Publications by authors named "Xiu Xu"

119 Publications

Deleterious Variation in BR Serine/Threonine Kinase 2 Classified a Subtype of Autism.

Front Mol Neurosci 2022 10;15:904935. Epub 2022 Jun 10.

Division of Child Health Care, National Children' Medical Center, Children's Hospital of Fudan University, Shanghai, China.

Recently, deleterious variants in the BR serine/threonine kinase 2 () gene have been reported in patients with autism spectrum disorder (ASD), suggesting that is a new high-confidence ASD risk gene, which presents an opportunity to understand the underlying neuropathological mechanisms of ASD. In this study, we performed clinical and neurobehavioral evaluations of a proband with a non-sense variant in (p.R222X) with other reported mutant patients. To validate as an ASD risk gene, we generated a novel -deficient zebrafish line through CRISPR/Cas9 and characterized its morphological and neurobehavioral features as well as performed molecular analysis of neurogenesis-related markers. The proband displayed typical ASD behaviors and language and motor delay, which were similar to other published mutant patients. Morphologically, larvae exhibited a higher embryonic mortality and rate of pericardium edema, severe developmental delay, and depigmentation as well as growth retardation in the early developmental stage. Behaviorally, zebrafish displayed significantly decreased activity in open field tests and enhanced anxiety levels in light/dark tests and thigmotaxis analysis. Specifically, zebrafish showed a prominent reduction of social interaction with peers and disrupted social cohesion among homogeneous groups. Molecularly, the mRNA expression levels of (a postsynaptic density scaffolding protein), and , and (molecular markers of oligodendrocytes and myelination) were increased in the brain tissues of adult zebrafish, while the expression level of , a marker of motor neurons, was decreased. Taken together, for the first time, we established a novel -deficient zebrafish model that showed prominent ASD-like behaviors. In addition, the disturbed mRNA expression levels of neurogenesis-related markers implied that the processes of postsynaptic signaling as well as oligodendrocytes and myelination may be involved. This discovery may suggest a path for further research to identify the underlying neuropathological mechanisms between and ASD.
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http://dx.doi.org/10.3389/fnmol.2022.904935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9231588PMC
June 2022

TEMPO-Promoted Mono- and Bisimidation of Tertiary Anilines: Synthesis of Symmetric and Unsymmetric -Mannich Bases.

J Org Chem 2022 Jun 24. Epub 2022 Jun 24.

School of Chemistry and Chemical Engineering, Xinjiang Normal University, Urumqi, Xinjiang 830054, P. R. of China.

A TEMPO-promoted method was developed for the synthesis of symmetric bis--Mannich bases via sequential activation of two α,α'-amino C(sp)-H bonds of ,-dimethylanilines under mild conditions. This methodology was further extended for monoimidation of α-amino-functionalized methylanilines to give unsymmetric -Mannich bases in good to high yields. Several control experiments were performed, and the coupling reaction outcomes indicated that the oxoammonium (TEMPO) species is involved in the reaction.
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http://dx.doi.org/10.1021/acs.joc.2c00700DOI Listing
June 2022

Clinical Targeted Panel Sequencing Analysis in Clinical Evaluation of Children with Autism Spectrum Disorder in China.

Genes (Basel) 2022 Jun 2;13(6). Epub 2022 Jun 2.

Department of Child Health Care, Children's Hospital of Fudan University, Shanghai 201102, China.

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder in which genetics play a major role. Molecular diagnosis may lead to a more accurate prognosis, improved clinical management, and potential treatment of the condition. Both copy number variations (CNVs) and single nucleotide variations (SNVs) have been reported to contribute to the genetic etiology of ASD. The effectiveness and validity of clinical targeted panel sequencing (CTPS) designed to analyze both CNVs and SNVs can be evaluated in different ASD cohorts. CTPS was performed on 573 patients with the diagnosis of ASD. Medical records of positive CTPS cases were further reviewed and analyzed. Additional medical examinations were performed for a group of selective cases. Positive molecular findings were confirmed by orthogonal methods. The overall positive rate was 19.16% (109/569) in our cohort. About 13.89% (79/569) and 4.40% (25/569) of cases had SNVs only and CNVs only findings, respectively, while 0.9% (5/569) of cases had both SNV and CNV findings. For cases with SNVs findings, the gene has the greatest number of reportable variants, followed by gene . Patients with variants share common and specific clinical characteristics. We found a child with compound heterozygous variants had an enlarged vestibular aqueduct syndrome and autistic phenotype. Our results showed that CTPS is an effective molecular diagnostic tool for ASD. Thorough clinical and genetic evaluation of ASD can lead to more accurate diagnosis and better management of the condition.
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http://dx.doi.org/10.3390/genes13061010DOI Listing
June 2022

Screening for Autism Spectrum Disorder in Toddlers During the 18- and 24-Month Well-Child Visits.

Front Psychiatry 2022 26;13:879625. Epub 2022 Apr 26.

Department of Child Healthcare, Children's Hospital of Fudan University, Shanghai, China.

Objective: Early screening contributes to the early detection of children with autism spectrum disorder (ASD). We conducted a longitudinal ASD screening study in a large community setting. The study was designed to investigate the diagnostic rate of ASD screening and determine the effectiveness of ASD screening model in a community-based sample.

Methods: We enrolled children who attended 18- and 24-month well-child care visits in Shanghai Xuhui District. Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F) and Binomial Observation Test (BOT) were selected as screening instruments. Screen-positive children were referred to a tertiary diagnostic center for comprehensive ASD diagnostic evaluation. Screen-negative children received well-child checkups and follow-up every 3-6 months until age three and were referred if they were suspected of having ASD.

Results: A total of 11,190 toddlers were screened, and 36 screen-positive toddlers were diagnosed with ASD. The mean age at diagnosis for these children was 23.1 ± 4.55 months, diagnosed 20 months earlier than ASD children not screened. The diagnostic rate of ASD was 0.32% (95% CI: 0.23-0.45%) in this community-based sample. In addition, 12 screen-negative children were diagnosed with ASD during subsequent well-child visit and follow-up. The average diagnostic rate of ASD rose to 0.43% (95% CI: 0.32-0.57%) when toddlers were followed up to 3 years old. The positive predictive values (PPVs) of M-CHAT-R/F, M-CHAT-R high risk, and BOT for ASD were 0.31, 0.43, and 0.38 respectively.

Conclusion: Our findings provide reliable data for estimating the rate of ASD detection and identifying the validity of community-based screening model. M-CHAT-R/F combined with BOT can be an effective tool for early detection of ASD. This community-based screening model is worth replicating.
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http://dx.doi.org/10.3389/fpsyt.2022.879625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097214PMC
April 2022

Adaptive Immune Deficiency Impairs Neural Activity After Training and Retrieval.

Front Neurosci 2021 15;15:739580. Epub 2021 Nov 15.

Department of Child Health Care, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Neuroimmune interactions have been studied for decades. Several neurodevelopmental disorders have been associated with immune dysfunction. However, the effects of immune system on neuronal function remain unknown. Herein, based on c-Fos protein expression, we characterized the brain areas that are activated after contextual fear conditioning (CFC) training or retrieval in severe combined immune deficiency (SCID) and wild-type mice. Further, we analyzed the interregional correlations of c-Fos activity that are affected by deficiency in adaptive immunity. Results showed significantly lower c-Fos density in learning and memory-associated brain regions of SCID mice after memory retrieval, but not during the CFC training. Moreover, SCID mice exhibited remarkably discordant interregional neuronal activities of learning neuron circuits after CFC training, which could be the cause of inefficient activation of the memory circuit after retrieval. These results provide a new perspective on how adaptive immunity affects neuronal function. Adaptive immune deficiency impairs the coordination of neural activity after training and retrieval, which might be a potential therapeutic target for neurodevelopmental disorders.
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http://dx.doi.org/10.3389/fnins.2021.739580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634587PMC
November 2021

Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients.

J Autism Dev Disord 2021 Nov 23. Epub 2021 Nov 23.

Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wanyuan Road, Shanghai, 201102, China.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing.
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http://dx.doi.org/10.1007/s10803-021-05365-2DOI Listing
November 2021

Common and Distinct Disruptions of Cortical Surface Morphology Between Autism Spectrum Disorder Children With and Without Deficiency.

Front Neurosci 2021 28;15:751364. Epub 2021 Oct 28.

Department of Child Health Care, Children's Hospital of Fudan University, Shanghai, China.

SH3 and Multiple Ankyrin Repeat Domains 3 ()-caused autism spectrum disorder (ASD) may present a unique opportunity to clarify the heterogeneous neuropathological mechanisms of ASD. However, the specificity and commonality of disrupted large-scale brain organization in deficient children remain largely unknown. The present study combined genetic tests, neurobehavioral evaluations, and magnetic resonance imaging, aiming to explore the disruptions of both local and networked cortical structural organization in ASD children with and without deficiency. Multiple surface morphological parameters such as cortical thickness (CT) and sulcus depth were estimated, and the graph theory was adopted to characterize the topological properties of structural covariance networks (SCNs). Finally, a correlation analysis between the alterations in brain morphological features and the neurobehavioral evaluations was performed. Compared with typically developed children, increased CT and reduced nodal degree were found in both ASD children with and without defects mainly in the lateral temporal cortex, prefrontal cortex (PFC), temporo-parietal junction (TPJ), superior temporal gyrus (STG), and limbic/paralimbic regions. Besides commonality, our findings showed some distinct abnormalities in ASD children with defects compared to those without. Locally, more changes in the STG and orbitofrontal cortex were exhibited in ASD children with defects, while more changes in the TPJ and inferior parietal lobe (IPL) in those without defects were observed. For the SCNs, a trend toward regular network topology was observed in ASD children with defects, but not in those without. In addition, ASD children with defects showed more alterations of nodal degrees in the anterior and posterior cingulate cortices and right insular, while there were more disruptions in the sensorimotor areas and the left insular and dorsomedial PFC in ASD without defects. Our findings indicate dissociable disruptions of local and networked brain morphological features in ASD children with and without deficiency. Moreover, this monogenic study may provide a valuable path for parsing the heterogeneity of brain disturbances in ASD.
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http://dx.doi.org/10.3389/fnins.2021.751364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581670PMC
October 2021

RNA-binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA.

Clin Transl Med 2021 10;11(10):e383

Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China.

Background: RNA-binding motif protein 24 (RBM24) functions as a splicing regulator, which is critical for organ development and is dysregulated in human cancers. Here, we aim to uncover the biological function of RBM24 in colorectal tumourigenesis.

Methods: Xenograft tumour model, Rbm24 knockout and Apc mouse models were utilised. Colorectal cancer cells overexpressing or silencing RBM24 were established. RNA immunoprecipitation (RIP) assay was conducted to detect protein-RNA associations. Gene expression was measured by immunohistochemistry, western blotting, or quantitative PCR (qPCR).

Results: Rbm24-knockout mice developed spontaneous colorectal adenomas with lower expression of phosphatase and tensin homolog (PTEN). Immunohistochemical staining for the proliferation markers Ki-67 and pHH3 and BrdU assay showed intestinal hyperplasia in Rbm24-knockout mice compared to wild-type mice. RBM24 expression in colorectal adenoma tissues of Apc mouse was downregulated compared with adjacent normal samples and was positively correlated with PTEN expression. In vitro, RBM24 overexpression suppressed cell proliferation, migration, invasion and increased sensitivity to 5-FU or cisplatin in CRC cells. Mechanistically, RBM24 maintained PTEN mRNA stability by directly binding to the GT-rich region at positions 8101-8251 in the 3'-UTR of PTEN mRNA, prolonging the half-life of PTEN mRNA, thereby increasing PTEN expression. Hence, low expression of RBM24 downregulated PTEN mRNA, causing the activation of PI3K-Akt signalling in CRC cells. Furthermore, RBM24 expression in CRC tissues was lower than adjacent normal samples. RBM24 expression was positively correlated with PTEN expression and negatively correlated with Ki-67 level. CRC patients with high RBM24 expression had a favourable outcome.

Conclusions: Taken together, RBM24 expression is markedly lower in colorectal tumours than in para-carcinoma tissues. Rbm24-knockout mice develop spontaneous colorectal adenomas. RBM24 directly binds and stabilises PTEN mRNA, which could cause the suppression of CRC cell proliferation, migration and invasion, thereby repressing colorectal tumourigenesis. These findings support the tumour-suppressive role of RBM24. Targeting RBM24 holds strong promise for the diagnosis and treatment of CRC.
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http://dx.doi.org/10.1002/ctm2.383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506628PMC
October 2021

Social Deficits and Repetitive Behaviors Are Improved by Early Postnatal Low-Dose VPA Intervention in a Novel -Deficient Zebrafish Model.

Front Neurosci 2021 10;15:682054. Epub 2021 Sep 10.

Department of Child Health Care, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

Mutations of the gene are found in some autism spectrum disorder (ASD) patients, and animal models harboring mutations exhibit a variety of ASD-like behaviors, presenting a unique opportunity to explore the underlying neuropathological mechanisms and potential pharmacological treatments. The histone deacetylase (HDAC) valproic acid (VPA) has demonstrated neuroprotective and neuroregenerative properties, suggesting possible therapeutic utility for ASD. Therefore, -associated ASD-like symptoms present a convenient model to evaluate the potential benefits, therapeutic window, and optimal dose of VPA. We constructed a novel -deficient ( ) zebrafish model through CRISPR/Cas9 editing and conducted comprehensive morphological and neurobehavioral evaluations, including of core ASD-like behaviors, as well as molecular analyses of synaptic proteins expression levels. Furthermore, different VPA doses and treatment durations were examined for effects on ASD-like phenotypes. Compared to wild types (WTs), zebrafish exhibited greater developmental mortality, more frequent abnormal tail bending, pervasive developmental delay, impaired social preference, repetitive swimming behaviors, and generally reduced locomotor activity. The expression levels of synaptic proteins were also dramatically reduced in zebrafish. These ASD-like behaviors were attenuated by low-dose (5 μM) VPA administered from 4 to 8 days post-fertilization (dpf), and the effects persisted to adulthood. In addition, the observed underexpression of , encoding glutamate metabotropic receptor 5, was significantly improved in VPA-treated zebrafish. We report for the first time that low-dose VPA administered after neural tube closure has lasting beneficial effects on the social deficits and repetitive behavioral patterns in -deficient ASD model zebrafish. These findings provide a promising strategy for ASD clinical drug development.
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http://dx.doi.org/10.3389/fnins.2021.682054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462462PMC
September 2021

Differential Metabolites in Chinese Autistic Children: A Multi-Center Study Based on Urinary H-NMR Metabolomics Analysis.

Front Psychiatry 2021 11;12:624767. Epub 2021 May 11.

Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.

Autism spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders. However, there is no valuable biomarker for the early diagnosis of ASD. Our large-scale and multi-center study aims to identify metabolic variations between ASD and healthy children and to investigate differential metabolites and associated pathogenic mechanisms. One hundred and seventeen autistic children and 119 healthy children were recruited from research centers of 7 cities. Urine samples were assayed by H-NMR metabolomics analysis to detect metabolic variations. Multivariate statistical analysis, including principal component analysis (PCA), and orthogonal projection to latent structure discriminant analysis (OPLS-DA), as well as univariate analysis were used to assess differential metabolites between the ASD and control groups. The differential metabolites were further analyzed by receiver operating characteristics (ROC) curve analysis and metabolic pathways analysis. Compared with the control group, the ASD group showed higher levels of glycine, guanidinoacetic acid, creatine, hydroxyphenylacetylglycine, phenylacetylglycine, and formate and lower levels of 3-aminoisobutanoic acid, alanine, taurine, creatinine, hypoxanthine, and N-methylnicotinamide. ROC curve showed relatively significant diagnostic values for hypoxanthine [area under the curve (AUC) = 0.657, 95% CI 0.588 to 0.726], creatinine (AUC = 0.639, 95% CI 0.569 to 0.709), creatine (AUC = 0.623, 95% CI 0.552 to 0.694), N-methylnicotinamide (AUC = 0.595, 95% CI 0.523 to 0.668), and guanidinoacetic acid (AUC = 0.574, 95% CI 0.501 to 0.647) in the ASD group. Combining the metabolites creatine, creatinine and hypoxanthine, the AUC of the ROC curve reached 0.720 (95% CI 0.659 to 0.777). Significantly altered metabolite pathways associated with differential metabolites were glycine, serine and threonine metabolism, arginine and proline metabolism, and taurine and hypotaurine metabolism. Urinary amino acid metabolites were significantly altered in children with ASD. Amino acid metabolic pathways might play important roles in the pathogenic mechanisms of ASD.
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http://dx.doi.org/10.3389/fpsyt.2021.624767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144639PMC
May 2021

LHPP-Mediated Histidine Dephosphorylation Suppresses the Self-Renewal of Mouse Embryonic Stem Cells.

Front Cell Dev Biol 2021 16;9:638815. Epub 2021 Mar 16.

Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, China.

Self-renewal of embryonic stem cells (ESCs) is orchestrated by a vast number of genes at the transcriptional and translational levels. However, the molecular mechanisms of post-translational regulatory factors in ESC self-renewal remain unclear. Histidine phosphorylation, also known as hidden phosphorylation, cannot be detected by conventional experimental methods. A recent study defined phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) as a histidine phosphatase, which regulates various biological behaviors in cells via histidine dephosphorylation. In this study, the doxycycline (DOX)-induced hLHPP-overexpressing mouse ESCs and mouse LHPP silenced mESCs were constructed. Quantitative polymerase chain reaction (qPCR), western blotting analysis, immunofluorescence, Flow cytometry, colony formation assays, alkaline phosphatase (AP) and bromodeoxyuridine (Brdu) staining were performed. We found that the histidine phosphorylation level was strikingly reduced following LHPP overexpression. Besides, the expression of and , indispensable genes in the process of ESCs self-renewal, was significantly down-regulated, while markers related to the differentiation were markedly elevated. Moreover, LHPP-mediated histidine dephosphorylation induced GG phase arrest in mESCs, suggesting LHPP was implicated in cell proliferation and cell cycle. Conversely, silencing of promoted the self-renewal of mESCs and reversed the RA induced increased expression of genes associated with differentiation. Mechanistically, our findings suggested that the enzymatic active site of LHPP was the cysteine residue at position 226, not 53. LHPP-mediated histidine dephosphorylation lowered the expression levels of β and the cell cycle-related genes and , while it up-regulated the cell cycle suppressor genes and . Taken together, our findings reveal that LHPP-mediated histidine dephosphorylation plays a role in the self-renewal of ESCs. LHPP-mediated histidine dephosphorylation inhibited the self-renewal of ESCs by negatively regulating the Wnt/β-catenin pathway and downstream cell cycle-related genes, providing a new perspective and regulatory target for ESCs self-renewal.
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http://dx.doi.org/10.3389/fcell.2021.638815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007871PMC
March 2021

One-electron reduction triggered nitric oxide release for ischemia-reperfusion protection.

Free Radic Biol Med 2021 02 5;164:13-19. Epub 2021 Jan 5.

State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address:

Nitric oxide donors (NODs) are indispensable in biological research and disease treatment. NODs had been utilized to treat cardiovascular diseases in clinic and many others are under trial. Thiols are typically required for these donors to release NO. Yet, their mechanism is complex and often lead to resistance. Herein, we reported that N-nitrosated electron-deficient dyes are capable of NO release with one-electron reduction. A fluorophore is generated simultaneously, whose fluorescence is harnessed to monitor the profile of NO release. Through electrochemical and spectral studies, NOD f3 was found to exhibit good biocompatibility and high reduction efficiency and its potentials in cell-protection in oxygen and glucose deprivation (OGD) models were showcased with endothelial cells. This work aims at offering a new approach to design reduction-triggered NOD, which have therapeutic potentials in ischemia-reperfusion.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.443DOI Listing
February 2021

Altered striatum centered brain structures in SHANK3 deficient Chinese children with genotype and phenotype profiling.

Prog Neurobiol 2021 05 31;200:101985. Epub 2020 Dec 31.

Department of Child Health Care, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, China. Electronic address:

SHANK3 deficiency represents one of the most replicated monogenic risk factors for autism spectrum disorder (ASD) and SHANK3 caused ASD presents a unique opportunity to understand the underlying neuropathological mechanisms of ASD. In this study, genetic tests, comprehensive clinical and neurobehavioral evaluations, as well as multimodal structural MRI using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were conducted in SHANK3 group (N = 14 with SHANK3 defects), ASD controls (N = 26 with idiopathic ASD without SHANK3 defects) and typically developing (TD) controls (N = 32). Phenotypically, we reported several new features in Chinese SHANK3 deficient children including anteverted nares, sensory stimulation seeking, dental abnormalities and hematological problems. In SHANK3 group, VBM revealed decreased grey matter volumes mainly in dorsal striatum, amygdala, hippocampus and parahippocampal gyrus; TBSS demonstrated decreased fractional anisotropy in multiple tracts involving projection, association and commissural fibers, including middle cerebral peduncle, corpus callosum, superior longitudinal fasciculus, corona radiata, external and internal capsule, and posterior thalamic radiation, etc. We report that the disrupted striatum centered brain structures are associated with SHANK3 deficient children. Study of subjects with monogenic cause offer specific insights into the neuroimaging studies of ASD. The discovery may support a path for future functional connectivity studies to allow for more in-depth understandings of the abnormal neural circuits and the underlying neuropathological mechanisms for ASD.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572121PMC
May 2021

Early Screening of Autism in Toddlers via Response-To-Instructions Protocol.

IEEE Trans Cybern 2022 May 19;52(5):3914-3924. Epub 2022 May 19.

Early screening of autism spectrum disorder (ASD) is crucial since early intervention evidently confirms significant improvement of functional social behavior in toddlers. This article attempts to bootstrap the response-to-instructions (RTIs) protocol with vision-based solutions in order to assist professional clinicians with an automatic autism diagnosis. The correlation between detected objects and toddler's emotional features, such as gaze, is constructed to analyze their autistic symptoms. Twenty toddlers between 16-32 months of age, 15 of whom diagnosed with ASD, participated in this study. The RTI method is validated against human codings, and group differences between ASD and typically developing (TD) toddlers are analyzed. The results suggest that the agreement between clinical diagnosis and the RTI method achieves 95% for all 20 subjects, which indicates vision-based solutions are highly feasible for automatic autistic diagnosis.
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http://dx.doi.org/10.1109/TCYB.2020.3017866DOI Listing
May 2022

Rbm24 regulates inner-ear-specific alternative splicing and is essential for maintaining auditory and motor coordination.

RNA Biol 2021 04 20;18(4):468-480. Epub 2020 Sep 20.

The Institute of Stem Cell and Regenerative Medicine, School of Medicine, Xiamen University, Xiamen, China.

Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.
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http://dx.doi.org/10.1080/15476286.2020.1817265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971244PMC
April 2021

Exacerbated obesogenic response in female mice exposed to early life stress is linked to fat depot-specific upregulation of leptin protein expression.

Am J Physiol Endocrinol Metab 2020 11 24;319(5):E852-E862. Epub 2020 Aug 24.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.

Early life stress (ELS) is an independent risk factor for increased BMI and cardiometabolic disease risk later in life. We have previously shown that a mouse model of ELS, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. Therefore, the aim of this study was to investigate ) whether the short- and long-term effects of HF on leptin expression are influenced by MSEW in a sex-specific manner and ) the potential epigenetic mechanisms underlying the MSEW-induced changes in leptin expression. After 1 wk of HF, both MSEW male and female mice displayed increased fat mass compared with controls ( < 0.05). However, only MSEW female mice showed elevated leptin mRNA expression in gonadal white adipose tissue (gWAT; < 0.05). After 12 wk of HF, fat mass remained increased only in female mice ( < 0.05). Moreover, plasma leptin and both leptin mRNA and protein expression in gWAT were augmented in MSEW female mice compered to controls ( < 0.05), but not in MSEW male mice. This association was not present in subcutaneous WAT. Furthermore, among 16 CpG sites in the leptin promoter, we identified three hypomethylated sites in tissue from HF-fed MSEW female mice compared with controls (3, 15, and 16, < 0.05). These hypomethylated sites showed greater binding of key adipogenic factors such as PPARγ ( < 0.05). Taken together, our study reveals that MSEW superimposed to HF increases leptin protein expression in a sex- and fat depot-specific fashion. Our data suggest that the mechanism by which MSEW increases leptin expression could be epigenetic.
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http://dx.doi.org/10.1152/ajpendo.00243.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790118PMC
November 2020

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination.

Autism Res 2020 10 19;13(10):1685-1697. Epub 2020 Aug 19.

Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

Mutations in CHD8 are among the most common autism-causing genetic defects identified in human genomics studies. Therefore, many labs have attempted to model this disorder by generating mice with mutations in Chd8. Using a gene trap inserted after Exon 31, we created a novel Chd8 mutant mouse (Chd8 ) and characterized its behavior on several different assays thought to have face validity for the human condition, attempting to model both the core symptoms (repetitive behaviors and social communication impairments) and common comorbidities (motor deficits, anxiety, and intellectual disability). We found that Chd8 mice showed no difference compared to wild-type mice in amount of self-grooming, reproducing the negative finding most other studies have reported. Unlike some of the other published lines, Chd8 mice did not show deficits in the three-chamber test for social novelty preference. A few studies have examined ultrasonic vocalizations in Chd8 mutant mice, but we are the first to report an increase in call length for adult mice. Additionally, we found that in contrast to previous published lines, Chd8 mice displayed no anxiety-like behaviors or learning impairments but showed paradoxically significant improvement in motor function. The inconsistencies in behavioral phenotypes in the Chd8 mutant mice generated by different laboratories poses a challenge for modeling autism spectrum disorder and preclinical studies in mice going forward and warrants further investigation into the molecular consequences of the different mutations in Chd8 and the functional impact on behavior. LAY SUMMARY: Several different mouse models carrying mutations in the Chd8 gene have been created to study the effects of these autism-causing mutations in the laboratory. The current study characterizes a novel Chd8 mutant mouse model as well as summarizes data from previously published Chd8 mutant mice. The inconsistencies between different studies are concerning, but future research into the reasons why these inconsistencies occur may help us understand why patients with various mutations have different degrees of symptom severity. Autism Res 2020, 13: 1685-1697. © 2020 International Society for Autism Research and Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/aur.2353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780289PMC
October 2020

A Virtual-Reality System Integrated With Neuro-Behavior Sensing for Attention-Deficit/Hyperactivity Disorder Intelligent Assessment.

IEEE Trans Neural Syst Rehabil Eng 2020 09 24;28(9):1899-1907. Epub 2020 Jun 24.

Attention-deficit/Hyperactivity disorder(ADHD) is a common neurodevelopmental disorder among children. Traditional assessment methods generally rely on behavioral rating scales (BRS) performed by clinicians, and sometimes parents or teachers. However, BRS assessment is time consuming, and the subjective ratings may lead to bias for the evaluation. Therefore, the major purpose of this study was to develop a Virtual Reality (VR) classroom associated with an intelligent assessment model to assist clinicians for the diagnosis of ADHD. In this study, an immersive VR classroom embedded with sustained and selective attention tasks was developed in which visual, audio, and visual-audio hybrid distractions, were triggered while attention tasks were conducted. A clinical experiment with 37 ADHD and 31 healthy subjects was performed. Data from BRS was compared with VR task performance and analyzed by rank-sum tests and Pearson Correlation. Results showed that 23 features out of total 28 were related to distinguish the ADHD and non-ADHD children. Several features of task performance and neuro-behavioral measurements were also correlated with features of the BRSs. Additionally, the machine learning models incorporating task performance and neuro-behavior were used to classify ADHD and non-ADHD children. The mean accuracy for the repeated cross-validation reached to 83.2%, which demonstrated a great potential for our system to provide more help for clinicians on assessment of ADHD.
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http://dx.doi.org/10.1109/TNSRE.2020.3004545DOI Listing
September 2020

Prevalence of Autism Spectrum Disorder in China: A Nationwide Multi-center Population-based Study Among Children Aged 6 to 12 Years.

Neurosci Bull 2020 Sep 30;36(9):961-971. Epub 2020 Jun 30.

Department of Neurology, Children's Hospital of Fudan University, Shanghai, 201102, China.

This study aimed to obtain the first national estimate of the prevalence of autism spectrum disorder (ASD) in Chinese children. We targeted the population of 6 to 12-year-old children for this prevalence study by multistage convenient cluster sampling. The Modified Chinese Autism Spectrum Rating Scale was used for the screening process. Of the target population of 142,086 children, 88.5% (n = 125,806) participated in the study. A total of 363 children were confirmed as having ASD. The observed ASD prevalence rate was 0.29% (95% CI: 0.26%-0.32%) for the overall population. After adjustment for response rates, the estimated number of ASD cases was 867 in the target population sample, thereby achieving an estimated prevalence of 0.70% (95% CI: 0.64%-0.74%). The prevalence was significantly higher in boys than in girls (0.95%; 95% CI: 0.87%-1.02% versus 0.30%; 95% CI: 0.26%-0.34%; P < 0.001). Of the 363 confirmed ASD cases, 43.3% were newly diagnosed, and most of those (90.4%) were attending regular schools, and 68.8% of the children with ASD had at least one neuropsychiatric comorbidity. Our findings provide reliable data on the estimated ASD prevalence and comorbidities in Chinese children.
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http://dx.doi.org/10.1007/s12264-020-00530-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475160PMC
September 2020

Diagnostic Classification for Human Autism and Obsessive-Compulsive Disorder Based on Machine Learning From a Primate Genetic Model.

Am J Psychiatry 2021 01 16;178(1):65-76. Epub 2020 Jun 16.

Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai (Zhan, Wang); University of Chinese Academy of Sciences, Beijing (Zhan, Wang); School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing (Wei); Institute of Automation, Center for Excellence in Brain Science and Intelligence Technology, National Laboratory of Pattern Recognition, Chinese Academy of Sciences, Beijing (Wei, Liang, He); Department of Child Health Care, Children's Hospital of Fudan University, Shanghai (Xu); Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, U.K. (Robbins); Institute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai (Robbins); Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai (Wang); and Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China (Wang).

Objective: Psychiatric disorders commonly comprise comorbid symptoms, such as autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD), raising controversies over accurate diagnosis and overlap of their neural underpinnings. The authors used noninvasive neuroimaging in humans and nonhuman primates to identify neural markers associated with DSM-5 diagnoses and quantitative measures of symptom severity.

Methods: Resting-state functional connectivity data obtained from both wild-type and methyl-CpG binding protein 2 () transgenic monkeys were used to construct monkey-derived classifiers for diagnostic classification in four human data sets (ASD: Autism Brain Imaging Data Exchange [ABIDE-I], N=1,112; ABIDE-II, N=1,114; ADHD-200 sample: N=776; OCD local institutional database: N=186). Stepwise linear regression models were applied to examine associations between functional connections of monkey-derived classifiers and dimensional symptom severity of psychiatric disorders.

Results: Nine core regions prominently distributed in frontal and temporal cortices were identified in monkeys and used as seeds to construct the monkey-derived classifier that informed diagnostic classification in human autism. This same set of core regions was useful for diagnostic classification in the OCD cohort but not the ADHD cohort. Models based on functional connections of the right ventrolateral prefrontal cortex with the left thalamus and right prefrontal polar cortex predicted communication scores of ASD patients and compulsivity scores of OCD patients, respectively.

Conclusions: The identified core regions may serve as a basis for building markers for ASD and OCD diagnoses, as well as measures of symptom severity. These findings may inform future development of machine-learning models for psychiatric disorders and may improve the accuracy and speed of clinical assessments.
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http://dx.doi.org/10.1176/appi.ajp.2020.19101091DOI Listing
January 2021

Response to children's physical and mental needs during the COVID-19 outbreak.

World J Pediatr 2020 06 25;16(3):278-279. Epub 2020 May 25.

Department of Nephrology, Children's Hospital of Fudan University, Shanghai, 201102, China.

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http://dx.doi.org/10.1007/s12519-020-00365-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246957PMC
June 2020

Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to Patients with Autism.

J Neurosci 2020 05 8;40(19):3799-3814. Epub 2020 Apr 8.

Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China

gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene-circuit-behavior analyses including coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 overexpressed monkeys (; 3 females) and 20 wild-type monkeys (; 11 females). Whole-genome expression analysis revealed coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced β-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, -induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders. Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene-circuit-behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.
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http://dx.doi.org/10.1523/JNEUROSCI.2727-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204082PMC
May 2020

Protective Effects of Human Milk-Derived Exosomes on Intestinal Stem Cells Damaged by Oxidative Stress.

Cell Transplant 2020 Jan-Dec;29:963689720912690

Department of Neonatology, Children's Hospital of Shanghai, China.

Breastfeeding has been shown to have a protective effect on the occurrence of necrotizing enterocolitis (NEC), but the mechanism remains unclear. In the context of NEC pathogenesis, many of the protective properties of exosomes on the intestinal epithelial compartment make it an ideal therapeutic target. In the present study, our hypothesis was that intestinal stem cells (ISCs) would be protected from injury by human milk-derived exosomes (HMDEs). Human breast milk was collected, and exosomes were isolated using ExoQuick reagent. Magnetic-activated cell sorting isolation of prominin-1 ISCs was performed from small intestines of neonatal rat. ISCs were treated with or without HO, and HMDEs, an equal volume of HMDE-free milk, or a control solution [phosphate-buffered solution (PBS)] was added, respectively. In the absence of HMDEs, exposure of ISCs to HO led to decreased cell viability. However, addition of HMDEs to ISCs exposed to HO led to significantly increased ISC viability. There was a significant upregulation of mRNA expression of Axin2, c-Myc, and Cyclin D1 genes of the Wnt/β-catenin axis in ISCs treated with HMDEs (6.99 ± 2.34, 4.21 ± 1.68, 6.17 ± 2.22, respectively, < 0.05 for all), as compared to control. In the presence of carnosic acid (a specific Wnt/β-catenin signaling inhibitor), the cell viability was significantly decreased. Thus, HMDEs protect ISCs from oxidative stress injury , which were possibly mediated via the Wnt/β-catenin signaling pathway. Our findings indicate that oral administration of HMDEs might be a promising measure in treating NEC or in preventing the development of NEC in high-risk infants when breast milk is not available.
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http://dx.doi.org/10.1177/0963689720912690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444213PMC
June 2021

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort.

J Med Genet 2020 08 31;57(8):558-566. Epub 2020 Jan 31.

Center for Molecular Medicine of Children's Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

Background: Developmental disorders (DDs) are early onset disorders affecting 5%-10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated.

Methods: Clinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data.

Results: An overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: , and . Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups.

Conclusion: With a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.
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http://dx.doi.org/10.1136/jmedgenet-2019-106377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418612PMC
August 2020

LncRNA TDRG1 promotes the aggressiveness of gastric carcinoma through regulating miR-873-5p/HDGF axis.

Biomed Pharmacother 2020 Jan 11;121:109425. Epub 2019 Nov 11.

Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China. Electronic address:

Gastric carcinoma (GC) is still one of the most common digestive system neoplasms and the primary reason for malignant cancer-associated death. Long non-coding RNAs (lncRNAs) have been reported to play critical roles in GC progression. In this study, we demonstrated that lncRNA testis development-related gene 1 (TDRG1) is markedly upregulated in clinical GC tissues and GC cells. High level of lncRNA TDRG1 correlates with the metastasis and prognosis of patients with GC. Overexpression of lncRNA TDRG1 promotes GC growth and metastatic-related traits in vitro and in vivo, and silencing TDRG1 causes opposite results. We future find that TDRG1 is inversely associated with miR-873-5p and positively modulates the expression of hepatoma-derived growth factor (HDGF), a functional target gene of miR-873-5p. Finally, lncRNA TDRG1 regulates the progression of GC through regulating miR-873-5p/HDGF pathway. Taken together, our data uncover the crucial function of TDRG1-miR-873-5p-HDGF axis in human gastric cancer.
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http://dx.doi.org/10.1016/j.biopha.2019.109425DOI Listing
January 2020

Orally administered Lactobacillus casei exhibited several probiotic properties in artificially suckling rabbits.

Asian-Australas J Anim Sci 2019 Apr 15:1352-1359. Epub 2019 Apr 15.

College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.

Objective: Lactobacilli in rabbit intestine is rare and its function on rabbit gut health is not fully understood. The present study aimed to evaluate in vivo the probiotic potential of Lactobacillus casei for suckling rabbits.

Methods: Two healthy 5-day-old suckling rabbits with similar weights from each of 12 New Zealand White litters were selected and disturbed to control group and treatment group. All rabbits were artificially fed. The treatment group had been supplemented with live Lactobacillus casei in the milk from the beginning of the trial to 13 days of age. At 15 days of age, healthy paired rabbits were slaughtered to collect intestinal samples.

Results: 1) Oral administration of Lactobacillus casei significantly increased the proportion of Lactobacilli in the total intestinal bacteria (P < 0.01) and obviously reduced that of Escherichia-Shigella (P < 0.01); 2) treatment increased the length of vermiform appendix (P < 0.05); 3) a higher percentage of degranulated paneth cells was observed in the duodenum and jejunum when rabbits administered with Lactobacillus casei (P < 0.01); and 4) the expression of toll-like receptor 9 (TLR9), Lysozyme (LYZ) and defensin-7-like (DEFEN) in the duodenum and jejunum was stimulated by supplemented Lactobacillus casei (P < 0.05).

Conclusion: orally administered Lactobacillus casei could increase the abundance of intestinal Lactobacilli, decrease the relative abundance of intestinal Escherichia-Shigella, promote the growth of appendix vermiform, stimulate the degranulation of paneth cells and induce the expression of defensin-7-like and Lysozyme. The results of the present study implied that Lactobacillus casei exhibited probiotic potential for suckling rabbit.
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http://dx.doi.org/10.5713/ajas.18.0973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322641PMC
April 2019

Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons.

Mol Autism 2018 19;9:65. Epub 2018 Dec 19.

3Department of Pediatrics, Duke University School of Medicine, Durham, 27710 NC USA.

Background: Mutations in , chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated.

Methods: We examined the expression of in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of deficiency.

Results: We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7.

Conclusion: Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.
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http://dx.doi.org/10.1186/s13229-018-0244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299922PMC
January 2019

Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells.

Cell Death Dis 2018 11 19;9(12):1147. Epub 2018 Nov 19.

Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, PR China.

Trefoil factor 3 (TFF3) expression is positively associated with advanced clinicopathological features of mammary carcinoma (MC). Herein, we provide evidence for a functional role of TFF3 in oncogenic transformation of immortalized, but otherwise normal human mammary epithelial cells (HMECs), namely, HMEC-hTERT, MCF10A, and MCF12A. Forced expression of TFF3 in immortalized-HMECs enhanced cell proliferation, cell survival, anchorage-independent growth, produced highly disorganised three-dimensional (3D) acinar structures and generated tumours in immunocompromised mice. Forced expression of TFF3 in immortalized-HMECs stimulated STAT3 activity that was required for TFF3-stimulated cell proliferation, survival, and anchorage-independent growth. TFF3 specifically utilised STAT3 activity to govern a transcriptional program, which was required for TFF3-stimulated oncogenic transformation of immortalized-HMECs, including transcriptional upregulation of CCND1 and BCL2. siRNA-mediated depletion or functional inhibition of STAT3 significantly inhibited the TFF3-stimulated transcription of CCND1 and BCL2 and oncogenicity in immortalized-HMECs. Furthermore, DOX-inducible expression of TFF3 in HMEC-hTERT cells also permitted anchorage-independent growth and produced disorganized acinar structures in 3D Matrigel culture. Removal of DOX-induced expression of TFF3 in HMEC-hTERT cells, previously grown with DOX, resulted in efficient normalisation of the disorganized acinar architecture and attenuated cell viability in Matrigel culture. Cumulatively, these findings suggest that TFF3 is a potent oncogene and its increased expression along with hTERT in HMECs is sufficient to produce oncogenic transformation.
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http://dx.doi.org/10.1038/s41419-018-1177-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242831PMC
November 2018

Reliability and validity of the translated Chinese version of Autism Spectrum Rating Scale (2-5 years).

World J Pediatr 2019 Feb 16;15(1):49-56. Epub 2018 Nov 16.

Department of Neurology, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, Shanghai, 201102, China.

Background: Early autism screening is of great value, but there is lack of a screening tool of early age (2-5 years) in China. The Autism Spectrum Rating Scale (ASRS, 2-5 years) is a newly developed autism screening tool in the USA. This study aimed to evaluate the reliability and validity of the translated Chinese version of ASRS (C_ASRS) in Chinese children population before its application in China for early autism screening.

Methods: Caregivers of general children aged 2-5 years from 17 kindergartens and autism spectrum disorder (ASD) cases from five special education schools in five cities were recruited to complete the C_ASRS. 1910 valid questionnaires from kindergarteners and 192 from ASD cases were included for analyses.

Results: The item reliability (Cronbach's alpha) was more than 0.80 in the screening scale and DSM-5 scale, and 0.51-0.81 in the treatment scale. ASD cases scored higher on total score and most subscales compared to the kindergarteners (Cohen's d ranging from 1.34 to 3.37). C_ASRS showed good discriminatory validity with an area under the receiver operating characteristic curve of 0.850 (95% confidence interval: 0.819-0.881). The cutoff ≥ 60 achieved sensitivity of 65.63% and specificity of 85.63% in discriminating autism children from the general population.

Conclusion: The results indicate that C_ASRS (2-5 years) could be used as an early level-2 screening tool for autism screening in China and should be further revised for level-1 screening.
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http://dx.doi.org/10.1007/s12519-018-0201-3DOI Listing
February 2019
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