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Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1–3. Here we used a base editor-enabled DNA barcoding system4to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apcgene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent cell lineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.

ABSTRACT15-15Ti is one of the potential candidate materials for fuel rod cladding of lead-based reactors, and its fatigue properties have been investigated. Low cycle fatigue (LCF) tests of 15-15Ti have been carried out under total strain amplitudes ranging from ±0.3% to ±0.9% at 20 and 550°C in vacuum. The results show the LCF life decreases with the increase of temperature. Crack propagates more tortuously and the fatigue crack propagation (FCP) rate is lower when it is tested at 20°C compared to 550°C. In addition, the effect of twin boundaries (TBs) and stacking fault energy (SFE) on FCP rate is discussed in this paper.

15-15Ti is one of the potential candidate materials for fuel rod cladding of lead-based reactors, and its fatigue properties have been investigated. Low cycle fatigue (LCF) tests of 15-15Ti have been carried out under total strain amplitudes ranging from ±0.3% to ±0.9% at 20 and 550°C in vacuum. The results show the LCF life decreases with the increase of temperature. Crack propagates more tortuously and the fatigue crack propagation (FCP) rate is lower when it is tested at 20°C compared to 550°C. In addition, the effect of twin boundaries (TBs) and stacking fault energy (SFE) on FCP rate is discussed in this paper.

Oogenesis is a very important process during mammalian development for it is the basis of fertilization and zygote development, and oogenesis in culture should contribute to various areas, including epigenetics and manipulation of the germ line, and advance studies on fertility treatment and germ and somatic cell interaction and differentiation. Thus, mammalian oogenesis has been studied extensively by means of the in vitro culture technology over the last few years. Mammalian oocytes are derived from a founder population of primordial germ cells (PGCs) that are determined early in embryogenesis and set aside for unique development. Primordial germ cells are closely related to embryonic stem (ES) cells and embryonic germ (EG) cells. In vitro derivation of oocytes from mouse ES cells would benefit the study of oogenesis, and recently, mouse ES cells can differentiate to PGCs in vitro and even oocytes by several laboratories. In previous study, we developed a method to induce PGCs to differentiate and develop into mature oocytes which can be fertilized and support embryonic development to term. Here we show a new method of inducing mouse ES cells to differentiate into oocyte-like cells by culture of embryoid body (EB) with stage-specific ovary conditioned medium and co-cultured with stage-specific granulosa cells in vitro. First, germ cell precursor cells, PGCs, were differentiated within EB which formed from mouse ES cells as identified by positive expression of specific germ cell markers such as Oct4, Mvh, c-kit, Stella, Fragilis and Stella. And then, the germ cell precursor cells within the EBs was induced to differentiate into gametes by the stage-specific ovary conditioned medium and co-cultured with stage-specific granulosa cells. The stagespecific ovary conditioned medium was collected from cultured 12.5 days post-coitum (dpc) fetal mouse ovaries in vitro every other day, because mouse ovaries at the different developmental stage containing most stagespecific growth factors required for the transformation of PGCs into differentiated oocytes. The stage-specific granulosa cells derived from 0, 7, 14, 21 days old mouse ovaries were prepared to co-culture with EB cells for the first, secondary, third and fourth week, respectively. When EBs was cultured in the conditioned medium and co-cultured with the granulosa cells, they developed into ovarian structures containing follicular oocytes. Then oocyte-like cells with typical zona pellucida and germinal vesicle were generated after culture of EB cells for three weeks, as shown by expression of meiotic specific genes Sycp3 and Dmc1 and oocyte-specific genes Fig alpha, GDF9, and ZP1-3. Our results demonstrated that the differentiation and growth of ES cell-derived PGCs could be induced by the stage-specific ovary conditioned medium and cocultured with granulosa cells in vitro. Immunocytochemistry analysis illustrated that the expression of GDF9 was detected among the EBderived colonies and the oocyte-like cells, which were 60 μm to 70 μm in size. Estradiol was first detected at Day 7 of EBs cultured and the concentration progressively increased with the preceding of incubation until Day 21, and stayed lower than that from control cultures of 12.5 fetal ovaries in vitro. The derivation of oocyte-like cells by our method offers a new model in vitro for studying oogenesis, especially for studying the control mechanism of the differentiation from mouse ESCs to oocytes. (platform)