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The advent of click chemistry has had a profound impact on many fields and fueled a need for reliable reactions to expand the click chemistry toolkit. However, developing new systems to fulfill the click chemistry criteria remains highly desirable yet challenging. Here, we report the development of light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) as a photoclick reaction via primary amines as direct click handle, to rapid and modular functionalization of diverse small molecules and native biomolecules. With intrinsic advantages of temporal control, good biocompatibility, reliable chemoselectivity, excellent efficiency, readily accessible reactants, operational simplicity and mild conditions, the PANAC photoclick is robust for direct diversification of pharmaceuticals and biorelevant molecules, lysine-specific modifications of unprotected peptides and native proteins in vitro, temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. This strategy provides a versatile platform for organic synthesis, bioconjugation, medicinal chemistry, chemical biology and materials science. Developing new click chemistry reactions for robust molecular assembly remains challenging. Here the authors report a light-induced primary amines and o -nitrobenzyl alcohols photoclick cyclization for rapid and modular functionalization of small molecules and native biomolecules, in vitro and in living systems.

Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican‐3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti‐GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer‐targeted next‐generation sequencing (NGS) and three‐dimensional patient‐derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT‐PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti‐GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS‐08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3‐positive cells was variable in the focal (+; 10%–30%; 8/45), partial (++; 31%–70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10−10). The anti‐GPC3 antibody efficiently inhibits Wnt/β‐catenin signaling and induces apoptosis in GPC3‐positive PDOs and PDXs, as opposed to GPC3‐negative PDOs and PDXs. The high frequency of GPC3 and CD133 co‐expression and the effectiveness of anti‐wild‐type GPC3‐Ab therapy in GPC3‐positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma. Lack of molecular target is a tricky problem in osteosarcoma treatment. In this study, we report (1) high frequency of GPC3 detection (73.77%; 45/61) and its overlapped expression with CD133 in OSs; (2) successful generation of patient‐derived organoids (PDOs) from 24 human osteosarcoma cases (OSs) as ex vivo experimental model; (3) the effectiveness of anti‐GPC3 strategy against GPC3‐expressing OS PDOs and PDXs, accompanied with suppressed Wnt/β‐catenin signaling. We therefor propose that GPC3 would be a promising target for personalized OS therapy.

The excessive carbon emissions not only intensify the global climate change, but also seriously restrict the sustainable development of social economy. However, improving industrial carbon emissions efficiency is the most directly effective way to reduce emissions. Therefore, accurate measurement and analysis of carbon emissions efficiency and evolution characteristics of China’s industrial system is the basis for China to improve carbon emissions efficiency. Based on this, we adopted energy consumption method and input-output method to calculate and analyze the industrial carbon emissions efficiency and evolution characteristics of China from 2002 to 2015. The results show that (1) If carbon emissions from cement production are ignored and only energy-related carbon emissions are considered, the calculation results of carbon emissions efficiency of heavy industry will be overestimated about 30%. (2) Compared with 2002, China’s industrial carbon emissions efficiency increased by about twice in 2015. Specifically, the optimization of carbon emissions efficiency in agriculture, construction, light industry and service industry is very obvious, which has increased by 5.65, 5.00, 4.69 and 4.68 times respectively; The optimization of carbon emissions efficiency in power sector, heavy industry, transportation and chemical industry was obvious, which increased by 2.55, 2.01, 1.86 and 1.47 times respectively; The carbon emissions efficiency of the fossil energy sector has decreased by 0.36 times. (3) The carbon emissions efficiency of various industries has significant differences. Among them, agriculture, service industry, light industry and construction industry are generally industries with higher carbon emissions efficiency, while power sector, fossil energy sector, transportation industry, chemical industry and heavy industry are generally industries with lower carbon emissions efficiency, especially power and fossil energy sectors. Based on these, this paper provides policy implications and scientific evidence for accurately improving carbon emissions efficiency from the perspective of carbon emissions efficiency.

Interleukin-35 (IL-35) is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35 that has recently been shown to play diverse and important roles in the tumor microenvironment (TME). Owing to its immunosuppressive activity and ability to promote tumor growth and progression, IL-35 is widely recognized as a key mediator of TME status. Immune cells are key mediators of diverse tumor-related phenotypes, and immunosuppressive cytokines such as IL-35 can promote tumor growth and metastasis in TME. These influences should be considered together. Since tumor immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance, a new target or efficacy enhancing factor is urgently needed. Suppressing IL-35 production and activity has been demonstrated as an effective factor that inhibits tumor cells viability, and further investigation of this cytokine is warranted. However, the mechanistic basis for IL-35-mediated regulation of immune cells in the TME remains to be fully clarified. In the present review, we explore the roles of IL-35 in regulating immune cells within the TME. In addition, we highlight IL-35 as a specific immunological target and discuss its possible relevance in the context of immunotherapy. Lastly, we sought to summarize potential future research directions that may guide the advancement of current understanding regarding the role of this important cytokine as a regulator of oncogenesis.

Treatment of bone defects remains a challenge in the clinic. Artificial bone grafts are the most promising alternative to autologous bone grafting. However, one of the limiting factors of artificial bone grafts is the limited means of regulating stem cell differentiation during bone regeneration. As a weight-bearing organ, bone is in a continuous mechanical environment. External mechanical force, a type of biophysical stimulation, plays an essential role in bone regeneration. It is generally accepted that osteocytes are mechanosensitive cells in bone. However, recent studies have shown that mesenchymal stem cells (MSCs) can also respond to mechanical signals. This article reviews the mechanotransduction mechanisms of MSCs, the regulation of mechanical stimulation on microenvironments surrounding MSCs by modulating the immune response, angiogenesis and osteogenesis, and the application of mechanical stimulation of MSCs in bone regeneration. The review provides a deep and extensive understanding of mechanical stimulation mechanisms, and prospects feasible designs of biomaterials for bone regeneration and the potential clinical applications of mechanical stimulation.

In recent years, the issues related to carbon emissions and environment have attracted extensive attentions. Considering four scenarios (the energy conversion, energy capital savings and loans, energy exports and cement production carbon emissions), this paper adopts the energy consumption method and input-output method to analyze China’s carbon emissions structure on the supply-side and demand-side of energy, and finally provides policy recommendations for China’s structural emission reduction. The results show that, if the four influencing factors were not considered, the measurement of carbon emissions from the final demand was 44.91% higher than the baseline scenario, 12.36% lower than the baseline scenario from intermediate demand, and 10.23% lower than the baseline scenario from the total. For China’s carbon emissions structure on the supply-side of energy, the carbon emissions from high-carbon energy, represented by raw coal, accounted for 66.805% of the total energy-related carbon emissions, while the carbon emissions from low-carbon energy, represented by natural gas, only accounted for 2.485%. For China’s carbon emissions structure on the demand-side of energy, the carbon emissions from intermediate demand (enterprise production) accounted for more than 95% of total energy-related carbon emissions, while the carbon emissions from final demand (residents and government use) accounted for less than 5%. For each specific industry in intermediate demand for energy, the heavy industry, electric power, fossil energy, and chemical industry have high carbon emissions and low carbon emissions efficiency. However, the agriculture, construction, light industry, and service are the opposite. Finally, we provide policy recommendations for improving the accuracy of carbon emissions measurement and carbon emissions efficiency.

Circular RNAs (circRNAs) are involved in many physiological functions. Whether circulating circRNAs serve as markers for coronary artery disease (CAD) is unknown. Seven CAD-related microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and were analyzed using clustering and functional enrichment to identify hub mRNAs and miRNAs. StarBase V3.0 and circinteractome databases were used to predict interactions between circRNAs and miRNAs whereas miRwalk and DIANA TOOLS were used to predict interactions between miRNAs and mRNAs. Altogether, this helped establish a circRNA-miRNA-mRNA triple network for diagnosis of CAD. Five non-coding RNAs (ncRNAs) were identified in our study population with the use of quantitative real-time PCR (RT-PCR). The prognostic values of circYOD1, hsa-miR-21-3p and hsa-miR-296-3p were evaluated using a receiver operating characteristic (ROC) curve. A CAD circRNA-miRNA-mRNA network was established from our analyses containing one circRNA, four miRNAs and thirteen mRNAs. After performing RT-PCR validation between CAD and non-CAD samples, only three ncRNAs of five ncRNAs showed significance for further analysis. The area under ROC curve (AUC) of circ-YOD1 was 0.824, the AUC of hsa-miR-21-3p was 0.731 and hsa-miR-296-3p was 0.776. The pairwise comparison results showed that circ-YOD1 had statistical significance ( P YOD1-21  < 0.01 and P YOD1-296  < 0.05). The results of functional enrichment analysis of interacting genes and microRNAs showed that the shared circ-YOD1 may act as a new biomarker for CAD. Our investigation of the triple regulatory networks of circRNA-miRNA-mRNA in CAD revealed circ-YOD1 as a potential biomarker for CAD.

F321 austenitic stainless steel is used in high-temperature, high-pressure, and severe irradiation conditions at high-temperature gas reactors, leading to the formation of irradiation defects such as point defect in the matrix. This study explores the displacement cascade process in F321 austenitic stainless steel based on molecular dynamics (MD) simulations with the aim of investigating the effect of PKA energy, PKA direction and temperature. MD results show that irradiation-induced Frenkel pairs (FPs) number increases with increasing PKA energy. The effect of different PKA directions is not significant when energy is lower than 30 keV, which becomes obviously at 50 keV and 100 keV. In addition, the increasing temperature leads to lower FPs. When it comes to defect cluster, both size and number of clusters increase with increasing PKA energy, which is consistent with the trend with FPs. Vacancy cluster is larger than that of interstitial cluster and the irradiation-induced defect cluster is not significantly dependent on PKA directions. Furthermore, five typical dislocation loops (1/2 < 110>, 1/6 < 112>, 1/3 < 111>, 1/6 < 110 > and 1/3 < 100> ) are observed in samples after displacement cascade, especially high-energy PKA cascades. More interestingly, 1/6 < 112 > dislocation loop is formed first in the displacement cascade process due to its high mobility. These insights reveal systematic irradiation defect formation mechanism during displacement cascade under varied irradiation conditions, offering a new perspective for novel understanding irradiation effect in F321 stainless steel. Based on that, the effect of various factors could be quantified precisely, governing the study of irradiation defects’ generation.

Organic manure is an ideal alternative fertilizer to provide phosphorus (P) but is not fully recycled in subtropical China. In order to identify if it can replace chemical P fertilizer, a 35-year field trail in a paddy soil under double-rice cropping system was conducted to assess the effects of substituting chemical P fertilizer with pig manure (NKM) on rice yield, phosphorus use efficiency (PUE) and P balance. The N, P and K input under NKM was 1.2, 0.8 and 1.2 times of the combined chemical fertilizer treatment (NPK), respectively. The NKM treatment reached the same level of grain yield with NPK after 20 years’ application, and showed significantly 4.0% decreased double-rice grain yield compared with NPK over the 35 years. The NKM treatment reduced the crop P uptake leading to decreased PUE compared with NPK. Long-term P budget showed that NKM may result in higher potential of P loss than NPK. Thus, substituting chemical P fertilizer with organic manure under this rate of nutrient input slightly sacrificed the crop yield and may increase the P loss. Considering the benefits of soil fertility, adjusting the substitution rate with a more balanced NPK input might be alternative in subtropical China.

Thoracic aortic dissection (TAD) is an aggressive vascular disease that requires early diagnosis and effective treatment. However, due to the particular vascular structure and narrowness of lesion location, there are no effective drug delivery systems for the therapy of TAD. Here, we report a multifunctional delivery nanosystem (TP-Gd/miRNA-ColIV) composed of gadolinium-chelated tannic acid (TA), low-toxic cationic PGEA (ethanolamine-aminated poly(glycidyl methacrylate)) and type IV collagen targeted peptide (ColIV) for targeted nucleic acid therapy, early diagnosis and noninvasive monitoring of TAD. Such targeted therapy with miR-145 exhibits impressive performances in stabilizing the vascular structures and preventing the deterioration of TAD. After the treatment with TP-Gd/miR-145-ColIV, nearly no dissection occurs in the thoracic aortic arches of the mice with TAD model. Moreover, TP-Gd/miRNA-ColIV also demonstrates good magnetic resonance imaging (MRI) ability and can be used to noninvasively monitor the development conditions of TAD. Thoracic aortic dissection has a high fatality rate and no effective treatment. Here, the authors develop cationic nanoparticles for the delivery of miR-145 and show that they stabilize vascular structures and prevent further deterioration of the aorta in mouse models of the disease.