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Polycomb group (PcG) proteins are known to repress developmental genes during embryonic development and tissue homeostasis. Here, we report that PCGF6 controls neuroectoderm specification of human pluripotent stem cells (PSCs) by activating SOX2 gene. Human PSCs with PCGF6 depletion display impaired neuroectoderm differentiation coupled with increased mesendoderm outcomes. Transcriptome analysis reveals that de-repression of the WNT/β-catenin signaling pathway is responsible for the differentiation of PSC toward the mesendodermal lineage. Interestingly, PCGF6 and MYC directly interact and co-occupy a distal regulatory element of SOX2 to activate SOX2 expression, which likely accounts for the regulation in neuroectoderm differentiation. Supporting this notion, genomic deletion of the SOX2-regulatory element phenocopies the impaired neuroectoderm differentiation, while overexpressing SOX2 rescues the neuroectoderm phenotype caused by PCGF6-depletion. Together, our study reveals that PCGF6 can function as lineage switcher between mesendoderm and neuroectoderm in human PSCs by both suppression and activation mechanisms. Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.

Background Extensive studies have revealed the function and mechanism of lncRNAs in development and differentiation, but the majority have focused on those lncRNAs adjacent to protein-coding genes. In contrast, lncRNAs located in gene deserts are rarely explored. Here, we utilize multiple differentiation systems to dissect the role of a desert lncRNA, HIDEN ( h uman I MP1-associated \" d esert\" definitive e ndoderm l n cRNA), in definitive endoderm differentiation from human pluripotent stem cells. Results We show that desert lncRNAs are highly expressed with cell-stage-specific patterns and conserved subcellular localization during stem cell differentiation. We then focus on the desert lncRNA HIDEN which is upregulated and plays a vital role during human endoderm differentiation. We find depletion of HIDEN by either shRNA or promoter deletion significantly impairs human endoderm differentiation. HIDEN functionally interacts with RNA-binding protein IMP1 (IGF2BP1), which is also required for endoderm differentiation. Loss of HIDEN or IMP1 results in reduced WNT activity, and WNT agonist rescues endoderm differentiation deficiency caused by the depletion of HIDEN or IMP1. Moreover, HIDEN depletion reduces the interaction between IMP1 protein and FZD5 mRNA and causes the destabilization of FZD5 mRNA, which is a WNT receptor and necessary for definitive endoderm differentiation. Conclusions These data suggest that desert lncRNA HIDEN facilitates the interaction between IMP1 and FZD5 mRNA, stabilizing FZD5 mRNA which activates WNT signaling and promotes human definitive endoderm differentiation.

Background Understanding the lineage differentiation of human prostate not only is crucial for basic research on human developmental biology but also significantly contributes to the management of prostate-related disorders. Current knowledge mainly relies on studies on rodent models, lacking human-derived alternatives despite clinical samples may provide a snapshot at certain stage. Human embryonic stem cells can generate all the embryonic lineages including the prostate, and indeed a few studies demonstrate such possibility based on co-culture or co-transplantation with urogenital mesenchyme into mouse renal capsule. Methods To establish a stepwise protocol to obtain prostatic organoids in vitro from human embryonic stem cells, we apply chemicals and growth factors by mimicking the regulation network of transcription factors and signal transduction pathways, and construct cell lines carrying an inducible NKX3-1 expressing cassette, together with three-dimensional culture system. Unpaired t test was applied for statistical analyses. Results We first successfully generate the definitive endoderm, hindgut, and urogenital sinus cells. The embryonic stem cell-derived urogenital sinus cells express prostatic key transcription factors AR and FOXA1, but fail to express NKX3-1. Therefore, we construct NKX3-1 -inducible cell line by homologous recombination, which is eventually able to yield AR, FOXA1, and NKX3-1 triple-positive urogenital prostatic lineage cells through stepwise differentiation. Finally, combined with 3D culture we successfully derive prostate-like organoids with certain structures and prostatic cell populations. Conclusions This study reveals the crucial role of NKX3-1 in prostatic differentiation and offers the inducible NKX3-1 cell line, as well as provides a stepwise differentiation protocol to generate human prostate-like organoids, which should facilitate the studies on prostate development and disease pathogenesis.

Functional CD8 + T cell immunity is essential for immune surveillance and host defense against infection and tumors. Epigenetic mechanisms, particularly RNA modification, in controlling CD8 + T cell immune response is not fully elucidated. Here, by T cell-specific deletion of fat mass and obesity-associated protein (FTO), a critical N6-methyladenosine (m 6 A) demethylase, we revealed that FTO was indispensable for adequate CD8 + T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8 + T cells, which was attributed to cell apoptosis. MeRIP-seq analysis revealed an increase in m 6 A methylation on Fas mRNA in FTO-deficient CD8 + T cells. The loss of FTO promoted Fas expression via enhancing the Fas mRNA stability, which depended on the m 6 A reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the Fas m 6 A sites or knockdown IGF2BP3 could normalize the upregulated Fas expression and apoptosis levels caused by FTO ablation in CD8 + T cells. Our findings delineate a novel epigenetic regulatory mechanism of FTO-mediated m 6 A modification in supporting CD8 + T cell survival and effector responses, providing new insights into understanding the post-transcriptional regulation in CD8 + T cell immunological functions and the potential therapeutic intervention.

Background T cell homeostasis is crucial for maintaining T cell population size and upcoming protective immunity in the peripheral organs. However, it remains largely unknown about the intracellular molecules and pathways beyond IL-7R signaling. Zfp335, as a key transcription factor, is involved in the multiple-stage development of thymocytes, and effector and memory T cell differentiation during immune responses. Results In current study, we found an upregulated expression of ZFP335 in both CD4 + and CD8 + T cells during peripheral homeostasis. In an adoptive transfer model, Zfp335 −/− T cells failed to undergo homeostatic proliferation without survival defect. Consistently, deletion of Zfp335 impaired T cell proliferation in in vitro culture with IL-7. Furthermore, both RNA-Sequencing and qPCR analysis showed that Zfp335 significantly affected the expression of cell cycle-related genes. Mechanistically, Zfp335 directly binds to the promoter of Lmnb1 gene and regulates its transcription. Overexpression of Lmnb1 significantly rescued the impaired proliferation of Zfp335 −/− T cells. Conclusion Our results reveal a previously unrecognized role of Zfp335 in maintaining T cell homeostasis within peripheral lymphoid tissues. Specifically, Zfp335 promotes the homeostatic proliferation of naïve T cells by directly modulating the expression of the Lmnb1 gene which ensuring the capacity of immune system.

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas unknown_T cells were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift- myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). The shift- myeloid signature was also found to be associated with KD treatment resistance, and effective therapies improve treatment outcomes by reducing this signaling. Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model PHARE ( https://xiazlab.org/phare/ ), which can apply to both scRNA-seq and bulk RNA-seq data. Using this model, we found patients with coronary artery disease (CAD) also exhibit accelerated aging compared to healthy individuals. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

The effect of cropping system on the distribution of organic carbon (OC) and nitrogen (N) in soil aggregates has not been well addressed, which is important for understanding the sequestration of OC and N in agricultural soils. We analyzed the distribution of OC and N associated with soil aggregates in three unfertilized cropping systems in a 27-year field experiment: continuously cropped alfalfa, continuously cropped wheat and a legume-grain rotation. The objectives were to understand the effect of cropping system on the distribution of OC and N in aggregates and to examine the relationships between the changes in OC and N stocks in total soils and in aggregates. The cropping systems increased the stocks of OC and N in total soils (0-40 cm) at mean rates of 15.6 g OC m-2 yr-1 and 1.2 g N m-2 yr-1 relative to a fallow control. The continuous cropping of alfalfa produced the largest increases at the 0-20 cm depth. The OC and N stocks in total soils were significantly correlated with the changes in the >0.053 mm aggregates. 27-year of cropping increased OC stocks in the >0.053 mm size class of aggregates and N stocks in the >0.25 mm size class but decreased OC stocks in the <0.053 mm size class and N stocks in the <0.25 mm size class. The increases in OC and N stocks in these aggregates accounted for 99.5 and 98.7% of the total increases, respectively, in the continuous alfalfa system. The increases in the OC and N stocks associated with the >0.25 mm aggregate size class accounted for more than 97% of the total increases in the continuous wheat and the legume-grain rotation systems. These results suggested that long-term cropping has the potential to sequester OC and N in soils and that the increases in soil OC and N stocks were mainly due to increases associated with aggregates >0.053 mm.

The electric power intelligent inspection robot is equipped with high-definition visible light camera, infrared thermal imager, sound-collecting equipment and other intelligent detection devices and intelligent analysis algorithm software to complete the control loop from rapid acquisition of all-weather data, real-time information transmission, intelligent analysis and early warning to fast decision feedback. Therefore, instead of manual inspection, the automatic detection and intelligent analysis of the state of the power equipment are realized, and the reliability of the operation of the power grid and the power equipment is improved. The use of electric power intelligent inspection robots is an important means to realize the intelligentization of power grids, and is an important direction for the future development of smart grids. Given the current research status and deficiencies at home and abroad, this paper discusses the electric power intelligent inspection robots from aspects of main technologies, cutting-edge technology, functional positioning and standard system, and discusses the research status of electric intelligent inspection robots. On this basis, future research and development direction are put forward. This paper has a guiding role and reference value for the research of electric power intelligent inspection robot.

Deep learning is good at abstract features from massive data and has good generalization ability, which has attracted more and more researchers' attention. The Convolutional Neural Network (CNN) is a classic structure of deep learning and which is being widely and successfully used in the fields of computer vision, target detection, natural language processing, and speech recognition. Based on a detailed analysis of the current status and needs of mechanical system fault diagnosis, this paper introduces the structure of CNN and summarizes the application of CNN in the field of mechanical faults from the aspects of input data type, network structure design, and migration learning. The problems of deep feature extraction and visualization are also discussed, and finally, the difficulties in mechanical fault diagnosis are analyzed and several problems to be solved in the field of mechanical fault diagnosis based on CNN prospect.

Epigenetic modifications play a crucial role in neurogenesis, learning, and memory, but the study of their role in early neuroectoderm commitment from pluripotent inner cell mass is relatively lacking. Here we utilized the system of directed neuroectoderm differentiation from human embryonic stem cells and identified that KDM6B, an enzyme responsible to erase H3K27me3, was the most upregulated enzyme of histone methylation during neuroectoderm differentiation by transcriptome analysis. We then constructed KDM6B-null embryonic stem cells and found strikingly that the pluripotent stem cells with KDM6B knockout exhibited much higher neuroectoderm induction efficiency. Furthermore, we constructed a series of embryonic stem cell lines knocking out the other H3K27 demethylase KDM6A, and depleting both KDM6A and KDM6B, respectively. These cell lines together confirmed that KDM6 impeded early neuroectoderm commitment. By RNA-seq, we found that the expression levels of a panel of WNT genes were significantly affected upon depletion of KDM6. Importantly, the result that WNT agonist and antagonist could abolish the differential neuroectoderm induction due to manipulating KDM6 further demonstrated that WNT was the major downstream of KDM6 during early neural induction. Moreover, we found that the chemical GSK-J1, an inhibitor of KDM6, could enhance neuroectoderm induction from both embryonic stem cells and induced pluripotent stem cells. Taken together, our findings not only illustrated the important role of the histone methylation modifier KDM6 in early neurogenesis, providing insights into the precise epigenetic regulation in cell fate determination, but also showed that the inhibitor of KDM6 could facilitate neuroectoderm differentiation from human pluripotent stem cells.