Objective To investigate the protective effect of inhibition of adenosine monophosphate activated protein kinase (AMPK) on blood brain barrier (BBB) and its mechanism in hypoxic/ischemic models.Methods Two hundred healthy male SD rats were randomly divided into sham-operated group,model group (ischemia 2 h-reperfusion 0,24 and 72 h [I/R]),and Compound C treated group (giving intraperitoneal injection of 20 mg/kg AMPK specific inhibitor Compound C).Focal cerebral ischemia rat models were established by occluding the middle cerebral artery (MCAO).Neurological deficit was determined by Zea Longa test,infarct size and brain water content were measured by TTC staining,leakage of BBB was determined by Evans blue (EB) staining.Expressions of matrix metalloproteinase (MMP)-2/MMP-9 and nuclear factor (NF)-κB,and release of inflammatory factors were detected by Western blotting.Results As compared with those in the model group,significantly reduced neurological deficit scores in Compound C treated group were noted at I/R 0,24 and 72 h (P＜0.05).After I/R 72 h,Compound C treated group had significantly reduced brain infarct size,brain water content and EB leakage as compared with model group (P＜0.05).The expressions of MMP2/MMP9 in model group (52.58±8.12 and 33.15±6.45) were significantly higher than those in the Compound C treated group (21.20±3.39 and 15.46±4.71,P＜0.05).What is more,as compared with the model group,Compound C treated group had significantly reduced expressions of NF-κB and inflammatory factors (P＜0.05).Conclusions Inhibition of AMPK shows a protective role in BBB after ischemic injury,mainly by inhibiting NF-κB signaling pathway,inhibiting the expression of MMP-2/MMP-9 to reduce the degradation of the base metal film,and maintain the integrity of BBB,thus,improving the ischemic symptoms,reducing the brain water content and reducing infarct size.

OBJECTIVE: To analyze the pathogenic variants of the KIF1A gene and its corresponding protein structure in an autism spectrum disorder (ASD) family trio carrying harmful missense variants in the KIF1A gene. METHODS: The peripheral blood DNA of the patient and his parents was extracted and sequenced using whole exome sequencing (WES) technology and verified by Sanger sequencing. Bioinformatics software SIFT, PolyPhen-2, Mutation Taster, and CADD software were used to analyze the harmfulness and conservation of variants. The Human Brain Transcriptome (HBT) database was used to analyze the expression of the KIF1A gene in the brain. PredictProtein and SWISS-MODEL were further used to predict the secondary structure and tertiary structure of KIF1A wild-type protein and variant protein. PyMOL V2.4 was utilized to investigate the change of hydrogen bond connection after protein variant. RESULTS: The WES sequencing revealed a missense variant c.664A>C (p.Asn222His) in the child's KIF1A gene, and this variant was a de novo variant. The harmfulness prediction results suggest that this variant is harmful. By analyzing expression level of KIF1A gene in the brain. It is found that KIF1A gene widely expressed in various brain regions during embryonic development. By analyzing the variant protein structure, the missense variant of KIF1A will cause many changes in the secondary structure of protein, such as alpha-helix, beta-strand, and protein binding domain. The connection of hydrogen bond and spatial structure will also change, thereby changing the original biological function. CONCLUSION The KIF1A gene may be a risk gene for ASD.
Autism Spectrum Disorder/genetics* ; Child ; Female ; Humans ; Kinesin/genetics* ; Mutation ; Mutation, Missense ; Pregnancy ; Protein Domains ; Whole Exome Sequencing

OBJECTIVE: To carry out genetic testing for a patient with 45,X/46,XY mosaicism and autism spectrum disorder (ASD). METHODS: Peripheral blood samples of the patient and his parents were collected for the extraction of genomic DNA. Trio-based whole exome sequencing and Sanger sequencing were carried out thereafter. RESULTS: The proband and his father were found to harbor a heterozygous c.4781G>A (p.Arg1594Gln) variant of the CACNA1I gene. In addition, the proband was also found to harbor a de novo c.268C>T (p.Arg90Trp) missense variant of the MTRR gene. Based on guidelines of the American College of Medical Genetics and Genomics (ACMG), the c.4781G>A (p.Arg1594Gln) variant of the CACNA1I gene was predicted to be pathogenic (PVS1, PM1, PM2, PP3), while the c.268C>T (p.Arg90Trp) variant of the MTRR gene was predicted to be of uncertain significance. CONCLUSION Variants of the CACNA1I and MTRR genes, together with the chromosomal mosaicism, may have predisposed to the susceptibility to the ASD in this patient.
Autism Spectrum Disorder/genetics* ; Genomics ; Heterozygote ; Humans ; Mosaicism ; Whole Exome Sequencing

BackgroundComorbid attention-deficit/hyperactivity disorder （ADHD） and emotional dysregulation may represent a distinct subtype of ADHD， which is characterized by an increased risk of anxiety or depressive disorder and a poor clinical prognosis， so research is urgently required to explore its unique executive functioning profile and clinical characteristics. However， there is limited research comparing the clinical symptoms and executive function in children with ADHD in terms of the presence or absence of emotional dysregulation. ObjectiveTo explore the executive function and clinical characteristics of ADHD children with emotional dysregulation. MethodsFrom June 2020 to December 2023， 118 children aged 7 to 12 with ADHD attending the Mental Health Center of West China Hospital， Sichuan University and fulfilling the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） diagnostic criteria were enrolled. Children were classified into emotional dysregulation group （n=68） and non-emotional dysregulation group （n=50） based on the standard T-scores of Achenbach's Child Behavior Checklist （CBCL）- anxious/depressed， aggressive behavior and attention problems subscales. All children were then subjected to complete the Chinese version of Swanson Nolan and Pelham，Version IV Scale-parent form （SNAP-IV）， Chinese Wechsler Intelligence Scale for Children （C-WISC）， Weiss Functional Impairment Scale-Parent form （WFIRS-P） and 4 tests of the Cambridge Neuropsychological Test Automated Battery （CANTAB）： ①Stockings of Cambridge （SOC） testing spatial planning. ②Intradimensional-extradimensional Set Shifting（IED） testing cognitive/attentional flexibility， adjusting the total errors across the task. ③Spatial Working Memory （SWM） testing spatial working memory. ④Rapid Visual Information Processing （RVP） testing sustained attention. ResultsThe SNAP-IV Inattention， Hyperactivity/Impulsivity and Oppositional Defiant Disorder domain scores and total score were all higher in emotional dysregulation group compared with non-emotional dysregulation group （t=3.206， 5.088， 6.316， 6.553， P<0.01）. The WFIRS-P family， school learning， life skills， self-concept， social activities and risky activities domain scores and total score were all higher in emotional dysregulation group compared with non-emotional dysregulation group （t=6.074， 4.406， 4.143， 3.984， 6.575， 6.662， 8.254， P<0.01）. In CANTAB， emotional dysregulation group made more total adjusted errors across the IED task compared with non-emotional dysregulation group （t=2.168， P<0.05）. ConclusionChildren with ADHD who exhibit emotional dysregulation have been observed to experience more severe core symptoms， impaired social functioning and poorer performance on tests assessing executive function， particularly in the area of cognitive flexibility. ［Funded by 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project， West China Hospital， Sichuan University （number， 2018HXFH045）]