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1.
Mol Psychiatry ; 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38438524

ABSTRACT

CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.

2.
JA Clin Rep ; 8(1): 36, 2022 May 24.
Article in English | MEDLINE | ID: mdl-35606669

ABSTRACT

BACKGROUND: The use of pressure-controlled ventilation (PCV) during one lung ventilation (OLV) has been popular to avoid high airway pressure. We experienced a case of a significant reduction of tidal volume (TV) after commencement of chest tube drainage under PCV following lower lobectomy, which required re-thoracotomy to evaluate the degree of air leak. CASE PRESENTATION: A 70-year-old man was scheduled for a lower lobectomy. OLV was managed by PCV. The driving pressure was set at 15-20 cmH2O with 4 cmH2O of positive end-expiratory pressure (PEEP). A chest drainage tube was placed after completion of lobectomy. To switch OLV to two lung ventilation (TLV), PCV settings were changed to the driving pressure at 10 cmH2O with 4 cmH2O of PEEP, which generated 450 ml of TV. Immediately after applying drainage (-10 cmH2O), TV decreased down to 250 ml. To maintain 450 ml of TV, PCV was switched to volume-controlled ventilation with 450 ml of TV, which raised the plateau pressure close to 24 cmH2O. Re-thoracotomy was done; however, significant findings were not detected. CONCLUSIONS: We experienced a case of a significant reduction of TV immediately after chest tube drainage following lower lobectomy. Probably, negative intrapleural pressure increased the residual volume, which might have significantly affected the limited lung volume after lobectomy, resulting in decreasing TV during PCV.

3.
Cell Rep ; 23(7): 1988-2000, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29768199

ABSTRACT

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein ß (C/EBPß) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPß regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.


Subject(s)
Adipogenesis , Autistic Disorder/metabolism , CCAAT-Enhancer-Binding Protein-beta/metabolism , DNA-Binding Proteins/metabolism , 3T3-L1 Cells , Adipocytes/metabolism , Adipocytes/pathology , Adipogenesis/genetics , Adipose Tissue, White/pathology , Animals , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Gene Expression Regulation , Genome , HEK293 Cells , Humans , Hypertrophy , Mice , Mice, Inbred C57BL , PPAR gamma/metabolism , Protein Binding
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