1. Bao X, Zhou B, Wen M. Effects of Arginine Vasopressin on Hippocampal Myelination in an Autism Rat Model: A RNA-seq and Mendelian Randomization Analysis. Front Biosci (Landmark Ed). 2024; 29(11): 394.

BACKGROUND: To explore the therapeutic role of arginine vasopressin (AVP) and its possible mechanisms in autism. METHODS: Mid-trimester pregnant rats treated with valproate on embryonic day 12.5 and their offspring were selected as autism model. The autism rats were randomly assigned to autism group and AVP treatment group that given AVP by inhalation per day from postnatal days 21 to 42. The changes in social behavior and the hippocampus transcriptome were compared, and the hub genes were confirmed by quantitative real-time polymerase chain reaction (qPCR) and Mendelian randomization (MR). RESULTS: 403 genes were found to be differentially expressed in the autism model, with the majority of these genes being involved in oligodendrocyte development and myelination. Only 11 genes associated with myelination exhibited statistically significant alterations following AVP treatment when compared to the autism group. Gene set enrichment, expression patterns, and weighted gene co-expression network analysis (WGCNA) analysis consistently indicated that the biological processes of oligodendrocyte development and myelination were markedly enriched in the autism group and exhibited improvement following treatment. The variation trend of various nerve cells demonstrated a notable increase in the proportion of oligodendrocytes and oligodendrocyte precursor cells in the autism group, which subsequently exhibited a significant decline following treatment. Five hub genes (MBP, PLIP, CNP, GFAP, and TAOK1) were verified by qPCR. Finally, MR studies have confirmed a causal relationship between hippocampal myelination-related gene expression and the risk of autism. CONCLUSIONS: AVP could markedly enhance social interaction abilities in the autism rat model, possibly due to the significantly improved hippocampus oligodendrocytes development and myelination.

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2. De Grandi AJ, Newsom DH. How does an autism diagnosis impact a child and their carer in regional Australia?. J Paediatr Child Health. 2024.

AIM: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. This study aims to investigate the impact of an ASD diagnosis on children and their carers from a regional/rural Australian perspective. METHODS: A three-part survey development study included: (i) Semi-structured individual ASD carer interviews to identify common themes; (ii) survey development and testing; and (iii) online survey circulation to wider group of carers, for data collection and analysis. RESULTS: Transcripts from eight carer interviews guided the development of 65 survey questions. The survey was circulated to 316 carers of children diagnosed with ASD. Of the 101 respondents, 95% were female, 86% regional and 12% were rural inhabitants. The average child’s age at diagnosis was 6.64 years. Most carers (93%) reported that diagnosis of ASD met their goal, for some an improved understanding of their child’s behaviour (39%) and allowing access to therapy (16%), government disability funding (National Disability Insurance Scheme) (19%) and learning support (9%). Some (44%) reported no downsides to an ASD diagnosis; however, 38% reported fears of discrimination, particularly with future relationships (5%) and employment (14%). Barriers included waiting times (16%), costs of appointments (9.9%) and difficulty navigating through the health system (5.9%). Only five participants reported having no costs associated with appointments. CONCLUSIONS: Carers had positive attitudes and experiences regarding their child’s ASD diagnosis. The benefits outweighed the perceived harms. Barriers to accessing services included waiting times, out-of-pocket expenses and travel distance.

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3. Jiang J, Zhang L, Wu D, Zhao D, Ying S, Ding S. Lipopolysaccharide induces neuroinflammation in a valproic acid male model of autism. Brain Res Bull. 2024: 111154.

BACKGROUND: Autism spectrum disorders (ASD) are characterized by social skill deficits and behavior impairments. Exposure to valproic acid (VPA) has been linked to ASD in humans and ASD-like behaviors in rodents. Clinical evidence suggests that immunological damage can worsen ASD symptoms in humans. OBJECTIVE: This study aimed to investigate the potential of lipopolysaccharide (LPS) to induce neuroinflammation in a VPA-induced autism male model. MATERIALS: and methods: Pregnant Sprague Dawley rats were injected with 500mg/kg of VPA on gestational day 12.5 to create an ASD rat model in their offspring. Male offspring from VPA-injected group received 10mg/kg of LPS on postnatal day 20. Immunohistochemistry, western blotting, and immunofluorescence were used to assess the expression of NF-κB signaling pathway-related proteins and microglia in the prefrontal cortex and hippocampus. Gene Ontology and pathway enrichment analyses were conducted to predict the function of key synaptic proteins, which were further validated through real-time polymerase chain reaction analysis. RESULTS: The results showed that VPA exposure led to increased locomotor activity, social impairment, and repetitive behaviors in male rats. NF-κB signaling pathway-related proteins were upregulated, and microglial numbers were elevated in the VPA-induced group. Furthermore, synaptic dysfunction was observed in the brains of offspring exposed to VPA. Importantly, LPS administration exacerbated autism-related behaviors in VPA-exposed male rats by promoting NF-κB signaling pathway activation, increasing microglial numbers, and downregulating key synaptic proteins. CONCLUSIONS: This study not only contributed to understanding the importance of the NF-κB signaling pathway, microglia, and synaptic proteins in the progression of ASD, but also identified that LPS induces neuroinflammation in a valproic acid-induced male model of autism.

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4. Kılıçaslan F, Öz Ö, Mutlu MB. Investigation of chromosomal anomalies and copy number variations in children diagnosed with autism spectrum disorder by array CGH method. Int J Dev Neurosci. 2024.

This study aimed to identify the chromosomal anomalies and copy number variations (CNVs) in autism spectrum disorder (ASD) and to provide genotype/phenotype correlations. Fifty-four patients diagnosed with ASD between March 2021 and June 2022 were included in the study. Patients were evaluated by cytogenetic analysis and array comparative genomic hybridisation analysis (aCGH). The structural and numerical chromosomal anomaly was detected in 3.7%, and the CNVs were identified in 18.52% of patients. Of the CNVs detected, 27.3% were identified as pathogenic, 18.2% as likely pathogenic and 54.5% as VUS. The copy number gain rate of the detected CNVs was higher than the copy number losses rate, 70% and 30% respectively. As an important finding in the study, a new pathogenic CNV with a 6.3-mb copy number gain in the 3p22.3p22.2 region, whose gene region had not been previously defined in OMIM, was detected. Identifying a genetic aetiology may provide clinicians with more information about disease prognosis and risk of recurrence.

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5. Kou R, Li Z, Li M, Zhou R, Zhu F, Ruan W, Zhang J. Comparative effectiveness of physical exercise interventions on sociability and communication in children and adolescents with autism: a systematic review and network meta-analysis. BMC Psychol. 2024; 12(1): 712.

OBJECTIVE: To investigate the efficacy of physical activity as a crucial intervention for Autism spectrum disorder (ASD) in clinical settings, we conducted a network meta-analysis to evaluate the effect of various exercise interventions on sociability and communication in individuals with ASD. Our aim was to identify the exercise modalities most conducive to enhancing these essential skills. METHODS: We searched Web of Science, PubMed, Cochrane Library, Scopus, Embase, and searched Chinese databases from inception to April 2024. We included randomized controlled trials that assessed the effects of different exercise types on sociability and communication in individuals with ASD. Network meta-analysis (NMA) was performed using a frequentist approach, and the node-splitting method was applied to assess inconsistency. RESULTS: We included 38 original studies published between 2009 and 2024, with a total of 1,382 participants analyzed for sociability outcomes. Results indicated that sports games [SMD = 1.12, 95%CI (0.51, 1.73)], combination therapy [SMD = 1.11, 95%CI (0.13, 2.09)], group ball sports [SMD = 1.06, 95%CI (0.37, 1.75)], and outdoor exercise [SMD = 1.02, 95%CI (0.50, 1.55)] were more effective than passive controls. A total of 25 original literatures were included in the analysis of communication ability, involving 904 subjects, and the results showed that combination therapy [SMD = 1.57, 95% CI (0.74, 2.40)], sports games [SMD = 1.01, 95% CI (0.45, 1.56)], group ball games [SMD = 0.85, 95% CI (0.45, 1.26)], outdoor exercise [SMD = 0.79, 95% CI (0.48, 1.11)], and mind-body exercise [SMD = 0.79, 95% CI (0.29, 1.30)], all of which were more effective than passive controls. CONCLUSION: Physical exercise plays a significant role in alleviating symptoms and enhancing sociability and communication in individuals with ASD. Our findings highlight that sports games, combination therapy, team ball sports, and outdoor exercise are particularly effective in improving sociability. In terms of communication skills, combination therapy, sports games, team ball sports, outdoor exercise, and mind-body exercise demonstrated the most substantial benefits. These results provide a robust foundation for future interventions aimed at improving the quality of life for individuals with ASD.

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6. Oh M, Yoon NH, Kim SA, Yoo HJ. Epigenetic Insights into Autism Spectrum Disorder: DNA Methylation Levels of NR3C1, ASCL1, and FOXO3 in Korean Autism Spectrum Disorder Sibling Pairs. Clin Psychopharmacol Neurosci. 2024; 22(4): 635-45.

OBJECTIVE: Previous research on autism spectrum disorder (ASD) in Koreans has primarily focused on genetic diversity because of its high heritability. However, the emerging recognition of transgenerational epigenetic changes has recently shifted research attention towards epigenetic perspectives. METHODS: This study investigated the DNA methylation patterns of the promoter regions of candidate genes such as NR3C1, ASCL1, and FOXO3 in blood samples from ASD probands and their unaffected siblings. The analysis included 54 families (ASD proband group: 54; unaffected biological sibling group: 63). The diagnostic process involved screening the probands and their siblings for ASD based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition. Intelligence, social ability, and medical history were thoroughly assessed using various scales and questionnaires. Genomic DNA from blood samples was analyzed using a methylation-sensitive quantitative polymerase chain reaction to examine the DNA methylation status of candidate genes. RESULTS: Methylation levels in candidate gene promoter regions differed significantly between the proband and sibling groups for all candidate genes. Correlation analysis between the proband and sibling groups revealed strong and significant correlations in NR3C1 and ASCL1 methylation. Additionally, in the analysis of the relationship between DNA and ASD phenotypes, FOXO3 methylation correlated with social quotient in probands, and ASCL1 methylation was associated with nonverbal communication, and daily living skills as measured by the Korean Vineland Adaptive Behavior Scale. Notably, ASCL1 methylation was significantly associated with parental age at pregnancy. CONCLUSION: This study proposes DNA methylation of NR3C1, ASCL1, and FOXO3 in peripheral blood samples is a potential epigenetic biomarker of ASD.

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7. Poupard L, Page G, Thoreau V, Kaouah Z. Relationships between Gut Microbiota and Autism Spectrum Disorders: Development and Treatment. Clin Psychopharmacol Neurosci. 2024; 22(4): 554-64.

Many studies have demonstrated the impact of intestinal microbiota on normal brain development. Moreover, the gut microbiota (GM) is impacted by multiple endogenous and environmental factors that may promote gut dysbiosis (GD). An increasing number of studies are investigating the possible role of the GD in the development of neurological and behavioral disorders. For autism spectrum disorders (ASD), specific intestinal bacterial signatures have been identified, knowing that gastrointestinal symptoms are frequently found in ASD. In this review, the peri and post-natal factors modulating the GM are described and the specific gut bacterial signature of ASD children is detailed. Through bidirectional communication between the GM and the brain, several mechanisms are involved in the development of ASD, such as cytokine-mediated neuroinflammation and decreased production of neuroprotective factors such as short-chain fatty acids by the GM. Imbalance of certain neurotransmitters such as serotonin or gamma-aminobutyric acid could also play a role in these gut-brain interactions. Some studies show that this GD in ASD is partly reversible by treatment with pre- and probiotics, or fecal microbiota transplantation with promising results. However, certain limitations have been raised, in particular concerning the short duration of treatment, the small sample sizes and the diversity of protocols. The development of standardized therapeutics acting on GD in large cohort could rescue the gastrointestinal symptoms and behavioral impairments, as well as patient management.

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8. Qiu Z, Du A. Revisiting the genetic architecture of autism spectrum disorders in the genomic era: Insights from East Asian studies. Curr Opin Neurobiol. 2024; 90: 102936.

This review delves into the genetic landscape of Autism Spectrum Disorder (ASD) in the genomic era, with a special focus on insights from East Asian populations. We analyze a spectrum of genetic research, including whole-exome and whole-genome sequencing, to elucidate both the challenges and advancements in comprehending the genetic foundations of ASD. Critical findings from this review highlight the identification of de novo variants, particularly noting the significant role of rare variants that differ from the common variants identified in earlier research. The review emphasizes the importance of large, diverse, and meticulously maintained ASD cohorts, which are essential for advancing genetic studies and developing potential therapeutic interventions. Through collaborative international efforts, we argue for a global perspective necessary to grasp the intricate genetic factors underlying ASD.

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9. Sun X, Zhang P, Cheng S, Wang X, Deng J, Zhan Y, Jianqiang C. The value of hippocampal sub-region imaging features for the diagnosis and severity grading of ASD in children. Brain Res. 2024: 149369.

BACKGROUND: Hippocampal structural changes in Autism Spectrum Disorder (ASD) are inconsistent. This study investigates hippocampal subregion changes in ASD patients to reveal intrinsic hippocampal anomalies. METHODS: A retrospective study from Hainan Children’s Hospital database (2020-2023) included ASD patients and matched controls. We classified ASD participants based on severity, dividing all subjects into four groups: normal, mild, moderate, and severe. High-resolution T1-weighted MRI images were analyzed for hippocampal subregion segmentation and volume calculations using Freesurfer. Texture features were extracted via the Gray-Level Co-occurrence Matrix. The Receiver Operating Characteristic curve was used to evaluate seven random forest predictive models constructed from volume, subregion, and texture features, as well as their combinations following feature selection. RESULTS: The study included 114 ASD patients (98 boys, 2-8 years; 16 girls, 2-6 years; 17 mild, 57 moderate, 40 severe) and 111 healthy controls (HCs). No significant differences in volumes were found between ASD patients and HCs (adjusted P-value >0.05). The seven random forest models showed that single volume and texture features performed poorly for ASD classification; however, integrating various feature types improved AUC values. Further selection of texture, subregion, and volume features enhanced AUC performance across normal and varying severity categories, demonstrating the potential value of specific subregions and integrated features in ASD diagnosis. CONCLUSION: Random forest models revealed that hippocampal volume, texture features, and subregion characteristics are crucial for diagnosing and assessing the severity of ASD. Integrating selected texture and subregion features optimized diagnostic efficacy, while combining texture, subregion, and volume features further improved severity grading effectiveness.

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10. Trancuccio A, Tarifa C, Bongianino R, Priori SG, Santiago DJ. A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome. Sci Rep. 2024; 14(1): 29792.

Timothy syndrome type 1 (TS1), a malignant variant of Long QT Syndrome, is caused by L-type Ca2+ Channel (LTCC) inactivation defects secondary to the p.Gly406Arg mutation in the CACNA1C gene. Leveraging on the experimental in vitro data from our TS1 knock-in swine model and their wild-type (WT) littermates, we first developed a mathematical model of WT large white swine ventricular cardiomyocyte electrophysiology that reproduces a wide range of experimental data, including ionic current properties, action potential (AP) dynamics, and Ca2+ handling. A sensitivity analysis tested robustness and facilitated comparison with the parent ORd human model. Introducing 22% of TS1-mutated LTCCs, the model faithfully reproduced key disease features, including marked AP prolongation, steeper rate-dependent adaptation of AP duration, Ca2+ overload, and CaMKII-mediated decreased upstroke velocity. Translational relevance of the TS1 model was investigated by: dissecting the roles of primary and secondary contributors to TS1 phenotype; demonstrating the arrhythmogenic potential of TS1 vs. WT cells; and evaluating the model’s capability to identify novel pharmacological targets which could modulate the cellular phenotype. In conclusion, we developed a mathematical large white swine ventricular myocyte model, demonstrating its utility in exploring arrhythmogenic mechanisms and therapeutic interventions in cardiac diseases, such as TS1.

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11. Zukerman G, Tikochinsky S, Yahav G, Ben-Itzchak E. Distinguishing autism spectrum disorder and social anxiety: Exploring adaptive skills among university students. Psychiatry Res. 2024; 343: 116304.

High comorbidity and diagnostic overlap between autism spectrum disorder and social anxiety disorder have been documented. We examined if differences in adaptive behavior, essential for daily functioning, could differentiate these conditions among young university students. Eighty-eight autistic and 123 non-autistic undergraduates were categorized into four groups: autistic individuals: with low (n = 26)/high (n = 62) social anxiety (SA) symptoms; non-autistic: with low (n = 63)/high (n = 60) SA. The Adaptive Behavior Assessment System (ABAS) was utilized to assess three domains of adaptive skills essential for daily functioning: conceptual (academic and communication abilities), social (relationships and understanding social cues), and practical (everyday tasks such as self-care and work). Autistic students, regardless of SA level, reported ABAS scores within the low average range for the conceptual adaptive behavior domain, while non-autistic students had average scores. In terms of ABAS social adaptive behavior scores, both autistic and non-autistic groups with high levels of SA had low average scores. Conversely, those with low SA, whether autistic or non-autistic, exhibited average scores. These results were supported by the regression analyses outcomes. While autism traits and social anxiety showed medium (β=-0.37) and small (β=-0.27) effects, respectively, on conceptual adaptive scores, only social anxiety exhibited significant (medium) effects on social (β=-0.41) and practical (β=-0.34) adaptive scores. Reduced conceptual skills, previously linked to communication and executive function, may distinguish autism from social anxiety. Implications for research and practice are discussed.

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