Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.

Sperm contributes essential paternal factors, including the paternal genome, centrosome, and oocyte-activation signals, to sexual reproduction. However, it remains unresolved how sperm contributes its RNA molecules to regulate early embryonic development. Here, we show that the Caenorhabditis elegans paternal protein SPE-11 assembles into granules during meiotic divisions of spermatogenesis and later matures into a perinuclear structure where sperm RNAs localize. We reconstitute an SPE-11 liquid-phase scaffold in vitro and find that SPE-11 condensates incorporate the nematode RNA, which, in turn, promotes SPE-11 phase separation. Loss of SPE-11 does not affect sperm motility or fertilization but causes pleiotropic development defects in early embryos, and spe-11 mutant males reduce mRNA levels of genes crucial for an oocyte-to-embryo transition or embryonic development. These results reveal that SPE-11 undergoes phase separation and associates with sperm RNAs that are delivered to oocytes during fertilization, providing insights into how a paternal protein regulates early embryonic development.

The discovery of biological activities of natural products plays a vital part in drug development. The mechanism by which organisms respond to temperature changes via biosynthesis of natural products remained largely cryptic. A thermophilic fungus under cold stress turned black and accumulated a polyketide metabolite 1 and lipid mass. Deficiency in 1 caused melanin loss and accumulated extra lipid mass, unexpectedly leading to seriously damaged mitochondria diagnostic for ferroptosis. Further analysis revealed that lipid mass induced by cold stress intensively increased ferroptosis risk and 1 functioned as cell wall reinforcer against mass lipid accumulation and as reactive oxygen species scavenger against lipid peroxidation. We also found that melanin in mice lowered lipid level but enhanced animal resistance to cold stress. Treatment with melanin precursors significantly increased mouse cell survival rate under cold stress. Our results unveiled a metabolite-lipid-ferroptosis-cold relationship, which provided mechanistic insights into the functions of most common metabolites and into diseases related to cold stress. These findings opened a perspective for developing anti-cold and anti-ferroptosis therapeutics and agents.

Ecology seeks to explain species coexistence, but experimental tests of mechanisms for coexistence are difficult to conduct. We synthesized an arbuscular mycorrhizal (AM) fungal community with three fungal species that differed in their capacity of foraging for orthophosphate (P) due to differences in soil exploration. We tested whether AM fungal species-specific hyphosphere bacterial assemblages recruited by hyphal exudates enabled differentiation among the fungi in the capacity of mobilizing soil organic P (Po). We found that the less efficient space explorer, Gigaspora margarita, obtained less 13C from the plant, whereas it had higher efficiencies in Po mobilization and alkaline phosphatase (AlPase) production per unit C than the two efficient space explorers, Rhizophagusintraradices and Funneliformis mosseae. Each AM fungus was associated with a distinct alp gene harboring bacterial assemblage, and the alp gene abundance and Po preference of the microbiome associated with the less efficient space explorer were higher than those of the two other species. We conclude that the traits of AM fungal associated bacterial consortia cause niche differentiation. The trade-off between foraging ability and the ability to recruit effective Po mobilizing microbiomes is a mechanism that allows co-existence of AM fungal species in a single plant root and surrounding soil habitat.

Mammalian embryogenesis begins with a totipotent zygote. Blastocyst-like structures can be captured by aggregated cells with extended pluripotent properties in a three-dimensional (3D) culture system. However, the efficiency of generating blastoids is low, and it remains unclear whether other reported totipotent-like stem cells retain a similar capacity. In this study, we demonstrated that spliceosomal repression-induced totipotent blastomere-like cells (TBLCs) form blastocyst-like structures within around 80% of all microwells. In addition, we generated blastoids initiating from a single TBLC. TBLC-blastoids express specific markers of constituent cell lineages of a blastocyst and resemble blastocyst in cell-lineage allocation. Moreover, single-cell RNA sequencing revealed that TBLC-blastoids share a similar transcriptional profile to natural embryos, albeit composed of fewer primitive endoderm-like cells. Furthermore, TBLC-blastoids can develop beyond the implantation stage in vitro and induce decidualization in vivo. In summary, our findings provided an alternative cell type to efficiently generate blastoids for the study of early mouse embryogenesis.