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Histone modifications regulate gene expression and development. To address how they are reprogrammed in human early development, we investigated key histone marks in human oocytes and early embryos. Unlike that in mouse oocytes, the permissive mark trimethylated histone H3 lysine 4 (H3K4me3) largely exhibits canonical patterns at promoters in human oocytes. After fertilization, prezygotic genome activation (pre-ZGA) embryos acquire permissive chromatin and widespread H3K4me3 in CpG-rich regulatory regions. By contrast, the repressive mark H3K27me3 undergoes global depletion. CpG-rich regulatory regions then resolve to either active or repressed states upon ZGA, followed by subsequent restoration of H3K27me3 at developmental genes. Finally, by combining chromatin and transcriptome maps, we revealed transcription circuitry and asymmetric H3K27me3 patterning during early lineage specification. Collectively, our data unveil a priming phase connecting human parental-to-zygotic epigenetic transition.

Upon fertilization, drastic chromatin reorganization occurs during preimplantation development 1 . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) 2 . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis -regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing 3 – 5 . Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization. By applying an optimized ATAC-seq protocol to human early embryos, distinct accessible chromatin landscapes are found before and after zygotic genome activation, revealing a marked epigenetic transition during zygotic genome activation and putative regulatory elements wiring human early development.

CO2-switchable poly(methyl methacrylate) (PMMA) latexes were prepared by surfactant-free emulsion polymerization using the initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044) and a small fraction of functional comonomer N,N-dimethylaminoethyl methacrylate (DMAEMA). The latexes demonstrated superior CO2 responsive behavior with rapid aggregation, and with a complete recovery of particle size and polydispersity upon redispersion without requiring high-energy mixing and within a short period of time. Particle size was successfully tuned in a range of 170 ~ 500 nm by varying the ratio of VA-044:DMAEMA, total amount of stabilizing moieties (VA-044 + DMAEMA), temperature, and solid content. Both particle size and CO2-switchable performance were closely related to the ratio of VA-044:DMAEMA, with the ratio of VA-044:DMAEMA = 1:3 yielding both the smallest particle size and the most efficient CO2 responsiveness.

Background Omics technologies are widely applied in assisted reproductive technology (ART), such as embryo selection, investigation of infertility causes, and mechanisms underlying reproductive cell development. While RNAomics has shown great potential in investigating the physiology and pathology in female reproductive system, its applications are still not fully developed. More studies on epitranscriptomic regulation mechanisms and novel sequencing methods are needed to advance the field. Results Here, we developed a method named Cap to Tail sequencing application (C2T-APP) and simultaneously characterized the m 7 G cap, poly(A) tail structure, and gene expression level for the intact RNA molecules in single cells. C2T-APP distinguished the N6, 2′-O-dimethyladenosine modification (m 6 A m ) from N 6 -methyladenosine (m 6 A) modification with our published single-cell m 6 A sequencing (scm 6 A-seq) data. During oocyte maturation, we found a positive correlation of m 7 G and m 6 A m with translation efficiency and finely dissected the step-wised maternal RNA de-capping and de-tailing of different types of genes. Strikingly, we uncovered a subtle structural mechanism regulating poly(A) tails in oocytes: maternal RNA translation is temporarily suppressed by removing the poly(A) tails without complete degradation, while the poly(A)-tail regulators themselves depend strictly on translation initiated after meiotic resumption. Furthermore, we profiled single-cell RNA-multi-omic features of human oocytes with different qualities during in vitro culture maturation (IVM). Defects of epi-transcriptome features, including m 6 A, m 6 A m , m 7 G, and poly(A) structure of maternal RNA in the oocytes with poor quality, were detected. Conclusions Our results provided a valuable tool for RNAomics research and data resources provided novel insights into human oocyte maturation, which is helpful for IVM and oocyte selection for ART.

This study combined field survey data with Gaofen 5 (GF-5) satellite hyperspectral images of the Yuncheng Basin (China), considering 15 environmental variables. Random forest (RF) was used to select the optimal satellite hyperspectral model, sequentially introducing natural and farmland management factors into the model to analyze the spatial distribution of farmland soil organic carbon (SOC). Furthermore, RF factorial experiments determined the contributions of farmland management, climate, vegetation, soil, and topography to the SOC. Structural equation modeling (SEM) elucidated the driving mechanisms of SOC variations. Integrating satellite hyperspectral data and environmental variables improved the prediction accuracy and SOC-mapping precision of the model. The integration of natural variables significantly improved the RF model performance (R2 = 0.78). The prediction accuracy enhanced with the introduction of crop phenology (R2 = 0.81) and farmland management factors (R2 = 0.87). The model that incorporated all 15 variables demonstrated the highest prediction accuracy (R2 = 0.89) and greatest spatial SOC variability, with minimal uncertainty. Farmland management activities exerted the strongest influence on SOC (0.38). The proposed method can support future investigations on soil carbon sequestration processes in river basins worldwide.

Mapping soil organic carbon (SOC) accurately is essential for sustainable soil resource management. Hyperspectral data, a vital tool for SOC mapping, is obtained through both laboratory and satellite-based sources. While laboratory data is limited to sample point monitoring, satellite hyperspectral imagery covers entire regions, albeit susceptible to external environmental interference. This study, conducted in the Yuncheng Basin of the Yellow River Basin, compared the predictive accuracy of laboratory hyperspectral data (ASD FieldSpec4) and GF-5 satellite hyperspectral imagery for SOC mapping. Leveraging fractional order derivatives (FODs), various denoising methods, feature band selection, and the Random Forest model, the research revealed that laboratory hyperspectral data outperform satellite data in predicting SOC. FOD processing enhanced spectral information, and discrete wavelet transform (DWT) proved effective for GF-5 satellite imagery denoising. Stability competitive adaptive re-weighted sampling (sCARS) emerged as the optimal feature band selection algorithm. The 0.6FOD-sCARS RF model was identified as the optimal laboratory hyperspectral prediction model for SOC, while the 0.8FOD-DWT-sCARS RF model was deemed optimal for satellite hyperspectral prediction. This research, offering insights into farmland soil quality monitoring and strategies for sustainable soil use, holds significance for enhancing agricultural production efficiency.

Background Recent studies about the effect of gonadotropin (Gn) dose on the clinical outcomes of IVF are still controversial, and no studies have analyzed the relationship between Gn dose and embryo quality. Since AMH is a strong predictor of oocyte quality, we aim to evaluate the relationship between total Gn dose and embryo quality and clinical outcomes at different AMH levels in IVF cycles. Methods A total of 12,588 patients were enrolled in the retrospective study. The included cycles were categorized by serum AMH levels (AMH ≤ 1 ng/ml, 1 ng/ml < AMH ≤ 3 ng/ml, 3 ng/ml < AMH ≤ 5 ng/ml, AMH > 5 ng/ml), total Gn dosage (< 1875 IU, 1875–3750 IU and ≥ 3750 IU) and female age (< 35 years and 35–42 years). The embryo quality and clinical outcomes were the measure outcomes. Results The top-day3 embryos rate decreased with the increase of total Gn dose in nearly all age and AMH subgroups, but this trend was not obvious in the AMH > 5 ng/ml group and AMH ≤ 1 ng/ml group. The blastocyst formation rate and high-quality blastulation rate had a negative relationship with Gn does for women aged < 35 years in the AMH ≤ 5 ng/ml groups, except for the AMH > 5 ng/ml group ( P  < 0.001). However, when women were 35–42 years old, regardless of AMH levels, the blastocyst formation rate and high-quality blastulation rate decreased as Gn dose increased. Clinical outcomes (implantation rate, clinical pregnancy rate and live birth rate) decreased with the increase of Gn dose in all ages and AMH stratifications. Conclusions The total dose of Gn may have different effects on embryo quality at different serum AMH levels, and the negative effects of total dose of Gn on clinical outcomes may be realized by impairing both embryo quality and endometrium.

Background Clinical trials have shown that neoadjuvant anlotinib combined with PD-1 blockade therapy can prolong the survival of patients with driver gene negative non-small cell lung cancer (NSCLC), but some patients fail to benefit from the combination therapy. Methods To explore the potential drug resistance mechanism and predict the efficacy of neoadjuvant therapy in NSCLC patients, we used scRNA-seq to observe and analyze the dynamic changes of immune cells, stromal cells and cancer cells in NSCLC patients who received neoadjuvant combination therapy. We analyzed transcriptome data of ~ 47,000 single cells from 9 NSCLC patients, including 3 treatment naïve patients, 3 post-treatment patients with major pathological response (MPR), and 3 Non-MPR patients. Subsequently, the infiltration of immune cells was detected by immunohistochemistry and multiplex immunofluorescence in NSCLC. Results In MPR patients, we found that neoadjuvant therapy reduced the expression of the T cell exhausted signature, reduced the transition of T_THEMIS cells to Tregs, and enhanced the positive feedback between CD4 + T cells and PAX5 + memory B cells. In Non-MPR patients, tumor-associated macrophages (TAMs) dampen therapeutic efficiency by being the hub of cell communication. TAMs and fibroblasts stimulate endothelial cells via VEGF, endothelial ZEB1 may up-regulate FLT1 (VEGFR) expression in response to anlotinib, and VEGFR + endothelial cell signature can predict survival of NSCLC cohort in TCGA. In addition, PLA2G4A, the key enzyme in the VEGF pathway, was highly expressed in the tumor cells of Non-MPR patients after anlotinib treatment. In 135 NSCLC patients, we confirmed by immunohistochemistry that PLA2G4A was positively correlated with poor prognosis and Tregs infiltration. Conclusion In conclusion, VEGF signaling dependent dynamic changes in endothelial and epithelial cells are deeply involved in the formation of anlotinib resistance and immunosuppression phenotypes in NSCLC patients.

Background Agar-like zona pellucida (ZP) is the most common type of abnormal ZP, and is one of the causes of low fertility or infertility. However, the molecular mechanism of agar-like ZP is unclear. Single-cell RNA-sequencing (scRNA-seq) analysis was used to assess the cellular and molecular landscape of oocytes with agar-like ZP. Methods Human metaphase I (MI) oocytes were collected from four patients with agar-like ZP and four healthy donors. Total RNA was isolated, cDNA was synthesized, and libraries were generated and subsequently sequenced on a HiSeq 2500 instrument. The scRNA-seq data were analyzed with R software. Results We identified 1320 genes that were differentially expressed between agar-like ZP oocytes and healthy donor oocytes. Gene Ontology term enrichment results showed that the genes downregulated in agar-like ZP oocytes were significantly related to extracellular matrix organization, while the genes upregulated in agar-like ZP oocytes were significantly related to the regulation of response to DNA damage stimulus. The Kyoto Encyclopedia of Genes and Genomes enrichment results showed that genes were enriched in the ECM-receptor interaction pathway and focal adhesion pathway. Other signaling pathways important in oocyte development were also enriched, such as PI3K-Akt. Differential expression analysis identified UBC , TLR4 , RELA , ANXA5 , CAV1 , KPNA2 , CCNA2 , ACTA2 , FYN and ITGB3 as genetic markers of oocytes with agar-like ZP. Conclusions Our findings suggest that agar-like ZP oocytes exhibit significant downregulation of genes involved in the ECM-receptor interaction signaling pathway and focal adhesion pathway, which could lead to aberrant ZP formation, while the upregulated genes were significantly related to regulation of the response to DNA damage stimulus. Agar-like ZP formation may interfere with the normal exchange of signals between oocytes and perivitelline granulosa cells, thereby preventing cumulus cells from participating in oocyte DNA damage repair and causing MI arrest.

Objectives To explore the incidence of retained embryos (REs) in embryo transfer (ET) cycles and its effects on pregnancy outcomes in women undergoing in vitro fertilization (IVF). Methods This was a matched retrospective cohort study involving 29,160 ET cycles conducted from March 2016 to February 2021, in which ET cycles without RE were matched to the RE group at a 2:1 ratio. Clinical pregnancy, implantation, miscarriage, and live birth rates were compared between the with-RE and without-RE groups. Results Our study showed that the overall incidence of REs was 0.33% (95/29,160). There was a statistically significant difference in RE rate among the operators ( P  < 0.001), suggesting that the embryo retention rate may be affected by the individual operator. A total of 95 repeated ET cycles due to RE were included in the study group, and 190 ET cycles without RE were matched to the study group (1:2). There were no significant differences between the RE and matched groups in terms of implantation rate (35.6 vs. 38.0%; P  = 0.608), clinical pregnancy rate (47.4 vs. 54.7%; P  = 0.240), biochemical pregnancy rate (5.3 vs. 4.7%; P  = 0.846), miscarriage rate (11.1 vs. 9.6%; P  = 0.781), ectopic pregnancy rate (2.2 vs. 1.9%; P  = 1.000) or live birth rate (41.1 vs. 48.9%; P  = 0.208). Conclusions The present findings demonstrated that immediate retransfer of REs did not significantly affect IVF outcomes, which may provide counselling information for patients when REs are identified and ET is reattempted. The incidence of REs was associated with the operator who expelled the embryos from the catheter. Attention to detail and frequent assessment of the operator’s technique may facilitate avoidance of embryo retention.