Identifying the Pathogenicity of a Novel NPRL3 Missense Mutation Using Personalized Cortical Organoid Model of Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) II is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, with or without balloon cells. Here, we systematically explored the pathophysiological role of the GATOR1 subunit NPRL3 variants including a novel mutation from iPSCs derived from one FCD II patient. Three FCD II children aged 0.

Lead exposure leads to premature neural differentiation via inhibiting Wnt signaling.

Heavy metals, such as Lead (Pb), are ubiquitous environmental pollutants that is a considerable problem worldwide. Increasing evidences suggest that Pb exposure negatively impact central nervous system. However, the exact toxic mechanism of Pb on early human brain development remain unclear due to the limitations of animal models and 2D cell models.

AAV-mediated Stambp gene replacement therapy rescues neurological defects in a mouse model of microcephaly-capillary malformation syndrome.

The microcephaly-capillary malformation (MIC-CAP) syndrome is a life-threatening disease caused by biallelic mutations of the STAMBP gene, which encodes an endosomal deubiquitinating enzyme. To establish a suitable preclinical animal model for clinical therapeutic practice, we generated a central nervous system (CNS)-specific Stambp knockout mouse model (Stambp ) that phenocopies Stambp null mice including progressive microcephaly, postnatal growth retardation and complete penetrance of preweaning death. In this MIC-CAP syndrome mouse model, early-onset neuronal death occurs specifically in the hippocampus and cortex, accompanied by aggregation of ubiquitinated proteins, and massive neuroinflammation.

A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids.

Focal malformations of cortical development (FMCDs) are brain disorders mainly caused by hyperactive mTOR signaling due to both inactivating and activating mutations of genes in the PI3K-AKT-mTOR pathway. Among them, mosaic and somatic activating mutations of the mTOR pathway activators are more frequently linked to severe form of FMCDs. A human stem cell-based FMCDs model to study these activating mutations is still lacking.

Generation and characterization of Chd7-iCreERT2-tdTomato mice.

Heterozygous mutation of CHD7 gene causes a severe developmental disorder called CHARGE syndrome. In order to further explore the expression and function of Chd7 in vivo, we generated a Chd7-P2A-iCreERT2-P2A-tdTomato (in short, Chd7-CT-tdT) knockin mouse line using the CRISPR/Cas9 technology. The specificity and efficiency of two knockin genetic elements were validated.

A single-cell atlas reveals the heterogeneity of meningeal immunity in a mouse model of Methyl CpG binding protein 2 deficiency.

Methyl CpG binding protein 2 (MeCP2) is a DNA methylation reader protein. Mutations in are the major cause of Rett syndrome (RTT). Increasing evidence has shown that dysregulated immunity and chronic subclinical inflammation are linked to MeCP2 deficiency and contribute to RTT development and deterioration.

Novel compound heterozygous mutation in causes a neurodevelopmental disorder by disrupting cortical proliferation.

Background: Mutations in the gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of variants require further elucidation.

Materials And Methods: Whole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder.

CHD7 in oocytes is essential for female fertility.

Background: Chromodomain helicase DNA-binding protein 7 (CHD7), which is associated with CHARGE (Coloboma, Heart defect, Atresia choanae, Restricted growth, Genital hypoplasia and Ear abnormality) syndrome is an important regulator in many vital developmental processes. However, its role during oocyte development remains unknown.

Methods: We screened the Gene Expression Omnibus (GEO) database for expression levels of CHD7 during folliculogenesis.

Risk stratification by long non-coding RNAs profiling in COVID-19 patients.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic worldwide. Long non-coding RNAs (lncRNAs) are a subclass of endogenous, non-protein-coding RNA, which lacks an open reading frame and is more than 200 nucleotides in length. However, the functions for lncRNAs in COVID-19 have not been unravelled.

A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis.

IL-10 is a potent anti-inflammatory cytokine capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease. Clinical use of human IL-10 (hIL-10) has been limited by anemia and thrombocytopenia following systemic injection, side effects that might be eliminated by a gut-restricted distribution. We have identified a transcytosis pathway used by cholix, an exotoxin secreted by nonpandemic forms of the intestinal pathogen A nontoxic fragment of the first 386 aa of cholix was genetically fused to hIL-10 to produce recombinant AMT-101.

Corosolic Acid Attenuates Hepatic Lipid Accumulation and Inflammatory Response via AMPK/SREBPs and NF-B/MAPK Signaling Pathways.

Corosolic acid (CA) is the main active component of and has been known to serve as several different pharmacological effects, such as antidiabetic, anti-oxidant, and anticancer effects. In this study, effects of CA on the hepatic lipid accumulation were examined using HepG2 cells and tyloxapol (TY)-induced hyperlipidemia ICR mice. CA significantly inhibited hepatic lipid accumulation via inhibition of SREBPs, and its target genes FAS, SCD1, and HMGCR transcription in HepG2 cells.

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis.

Cholix (Chx) is expressed by the intestinal pathogen as a single chain of 634 amino acids (~70.7 kDa protein) that folds into three distinct domains, with elements of the second and third domains being involved in accessing the cytoplasm of nonpolarized cells and inciting cell death via ADP-ribosylation of elongation factor 2, respectively. In order to reach nonpolarized cells within the intestinal lamina propria, however, Chx must cross the polarized epithelial barrier in an intact form.

CRISPR-mediated Loss of Function Analysis in Cerebellar Granule Cells Using In Utero Electroporation-based Gene Transfer.

Brain malformation is often caused by genetic mutations. Deciphering the mutations in patient-derived tissues has identified potential causative factors of the diseases. To validate the contribution of a dysfunction of the mutated genes to disease development, the generation of animal models carrying the mutations is one obvious approach.

Versatile Roles of the Chromatin Remodeler CHD7 during Brain Development and Disease.

CHD7 (Chromo-Helicase-DNA binding protein 7) protein is an ATP-dependent chromatin remodeler. Heterozygous mutation of the gene causes a severe congenital disease known as CHARGE syndrome. Most CHARGE syndrome patients have brain structural anomalies, implicating an important role of CHD7 during brain development.

CRISPR-engineered genome editing for the next generation neurological disease modeling.

Neurological disorders often occur because of failure of proper brain development and/or appropriate maintenance of neuronal circuits. In order to understand roles of causative factors (e.g.

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme.

Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients.

Revealing the Hidden Powers that Fuel Adult Neurogenesis.

A defining characteristic of diverse stem cell populations is their distinct metabolic state, although how these states change during adult hippocampal neurogenesis is unclear. Recently in Neuron, Beckervordersandforth et al. (2017) report that adult neurogenesis requires mitochondrial electron transport and oxidative phosphorylation and that disrupting these pathways induces premature aging phenotypes.

The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors.

Chromatin factors that regulate neurogenesis in the central nervous system remain to be explored. Here, we demonstrate that the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7), a protein frequently mutated in human CHARGE syndrome, is a master regulator of neurogenesis in mammalian brain. CHD7 is selectively expressed in actively dividing neural stem cells (NSCs) and progenitors.

The chromatin remodeling complex NuRD establishes the poised state of rRNA genes characterized by bivalent histone modifications and altered nucleosome positions.

rRNA genes (rDNA) exist in two distinct epigenetic states, active promoters being unmethylated and marked by euchromatic histone modifications, whereas silent ones are methylated and exhibit heterochromatic features. Here we show that the nucleosome remodeling and deacetylation (NuRD) complex establishes a specific chromatin structure at rRNA genes that are poised for transcription activation. The promoter of poised rRNA genes is unmethylated, associated with components of the preinitiation complex, marked by bivalent histone modifications and covered by a nucleosome in the "off" position, which is refractory to transcription initiation.

PHF8 activates transcription of rRNA genes through H3K4me3 binding and H3K9me1/2 demethylation.

Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat-containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes.

Activation of RNA polymerase I transcription by cockayne syndrome group B protein and histone methyltransferase G9a.

Cockayne syndrome group B (CSB) protein plays a role in both transcription-coupled DNA repair and transcriptional regulation of all three classes of nuclear RNA polymerases. Here we show that a complex consisting of CSB, RNA polymerase I (Pol I), and histone methyltransferase G9a is present at active rRNA genes. G9a methylates histone H3 on lysine 9 (H3K9me2) in the pre-rRNA coding region and facilitates the association of heterochromatin protein 1gamma (HP1gamma) with rDNA.

Intranasal immunization strategy to impede pilin-mediated binding of Pseudomonas aeruginosa to airway epithelial cells.

Prevention of pulmonary Pseudomonas aeruginosa infections represents a critical unmet medical need for cystic fibrosis (CF) patients. We have examined the tenet that a mucosal immunization approach can reduce interactions of a piliated form of this opportunistic pathogen with respiratory epithelial cells. Vaccinations were performed using ntPEpilinPAK, a protein chimera composed of a nontoxic form of P.

[Observation and analysis on mutation of routine STR locus].

Objective: To observe and analyze the characteristic of mutation at STR locus.

Methods: 27 mutant genes observed in 1211 paternity testing cases were checked by PAGE-silver stained and PowerPlex 16 System Kit and validated by sequencing.

Results: Mutant genes locate on 15 loci.