Effects of transcription factor SOX11 on the biological behavior of neuroblastoma cell and potential regulatory mechanism.

Purpose: This study aimed to analyze the expression and prognosis of SRY-box transcription factor 11 (SOX11) in neuroblastoma (NB), as well as the biological function and potential regulatory mechanism of SOX11 in NB. Methods: Public RNA sequencing was used to detect the expression level of SOX11. The Kaplan-Meier curve and hazard ratios (HR) were used to determine the prognostic value of SOX11 in NB. Functional analyses were performed using CCK8, wound healing assay, and transwell invasion assay. Finally, the potential target genes of SOX11 were predicted by Harmonizonme (Ma'ayan Laboratory) and Cistrome Data Browser (Cistrome Project) database to explore the potential molecular mechanism of SOX11 in NB. Results: Compared with normal adrenal tissue, the expression of SOX11 in NB tissue was significantly upregulated. The Kaplan-Meier curve showed that high expression of SOX11 was associated with poor prognosis in children with NB (HR, 1.719; P = 0.049). SOX11 knockdown suppressed the migration capacity of SK-N-SH cells but did not affect proliferation and invasion capacity. Enhancer of zeste homolog 2 (EZH2) may be a potential downstream target gene for the transcription factor SOX11 to play a role in NB. Conclusion: The transcription factor SOX11 was significantly upregulated in NB. SOX11 knockdown suppressed the migration capacity of NB cell SK-N-SH. SOX11 may promote the progression of NB by targeting EZH2.

Regulatory effect of Yinchenhao decoction on bile acid metabolism to improve the inflammatory microenvironment of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the "soil" of its occurrence and development, and the inflammatory microenvironment is an important part of the "soil". Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.

Insight into chemically reactive metabolites of aliphatic amine pollutants: A de novo prediction strategy and case study of sertraline.

The uncommon metabolic pathways of organic pollutants are easily overlooked, potentially leading to idiosyncratic toxicity. Prediction of their biotransformation associated with the toxic effects is the very purpose that this work focuses, to develop a de novo method to mechanistically predict the reactive toxicity pathways of uncommon metabolites from start aliphatic amine molecules, which employed sertraline triggered by CYP450 enzymes as a model system, as there are growing concerns about the effects on human health posed by antidepressants in the aquatic environment. This de novo prediction strategy combines computational and experimental methods, involving DFT calculations upon sequential growth, in vitro and in vivo assays, dissecting chemically reactive mechanism relevant to toxicity, and rationalizing the fundamental factors. Significantly, desaturation and debenzylation-aromatization as the emerging metabolic pathways of sertraline have been elucidated, with the detection of DNA adducts of oxaziridine metabolite in mice, highlighting the potential reactive toxicity. Molecular orbital analysis supports the reactivity preference for toxicological-relevant C-N desaturation over N-hydroxylation of sertraline, possibly extended to several other aliphatic amines based on the Bell-Evans-Polanyi principle. It was further validated toward some other wide-concerned aliphatic amine pollutants involving atrazine, ε-caprolactam, 6PPD via in silico and in vitro assays, thereby constituting a complete path for de novo prediction from case study to general applications.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

BACKGROUND: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. METHODS: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. RESULTS: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs, short-term HSCs, and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. CONCLUSION: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. This novel and robust deep learning-based platform will provide a basis for the future development of a new generation stem cell identification and separation system. It may also provide new insight into the molecular mechanisms underlying stem cell self-renewal.

Nanoplastic propels diet-induced NAFL to NASH via ER-mitochondrial tether-controlled redox switch.

Nonalcoholic steatohepatitis (NASH) is multifactorial that lifestyle, genetic, and environmental factors contribute to its onset and progression, thereby posing a challenge for therapeutic intervention. Nanoplastic (NP) is emerged as a novel environmental metabolism disruptor but the etiopathogenesis remains largely unknown. In this study, C57BL/6 J mice were fed with normal chow diet (NCD) and high-fat diet (HFD) containing 70 nm polystyrene microspheres (NP). We found that dietary-derived NP adsorbed proteins and agglomerated during the in vivo transportation, enabling diet-induced hepatic steatosis to NASH. Mechanistically, NP promoted liver steatosis by upregulating Fatp2. Furthermore, NP stabilized the Ip3r1, and facilitated ER-mitochondria contacts (MAMs) assembly in the hepatocytes, resulting in mitochondrial Ca2+ overload and redox imbalance. The redox-sensitive Nrf2 was decreased in the liver of NP-exposed mice, which positively regulated miR26a via direct binding to its promoter region [-970 bp to -847 bp and -318 bp to -176 bp]. NP decreased miR26a simultaneously upregulated 10 genes involved in MAMs formation, lipid uptake, inflammation, and fibrosis. Moreover, miR26a inhibition elevated MAMs-tether Vdac1, which promoted the nucleus translocation of NF-κB P65 and Keap1 and functionally inactivated Nrf2, leading to a vicious cycle. Hepatocyte-specific overexpressing miR26a effectively restored ER-mitochondria miscommunication and ameliorated NASH phenotype in NP-exposed and Keap1-overexpressed mice on HFD. The hepatic MAM-tethers/Nrf2/miR26a feedback loop is an essential metabolic switch from simple steatosis to NASH and a promising therapeutic target for oxidative stress-associated liver damage and NASH.

Association between Hepatitis B virus and gastric cancer: A systematic review and meta-analysis.

An increasing number of studies are suggesting that hepatitis B virus (HBV) infection may be associated with an increased risk of not only hepatocellular carcinoma but also gastric cancer (GC). Whether HBV infection can be a risk factor for GC remains to be explored. In this study, we systematically searched for all eligible literature in 7 databases (China National Knowledge Infrastructure, WanFang, China Science and Technology Journal, PubMed, Cochrane Library, Web of Science and Embase). Eligible studies were required to have a case-control or cohort design. Sixteen studies were included and a meta-analysis was performed using Stata version 17.0. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. The association between HBV infection and risk of GC was quantified by calculating the odds ratio and 95% confidence interval. The proportion of high-quality studies was 87.5% (14/16). The risk of GC was higher when HBV infection was present than when it was not (combined odds ratio 1.29, 95% confidence interval 1.16-1.44; I2 = 62.7%, p < 0.001). The results of subgroup analyses were consistent with the main results. In conclusion, this systematic review and meta-analysis identified a positive association between HBV infection and an increased risk of GC.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

Background: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. Methods: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. Results: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. Conclusion: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. With ongoing advancements in model algorithms and their integration into various imaging systems, deep learning stands poised to become an invaluable tool, significantly impacting stem cell research.

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation.

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases.

Association of food intake with a risk of metabolic dysfunction-associated fatty liver disease: a cross-sectional study.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common liver disease, the risk of which can be increased by poor diet. The objective of this study was to evaluate the associations between food items and MAFLD, and to propose reasonable dietary recommendations for the prevention of MAFLD. Methods: Physical examination data were collected from April 2015 through August 2017 at Nanping First Hospital (n = 3,563). Dietary intakes were assessed using a semi-quantitative food frequency questionnaire. The association between food intake and the risk of MAFLD was assessed by using the inverse probability weighted propensity score. Results: Beverages (soft drinks and sugar-sweetened beverages) and instant noodles were positively associated with MAFLD risk, adjusting for smoking, drinking, tea intake, and weekly hours of physical activity [adjusted odds ratio (ORadjusted): 1.568; P = 0.044; ORadjusted: 4.363; P = 0.001]. Milk, tubers, and vegetables were negatively associated with MAFLD risk (ORadjusted: 0.912; P = 0.002; ORadjusted: 0.633; P = 0.007; ORadjusted: 0.962; P = 0.028). In subgroup analysis, the results showed that women [odds ratio (OR): 0.341, 95% confidence interval (CI): 0.172-0.676] had a significantly lower risk of MAFLD through consuming more tubers than men (OR: 0.732, 95% CI: 0.564-0.951). Conclusions: These findings suggest that reducing consumption of beverages (soft drinks and sugar-sweetened beverages) and instant noodles, and consuming more milk, vegetables, and tubers may reduce the risk of MAFLD.

The first high-quality chromosome-level genome of Eretmochelys imbricata using HiFi and Hi-C data.

Eretmochelys imbricata, a critically endangered sea turtle inhabiting tropical oceans and protected across the world, had an unknown genome sequence until now. In this study, we used HiFi reads and Hi-C technology to assemble a high-quality, chromosome-level genome of E. imbricata. The genome size was 2,138.26 Mb, with contig N50 length of 123.49 Mb and scaffold N50 of 137.21 Mb. Approximately 97.52% of the genome sequence was anchored to 28 chromosomes. A total of 20,206 protein-coding genes were predicted. We also analyzed the evolutionary relationships, gene family expansions, and positive selection of E. imbricata. Our results revealed that E. imbricata diverged from Chelonia mydas 38 million years ago and had enriched olfactory receptors and aging-related genes. Our genome will be useful for studying E. imbricata and its conservation.

Design and Application of Thymol Electrochemical Sensor Based on the PtNPs-CPOFs-MWCNTs Composite.

In this study, the preparation of covalent polyoxometalate organic frameworks (CPOFs) is introduced using the idea of polyoxometalate and covalent organic frameworks. Firstly, the prepared polyoxometalate was functionalized with an amine group (NH2-POM-NH2), and then the CPOFs were prepared by a solvothermal Schiff base reaction with NH2-POM-NH2 and 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde (Tp) as monomers. After the incorporation of PtNPs and MWCNTs into the CPOFs material, the PtNPs-CPOFs-MWCNTs nanocomposites, which possess excellent catalytic activity and electrical conductivity, were formed and utilized as new electrode materials for the electrochemical thymol sensors. The obtained PtNPs-CPOFs-MWCNTs composite exhibits excellent activity toward thymol, which is attributable to its large special surface area, good conductivity and the synergistic catalysis of each component. Under optimal experimental conditions, the sensor presented a good electrochemical response to thymol. The sensor shows two good linear relationships between the current and thymol concentration in the range of 2-65 µM (R2 = 0.996) and 65-810 µM (R2 = 0.997), with the corresponding sensitivity of 72.7 µA mM-1 and 30.5 µA mM-1, respectively. Additionally, the limit of detection (LOD) was calculated to be 0.2 µM (S/N = 3). At the same time, the prepared thymol electrochemical sensor revealed superior stability and selectivity. The constructed PtNPs-CPOFs-MWCNT electrochemical sensor is the first example of thymol detection.

Development and validation of an online dynamic nomogram based on the atherogenic index of plasma to screen nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), a common liver disease worldwide, can be reversed early in life with lifestyle and medical interventions. This study aimed to develop a noninvasive tool to screen NAFLD accurately. METHODS: Risk factors for NAFLD were identified using multivariate logistic regression analysis, and an online NAFLD screening nomogram was developed. The nomogram was compared with reported models (fatty liver index (FLI), atherogenic index of plasma (AIP), and hepatic steatosis index (HSI)). Nomogram performance was evaluated through internal and external validation (National Health and Nutrition Examination Survey (NHANES) database). RESULTS: The nomogram was developed based on six variables. The diagnostic performance of the present nomogram for NAFLD (area under the receiver operator characteristic curve (AUROC): 0.863, 0.864, and 0.833, respectively) was superior to that of the HSI (AUROC: 0.835, 0.833, and 0.810, respectively) and AIP (AUROC: 0.782, 0.773, and 0.728, respectively) in the training, validation, and NHANES sets. Decision curve analysis and clinical impact curve analysis presented good clinical utility. CONCLUSION: This study establishes a new online dynamic nomogram with excellent diagnostic and clinical performance. It has the potential to be a noninvasive and convenient method for screening individuals at high risk for NAFLD.

RBM24 controls cardiac QT interval through CaMKIIδ splicing.

Calcium/calmodulin-dependent kinase II delta (CaMKIIδ) is the predominant cardiac isoform and it is alternatively spliced to generate multiple variants. Variable variants allow for distinct localization and potentially different functions in the heart. Dysregulation of CaMKIIδ splicing has been demonstrated to be involved in the pathogenesis of heart diseases, such as cardiac hypertrophy, arrhythmia, and diastolic dysfunction. However, the mechanisms that regulate CaMKIIδ are incompletely understood. Here, we show that RNA binding motif protein 24 (RBM24) is a key splicing regulator of CaMKIIδ. RBM24 ablation leads to the aberrant shift of CaMKIIδ towards the δ-C isoform, which is known to activate the L-type Ca current. In line with this, we found marked alteration in Ca2+ handling followed by prolongation of the ventricular cardiac action potential and QT interval in RBM24 knockout mice, and these changes could be attenuated by treatment with an inhibitor of CaMKIIδ. Importantly, knockdown of RBM24 in human embryonic stem cell-derived cardiomyocytes showed similar electrophysiological abnormalities, suggesting the important role of RBM24 in the human heart. Thus, our data suggest that RBM24 is a critical regulator of CaMKIIδ to control the cardiac QT interval, highlighting the key role of splicing regulation in cardiac rhythm.

Relative acquisition evaluation of health poverty alleviation project: a quantitative study of data from different regions of China.

BACKGROUND: Poverty is the greatest obstacle to the realization of human rights, among which illness is the leading cause in China. In 2015, China began to implement the health poverty alleviation project (HPAP). By 2020, all rural households living below the current poverty level (2300 yuan per person per year) have been lifted out of poverty. METHODS: This study introduces the concept of relative acquisition and constructs a scale based on the capability approach to measure the relative acquisition and compares its fairness of HPAP. RESULTS: The findings show that the values of the relative acquisition of HPAP in survey areas are all reached middle level (0.4-0.6), with 0 indicating the worst level and 1 indicating the best level. Specifically, the values of the functional activities of "health care", "health ability", "equal treatment opportunities" and "social support" are all above 0.4, while the values of "economic conditions" and "health education" are below 0.4. CONCLUSIONS: The HPAP plays a significant role in reducing the economic burden of disease on patients. However, due to insufficient social support and health education, the HPAP objects lack endogenous motivation to fight against poverty, and the fairness also needs to be improved.

Population genetic characteristics of Hainan medaka with whole-genome resequencing.

The DMY gene is deleted in all males of the Sanya population (SY-medaka) of the Hainan medaka, Oryzias curvinotus, as recently reported by us. However, due to limited knowledge regarding their population genetic background, it is difficult to explore the possible evolutionary pathway. Herein, we resequenced the whole genome of four populations, including SY-medaka. A total of 56 mitogenomes and 32,826,105 SNPs were identified. We found that the genetic differentiation is highest between SY-medaka and the other populations. The results of the population history of the O. curvinotus suggest that the SY-medaka has been in a bottleneck period recently. Further analysis shows that SY-medaka are the most strongly affected by environmental selection. Moreover, we screened some potential genomic regions, and the genes contained in these regions may explain the potential mechanism of the selection process of the SY-medaka. In conclusion, our study can provide new clues for the adaptation process of medaka in the new environment of Sanya.

The effect of the universal two-child policy on medical insurance funds with a rapidly ageing population: evidence from China's urban and rural residents' medical insurance.

BACKGROUND: With the rapid growth of the ageing population, the operating burden of China's basic medical insurance fund is becoming increasingly heavy. To counter rapid population ageing and ameliorate a series of problems, China has adjusted its fertility policies several times. On January 1, 2016, the universal two-child policy was implemented. This study analysed the impacts of the adjustment to the fertility policy and potential improvements in fertility intention on the insured population and medical insurance fund sustainability. METHODS: We used an actuarial science method and took the urban and rural residents' basic medical insurance (URRBMI) of China, which covers most urban and rural residents, as an example to build a dynamic forecast model of population growth and a dynamic actuarial model of medical insurance funds. RESULTS: Compared with the original policy, under the current fertility intention (40%) with the universal two-child policy, the ageing of the population structure of URRBMI participants will decline significantly after 2026, and individuals aged 65 and over will account for only 19.01% of the total participants in 2050. The occurrence of the current deficit and accumulated deficit of the URRBMI fund will be postponed for one year to 2022 and 2028, respectively. If fertility intentions continue to rise, the ageing degree of the population structure will decrease, and the deficit would be further delayed. CONCLUSIONS: The universal two-child policy is conducive to improving the degree of overall population ageing, delaying the occurrence of a URRBMI fund deficit, and improving the sustainability of URRBMI funds. If fertility intention increases, the effects would be stronger. However, since the adjustment of the universal two-child policy has a certain time lag, it will take time to demonstrate this impact. Therefore, while actively promoting the universal two-child policy, other measures should be taken, such as improving the fertility desire among couples of childbearing age and reforming medical insurance payment methods.

Construction and evaluation of red blood cells-based drug delivery system for chemo-photothermal therapy.

In this study, a novel tumor-targeting drug delivery system (DDS) based on red blood cells (RBCs) were fabricated for combinational chemo-phototherapy against cancer. Cyclic peptide (cRGD) and indocyanine green (ICG) were applied to the surface of RBCs to increase the targeting and photothermal effect, respectively. Doxorubicin (DOX) as a model drug was loaded into RBCs by the hypotonic dialysis method. A series of tests have been carried out to evaluate the RBCs-based DDS and these tasks include physicochemical properties, cellular uptake, targeting ability, and combination therapeutic efficiency. As a result, the DOX was successfully loaded into RBCs and the drug loading amount was 0.84 ±â€¯0.09 mg/mL. There was no significant change of particle size after surface modification of RBCs. The RBCs-based DDS could target to the surface of cancer cells, which delivery DOX to the lesions efficiently and accurately. Meanwhile, due to the combined treatment effect, the RBCs-based DDS can effectively inhibit tumor growth. The RBCs-based DDS constructed in this research may have promising applications in cancer therapy due to their highly synergistic efficient therapy and to investigate its possibility for tumor therapy.

SARS-CoV-2 nucleocapsid protein intranasal inoculation induces local and systemic T cell responses in mice.

SARS-CoV-2 nucleocapsid (N) protein has been proposed as a good vaccine target. N-specific T cells were observed in SARS-CoV-2 N immunized mice and COVID-19 convalescents. It is of importance to identify the T cell responses triggered by SARS-CoV-2 N protein. Intradermal immunization with SARS-CoV N protein was demonstrated to elicit non-protective T cell responses which may be avoided by intranasal vaccination. Therefore, we conducted intranasal vaccination of BALB/c mice with recombinant adenovirus type-5 expressing SARS-CoV-2 N protein. Such procedure induced CD8 T cell responses in the lung. Meanwhile CD4 T cell responses were observed in the spleen, which was associated with robust antibody production. Our study further supports the notion that SARS-CoV-2 N protein can work as a target for vaccine development.

Carbon Emissions Trading and Sustainable Development in China: Empirical Analysis Based on the Coupling Coordination Degree Model.

Despite the extensive attention paid to emissions trading scheme (ETS) approaches, few studies have examined whether such ETS policies can lead to sustainable development in China. Drawing on the ideas of coupling and synergistic development, this study views sustainable development as the result of the interactions between the economy and the environment and constructs an index system to measure economic development and environmental quality. The system coupling model is used to reflect the synergistic interactions between the economy and the environment systems. The coordination degree model is then used to assess the economic-environmental coupling coordination degree in order to measure sustainable development. The empirical results show that the ETS can help in achieving economic-environmental sustainable development in the pilot cities. Moreover, the better the socioeconomic development of a city, the better effects of the ETS on sustainable development. However, it is more difficult to achieve economic-environmental coordinated development in industrially developed areas (e.g., Guangdong). These findings provide empirical evidence that the market-based ETS could alleviate the conflict between economic development and environmental pollution and could help in achieving sustainable development in emerging economies.

Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid ß-oxidation.

Neddylation is a ubiquitination-like pathway that controls cell survival and proliferation by covalently conjugating NEDD8 to lysines in specific substrate proteins. However, the physiological role of neddylation in mammalian metabolism remains elusive, and no mitochondrial targets have been identified. Here, we report that mouse models with liver-specific deficiency of NEDD8 or ubiquitin-like modifier activating enzyme 3 (UBA3), the catalytic subunit of the NEDD8-activating enzyme, exhibit neonatal death with spontaneous fatty liver as well as hepatic cellular senescence. In particular, liver-specific UBA3 deficiency leads to systemic abnormalities similar to glutaric aciduria type II (GA-II), a rare autosomal recessive inherited fatty acid oxidation disorder resulting from defects in mitochondrial electron transfer flavoproteins (ETFs: ETFA and ETFB) or the corresponding ubiquinone oxidoreductase. Neddylation inhibition by various strategies results in decreased protein levels of ETFs in neonatal livers and embryonic hepatocytes. Hepatic neddylation also enhances ETF expression in adult mice and prevents fasting-induced steatosis and mortality. Interestingly, neddylation is active in hepatic mitochondria. ETFs are neddylation substrates, and neddylation stabilizes ETFs by inhibiting their ubiquitination and degradation. Moreover, certain mutations of ETFs found in GA-II patients hinder the neddylation of these substrates. Taken together, our results reveal substrates for neddylation and add insight into GA-II.