3D reconstruction of a gastrulating human embryo.

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.

The knockdown of miR-23b enhances radio-sensitivity of lung cancer A549 cell via targeting PTEN / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect of miR-23b/PTEN molecular axis on radio-sensitivity of lung cancerA549 cells and its mechanism. Methods: Lung cancer cell lines NCI-H1650, NCI-H175, Calu-1, LT-P-A-2, MSTO-211H, A549 and human normal lung epithelial cell line BEAS-2B were selected. The expression level of miR-23b in lung cancer cell lines was detected by qPCR. Dual-luciferase reporter gene assay was used to verify the relationship between miR-23b and PTEN. Plasmids miR-23b mimics, miR-23b inhibitor and pcDNA3.1-PTEN were transfected intoA549 cells by lipofection; PTEN expression levels in cells was detected by WB. CCK-8, Transwell andAnnexin V-FITC/PI staining flow cytometry were used to detect the effect of miR-23b/PTEN axis on proliferation, invasion and apoptosis ofA549 cells treated with 60Co γ-ray. Results: miR-23b was upregulated in lung cancer cell lines with the highest expression in A549 cells (P<0.05 or P<0.01). Knockdown of miR-23b reversed the inhibitory effect of 3 Gy 60Co γ-rays on proliferation and invasion of A549 cells, and induced apoptosis (P<0.05 or P<0.01). Dual-luciferase reporter gene assay results confirmed that miR23b could negatively regulate PTEN (P<0.05). Furthermore, knockdown of miR-23b up-regulated PTEN expression level, and furhter enhanced the inhibitory effect of 3 Gy 60Co γ-ray on the proliferation and invasion of A549 cells as well as induced apoptosis of A549 cells (P<0.05 or P<0.01). Conclusion: Knockdown of miR-23b can enhance the radio-sensitivity of A549 cells, the mechanism of which is that 60Co γ-ray down-regulates the inhibitory effect of miR-23b on PTEN, thereby inhibiting the proliferation, invasion and inducing apoptosis ofA549 cells.