Silicate Microfiber Scaffolds Support the Formation and Expansion of the Cortical Neuronal Layer of Cerebral Organoids With a Sheet-Like Configuration

Terada Eisaku, Bamba Yohei, Takagaki Masatoshi, et al. Silicate Microfiber Scaffolds Support the Formation and Expansion of the Cortical Neuronal Layer of Cerebral Organoids With a Sheet-Like Configuration. Stem Cells Translational Medicine 9, 519 (2023); https://doi.org/10.1093/stcltm/szad066.Cerebral organoids (COs) are derived from human-induced pluripotent stem cells in vitro and mimic the features of the human fetal brain. The development of COs is largely dependent on “self-organization” mechanisms, in which differentiating cells committed to cortical cells autonomously organize into the cerebral cortex-like tissue. However, extrinsic manipulation of their morphology, including size and thickness, remains challenging. In this study, we discovered that silicate microfiber scaffolds could support the formation of cortical neuronal layers and successfully generated cortical neuronal layers, which are 9 times thicker than conventional COs, in 70 days. These cortical neurons in the silicate microfiber layer were differentiated in a fetal brain-like lamination pattern. While these cellular characteristics such as cortical neurons and neural stem/progenitor cells were like those of conventional COs, the cortical neuronal layers were greatly thickened in sheet-like configuration. Moreover, the cortical neurons in the scaffolds showed spontaneous electrical activity. We concluded that silicate microfiber scaffolds support the formation of the cortical neuronal layers of COs without disturbing self-organization-driven corticogenesis. The extrinsic manipulation of the formation of the cortical neuronal layers of COs may be useful for the research of developmental mechanisms or pathogenesis of the human cerebral cortex, particularly for the development of regenerative therapy and bioengineering

Genome-wide association study on meningioma risk in Japan: a multicenter prospective study

The version of record of this article, first published in Journal of Neuro-Oncology, is available online at Publisher’s website: https://doi.org/10.1007/s11060-024-04727-x.Purpose: Although meningiomas are the most common primary intracranial tumors, their genetic etiologies have not been fully elucidated. To date, only two genome-wide association studies (GWASs) have focused on European ancestries, despite ethnic differences in the incidence of meningiomas. The aim of this study was to conduct the first GWAS of Japanese patients with meningiomas to identify the SNPs associated with meningioma susceptibility. Methods: In this multicenter prospective case-control study, we studied 401 Japanese patients with meningioma admitted in five institutions in Japan, and 50,876 control participants of Japanese ancestry enrolled in Biobank Japan. Results: The quality control process yielded 536,319 variants and imputation resulted in 8,224,735 variants on the autosomes and 224,820 variants on the X chromosomes. This GWAS eventually revealed no genetic variants with genome-wide significance (P < 5 × 10 − 8) and observed no significant association in the previously reported risk variants rs11012732 and rs2686876 due to low minor allele frequency in the Japanese population. Conclusion: This is the first GWAS of meningiomas in East Asian populations and is expected to contribute to the development of GWAS research for meningiomas

Discrimination of Dormant and Active Hematopoietic Stem Cells by G₀ Marker Reveals Dormancy Regulation by Cytoplasmic Calcium

Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generate a G0 marker (G0M) mouse line that visualizes quiescent cells and identify a small population of active HSCs (G0Mlow), which are distinct from dormant HSCs (G0Mhigh), within the conventional quiescent HSC fraction. Single-cell RNA-seq analyses show that the gene expression profiles of these populations are nearly identical but differ in their Cdk4/6 activity. Furthermore, high-throughput small-molecule screening reveals that high concentrations of cytoplasmic calcium ([Ca2+]c) are linked to dormancy of HSCs. These findings indicate that G0M separates dormant and active adult HSCs, which are regulated by Cdk4/6 and [Ca2+]c. This G0M mouse line represents a useful resource for investigating physiologically important stem cell subpopulations

Discrimination of Dormant and Active Hematopoietic Stem Cells by G₀ Marker Reveals Dormancy Regulation by Cytoplasmic Calcium

Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generate a G0 marker (G0M) mouse line that visualizes quiescent cells and identify a small population of active HSCs (G0Mlow), which are distinct from dormant HSCs (G0Mhigh), within the conventional quiescent HSC fraction. Single-cell RNA-seq analyses show that the gene expression profiles of these populations are nearly identical but differ in their Cdk4/6 activity. Furthermore, high-throughput small-molecule screening reveals that high concentrations of cytoplasmic calcium ([Ca2+]c) are linked to dormancy of HSCs. These findings indicate that G0M separates dormant and active adult HSCs, which are regulated by Cdk4/6 and [Ca2+]c. This G0M mouse line represents a useful resource for investigating physiologically important stem cell subpopulations

Solar System Exploration Sciences by EQUULEUS on SLS EM-1 and Science Instruments Development Status

EQUULEUS is a spacecraft to explore the cislunar region including the Earth-Moon Lagrange point L2 (EML2) and will be launched by NASA’s SLS EM-1 rocket. Although the size of EQUULEUS is only 6U, the spacecraft carries three different science instruments. By using these instruments, the spacecraft will demonstrate three missions for solar system exploration science during and after the flight to EML2; imaging of the plasmasphere around the earth, observation of space dust flux in the cislunar region, and observation of lunar impact flashes at the far side of the moon. The developments and verifications of the flight models of these science instruments were completed by the end of 2018, and we started flight model integration and testing. This paper introduces the details of the scientific objectives, design results and development statuses of the instruments. In addition, results of the integration and pre-flight tests are also described

Analysis of gut microbiome, host genetics, and plasma metabolites reveals gut microbiome-host interactions in the Japanese population

Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7β-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.Tomofuji Yoshihiko, Kishikawa Toshihiro, Sonehara Kyuto, et al. Analysis of gut microbiome, host genetics, and plasma metabolites reveals gut microbiome-host interactions in the Japanese population. Cell Reports 42, 113324 (2023); https://doi.org/10.1016/j.celrep.2023.113324

Intracoronary Autologous Cardiac Progenitor Cell Transfer in Patients With Hypoplastic Left Heart Syndrome (TICAP) : A Prospective Phase 1 Controlled Trial

RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes

Functional annotation of human long noncoding RNAs via molecular phenotyping

Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, we systematically knocked down the expression of 285 lncRNAs in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNAs exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest-todate lncRNA knockdown data set with molecular phenotyping (over 1000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.Peer reviewe

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target