No abstract

A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway.

Loss of Tsc1/Tsc2 results in excess cell growth that eventually forms hamartoma in multiple organs. Our study using a mouse model with Tsc1 conditionally knockout in mammary epithelium showed that Tsc1 deficiency impaired mammary development. Phosphorylated S6 was up-regulated in Tsc1−/− mammary epithelium, which could be reversed by rapamycin, suggesting that mTORC1 was hyperactivated in Tsc1−/− mammary epithelium. The mTORC1 inhibitor rapamycin restored the development of Tsc1−/− mammary glands whereas suppressed the development of Tsc1wt/wt mammary glands, indicating that a modest activation of mTORC1 is critical for mammary development. Phosphorylated PDK1 and AKT, nuclear ERα, nuclear IRS-1, SGK3, and cell cycle regulators such as Cyclin D1, Cyclin E, CDK2, CDK4 and their target pRB were all apparently down-regulated in Tsc1−/− mammary glands, which could be reversed by rapamycin, suggesting that suppression of AKT by hyperactivation of mTORC1, inhibition on nuclear ERα signaling, and down-regulation of cell-cycle-driving proteins play important roles in the retarded mammary development induced by Tsc1 deletion. This study demonstrated for the first time the in vivo role of Tsc1 in pubertal mammary development of mice, and revealed that loss of Tsc1 does not necessarily lead to tissue hyperplasia.

In this study, uneven urban streets are explored with different standard deviations (σH = 0–0.6) through numerical simulations. The ventilation and pollutant diffusion conditions are investigated under the combined action between the thermal buoyancy force and mechanical wind force. When the thermal buoyancy is uniformly distributed, the upstream vortex gradually occupies the most area of the flow unit with the increase in σH. Three configurations of green roof systems (roof, leeward, and windward cooling schemes) are assumed to represent different thermal buoyancy distributions in the street canyon. The average air exchange rate and pollutant retention time (τ) are proposed to evaluate the ventilation efficiency and pollutant dispersion condition. The “free airflow” phenomenon occurs and gradually expands with the increase in the standard deviation of each model. The flow structure and pollutant distribution inside the urban canopy are similar in the uniformly heated and leeward cooling scheme. The windward cooling scheme presents the least local retention time in most working conditions. The roof cooling scheme aggravates the pollutant accumulation conditions inside the street canyon. This study can provide some constructive guidelines in the urban planning process and benefit the design of urban greening with different building morphologies.

Curved vane demisters with high efficiency are widely used in power, chemical, and gas industries. To reveal the relationship between the separation performance and the basic geometric parameters used in the steam generator. In this paper, the influence of wavelength on droplet separation performance has been numerically studied. Additionally, the pressure drops, friction factor, and separation efficiency of the two-phase flow are numerically analyzed. Then, grade separation efficiency is numerically investigated, and the overall separation efficiency is obtained to evaluate the separation performance. It is found that a prolonged wavelength L can initially increase and thereafter decrease the separation efficiency. However, when the wavelength increases to a high level, continuously increasing the wavelength decreases the droplet re-entrainment mass source.