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As an environmentally friendly means of transport, the high-speed rail (HSR) is conducive to promoting corporate performance. An innovative approach extends the impact of HSR networks on pollution emissions from the regional level to the micro-enterprise level. Based on the quasi-natural experiment of the opening of HSR, a difference-in-difference model is used to investigate the impact of HSR on enterprise pollution emission levels and its action mechanism by using the matched data from the Chinese Enterprise Pollution Emission Database, the Chinese Industrial Enterprise Database, and the Chinese City Statistical Yearbook from 2000 to 2010. The results show that opening HSR significantly reduces the enterprises' pollution emission level, while reducing the number of polluting enterprises and transportation costs as well as improving the innovation capacity of enterprises are the corresponding action mechanisms. The impact of HSR on the enterprises' pollution emission varies with industry intensity, population size, and regional economic development level. The conclusions not only provide important insights to increase the ecological quality of China's environment through transportation infrastructure upgrades but also bring some guidance to more developing countries to improve their air environment.

Biological importance of Gab1 in HNSCC cells

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin.Significance:This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.

Cell line information and SHP099 screen data

Supplemental Figure 3. Chemotherapy and venetoclax combination cell viability assays. Cell viability assays were performed for 72h treatment of cyclophosphamide and topotecan, venetoclax, or combination at indicated concentrations, with bliss synergy scores in (A) MYCN-amplified, and (B) MYCN-wild-type cell lines. (C) Plot of Bliss sum of cell lines in A-B, calculated by the summation of the bliss synergy scores across the doses presented.

Supplemental Figure 2. PDX ex vivo model demonstrated cleavage of PARP with corresponding NOXA upregulation (A) Western blot of COG-N-561 ex vivo cell line treated overnight with antibodies as indicated.

Supplemental Figure 4. Body Weight of Mice for in vivo treatments. (A) Plot of percent change in body weight from pre-treatment body weight in all in-vivo treatments.

Supplemental Figure 1. NVP-CGM097 and venetoclax combination cell viability assays. Cell viability assays were performed for 16h treatment of NVP-CGM097, venetoclax, or combination at indicated concentrations, with bliss synergy scores in (A) MYCN-wild-type, p53-wild-type, (B) MYCN-amplified, p53-mutant, and (C) MYCN-wild-type, p53-mutant NB cell lines. Red indicates synergy, blue indicates antagonism. (D) Plot of Bliss sum of cell lines in A-C along with cell lines in Fig. 1B, calculated by the summation of the bliss synergy scores across the doses presented.

Figure S4. SLC40A1 promoter and first exon are highly methylated in the MYCN overexpressing NBs.

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway.Significance:This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.

Supplemental data

Preclinical and clinical studies have evidenced that effective targeted therapy treatment designed against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, reactivation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found head and neck squamous cell carcinoma (HNSCC) was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCCs, resulting in downregulation of mTORC signaling and antitumor effects across several HNSCC mouse models, including an human papillomavirus (HPV+) patient-derived xenograft. Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2–GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. In the presence of SHP2 inhibitor, HNSCCs are highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin. Significance: This work identifies a novel role of SHP2 inhibitor by dual downregulation of PI3K and MEK pathways, through loss of GAB1 activation and disruption of GAB1 complexes in low-epiregulin HNSCC.

This study analyzes the economic and environmental performance of OECD countries over 2000–2019. A by-production approach is applied and the efficiency score is decomposed into its economic and environmental components. Unlike previous studies, we apply a refined model that allows for the correct modeling of by-production technology. The refined model can provide clear economic illustrations for balancing economic growth and environmental protection. The results indicate that environmental inefficiency is higher than the potential economic improvement. The environmental efficiency of OECD countries is improving, while economic performance is worsening over time. Therefore, instead of highly polluting energy, clean energy should be used to build a low-carbon economy. Worldwide, carbon-emitting countries and developed countries should shoulder their responsibilities to reduce carbon emissions and provide emission reduction funds for developing countries, while simultaneously sharing the green production technologies needed to reduce emissions.

Climate change related environmental problems are pushing a constantly growing number of countries to set carbon neutrality goals. Increasing reliance on ecologically friendly technologies is widely considered to be a crucial means of achieving this objective. Many existing studies measure environmental performance using carbon dioxide emissions, or carbon sources, but do not consider the amount of carbon offset through sequestration in carbon sinks. We define carbon neutrality performance as the difference between the carbon sinks and carbon sources and quantify its relationship with green technological innovation, approximated using the notion of environmental productivity. We rely on the Chinese province-level data from 2001 to 2019 and demonstrate that green innovation can significantly facilitate the attainment of carbon neutrality objectives. Our mediation model suggests that low-carbon innovation can help reach carbon neutrality by decreasing net emissions directly, but also by inhibiting the urbanization rate and promoting renewable energy generation. Our analysis helps shed light on the possible strategies that policymakers in China and other developing countries can follow to realize their carbon neutrality aspirations.

Agricultural extension is a key instrument to bridge the gap between new technologies and farmers. As a popular extension approach, farmer field schools (FFS) usually improve farmers’ knowledge and...

Aroma is a key grain quality trait that directly influences the market price of rice globally. Loss of function of betaine aldehyde dehydrogenase 2 (OsBADH2) affects the biosynthesis of 2‐acetyl‐1‐pyrroline (2‐AP), which is responsible for aroma in fragrant rice. The current study was aimed at creating new alleles of BADH2 using CRISPR/Cas9 gene editing technology under the genetic background of the japonica Ningjing 1 (NJ1) and indica Huang Huazhan (HHZ) varieties. Sensory evaluation and analysis using headspace solid‐phase microextraction gas chromatography–mass spectrometry (HS‐SPME‐GC‐MS) showed that the grains of the four homozygous T1 lines with new alleles of BADH2 (nj1‐cr BADH2‐1, nj1‐cr BADH2‐2, hhz‐cr BADH2‐1 and hhz‐cr BADH2‐2) produced moderate fragrance and had significantly increased 2‐AP content compared with wild‐types. Moreover, there were no significant differences in the amylose content and gelatinization temperature among the four lines with new alleles of BADH2 to the wild‐types. Thereafter, we crossed the HHZ background new alleles of BADH2 with CMS line Taonong 1A (TN1A) to produce a three‐line hybrid variety B‐Tao‐You‐Xiangzhan (BTYXZ) with increased grain aroma. The 2‐AP content in grains of the improved BTYXZ‐1 and BTYXZ‐2 reached at 26.16 and 18.74 μg/kg, and the gel consistency of BTYXZ‐1 and BTYXZ‐2 increased significantly by 9.1% and 6.5%, respectively, compared with the wild‐type Tao‐You‐Xiangzhan (TYXZ). However, the γ‐aminobutyric acid (GABA) content in the improved three‐line hybrid rice BTYXZ‐1 (5.6 mg/100 g) and BTYXZ‐2 (10.7 mg/100 g) was significantly lower than that of the TYXZ. These results demonstrated that CRISPR/Cas9 gene editing technology could be successfully utilized in improving aroma in non‐fragrant japonica and indica varieties. In addition, the newly developed BADH2 alleles provided important genetic resources for grain aroma improvement in three‐line hybrid rice.

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer (BC)-related deaths, despite accounting for only 10% to 15% of total BC cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the ubiquitin-like modifier activating enzyme 1 (UBA1). Targeting UBA1 with the first-in-class UBA1 inhibitor TAK-243 induced unresolvable endoplasmic reticulum (ER)-stress and activating transcription factor 4 (ATF4)-mediated upregulation of proapoptotic NOXA, leading to cell death. c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. Moreover, in an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden, indicating UBA1 is a potential new target in TNBC expressing high levels of c-MYC.

Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2–dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified MYCN. We previously demonstrated that venetoclax is active in MYCN-amplified neuroblastoma but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient prodeath protein mobilization. As the relative tolerability of venetoclax makes it amenable to combining with other therapies, we evaluated the sensitivity of MYCN-amplified neuroblastoma models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, the MDM2 inhibitor NVP-CGM097 increases the prodeath BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified neuroblastomas to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified neuroblastoma through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified patient-derived xenograft models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). Although establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in patients with amplified MYCN with neuroblastoma.

Studying the effect of leading-edge parameters of 30P30N on aerodynamic characteristic was carried out. Effect of changing the gap and overlap of the slat of the airfoil were mainly investigated. Numerical simulation was applied to obtain aerodynamic characteristics, results show that: the lift coefficient in the linear segment basically does not change with the gap, the drag coefficient decreases with change of the gap. The overlap and gap of slat have obvious effect on the lift-to-drag ratio. The smaller the gap between slat and fixed wing, the greater the lift-to-drag ratio is achieved. With the increase of overlap between slat and fixed wing, lift to drag ratio increases.

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. Significance: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%–15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC.SignificanceGenomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.

Since a variety of barriers pose challenges to the Indian wind energy sector, the extent to which these barriers hamper this sector and the alternative solutions are largely unknown. We identify several barriers using existing literature, and then using the modified Delphi approach, refine 25 barriers and classify them into five significant dimensions. Later, the Analytical Hierarchical Process determined the ranking of barriers using pairwise comparison matrices. The Grey Technique for Order Preference by Similarity to Ideal Solution method ranked alternative solutions to these barriers. Results indicate that “financial barrier” is the most important barrier among all dimensions, while “limited government subsidy” is most influential among all sub-barriers. “Availability of adequate funds” is the best alternative to overcome these barriers. Finally, a sensitivity analysis is performed to validate the study findings. The study findings may assist practitioners and policymakers in boosting the current sluggish growth of the Indian wind sector.

This research utilizes a bootstrap rolling-window (BRW) causality test to explore the causal interrelationship between nuclear energy consumption (NUC) and carbon dioxide emissions (CO2) in 6 developed countries from 1980 to 2020. When there are structural shifts in the full-sample time series, empirical research exploring causality between two-time series generates erroneous conclusions. On the other hand, the BRW method allows researchers to find potential time-varying causality between time series using sub-sample data. The outcomes of the BRW causality test disclosed the following results: (i) a unidirectional negative causality from NUC to CO2 without feedback was found for Japan; (ii) a negative causality at sup-sample periods from NUC to CO2 surfaced at the sub-sample period while a positive causality surfaced from NUC to CO2 in sub-sample period for the United States of America (USA) and France; (iii) a negative feedback causality between NUC and CO2 was found For Canada; (iv) a positive unidirectional causality surfaced from NUC to CO2 was found for Germany, which implies that consumption of NUC worsens the environment in the sub-sampled period. The results may have policy consequences for the selected developed countries regarding NUC and CO2 nexus.

This study investigates economic convergence and sustainable development in Africa. By introducing an aggregate production technology and directional distance function, it examines the productivity growth of 28 African economies from 1990 to 2019. The proposed approach considers all decision-making units (countries) as a whole, and the productivity gains are then estimated under a nonparametric framework. In the empirical analysis, the carbon emissions are included in the Luenberger productivity measurement, called green productivity. The results show that the annual average growth rate of green productivity is 1.51% in African, and different types of club convergence for green productivity indicator and its decomposition are observed during the sample period. The decomposition of the Luenberger indicator shows that green African growth is mainly driven by technological progress, not efficiency change. Furthermore, the overall inefficiency is decomposed into technical and structural effects. The latter measure the potential improvement in terms of resource reallocation. Structural inefficiency is larger than technical inefficiency, suggesting that African countries could improve their economic and environmental performances by optimizing input/output mixes.

China’s research and development (RD human research capacity exhibits the greatest contribution to the output of patents; past knowledge accumulation helps produce more patents; and entry barriers to patent production exist in China’s agricultural biotechnology sector. Moreover, the patent explosion in China may have been largely caused by improvements in the human capital input quality.

Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2-dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified