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Animal cloning can be achieved by somatic cell nuclear transfer (SCNT), but the resulting live birth rate is relatively low. We previously improved the efficiency of bovine SCNT by exogenous melatonin treatment or by overexpression of lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E). In this study, we revealed abundant alternative splicing (AS) transitions during fertilization and embryonic genome activation, and demonstrated abnormal AS in bovine SCNT embryos compared with in vitro fertilized embryos. We used the CRISPR-Cas13d RNA-targeting system to target cis-elements of ABI2 and ZNF106 pre-mRNA to modify AS, thus reducing the ratio of abnormal-isoform SCNT embryos by nearly 50% and achieving a high survival rate (11%-19%). These results indicate that this system may provide an efficient method for bovine cloning, while also paving the way for further improvements in the efficiency of SCNT.

DNA methylation is an epigenetic modification that plays a vital role in a variety of biological processes, including the regulation of gene expression, cell differentiation, early embryonic development, genomic imprinting, and X chromosome inactivation. PGC7 is a maternal factor that maintains DNA methylation during early embryonic development. One mechanism of action has been identified by analyzing the interactions between PGC7 and UHRF1, H3K9 me2, or TET2/TET3, which reveals how PGC7 regulates DNA methylation in oocytes or fertilized embryos. However, the mechanism by which PGC7 regulates the post-translational modification of methylation-related enzymes remains to be elucidated. This study focused on F9 cells (embryonic cancer cells), which display high levels of PGC7 expression. We found that both knockdown of Pgc7 and inhibition of ERK activity resulted in increased genome-wide DNA methylation levels. Mechanistic experiments confirmed that inhibition of ERK activity led to the accumulation of DNMT1 in the nucleus, ERK phosphorylated DNMT1 at ser717, and DNMT1 Ser717-Ala mutation promoted the nuclear localization of DNMT1. Moreover, knockdown of Pgc7 also caused downregulation of ERK phosphorylation and promoted the accumulation of DNMT1 in the nucleus. In conclusion, we reveal a new mechanism by which PGC7 regulates genome-wide DNA methylation via phosphorylation of DNMT1 at ser717 by ERK. These findings may provide new insights into treatments for DNA methylation-related diseases.

Various geological disasters such as collapses, landslides, and mudslides occur frequently in Yili, Xinjiang. The loess in this area provides a basis for the occurrence of landslides and other disasters. At the same time, Yili Valley is typically a seasonally frozen soil region. The freeze–thaw cycle is an essential disaster-inducing factor. However, scholars have lain a research emphasis on the material source of the Yili Loess, while lacking a systematic investigation of the degradation mechanism of the soil’s physical and mechanical properties under the freeze–thaw action. Therefore, it is prudent to investigate the changes in mechanical properties of loess in this region under the freeze–thaw cycle. In this study, focusing on a typical loess landslide in Yili, some in situ soil samples were collected to conduct related physical and mechanical tests. According to the maximum dry density and optimum moisture content of the loess in the region, four different groups of soil samples with varying moisture contents were prepared and subjected to different freeze–thaw cycles. The changes of apparent individual characteristics under freeze–thaw cycles were observed, and a consolidated undrained (CU) shear test was carried out to obtain the changes of shear strength indices of loess samples with varying moisture contents under freeze–thaw cycles. The results showed the obvious development of characteristics during freeze–thaw cycles, with the growth of many frost and ice crystals. At the freezing stage, the growth of ice crystals led to hexagonal peeling bodies on the surface layer. At the thawing stage, a rapidly melting network ice crystal pattern imposed a thermal thawing disturbance on the surface rock soil. After multiple freeze–thaw cycles, the soil’s peak strength dropped significantly and the internal friction angle changed slightly, but the cohesion was adversely affected, with frequent fluctuations. The present study enhances the research level of loess’s mechanical and strength properties under freeze–thaw cycles and provides a theoretical foundation for preventing loess landslides in this region.

Loess landslides caused by the dry-wet cycling processes are the most common geological disasters in the Yili region of China and have caused significant economic loss and casualties. Therefore, there is an urgency to study the mechanism of landslide disasters. However, research on loess landslide disasters under dry-wet cycling conditions in the Yili River Valley is still underdeveloped, and the research foundations are relatively weak. Based on the characteristics of high and stable mica content in Yili loess, this research probed the changes in shear strength and microstructure of loess with different mica contents (0%, 5%, 10%, and 15%) after different dry-wet cycles (0, 1, 3, 5, 7, 10, 15, and 20) using direct shear testing and a scanning electron microscopy. The results showed that the mica content had a negative relationship with the shear strength of loess. For the same number of dry-wet cycles, the higher the mica content was, the lower the loess’ shear strength, especially in the first five dry-wet cycles. The influence of mica content on shear strength parameters was not similar. The impact was more significant for cohesion. With increased mica content, cohesion gradually decreased. The effect was minor with the internal friction angle. With the rise in mica content, the angle slightly increased with slight variations. Under certain dry-wet cycling conditions, micro-particle content in the loess decreased continuously, the average reduction can reach 11.25%, the content of small and medium particles tends to increase, the average increments were 6.21% and 3.1%, and volatility changes in large particle content. However, the overall increasing trend remains. Accordingly, the number of micropores and small pores decreased, the average reduction was 7.63% and 5.48%, the number of medium pores and large pores increased, and the average increments were 6.13% and 6.99%, respectively. All these changes were more evident in the first three dry-wet cycles and when the mica content increased from 0% to 5%. This study will be beneficial as a reference for the occurrence mechanisms of loess landslide under dry-wet cycling conditions in the Yili area.

The effect of Vitamin C (Vc) in oncotherapy was controversial for decades. And hyperactivation of extracellular signal-regulated kinase (ERK) drove tumorigenesis. Herein, we demonstrated that Vc activated ERK through sodium-dependent Vc transporter 2 (SVCT2), while high-dose Vc resulted in persistent ERK feedback inhibition following activation. Extracellular Vc binding to SVCT2 initiated ERK activation, then transmembrane transport of Vc induced dimerization of SVCT2. Activated ERK phosphorylated protein tyrosine phosphatase non-receptor type 12 (PTPN12) at Ser434and inhibited PTPN12 activity, thus enhancing phosphorylation of Janus kinase 2 (JAK2), which phosphorylated growth factor receptor bound protein 2 (GRB2) at Tyr160to promote GRB2 dimers dissociation and recruitment of GRB2 to SVCT2, leading to further ERK activation. Different cancers have different sensitivities to Vc, the dose effects of Vc on cancer phenotypes depended on that ERK was activated or inhibited. These findings suggest SVCT2 is a Vc receptor mediating the ERK-PTPN12-JAK2-GRB2-ERK positive feedback loop and a potential target for oncotherapy.Abstract graphic

Natural disasters, including collapse, landslides, and debris flows, commonly occur in the Yili River Valley as a result of its distinctive terrain and climate. A large proportion of these are loess landslides. Hence, studying the mechanism of their occurrence is crucial. The loess in the Yili River Valley has a high mica content. By using freeze-thaw (FT) cycling tests, unconsolidated and undrained triaxial shear tests, and FT cycling experiments, the study clarifies the impact of mica content on the mechanical properties of the loess in the Yili River Valley under FT cycling conditions. The findings demonstrated that the loess’s shear strength was negatively impacted by both the mica content and freeze-thaw cycles (FTCs). Under the same FT cycle conditions, the shear strength of the Yili Valley loess decreased with an increase in the mica content, particularly during the first ten cycles. Cohesion represented the impact of the mica content on the shear strength parameters. The cohesion decreases as the mica content increases. After ten cycles, the values of the cohesion tended to become stable, while the internal friction angle showed the opposite trend. For the same mica content, the shear strength of the Yili valley loess decreased with the increase in the number of FTCs, while the cohesion decreased, and the internal friction angle first increased and then decreased. The study’s findings might offer a theoretical foundation for preventing and reducing loess landslides in the Yili River Valley caused by FTCs and high mica content.