SUMMARY The specification of neuronal subtypes in the cerebral cortex proceeds in a temporal manner; however, the regulation of the transitions between the sequentially generated subtypes is poorly understood. Here, we report that the forkhead-box transcription factor Foxg1 coordinates the production of neocortical projection neurons through the global repression of a default gene program. The delayed activation of Foxg1 was necessary and sufficient to induce deep-layer neurogenesis, followed by a sequential wave of upper-layer neurogenesis. A genome-wide analysis revealed that Foxg1 binds to mammalian-specific non-coding sequences to repress over 12 transcription factors expressed in early progenitors, including Ebf2/3, Dmrt3, Dmrta1 and Eya2. These findings reveal an unexpected prolonged competence of progenitors to initiate corticogenesis at a progressed stage during development and identify Foxg1 as a critical initiator of neocorticogenesis through spatiotemporal repression, a system that balances the production of non-radially and radially migrating glutamatergic subtypes during mammalian cortical expansion.
Although most patients with spinal muscular atrophy (SMA) are homozygous for deletion of the SMN1 gene, some patients bear one SMN1 copy with a subtle mutation. Detection of such an intragenic mutation may be helpful not only in confirming diagnosis but also in elucidating functional domains of the SMN protein. In this study, we identified a novel mutation in SMN1 of two Japanese patients with type I SMA. DHPLC and sequencing analysis revealed that they harbored a point mutation in SMN1 exon 3, 275G > C, leading to tryptophan-to-serine substitution at amino acid 92 (W92S) at the Nterminal of SMN Tudor domain. In-vitro protein binding assays showed that the mutation severely reduced interaction of the domain with SmB protein and fibrillarin, suggesting that it impairs the critical function of SMN. In conclusion, we reported here that a novel mutation, W92S, in the Tudor domain affects the interaction of SMN with the target proteins.
Background Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract in neonates. Three polymorphisms, rs2435357, within a conserved transcriptional enhancer of RET, and, rs7835688 and rs16879552, within intron 1 of NRG1, have been shown to be associated with isolated forms of HSCR. We wished to replicate these findings, and study the interactions between these variants, in Indonesian HSCR patients. Methods Sixty isolated HSCR patients and 124 controls were ascertained for this study. The three genetic markers were examined using TaqMan Genotyping Assays in genomic DNA for association studies. Results RET rs2435357 showed the strongest association with HSCR both by case–control analysis (p = 2.5 × 10−8) and transmission disequilibrium test (p = 4.2 × 10−6). NRG1 rs7835688 was modestly associated with HSCR only by case–control analysis (p = 4.3 × 10−3), whereas rs16879552 demonstrated no association (p > 0.097). Two locus analyses of variants showed significant interactions with increased and decreased disease risks of HSCR at NRG1 but conditional on rs2435357 genotype. Conclusions RET and NRG1 variants are common susceptibility factors for HSCR in Indonesia. These common variants demonstrate that development of HSCR requires joint effects of RET and NRG1 early in gut development.
BackgroundMany biomarkers for diagnosis of acute appendicitis in children have been reported, however, the results are still controversial. We assessed the accuracy of neutrophil-lymphocyte ratio (NLR) for diagnosis of acute appendicitis and discriminating simple and complicated appendicitis in children.MethodsWe included 121 patients with acute appendicitis and 49 children with intussusception as controls who were admitted at our hospital from 2013 to 2017. White blood count (WBC), neutrophil, and NLR were compared between groups.ResultsNeutrophil and NLR were significantly higher in the acute appendicitis group than control (76.17 ± 14.41 vs. 62.43 ± 15.9%, p=<0.0001; and 8.44 ± 6.63 vs. 3.38 ± 2.84, p=<0.0001, respectively), while WBC, neutrophil, and NLR were significantly greater in complicated than simple appendicitis (15.86 ± 6.48 vs. 12.64 ± 6.27 × 103/μL, p = 0,008; 82.64 ± 8.41 vs. 68.99 ± 16.23%, p=<0.0001; and 11.32 ± 6.87 vs. 5.25 ± 4.65, p=<0.0001, respectively). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristic (ROC) curve, and cutoff point of NLR for diagnosis of acute appendicitis were 83.5%, 57.7%, 81.4%, 61.2%, 0.764, and 2.87, respectively; whereas the sensitivity, specificity, PPV, NPV, area under the ROC curve, and cutoff point of NLR for differentiating complicated and simple appendicitis were 84.6%, 56.5%, 35.5%, 92.9%, 0.790, and 6.59, respectively.ConclusionNLR shows a high accuracy for diagnosis of acute appendicitis and distinguishing a complicated appendicitis from the simple one.
Background Recently, SARS-CoV-2 virus with the D614G mutation has become a public concern due to rapid dissemination of this variant across many countries. Our study aims were (1) to report full-length genome sequences of SARS-CoV-2 collected from four COVID-19 patients in the Special Region of Yogyakarta and Central Java provinces, Indonesia; (2) to compare the clade distribution of full-length genome sequences from Indonesia (n = 60) from March to September 2020 and (3) to perform phylogenetic analysis of SARS-CoV-2 complete genomes from different countries, including Indonesia. Methods Whole genome sequencing (WGS) was performed using next-generation sequencing (NGS) applied in the Illumina MiSeq instrument. Full-length virus genomes were annotated using the reference genome of hCoV-19/Wuhan/Hu-1/2019 (NC_045512.2) and then visualized in UGENE v. 1.30. For phylogenetic analysis, a dataset of 88 available SARS-CoV-2 complete genomes from different countries, including Indonesia, was retrieved from GISAID. Results All patients were hospitalized with various severities of COVID-19. Phylogenetic analysis revealed that one and three virus samples belong to clade L and GH. These three clade GH virus samples (EPI_ISL_525492, EPI_ISL_516800 and EPI_ISL_516829) were not only located in a cluster with SARS-CoV-2 genomes from Asia but also those from Europe, whereas the clade L virus sample (EPI_ISL_516806) was located amongst SARS-CoV-2 genomes from Asia. Using full-length sequences available in the GISAID EpiCoV Database, 39 of 60 SARS-CoV-2 (65%) from Indonesia harbor the D614G mutation. Conclusion These findings indicate that SARS-CoV-2 with the D614G mutation appears to become the major circulating virus in Indonesia, concurrent with the COVID-19 situation worldwide.
The number of laboratory-confirmed CRS cases among Indonesian infants is high. Furthermore, hearing impairment is the most common clinical feature of CRS in infants. Our findings indicate the importance of implementation of rubella vaccine in Indonesia. Conducting hospital-based surveillance of CRS in other hospitals in Indonesia may be appropriate. What is Known: •Congenital rubella syndrome (CRS) has serious consequences in infants resulting from rubella virus infection during pregnancy. •The incidence of CRS in most developed countries has greatly decreased since implementation of rubella vaccination. •Rubella vaccine has not yet been implemented in many developing countries. What is New: •The number of laboratory-confirmed CRS cases among Indonesian infants was high. •Implementation of rubella vaccine into immunization programs in Indonesia is important because of the high number of CRS cases. •Our study highlights the need for ongoing prospective surveillance of CRS in Indonesia.
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