1977, 2005), it is speculated that there is a special relationship between the two disorders, yet there has been a lack of systematic studies comparing the behavioral phenotype between autistic individuals and autistic individuals with epilepsy. This study aims to investigate how the co-occurrence of epilepsy and Autism Spectrum Disorder (ASD) affects autistic characteristics assessed by the Social Responsiveness Scale (SRS), which has been used as a measure of autism symptoms in previous studies. In this research we referred to all individuals with Autism or Autistic Disorder as individuals with ASD. METHODS: We reviewed the complete medical records of 182 participants who presented to a single tertiary care referral center from January 1, 2013 to July 28, 2015, and subsequently received complete child and adolescent psychiatric assessments. Of the 182 participants, 22 were diagnosed with Autism Spectrum Disorder and epilepsy. Types of epilepsy observed in these individuals included complex partial seizure, generalized tonic-clonic seizure, or infantile spasm. Using 'Propensity Score Matching' we selected 44 children, diagnosed with only Autism Spectrum Disorder, whose age, gender, and intelligence quotient (IQ) were closely matched with the 22 children diagnosed with Autism Spectrum Disorder and epilepsy. Social functioning of participants was assessed by the social responsiveness scale, which consists of five categories: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. Bivariate analyses were conducted to compare the ASD participants with epilepsy group with the ASD-only group on demographic and clinical characteristics. Chi square and t test p values were calculated when appropriate. RESULTS: There was no significant difference in age (p = 0.172), gender (p > 0.999), IQ (FSIQ, p = 0.139; VIQ, p = 0.114; PIQ, p = 0.295) between the two groups. ASD participants with epilepsy were significantly more impaired than ASD participants on some measures of social functioning such as social awareness (p = 0.03) and social communication (p = 0.027). ASD participants with epilepsy also scored significantly higher on total SRS t-score than ASD participants (p = 0.023). CONCLUSIONS: Understanding the relationship between ASD and epilepsy is critical for appropriate management (e.g. social skills training, seizure control) of ASD participants with co-occurring epilepsy. Results of this study suggest that mechanisms involved in producing epilepsy may play a role in producing or augmenting autistic features such as poor social functioning. Prospective study with larger sample sizes is warranted to further explore this association.

Characteristics of Brains in Autism Spectrum Disorder: Structure, Function and Connectivity across the Lifespan.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by impaired social communication and restricted and repetitive behaviors (RRBs). Over the past decade, neuroimaging studies have provided considerable insights underlying neurobiological mechanisms of ASD. In this review, we introduce recent findings from brain imaging studies to characterize the brains of ASD across the human lifespan. Results of structural Magnetic Resonance Imaging (MRI) studies dealing with total brain volume, regional brain structure and cortical area are summarized. Using task-based functional MRI (fMRI), many studies have shown dysfunctional activation in critical areas of social communication and RRBs. We also describe several data to show abnormal connectivity in the ASD brains. Finally, we suggest the possible strategies to study ASD brains in the future.

Unique expression of a small IL-32 protein in the Jurkat leukemic T cell line.

Interleukin (IL)-32 was recently identified as a new cytokine which induces various proinflammatory cytokines in human monocytes and macrophages. Therefore, IL-32 has been primarily studied in inflammatory models such as rheumatoid arthritis and inflammatory bowel diseases. The regulation of endogenous IL-32 in other immune cells remains unknown. In the present study, we stimulated Jurkat T cells with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) and examined IL-32 expression at both the mRNA and protein levels. All mRNAs of the four IL-32 isoforms and the 12-15 kDa IL-32 protein were independent of PHA and PMA stimulation, however a 9 kDa molecular weight IL-32 protein in the cell culture supernatant was induced by PHA and PMA after 16 h of stimulation. Compared to other human cell lines, the Jurkat cell line constitutively expressed a 12-15 kDa molecule of IL-32, which is smaller than the known IL-32 isoforms. We used IL-32 shRNA to examine the specificity of the 12-15 kDa molecule. Upon IL-32 shRNA transfection, the 12-15 kDa band was decreased specifically as compared to the control scrambled clone. Thus, the constitutive expression of IL-32 mRNA as well as the predominant production of a smaller sized IL-32 isoform in Jurkat cells may implicate a role for IL-32 in human T cell leukemia.