Cip2a induces arginine biosynthesis and promotes tumor progression in non-small cell lung cancer.

Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncoprotein, playing important roles in tumor progression. However, the underlying mechanisms by which Cip2a promotes tumor aggressiveness in NSCLC remain to be further investigated. In this study, we found that Cip2a expression is elevated in NSCLC and correlates with poor prognosis. Knockdown of Cip2a significantly reduced the ability of cell proliferation, invasion, and metastasis of NSCLC both in vitro and in vivo. Furthermore, we found that Cip2a promotes tumor progression partly by inducing arginine biosynthesis, and knockdown of Cip2a exhibited a significantly increased sensitivity to arginine deprivation and mTOR inhibition. In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.

Vertical Cu Nanoneedle Arrays Enhance the Local Electric Field Promoting C2 Hydrocarbons in the CO2 Electroreduction.

Electrocatalytic reduction of CO2 to multicarbon products is a potential strategy to solve the energy crisis while achieving carbon neutrality. To improve the efficiency of multicarbon products in Cu-based catalysts, optimizing the *CO adsorption and reducing the energy barrier for carbon-carbon (C-C) coupling are essential features. In this work, a strong local electric field is obtained by regulating the arrangement of Cu nanoneedle arrays (CuNNAs). CO2 reduction performance tests indicate that an ordered nanoneedle array reaches a 59% Faraday efficiency for multicarbon products (FEC2) at -1.2 V (vs RHE), compared to a FEC2 of 20% for a disordered nanoneedle array (CuNNs). As such, the very high and local electric fields achieved by an ordered Cu nanoneedle array leads to the accumulation of K+ ions, which benefit both *CO adsorption and C-C coupling. Our results contribute to the design of highly efficient catalysts for multicarbon products.

The RING-Finger Protein NbRFP1 Contributes to Regulating the Host Hypersensitive Response Induced by Oat Dwarf Virus RepA.

Our previous study identified that the RepA protein encoded by the oat dwarf virus (ODV) was responsible for inducing a strong hypersensitive response (HR) during the virus infection in non-host tobacco plants. However, little was known about the molecular mechanism of the RepA-elicited HR. Here, a RING-finger protein, which is described as NbRFP1 and is mainly located in the cytoplasm and nucleus in Nicotiana benthamiana cells, was confirmed to interact with RepA. In addition, the accumulation level of NbRFP1 in N. benthamiana leaves was enhanced by either ODV infection or by only RepA expression. The knockdown of NbRFP1 by a TRV-mediated virus-induced gene silencing markedly delayed the ODV or RepA-elicited HR. By contrast, the overexpression of NbRFP1 in N. benthamiana conferred enhanced resistance to ODV infection and promoted RepA-induced HR. Further mutation analysis showed that a RING-finger domain located in NbRFP1 plays important roles in modulating RepA-induced HR, as well as in mediating the interaction between NbRFP1 and RepA.

[Suitable harvest period of Aurantii Fructus based on UPLC-Q-TOF-MS metabolomics].

The types of secondary metabolites of Aurantii Fructus samples from GAP base in different harvest periods were detected by UPLC-Q-TOF-MS metabolomics, and the differential metabolites were screened out by multivariate statistical analysis. The variation of the content of differential metabolites with different harvest periods was analyzed, and the correlation analysis was carried out on the differential metabolites to determine the suitable harvest period for different components. Sixteen differential metabolites were obtained. With the delay of harvest time, the content of flavonoid glycosides, including naringin, neohesperidin, poncirin, narirutin, and hesperidin, gradually decreased. It is suggested that the suitable harvest period for raw materials of Aurantii Fructus with flavonoids as active components is from July 18 to July 25(within one week before and after the Great heat). The content of nobiletin, tangeretin, natsudaidain, 7-hydroxyl-4',3,5,6,8-pentamethoxyflavone, sinensetin, isosinensetin, 5,6,7,4'-tetramethoxyflavone, and isomeranzin decreased first, then increased, and finally decreased. It is suggested that the suitable harvest time for raw materials of Aurantii Fructus with these components as the active components is July 18. The content changes of meranzin, limonin, and 3,5,6,7,8,3',4'-heptamethoxyflavone have their characteristics. According to the conditions of actual production, it is suggested that the suitable harvest time is June 27, July 11, and July 25, respectively. The results showed that there were differences in the content of chemical components of Aurantii Fructus in different harvest periods, and the suitable harvest period should be determined according to the differences in chemical component content. This study is expected to provide a scientific basis for the purchase of raw materials of Aurantii Fructus for Chinese patent medicines with different effects.

The mechanisms of EGFR in the regulation of axon regeneration.

To understand the relationship between epidermal growth factor receptor (EGFR) and axon regeneration and the mechanisms of how EGFR regulates the neuronal intrinsic regenerative ability, we evaluated the levels of mRNA and protein of EGFR、total mammalian target of rapamycin (mTOR), p-mTOR(Ser2448) , total Akt and p-Akt(Ser473) in rats of different developmental stage by using Western blot and real-time polymerase chain reaction analysis. Axon protein tau and neuron proteins ß-tubulin/neurofilament (NF) were assessed to evaluate the extent of the axon regeneration in cultured neuron cells. Expressions of EGFR、total mTOR, p-mTOR(Ser2448) , total Akt and p-Akt(Ser473) in cultured neuron cells were also detected using Western blot analysis. Our results showed that the expressions of EGFR and mTOR dropped off with the ageing of the rats, and Ser473 phosphorylation of Akt and Ser2448 phosphorylation of mTOR were highly expressed in foetal and newborn rats but decreased obviously in adult rats. tau, ß-tubulin and NF were upregulated when EGFR was overexpressed and down-regulated after EGFR was blocked. The phosphorylation of mTOR and Akt was apparently elevated when EGFR was overexpressed and decreased when EGFR was blocked, which suggested that EGFR has the potential to regulate the neuronal intrinsic regeneration and mTOR and PI3K/Akt pathway activation may have an important role in it.

METTL14-mediated Bim mRNA m6A modification augments osimertinib sensitivity in EGFR-mutant NSCLC cells.

Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in epidermal growth factor receptor (EGFR). N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assay showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs. Implications: This study offers more evidences for the involvement of METTL14-mediated m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs.

Dynamic evolution of urban infrastructure resilience and its spatial spillover effects: An empirical study from China.

Urban infrastructure resilience is an important perspective for measuring the development quality of resilient cities and an important way to measure the level of infrastructure development. This paper uses the kernel density estimation, exploratory spatial data analysis, and spatial econometric models to analyze the characteristics of dynamic evolution and the spillover effects of the infrastructure resilience levels in 283 prefecture-level and above cities in China from 2010 to 2019. Our results are as follows. (1) The overall level of urban infrastructure resilience increased. The eastern region had a higher level than the national average. In contrast, the central, western and north-eastern regions had a slightly lower level than the national average. (2) The areas with high and higher resilience levels were mostly cities with more developed economic and social conditions in Eastern China. The areas below moderate resilience levels show a certain degree of clustering and mainly include some cities in Central, Western, and Northeast China. (3) The national level of urban infrastructure resilience shows significant spatial clustering characteristics, and the spatial pattern from coastal to inland regions presents a hotspot-subhotspot-subcoldspot-coldspot distribution. (4) There is a differential spatial spillover effect of national urban infrastructure resilience, which is gradually strengthened under the role of the economy, financial development, population agglomeration and government funding and weakened under the role of urbanization, market consumption and infrastructure investment. By exploring the dynamic evolution of infrastructure resilience in cities at the prefecture level and above and its spatial spillover effects, we provide a scientific basis for avoiding the siphoning effect among cities, improving the level of infrastructure resilience, and guiding the construction and development of resilient cities.

Spatiotemporal pattern and coordination relationship between urban residential land price and land use intensity in 31 provinces and cities in China.

The trend towards efficient and intensive use of land resources is an inevitable outcome of current social development. The rational matching of urban land prices and land use intensity has become an important factor under accelerating urbanization, and promotes the healthy development of the social economy. Using data on residential land price and on land use intensity for 31 provinces and cities in China, we employ the E-G cointegration test and quadrant map classification to determine the coordination relationship between land price and land use intensity. We then employ HR coordination to calculate the coordination degree of land price and land use intensity, and classify the coordination type accordingly. Our results are as follows. (1) The spatio-temporal distribution of urban land price shows high variability with multiple maxima, and follows a decreasing trend from the southeast coastal area to the northwest inland area and the northeast. (2) The overall land use intensity is at or above the middle level, and shows large spatial differences between provinces, but the agglomeration between provinces is increasing. (3) From the perspective of the relationship between urban land price and land use intensity at the inter-provincial scale, we find that the land price and land use intensity are well coordinated, and the number of provinces has been dynamically changing during different development periods. There is an east-west difference in the spatial distribution of land price and land use intensity coordination level. Different provinces and cities with the same coordination stage show differences in their land price and land use intensity level.

Annexin A2 Silencing Inhibits Proliferation and Epithelial-to-mesenchymal Transition through p53-Dependent Pathway in NSCLCs.

Annexin A2 has been involved in cancer cell adhesion, invasion and metastasis. However, the exact function and mechanism of Annexin A2 in tumor progression of NSCLCs have not been elucidated. In this study, we showed that Annexin A2 was evidently overexpressed in human NSCLCs cell lines and NSCLCs tissues. Clinicopathologic analysis showed that Annexin A2 expression was significantly correlated with clinical stage, and lymph node metastasis. Kaplan-Meier analysis revealed that patients with high Annexin A2 expression had poorer overall survival rates than those with low Annexin A2 expression. Moreover, we found that knockdown of Annexin A2 significantly suppressed cell proliferation and invasion of NSCLCs cells. Mechanistically, our studies showed that knockdown of Annexin A2 increased the expression of p53, which in turn, induced cell cycle G2 arrest and inhibited epithelial-to-mesenchymal transition (EMT). Taken together, these data suggest that Annexin A2 plays an important role in NSCLCs progression, which could serve as a potential prognosis marker and a novel therapeutic target for NSCLCs.