1. Li YQ, Sun YH, Liang YP, Zhou F, Yang J, Jin SL. Effect of probiotics combined with applied behavior analysis in the treatment of children with autism spectrum disorder: a prospective randomized controlled trial. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2021; 23(11): 1103-10.

OBJECTIVES: To study the effect of probiotics combined with applied behavior analysis (ABA) in the treatment of children with autism spectrum disorder (ASD). METHODS: A total of 41 children with ASD who attended the Affiliated Hospital of Jiangsu University from May 2019 to December 2020 were enrolled and randomly divided into an observation group with 21 children and a control group with 20 children. The children in the observation group were given oral probiotics combined with ABA intervention, while those in the control group were given ABA intervention alone. The treatment outcomes were compared between the two groups. Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the severity of behavioral symptoms in both groups before intervention and at 3 months after intervention. The fecal samples were collected to analyze the difference in intestinal flora between the two groups based on 16s rRNA high-throughput sequencing. RESULTS: Before intervention, there was no significant difference in the ATEC score between the observation and control groups (P>0.05). At 3 months after intervention, both groups had a significant reduction in the ATEC score, and the observation group had a significantly lower ATEC score than the control group (P<0.05). Before intervention, there was no significant difference in the composition of intestinal flora between the observation and control groups. At 3 months after intervention, there was a significant difference in the composition of intestinal flora between the observation and control groups. Compared with the control group, the observation group had significantly higher relative abundances of Bifidobacterium, Lactobacillus, Coprobacillus, Ruminococcus, Prevotella, and Blautia (P<0.05) and significantly lower relative abundances of Shigella and Clostridium (P<0.05). CONCLUSIONS: Probiotics may improve the effect of conventional ABA intervention in children with ASD by regulating intestinal flora. OBJECTIVE: To study the effect of probiotics combined with applied behavior analysis (ABA) in the treatment of children with autism spectrum disorder (ASD). METHODS: A total of 41 children with ASD who attended the Affiliated Hospital of Jiangsu University from May 2019 to December 2020 were enrolled and randomly divided into an observation group with 21 children and a control group with 20 children. The children in the observation group were given oral probiotics combined with ABA intervention, while those in the control group were given ABA intervention alone. The treatment outcomes were compared between the two groups. Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the severity of behavioral symptoms in both groups before intervention and at 3 months after intervention. The fecal samples were collected to analyze the difference in intestinal flora between the two groups based on 16s rRNA high-throughput sequencing. RESULTS: Before intervention, there was no significant difference in the ATEC score between the observation and control groups (P>0.05). At 3 months after intervention, both groups had a significant reduction in the ATEC score, and the observation group had a significantly lower ATEC score than the control group (P<0.05). Before intervention, there was no significant difference in the composition of intestinal flora between the observation and control groups. At 3 months after intervention, there was a significant difference in the composition of intestinal flora between the observation and control groups. Compared with the control group, the observation group had significantly higher relative abundances of Bifidobacterium, Lactobacillus, Coprobacillus, Ruminococcus, Prevotella, and Blautia (P<0.05) and significantly lower relative abundances of Shigella and Clostridium (P<0.05). CONCLUSIONS: Probiotics may improve the effect of conventional ABA intervention in children with ASD by regulating intestinal flora. eng.

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2. Li Z, Zhu YX, Gu LJ, Cheng Y. Understanding autism spectrum disorders with animal models: applications, insights, and perspectives. Zoological research. 2021; 42(6): 800-24.

Autism spectrum disorder (ASD) is typically characterized by common deficits in social skills and repetitive/stereotyped behaviors. It is widely accepted that genetic and environmental factors solely or in combination cause ASD. However, the underlying pathogenic mechanism is unclear due to its highly heterogeneous nature. To better understand the pathogenesis of ASD, various animal models have been generated, which can be generally divided into genetic, environment-induced, and idiopathic animal models. In this review, we summarize the common animals used for ASD study and then discuss the applications, clinical insights, as well as challenges and prospects of current ASD animal models.

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3. Maddirevula S, Alameer S, Ewida N, de Sousa MML, Bjørås M, Vågbø CB, Alkuraya FS. Insight into ALKBH8-related intellectual developmental disability based on the first pathogenic missense variant. Human genetics. 2022; 141(2): 209-15.

ALKBH8 is a methyltransferase that modifies tRNAs by methylating the anticodon wobble uridine residue. The syndrome of ALKBH8-related intellectual developmental disability (MRT71) has thus far been reported solely in the context of homozygous truncating variants that cluster in the last exon. This raises interesting questions about the disease mechanism, because these variants are predicted to escape nonsense mediated decay and yet they appear to be loss of function. Furthermore, the limited class of reported variants complicates the future interpretation of missense variants in ALKBH8. Here, we report a consanguineous family in which two children with MRT71-compatible phenotype are homozygous for a novel missense variant in the methyltransferase domain. We confirm the pathogenicity of this variant by demonstrating complete absence of ALKBH8-dependent modifications in patient cells. Targeted proteomics analysis of ALKBH8 indicates that the variant does not lead to loss of ALKBH8 protein expression. This report adds to the clinical delineation of MRT71, confirms loss of function of ALKBH8 as the disease mechanism and expands the repertoire of its molecular lesions.

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4. Paterno R, Marafiga JR, Ramsay H, Li T, Salvati KA, Baraban SC. Hippocampal gamma and sharp-wave ripple oscillations are altered in a Cntnap2 mouse model of autism spectrum disorder. Cell reports. 2021; 37(6): 109970.

Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2(-/-) mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target.

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5. Pouchelon G, Dwivedi D, Bollmann Y, Agba CK, Xu Q, Mirow AMC, Kim S, Qiu Y, Sevier E, Ritola KD, Cossart R, Fishell G. The organization and development of cortical interneuron presynaptic circuits are area specific. Cell reports. 2021; 37(6): 109993.

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

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6. Roording-Ragetlie S, Spaltman M, de Groot E, Klip H, Buitelaar J, Slaats-Willemse D. Working memory training in children with borderline intellectual functioning and neuropsychiatric disorders: a triple-blind randomised controlled trial. Journal of intellectual disability research : JIDR. 2022; 66(1-2): 178-94.

BACKGROUND: Poor working memory, lower IQ and maladaptive behaviour form a triple disability known to have negative effects on the academic and social development of children with borderline intellectual functioning (BIF; IQ: 70 < IQ < 85) and neuropsychiatric disorders [attention-deficit hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD)]. Treatment possibilities for these children are scarce and hardly evidence based. This study primarily investigated whether adaptive computerised working memory training (WMT) may lead to significantly more improvement on a non-trained visuospatial WM task compared with a non-adaptive control WMT (placebo) in children with BIF and neuropsychiatric disorders. As secondary outcome measures, we used the scores on several non-trained neuropsychological near-transfer and far-transfer tasks as well as behavioural measures. METHOD: We conducted a triple-blind placebo-controlled randomised clinical trial in 72 children (aged 10;0-13;11 years, 53 boys, 19 girls) with BIF and comorbid neuropsychiatric disorders (ADHD = 37, ASD = 21, both = 14) that were referred to child and adolescent psychiatry care, between May 2012 and March 2019. Children completed the Dutch version of Cogmed WMT, either the adaptive training version or the non-adaptive placebo version, 25 sessions (30-45 min a day), for 5 weeks. The primary outcome measure was the score on a non-trained visuospatial working memory task. The primary outcome was measured before and directly after 5 weeks of WMT and again 6 months after training. RESULTS: A total of 375 children were screened for eligibility and 72 were randomised. No significantly higher levels of improvement over time were found on our primary outcome measure in the experimental WMT group compared with the placebo control WMT, nor in the secondary (near-transfer and far-transfer tasks) or tertiary (behavioural measures) outcome measures. However, this study did show changes over time for these measurements for both the experimental and placebo conditions. CONCLUSIONS: This study was unable to document superior training effects over time of an adaptive WMT in children with BIF and neuropsychiatric disorders, compared with a placebo (non-adaptive) WMT. The objectively documented changes over time in the non-adaptive WMT arm suggest that these children with persistent impairments in WM may benefit from a structured learning environment that is associated with improvement of neurocognitive functioning and coping strategies. Further research is needed to examine which elements of cognitive training may be useful for which specific patients and to study long-term effects of training.

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