Discovery and optimization of selective RET inhibitors via scaffold hopping.

Aberrant alterations of rearranged during transfection (RET) have been identified as actionable drivers of multiple cancers, including thyroid carcinoma and lung cancer. Currently, several approved multikinase inhibitors such as vandetanib and cabozantinib demonstrate clinical activity in patients with RET-rearranged or RET-mutant cancers. However, the observed response rates are only modest and the 'off-target' toxicities resulted from the inhibition of other kinases is also a concern. Herein, we designed and synthesized a series of RET inhibitors based on the structure of selective RET inhibitor BLU-667 and investigated their biological activities. We identified compound 9 as a novel potent and selective RET inhibitor with improved drug-like properties. Compound 9 exhibits a selective inhibitory profile with an inhibitory concentration 50 (IC50) of 1.29 nM for RET and 1.97 (RET V804M) or 0.99 (RET M918T) for mutant RETs. The proliferation of Ba/F3 cells transformed with NSCLC related KIF5B-RET fusion was effectively suppressed by compound 9 (IC50 = 19 nM). Additionally, compound 9 displayed less 'off-target' effects than BLU-667. In mouse xenograft models, compound 9 repressed tumor growth driven by KIF5B-RET-Ba/F3 cells in a dose-dependent manner. Based on its exceptional kinase selectivity, good potency and high exposure in tumor tissues, compound 9 represents a promising lead for the discovery of RET directed therapeutic agents and the study of RET-driven tumor biology.

2D van der Waals heterostructures of graphitic BCN as direct Z-scheme photocatalysts for overall water splitting: the role of polar π-conjugated moieties.

The application of two-dimensional (2D) graphitic carbon-based materials in photocatalysis has been limited to date, because the nature and role of π-conjugated moieties in them remain unclear. Herein we propose and study bilayer BC3/C3N and BC3/BC6N van der Waals heterostructures as direct Z-scheme photocatalysts for overall water splitting using density functional theory calculations. The roles of polar π-conjugated moieties in the formation, stacking configuration, and electronic and optical properties of bilayer van der Waals heterostructures are discussed. It is shown that polar π-conjugated moieties of graphitic BCN monolayers lead to a favorable π-π interaction, determining the most stable stacking configuration, and a long-range charge transfer between components. The former makes the electronic band structure of heterostructures favor photocatalytic water splitting in efficiency and energetics. The latter generates a built-in electric field for the interface recombination of photogenerated electron-hole pairs, indicating a Z-scheme mechanism. The delocalized nature of π-conjugated electrons in monolayer components allows for high carrier mobility of bilayer heterostructures, promoting the photocatalytic reactions on graphitic BCN monolayers. These findings show that 2D π-conjugated materials, including graphitic carbon-based materials and biological systems, have great potential in the design and development of 2D metal-free direct Z-scheme photocatalysts for environmental purification and energy conversion.

N-Promoted Ru1/TiO2 single-atom catalysts for photocatalytic water splitting for hydrogen production: a density functional theory study.

We propose a universal dimer-doping strategy to improve the photocatalytic water splitting activity of Ru1/TiO2 single-atom catalysts, in which the N atom is simultaneously doped. First-principles calculations show that the N dopants promote the substitution of Ti with Ru on the anatase TiO2(101) surface by chemical bonding between Ru and N, and increase the stability of the system. Isolated Ru1 atoms act as active sites for the reduction of protons, and Ru1-N1/TiO2 has a hydrogen evolution activity comparable to that of Pd. The impurity bands within the band gap lead to a significant red-shift of the absorption edge towards the visible region, improving the photoabsorption and photocatalytic performance of TiO2 under sunlight. The reason is the charge compensation effect localized to the doped Ru-N dimers. We expect that this generic scheme that simultaneously realizes band-structure tailoring and reaction control also applies to other single-atom loaded oxide-based photocatalytic systems.

From Production to Consumption: A Coupled Human-Environmental Nitrogen Flow Analysis in China.

Anthropogenic inputs of reactive nitrogen (Nr) provide sufficient food, energy, and industrial products to meet human demands; however, only a fraction of Nr is consumed as food and nonfood goods, and the rest is lost to the environment and negatively affects ecosystems. High-resolution studies of nitrogen flows are invaluable to increase nitrogen use efficiencies and reduce environmental emissions. In this study, a comprehensive substance flow analysis of nitrogen for China in 2014 is presented. Based on the conceptual framework, which highlights the key roles of human drivers, the analysis of the synthetic ammonia supply and demand balance shows that 75% of ammonia is used for agricultural purposes. Moreover, the life cycle analysis of food nitrogen shows that human food consumption accounts for approximately 7% of the total Nr inputs. A quantitative analysis of pollutant emissions shows that industrial and crop production are the main sources of atmospheric emissions, while livestock farming and crop production are the main sources of water emissions. Finally, we investigate four scenarios (efficiency improvement, high recycling rate, nitrogen oxide emission reduction, and a combined scenario) and provide relevant policy recommendations (large farm size, standardized agricultural production model, flue gas denitration, etc.) for improving nitrogen management practices.

[Adjunctive therapy of xuezhikang capsule for coronary heart disease: a systematic review and meta-analysis of randomized controlled trials].

OBJECTIVE: To systematically evaluate the effect and safety of Xuezhikang Capsule (XZKC) for adjuvant treatment for coronary heart disease (CHD) patients accompanied with or without dyslipidemia. METHODS: China National Knowledge Infrastructure (CNKI) Database, Chongqing VIP Database (VIP), Wanfang Data base, Cochrane Library, and Medline (PubMed) were retrieved with the deadline of August 30, 2013. Randomized controlled trials (RCT) of XZKC in treating CHD patients with or without dyslipidemia were all included. Assessment of bias risk for included studies was conducted according to the Cochrane Handbook for Systematic Reviews of Intervention (Version 5.0.2): Criteria for judging risk of bias in the "risk of bias" assessment tool. Review Management (5.1.0) was employed for data statistics. If there was no significant heterogeneity, results from the random-effect model were presented. If the heterogeneity was not substantial, a meta-analysis was not performed and a narrative and qualitative summary was performed instead. RESULTS: A total of 28 RCTs (6,949 patients) were included after screening results. The methodological quality of included trial was generally lower. Results of Metaanalysis showed that XZKC was beneficial for CHD patients in decreasing cardiovascular events: when compared with the basic treatment group, the relative risk (RR) was 0.53 and 95% confidence interval (CI) was [0.35, 0.81]; when compared with the placebo + basic treatment group, RR was 0.52 and 95% CI was [0.42, 0.65]; when compared with the basic treatment group, RR for improving symptoms of angina was 1.20 and 95% CI was [1. 12, 1.30]; when compared with the basic treatment group, RR for improving abnormal ECG was 1.38 and 95% CI was [1.21, 1.57]. Thirteen studies showed that XZKC + basic treatment was obviously superior in lowering total cholesterol (TC) to that of the basic treatment group. Three studies showed that XZKC + basic treatment was obviously superior in lowering total cholesterol (TC) to that of the placebo + basic treatment group. Thirteen studies showed that XZKC + basic treatment was obviously superior in lowering low density lipoprotein cholesterol (LDL-C) to that of the basic treatment group. Three studies showed that XZKC + basic treatment was obviously superior in lowering LDL-C to that of the placebo + basic treatment group. A total of 18 studies describing adverse reactions (ADs) involved 61 ADs in the XZKC + basic treatment group. All suffered from mild symptoms or were improved after treatment. No severe ADs occurred. CONCLUSION: Treatment of CHD by XZKC might lower the occurrence of cardiovascular events in CHD patients accompanied with or without dyslipidemia, relieve clinical symptoms, improve ECG, lower blood lipid levels, and with less adverse reactions.

Sheep Face Detection Based on an Improved RetinaFace Algorithm.

The accurate breeding of individual sheep has shown outstanding effectiveness in food quality tracing, prevention of fake insurance claims, etc., for which sheep identification is the key to guaranteeing its high performance. As a promising solution, sheep identification based on sheep face detection has shown potential effectiveness in recent studies. Unfortunately, the performance of sheep face detection has still been a challenge due to diverse background illumination, sheep face angles and scales, etc. In this paper, an effective and lightweight sheep face detection method based on an improved RetinaFace algorithm is proposed. In order to achieve an accurate and real-time detection of sheep faces on actual sheep farms, the original RetinaFace algorithm is improved in two main aspects. Firstly, to accelerate the speed of multi-scale sheep face feature extraction, an improved MobileNetV3-large with a switchable atrous convolution is optimally used as the backbone network of the proposed algorithm. Secondly, the channel and spatial attention modules are added into the original detector module to highlight important facial features of the sheep. This helps obtain more discriminative sheep face features to mitigate against the challenges of diverse face angles and scale in sheep. The experimental results on our collected real-world scenarios have shown that the proposed method outperforms others with an F1score of 95.25%, an average precision of 96.00%, a model size of 13.20 M, an average processing time of 26.83 ms, and a parameter of 3.20 M.

Hotspots of reactive nitrogen loss in China: Production, consumption, spatiotemporal trend and reduction responsibility.

Effective and fair mitigation measures hinge on the identification of hotspots and tracking provenance on reactive nitrogen (Nr) loss at a high spatial resolution. We assessed the Nr loss intensity in China at 1 km spatial resolution from 1980 to 2015. The total Nr loss increased from 20.2 to 54.5 Tg N yr-1, with hotspots (>100 kg N ha-1 yr-1) concentrated in the North China Plain, the Middle and Lower Yangtze River and the Sichuan Basin. The Nr loss hotspots covered less than 20% of the Chinese territory but contributed more than 90% of total Nr loss since 1990. Geographical disparity in Nr loss has increased and calls for a fair regional policy synergy. Compared to managing Nr loss based only on production, we demonstrate that the estimation of Nr loss responsibility driven by consumption has greater potential to allocate a fair share of responsibility for reducing Nr loss.

Effect of balanced nutrient fertilizer: A case study in Pinggu District, Beijing, China.

Agriculture has played an indispensable role in the economic and social development of China. However, the inappropriate application of fertilizers in agriculture has brought about environmental pollution. Therefore, under the requirements of green development, the inevitable choice has been reducing the application amount while increasing the utilization rate of fertilizers. To solve the problems resulting from fertilizers, this research designed and made Balanced Nutrient Fertilizer based on the nutrient balance method. To test Balanced Nutrient Fertilizer, continuous planting experiments on three crops (peas, corns, and peaches) were carried out in Pinggu District, Beijing. Furthermore, a substance flow analysis (SFA) was conducted to obtain a deeper understanding of the Balanced Nutrient Fertilizer. Through a series of tests, the application of Balanced Nutrient Fertilizer was shown to increase the crop yield by 3%. The product quality was also improved. In addition, the amount of nutrients applied was significantly reduced in the experimental group (specifically, 35%-88% for nitrogen, 69%-93% for phosphorus, and 8%-82% for potassium). The results of the SFA revealed that applying the Balanced Nutrient Fertilizer could meet the required amount of nutrients for the best crop growth, greatly decrease the negative influence of chemical fertilizers on the soil and reduce agricultural non-point source pollution.

A temporal-spatial analysis and future trends of ammonia emissions in China.

Excessive anthropogenic activities have led to high-level ammonia loss and volatilization, which is regarded as a key factor in Chinese haze formation. In this study, a comprehensive analysis of ammonia emission estimations is accomplished at both temporal (1980-2016) and spatial (provincial) scales using a mass-balanced model, and emission projections through 2030 are also studied in different development scenarios. The results show that the ammonia emissions increased from 4.7 Tg N yr-1 in 1980 to 11 Tg N yr-1 in 2016, which is an approximately 2.4-fold increase. The cropland and livestock emissions are the largest contributors, as most reports show approximately 80% contributions; however, nonagriculture sources of fuel combustion, waste treatment and ammonia escape have grown rapidly in recent years, accounting for 14% in 2016. The spatial differences also reveal the complex heterogeneity in Chinese provinces. In addition, the emission intensities of major agriculture and non-agriculture sources are 0-80 kg N ha-1 yr-1 and over 100 kg N ha-1 yr-1, respectively, indicating a higher degree of ammonia concentration from non-agriculture emissions, which should attract wide concern. In terms of scenario analysis, emissions would reach 12.8 Tg N yr-1 in 2030 under the currently developed model and 7.3 Tg N yr-1 under a series of reduction policies; the spatial analysis also shows that the North China Plain has a 2.1 Tg N yr-1 reduction potential. The results of this study provide new insights into ammonia emission estimations and a better understanding of the environmental impacts of ammonia emitted from different sources.

The trends of aquacultural nitrogen budget and its environmental implications in China.

The rapid development of aquaculture has sustained aquatic food production but has also led to a host of environmental problems, ranging from eutrophication of aquatic ecosystems to global acidification. China has become the world's largest producer and consumer of aquaculture products. Nitrogen is an essential nutrient in aquaculture ecosystems, and the quantitative environmental fate and impact of nitrogen during aquaculture processes have notable environmental consequences but have received little attention. Here, we established a nitrogen cycling model for China's aquaculture ecosystem to investigate the creation and fate of reactive nitrogen over a decadal time scale. A nitrogen balance analysis showed that reactive nitrogen input in the aquaculture ecosystem increased from 9.43 Tg N yr-1 in 1978 to 18.54 Tg N yr-1 in 2015, while aquaculture production increased from 0.034 to 1.33 Tg N yr-1 during the same period. The environmental fate analysis showed that nitrogen emissions, accumulation, sediment deposition, and export into the oceans increased by 9.05-fold, 0.24-fold, 9.04-fold, and 2.56-fold, respectively. Finally, we investigated four scenarios representing different consumption levels of aquatic products and provided policy recommendations (larger aquaculture size, standardized aquaculture production model, nutritional element management and balanced dietary structure, etc.) on improved management practices in aquaculture ecosystems.

Promoting information technology for the sustainable development of the phosphate fertilizer industry: a case study of Guizhou Province, China.

The information technology revolution has brought unprecedented opportunities to the sustainable development of the traditional phosphate fertilizer industry. In this paper, the changes in characteristic indexes during this technological progress and business innovation are investigated at the industrial level and for different stakeholders using scenario simulation analysis based on system dynamics. The results show that information technology will have a significant impact on the traditional fertilizer industry. The popularity of information technology represents a win-win situation for industries, farmers, enterprises and governments. The sustainable development of the phosphate fertilizer industry promoted by information technology means that agrochemical services are a new growth point for the industry, and farmers will be the largest beneficiaries. Enterprises will adjust their product structures to achieve the relevant phosphate reduction goals before 2020. At the government level, the indirect benefits from energy savings, water conservation and reductions in non-point source pollution control treatment also increase significantly. In the new production and sales model, the development of the phosphate fertilizer industry is completely decoupled from resource consumption. In the future, this technological progress will eventually form a sustainable network of industrial innovation patterns. Our finding suggests that the application of information technology in the phosphate fertilizer industry can stimulate the vitality of each entity in the industry and achieve a win-win situation.

Biomodification of PCL Scaffolds with Matrigel, HA, and SR1 Enhances De Novo Ectopic Bone Marrow Formation Induced by rhBMP-2.

The de novo formation of ectopic bone marrow was induced using 1.2-mm-thin polycaprolactone (PCL) scaffolds biomodified with several different biomaterials. In vivo investigations of de novo bone and bone marrow formation indicated that subcutaneous implantation of PCL scaffolds coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) plus Matrigel, hydroxyapatite (HA), or StemRegenin 1 (SR1) improved formation of bone and hematopoietic bone marrow as determined by microcomputed tomography, and histological and hematopoietic characterizations. Our study provides evidence that thin PCL scaffolds biomodified with Matrigel, HA, and SR1 mimic the environments of real bone and bone marrow, thereby enhancing the de novo ectopic bone marrow formation induced by rhBMP-2. This ectopic bone marrow model will serve as a unique and essential tool for basic research and for clinical applications of postnatal tissue engineering and organ regeneration.