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KMT2D, a H3K4me1 methyltransferase primarily regulating enhancers, is a leading cause of KABUKI syndrome. This multisystem disorder leads to craniofacial and cognitive abnormalities, possibly through neural crest and neuronal lineages. However, the impacted cell-of-origin and molecular mechanism of KMT2D during the development of KABUKI disease remains unknown. Here we have optimized a brain organoid model to investigate neural crest and neuronal differentiation. To pinpoint KMT2D's enhancer target, we developed a genome-wide cis-regulatory element explorer (GREE) based on single-cell multiomic integration. Single cell RNA-seq revealed that KMT2D-knockout (KO) and patient-derived organoids exhibited neural crest deformities and GABAergic overproduction. Mechanistically, GREE identified that KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer, providing the microenvironment for neural crest and neuronal development. Interestingly, KMT2D-mutated mice displayed decreased WNT3A expression in the diencephalon roof plate, indicating impaired niche cell function. Deleting the WNT3A enhancer in the organoids presented phenotypic similarities to KMT2D-depletion, emphasizing the WNT3A enhancer as the predominant target of KMT2D. Conversely, reactivating WNT signaling in KMT2D-KO rescued the lineage defects by restoring the microenvironment. Overall, our discovery of KMT2D's primary target provides insights for reconciling complex phenotypes of KABUKI syndrome and establishes a new paradigm for dissecting the mechanisms of genetic disorders from genotype to phenotype.
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This study aimed to investigate the gap between adaptive functioning and cognitive functioning, especially verbal and nonverbal intelligence quotient (IQ) in Chinese children with ASD. We systematically explored cognitive functioning, ASD severity, early signs of developmental abnormalities, and socioeconomic factors as mediating factors of adaptive functioning. We enrolled 151 children (age: 2.5?6 years) with ASD and categorized them into one group with IQ ≥ 70 and another with IQ < 70. The two groups were calibrated for age, age at diagnosis, and IQ, and the relationship of adaptive skills with vocabulary acquisition index (VAI) and nonverbal index (NVI) were separately analyzed. Results show that the gap between IQ and adaptive functioning was significant in children with ASD having IQ ≥ 70, with both VAI and NVI showing statistically significant differences (all P < 0.001). VAI correlated positively with scores for overall adaptive skills and specific domains, whereas NVI had no significant correlations with adaptive skill scores. Age of first walking unaided had an independent positive correlation (all P < 0.05) with scores of adaptive skills and specific domains. IQ-adaptive functioning gap is significant in children with ASD having IQ ≥ 70, suggesting that defining "high-functioning autism" merely on the basis of IQ is not appropriate. Verbal IQ and early signs of motor development are specific and possible predictors of adaptive functioning in children with ASD, respectively.
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Rechargeable lithium-ion batteries (LIBs) have a wide range of applications but face challenges in harsh working or operating environments at high temperatures. In this work, a solid polymer electrolyte with MWCNT-COOH as an additive (MWCNT-SPE) was obtained. MWCNT-SPE has a high thermal stability and can be used in high-temperature operating environments. Solid-state lithium batteries based on MWCNT-SPE and LiFePO4 were assembled. The resulting lithium batteries exhibited excellent electrochemical properties at 70 and 120 °C, demonstrating a wide range of operations suitable for solid-state batteries with extreme demands. The symmetrical Li/MWCNT-SPE/Li cell operated for 1800 h with low polarization voltage and no short circuit, and the LiFePO4/MWCNT-SPE/Li cell delivered superior cycling performance under both 0.2 and 0.5 C-rates, indicating that the interface compatibility between the lithium metal and MWCNT-SPE membrane was good and could effectively suppress the formation of lithium dendrites. The superior performance of the resulting MWCNT-SPE was due to the weak interaction between PEO, PVDF-HFP, and MWCNT-COOH, which reduced the tendency of PEO's crystallinity and thereby significantly increased the Li+ migration ability and improved the cycling life of the batteries.
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Diamond is the hardest naturally occurring material found on earth but single crystal diamond is brittle due to the nature of catastrophic cleavage fracture. Polycrystalline diamond compact (PDC) materials are made by high pressure and high temperature (HPHT) technology. PDC materials have been widely used in several industries. Wear resistance is a key material property that has long been pursued for its valuable industrial applications. However, the inevitable use of catalysts introduced by the conventional manufacturing process significantly reduces their end-use performance and limits many of their potential applications. In this work, an ultra-strong catalyst-free polycrystalline diamond compact material has been successfully synthesized through innovative ultra-high pressure and ultra-high temperature (UHPHT) technology. These results set up new industry records for wear resistance and thermal stability for PDC cutters utilized for drilling in the oil and gas industry. The new material also broke all single-crystal diamond indenters, suggesting that the new material is too hard to be measured by the current standard single-crystal diamond indentation method. This represents a major breakthrough in hard materials that can expand many potential scientific research and industrial applications.
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Wurtzite boron nitride (wBN), due to its superior properties and many potential practical and scientific applications, such as ideal machining/cutting/milling ferrous and carbide materials, especially as an ideal dielectric substrate material for optical, electronic, and 2-D graphene-based devices, has recently attracted much attention from both academic and industrial fields. Despite decades of research, there is an ongoing debate about if the single-phase wBN is harder than diamond because of the difficulty to make pure wBN material. Here we report the successful synthesis of pure single-phase polycrystalline wurtzite-type boron nitride (wBN) bulk material by using wBN powder as a starting material with a well-controlled process under ultra-high pressure and high temperature. The cubic boron nitride (cBN) was also successfully prepared for the first time from wBN starting material for comparison and verification. The X-ray diffraction (XRD) and TEM clearly confirmed that a pure single-phase wBN compact was produced. The microstructure and mechanical properties including Vickers hardness, fracture toughness, and thermal stability for the pure single-phase wBN was first evaluated.
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Encéfalo/crescimento & desenvolvimento , Deficiência Intelectual/genética , Proteína Proto-Oncogênica N-Myc/genética , Animais , Criança , Pálpebras/anormalidades , Feminino , Humanos , Deformidades Congênitas dos Membros/genética , Camundongos , Microcefalia/genética , Mutação de Sentido Incorreto , Fístula Traqueoesofágica/genéticaRESUMO
BACKGROUND: Alström syndrome is a rare multi-systemic disorder with a broad spectrum of symptoms. This syndrome is characterized by childhood retinal degeneration; sensorineural hearing loss; obesity; type 2 diabetes mellitus; cardiomyopathy; systemic fibrosis; and pulmonary, hepatic, and renal failure. CASE PRESENTATION: A Chinese quartet family with two siblings predominantly affected by cone-rod dystrophy and short stature were recruited. The craniofacial dysmorphism and on-set age-of-cone-rod dystrophy in the proband showed a minor intrafamilial variability. Whole genome sequencing was performed to provide the full spectrum of the two siblings' genetic variations. In this study, we present the patients' clinical features and our interpretation of the whole genome sequencing data. After examining the data, we focus on two compound heterozygous mutations, (c.3902C > A, p.S1301X; c.6436C > T, p.R2146X) in ALMS1, which are shared by two siblings. CONCLUSION: We reported a novel ALMS1 mutation. Whole genome sequencing is a powerful tool to provide the full spectrum of genetic variations for heterogeneous disorders such as Alström syndrome.
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Síndrome de Alstrom/genética , Mutação , Proteínas/genética , Adolescente , Povo Asiático , Proteínas de Ciclo Celular , Criança , Genoma Humano , Humanos , Masculino , Análise de Sequência de DNA , IrmãosRESUMO
OBJECTIVE: To screen for genomic copy number variations (CNVs) in two unrelated neonates with multiple congenital abnormalities using Affymetrix SNP chip and try to find the critical region associated with congenital heart disease. METHOD: Two neonates were tested for genomic copy number variations by using Cytogenetic SNP chip.Rare CNVs with potential clinical significance were selected of which deletion segments' size was larger than 50 kb and duplication segments' size was larger than 150 kb based on the analysis of ChAs software, without false positive CNVs and segments of normal population. The identified CNVs were compared with those of the cases in DECIPHER and ISCA databases. RESULT: Eleven rare CNVs with size from 546.6-27 892 kb were identified in the 2 neonates. The deletion region and size of case 1 were 8p23.3-p23.1 (387 912-11 506 771 bp) and 11.1 Mb respectively, the duplication region and size of case 1 were 8p23.1-p11.1 (11 508 387-43 321 279 bp) and 31.8 Mb respectively. The deletion region and size of case 2 were 8p23.3-p23.1 (46 385-7 809 878 bp) and 7.8 Mb respectively, the duplication region and size of case 2 were 8p23.1-p11.21 (12 260 914-40 917 092 bp) and 28.7 Mb respectively. The comparison with Decipher and ISCA databases supported previous viewpoint that 8p23.1 had been associated with congenital heart disease and the region between 7 809 878-11 506 771 bp may play a role in the severe cardiac defects associated with 8p23.1 deletions. Case 1 had serious cardiac abnormalities whose GATA4 was located in the duplication segment and the copy number increased while SOX7 was located in the deletion segment and the copy number decreased. CONCLUSION: The region between 7 809 878-11 506 771 bp in 8p23.1 is associated with heart defects and copy number variants of SOX7 and GATA4 may result in congenital heart disease.
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Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 8 , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Duplicação Cromossômica/genética , Inversão Cromossômica , Hibridização Genômica Comparativa , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , UltrassonografiaRESUMO
Esophageal atresia is a common and life-threatening birth defect with a poorly understood etiology. In this study, we analyzed the sequence variants of coding regions for a set of esophageal atresia-related genes including MYCN, SOX2, CHD7, GLI3, FGFR2 and PTEN for mutations using PCR-based target enrichment and next-generation sequencing in 27 patients with esophageal atresia. Genomic copy number variation analysis was performed using Affymetrix SNP 6.0. We found a de novo heterozygous mutation in the N-terminal region of the GLI3 gene (c.332T>C, p.M111T) in a patient with esophageal atresia and hemivertebrae. The N-terminal region (amino acids 1-397) of GLI3 contains the repressor domain, which interacts with SKI family proteins. Using the co-immunoprecipitation assay, we found that interaction of GLI3 with the SKI family protein SKIL was significantly compromised by the p.M111T mutation of GLI3. Thus far, all the identified mutations mapped within the repressor domain of GLI3 were nonsense and frame-shift mutations. In this study, a missense mutation was initially detected in this region. Our finding is the first to link this GLI3 gene mutation with esophageal atresia in humans, which was previously suggested in an animal model.
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Biomarcadores Tumorais/genética , Modelos Animais de Doenças , Atresia Esofágica/genética , Fatores de Transcrição Kruppel-Like/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Fístula Traqueoesofágica/genética , Animais , Biomarcadores Tumorais/metabolismo , Variações do Número de Cópias de DNA , Atresia Esofágica/metabolismo , Atresia Esofágica/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoprecipitação , Recém-Nascido , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome , Fístula Traqueoesofágica/metabolismo , Fístula Traqueoesofágica/patologia , Proteína Gli3 com Dedos de ZincoRESUMO
BACKGROUND AND OBJECTIVES: Several studies have suggested a difference in clinical features of intellectual ability and psychiatric illness in the Prader-Willi syndrome (PWS) with the 15q11-q13 paternal deletion and maternal uniparental disomy (mUPD). Our objective was to appraise evidence on this association through a meta-analysis. METHODS: The electronic records PubMed and EMBASE from 1956 to 2012 were extracted for meta-analysis. Meta-analyses were performed by using fixed effect model. Mean difference, odds ratio, and 95% confidence interval were calculated. RESULTS: We retrieved a total of 744 PWS cases from 13 studies. These include 423 cases with paternal 15q11-q13 deletions and 318 cases of mUPD. Compare to the PWS cases with mUPD, PWS patients with the paternal 15q11-q13 deletion associated with significantly lower full scale IQ (FSIQ) [mean difference (MD), -2.69; 95%CI, -4.86 to -0.52; p=0.02] and verbal IQ (VIQ) (MD, -7.5; 95%CI, -9.75 to -5.26; p<0.00001) but higher performance IQ (PIQ) (MD, 4.02; 95%CI, 1.13 to 6.91; p=0.006). In contrast, PWS patients with mUPD are associated with significantly higher risk of psychiatric illness [odds rate (OR), 0.14; 95%CI, 0.08 to 0.23; p<0.00001] and higher risk of bipolar disorder (OR, 0.04; 95%CI, 0.01 to 0.23; p=0.0002). CONCLUSIONS: Significant different clinical features of cognitive development and psychiatric illness are associated with PWS with different molecular defects. These findings provide support for evidence based practice to evaluate and manage the PWS syndrome with different molecular defects.
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Deficiência Intelectual/complicações , Transtornos Mentais/complicações , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Transtorno Bipolar/complicações , Deleção Cromossômica , Humanos , Deficiência Intelectual/genética , Transtornos Mentais/genética , Dissomia UniparentalRESUMO
We report the successful demonstration for low-temperature and high-strain-rate superplastic forming of nanoceramic composites for the first time. Porous preforms of nanoceramic composites that were partially densified at low temperatures were superplastically deformed by SPS at the record low temperatures of approximately 1000 to 1050 degrees C, which are comparable to those of Ni-based superalloys. The maximum strain rate achieved is over 10(-2) s(-1), and a compressive strain over 200% can be obtained without cracking. The final products have nanosized grains with excellent optical properties. The present findings present a new strategy for nanoceramic superplasticity, demonstrating that a more practical application of nanoceramic superplasticity is not in the shaping of already-dense materials but in the near-net-shape forming of partially dense parts.
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Óxido de Alumínio/química , Cerâmica/química , Cristalização/métodos , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Nanotecnologia/métodos , Elasticidade , Dureza , Teste de Materiais , Pós , Propriedades de Superfície , TemperaturaRESUMO
The extraordinary mechanical, thermal and electrical properties of carbon nanotubes have prompted intense research into a wide range of applications in structural materials, electronics, chemical processing and energy management. Attempts have been made to develop advanced engineering materials with improved or novel properties through the incorporation of carbon nanotubes in selected matrices (polymers, metals and ceramics). But the use of carbon nanotubes to reinforce ceramic composites has not been very successful; for example, in alumina-based systems only a 24% increase in toughness has been obtained so far. Here we demonstrate their potential use in reinforcing nanocrystalline ceramics. We have fabricated fully dense nanocomposites of single-wall carbon nanotubes with nanocrystalline alumina (Al2O3) matrix at sintering temperatures as low as 1,150 degrees C by spark-plasma sintering. A fracture toughness of 9.7 MPa m 1/2, nearly three times that of pure nanocrystalline alumina, can be achieved.