Accelerating the energy transition towards photovoltaic and wind in China.

China's goal to achieve carbon (C) neutrality by 2060 requires scaling up photovoltaic (PV) and wind power from 1 to 10-15 PWh year-1 (refs. 1-5). Following the historical rates of renewable installation1, a recent high-resolution energy-system model6 and forecasts based on China's 14th Five-year Energy Development (CFED)7, however, only indicate that the capacity will reach 5-9.5 PWh year-1 by 2060. Here we show that, by individually optimizing the deployment of 3,844 new utility-scale PV and wind power plants coordinated with ultra-high-voltage (UHV) transmission and energy storage and accounting for power-load flexibility and learning dynamics, the capacity of PV and wind power can be increased from 9 PWh year-1 (corresponding to the CFED path) to 15 PWh year-1, accompanied by a reduction in the average abatement cost from US$97 to US$6 per tonne of carbon dioxide (tCO2). To achieve this, annualized investment in PV and wind power should ramp up from US$77 billion in 2020 (current level) to US$127 billion in the 2020s and further to US$426 billion year-1 in the 2050s. The large-scale deployment of PV and wind power increases income for residents in the poorest regions as co-benefits. Our results highlight the importance of upgrading power systems by building energy storage, expanding transmission capacity and adjusting power load at the demand side to reduce the economic cost of deploying PV and wind power to achieve carbon neutrality in China.

The I7L protein of African swine fever virus is involved in viral pathogenicity by antagonizing the IFN-γ-triggered JAK-STAT signaling pathway through inhibiting the phosphorylation of STAT1.

Cell-passage-adapted strains of African swine fever virus (ASFV) typically exhibit substantial genomic alterations and attenuated virulence in pigs. We have indicated that the human embryonic kidney (HEK293T) cells-adapted ASFV strain underwent genetic alterations and the I7L gene in the right variable region was deleted compared with the ASFV HLJ/2018 strain (ASFV-WT). A recent study has revealed that the deletion of the I7L-I11L genes results in attenuation of virulent ASFV in vivo, but the underlying mechanism remains largely unknown. Therefore, we hypothesized that the deletion of the I7L gene may be related to the pathogenicity of ASFV in pigs. We generated the I7L gene-deleted ASFV mutant (ASFV-ΔI7L) and found that the I7L gene deletion does not influence the replication of ASFV in primary porcine alveolar macrophages (PAMs). Using transcriptome sequencing analysis, we identified that the differentially expressed genes in the PAMs infected with ASFV-ΔI7L were mainly involved in antiviral immune responses induced by interferon gamma (IFN-γ) compared with those in the ASFV-WT-infected PAMs. Meanwhile, we further confirmed that the I7L protein (pI7L) suppressed the IFN-γ-triggered JAK-STAT signaling pathway. Mechanistically, pI7L interacts with STAT1 and inhibits its phosphorylation and homodimerization, which depends on the tyrosine at position 98 (Y98) of pI7L, thereby preventing the nuclear translocation of STAT1 and leading to the decreased production of IFN-γ-stimulated genes. Importantly, ASFV-ΔI7L exhibited reduced replication and virulence compared with ASFV-WT in pigs, likely due to the increased production of IFN-γ-stimulated genes, indicating that pI7L is involved in the virulence of ASFV. Taken together, our findings demonstrate that pI7L is associated with pathogenicity and antagonizes the IFN-γ-triggered JAK-STAT signaling pathway via inhibiting the phosphorylation and homodimerization of STAT1 depending on the Y98 residue of pI7L and the Src homology 2 domain of STAT1, which provides more information for understanding the immunoevasion strategies and designing the live attenuated vaccines against ASFV infection.

VarCards2: an integrated genetic and clinical database for ACMG-AMP variant-interpretation guidelines in the human whole genome.

VarCards, an online database, combines comprehensive variant- and gene-level annotation data to streamline genetic counselling for coding variants. Recognising the increasing clinical relevance of non-coding variations, there has been an accelerated development of bioinformatics tools dedicated to interpreting non-coding variations, including single-nucleotide variants and copy number variations. Regrettably, most tools remain as either locally installed databases or command-line tools dispersed across diverse online platforms. Such a landscape poses inconveniences and challenges for genetic counsellors seeking to utilise these resources without advanced bioinformatics expertise. Consequently, we developed VarCards2, which incorporates nearly nine billion artificially generated single-nucleotide variants (including those from mitochondrial DNA) and compiles vital annotation information for genetic counselling based on ACMG-AMP variant-interpretation guidelines. These annotations include (I) functional effects; (II) minor allele frequencies; (III) comprehensive function and pathogenicity predictions covering all potential variants, such as non-synonymous substitutions, non-canonical splicing variants, and non-coding variations and (IV) gene-level information. Furthermore, VarCards2 incorporates 368 820 266 documented short insertions and deletions and 2 773 555 documented copy number variations, complemented by their corresponding annotation and prediction tools. In conclusion, VarCards2, by integrating over 150 variant- and gene-level annotation sources, significantly enhances the efficiency of genetic counselling and can be freely accessed at http://www.genemed.tech/varcards2/.

The roles of cell wall polysaccharides in response to waterlogging stress in Brassica napus L. root.

BACKGROUND: Brassica napus L. (B. napus) is susceptible to waterlogging stress during different cultivation periods. Therefore, it is crucial to enhance the resistance to waterlogging stress to achieve a high and stable yield of B. napus. RESULTS: Here we observed significant differences in the responses of two B. napus varieties in root under waterlogging stress. The sensitive variety (23651) exhibited a more pronounced and rapid reduction in cell wall thickness and root integrity compared with the tolerant variety (Santana) under waterlogging stress. By module clustering analysis based on transcriptome data, we identified that cell wall polysaccharide metabolism responded to waterlogging stress in root. It was found that pectin content was significantly reduced in the sensitive variety compared with the tolerant variety. Furthermore, transcriptome analysis revealed that the expression of two homologous genes encoding polygalacturonase-inhibiting protein 2 (PGIP2), involved in polysaccharide metabolic pathways, was highly upregulated in root of the tolerant variety under waterlogging stress. BnaPGIP2s probably confer waterlogging resistance by inhibiting the activity of polygalacturonases (PGs), which in turn reduces the degradation of the pectin backbone polygalacturonic acid. CONCLUSIONS: Our findings demonstrate that cell wall polysaccharides in root plays a vital role in response to the waterlogging stress and provide a theoretical foundation for breeding waterlogging resistance in B. napus varieties.

Genetic landscape of human mitochondrial genome using whole-genome sequencing.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.

Ceftazidime-avibactam resistance in KPC-producing Klebsiella pneumoniae accompanied hypermucoviscosity acquisition.

BACKGROUND: Antimicrobial resistance and bacterial hypermucoviscosity, associated with escalating production of capsules, constitute major challenges for the clinical management of Klebsiella pneumoniae (K. pneumoniae) infections. This study investigates the association and underlying mechanism between ceftazidime-avibactam (CAZ-AVI) resistance and bacterial hypermucoviscosity in Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp). RESULTS: The proportion of CAZ-AVI-sensitive clinical isolates exhibiting the hypermucoviscous phenotype was significantly lower than that of the resistant strains (5.6% vs. 46.7%, P < 0.001). To further verify the correlation and molecular mechanism between CAZ-AVI resistance and hypermucoviscosity, 10 CAZ-AVI-resistant isolates were generated through in vitro resistance selection from CAZ-AVI-sensitive KPC-Kp. The results showed the same association as it showed in the clinical isolates, with four out of ten induced CAZ-AVI-resistant isolates transitioning from negative to positive in the string tests. Comparative genomic analysis identified diverse mutations in the wzc gene, crucial for capsule polysaccharide (CPS) synthesis, in all four CAZ-AVI-resistant hypermucoviscous KPC-Kp strains compared to the parent strains. However, these mutations were absent in the other six KPC-Kp strains that did not exhibit induced hypermucoviscosity. Cloning of the wzc gene variants and their expression in wild-type strains confirmed that mutations in the wzc gene can induce bacterial hypermucoviscosity and heightened virulence, however, they do not confer resistance to CAZ-AVI. CONCLUSIONS: These results indicated that resistance to CAZ-AVI in KPC-Kp isolates may be accompanied by the acquisition of hypermucoviscosity, with mutations in the wzc gene often involving in this process.

Predicting the effect of confinement on the COVID-19 spread using machine learning enriched with satellite air pollution observations.

The real-time monitoring of reductions of economic activity by containment measures and its effect on the transmission of the coronavirus (COVID-19) is a critical unanswered question. We inferred 5,642 weekly activity anomalies from the meteorology-adjusted differences in spaceborne tropospheric NO2 column concentrations after the 2020 COVID-19 outbreak relative to the baseline from 2016 to 2019. Two satellite observations reveal reincreasing economic activity associated with lifting control measures that comes together with accelerating COVID-19 cases before the winter of 2020/2021. Application of the near-real-time satellite NO2 observations produces a much better prediction of the deceleration of COVID-19 cases than applying the Oxford Government Response Tracker, the Public Health and Social Measures, or human mobility data as alternative predictors. A convergent cross-mapping suggests that economic activity reduction inferred from NO2 is a driver of case deceleration in most of the territories. This effect, however, is not linear, while further activity reductions were associated with weaker deceleration. Over the winter of 2020/2021, nearly 1 million daily COVID-19 cases could have been avoided by optimizing the timing and strength of activity reduction relative to a scenario based on the real distribution. Our study shows how satellite observations can provide surrogate data for activity reduction during the COVID-19 pandemic and monitor the effectiveness of containment to the pandemic before vaccines become widely available.

Saponins as therapeutic candidates for atherosclerosis.

Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid-lowering, anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti-inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

The effect of drugs and guns on life expectancy in the United States, 2000-2020.

OBJECTIVES: This study estimated the effect of changing trends in drug- and firearm-related mortality on life expectancy in the U.S. over the last two decades. STUDY DESIGN: Retrospective cross-sectional study. METHODS: We used national vital registration data from CDC WONDER, stratified by sex, to estimate the mortality rate due to accidental and intentional poisoning (ICD Codes X40-X49, X60-X69, Y10-Y19 and X85), and firearm deaths (ICD codes W32-W34, X72-X74, X93-X95, Y22-Y24) for the period 2000-2020. We applied standard life table methods to all cause mortality rates with and without these mortality causes to estimate the life expectancy at each age over this period. RESULTS: In 2020, mortality due to drugs and firearms combined reduced male life expectancy by1.67 years compared to 0.67 years in 2000, and without the effect of these two causes of death, male life expectancy in 2019 would have been 78.02 years. For women, drugs and firearm-related mortality reduced life expectancy by 0.20 years in 2000 and 0.63 years in 2020, and female life expectancy would have been 82.25 years in 2019 without the retarding effect of these two preventable causes. CONCLUSIONS: Drug- and firearm-related deaths have increased so rapidly, especially among younger populations, that life expectancy at birth is significantly reduced by these causes of death. Without urgent action to tackle these preventable causes of death, US life expectancy will continue to stagnate and may even decline, even without the effect of COVID-19.

LESM-YOLO: An Improved Aircraft Ducts Defect Detection Model.

Aircraft ducts play an indispensable role in various systems of an aircraft. The regular inspection and maintenance of aircraft ducts are of great significance for preventing potential failures and ensuring the normal operation of the aircraft. Traditional manual inspection methods are costly and inefficient, especially under low-light conditions. To address these issues, we propose a new defect detection model called LESM-YOLO. In this study, we integrate a lighting enhancement module to improve the accuracy and recognition of the model under low-light conditions. Additionally, to reduce the model's parameter count, we employ space-to-depth convolution, making the model more lightweight and suitable for deployment on edge detection devices. Furthermore, we introduce Mixed Local Channel Attention (MLCA), which balances complexity and accuracy by combining local channel and spatial attention mechanisms, enhancing the overall performance of the model and improving the accuracy and robustness of defect detection. Finally, we compare the proposed model with other existing models to validate the effectiveness of LESM-YOLO. The test results show that our proposed model achieves an mAP of 96.3%, a 5.4% improvement over the original model, while maintaining a detection speed of 138.7, meeting real-time monitoring requirements. The model proposed in this paper provides valuable technical support for the detection of dark defects in aircraft ducts.

Dynamic Changes and Potential Correlations between Microbial Diversity and Volatile Flavor Compounds in Chinese Medium-Temperature Daqu during Manufacturing.

To investigate the dynamic changes and potential correlations between microbial diversity and volatile organic compounds (VOCs) during Chinese medium-temperature Daqu (MTD) manufacturing at different key stages, in this study, high-throughput sequencing (HTS) and gas chromatography-ion mobility spectrometry (GC-IMS) were employed to analyze the microbial diversity and VOCs of MTD, respectively. The results showed that Weissella, Staphylococcus, Thermoactinomyces, Kroppenstedtia, and Lactobacillus were the dominant bacterial genera, while Aspergillus, Alternaria, Thermoascus, Thermomyces, Wickerhamomyces, and Saccharomyces were the dominant fungal genera. A total of 61 VOCs were detected by GC-IMS, among which, 13 differential VOCs (VIP > 1) were identified, that could be used as potential biomarkers to judge the fermentation stage of MTD. Kroppenstedtia and Saccharopolyspora were positively correlated with 3-methyl-2-butenal and 2,2,4,6,6-pentamethylheptane-D, respectively, and both of these were positively correlated with butanal-D. Acetobacter, Streptomyces, and lactic acid bacteria (LAB) including Leuconostoc, Pediococcus, Weissella, and Lactobacillus were negatively correlated with their associated VOCs, while fungi were generally positively correlated with VOCs. Wickerhamomyces, Saccharomyces, and Candida were positively correlated with butan-2-one-M. This study provides a theoretical basis for explaining the mechanisms of MTD flavor formation and screening functional microorganisms to improve the quality of MTD.

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA-Gene Interaction Network Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. METHODS: We performed a miRNA-gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM-DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. RESULTS: By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term "Liver" with a statistical p-value of 1.71 × 10-26. Function enrichment analysis indicated that these genes were significantly overrepresented in the term "monocarboxylic acid metabolic process" with a p-value = 2.94 × 10-18. Two sets (fourteen genes and five miRNAs) were screened by a miRNA-gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. CONCLUSION: We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC.

Association between ovarian reserve and spontaneous miscarriage and their shared genetic architecture.

STUDY QUESTION: Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data? SUMMARY ANSWER: Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways. WHAT IS KNOWN ALREADY: Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data. STUDY DESIGN, SIZE, DURATION: Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17 786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause. MAIN RESULTS AND THE ROLE OF CHANCE: In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways. LIMITATIONS, REASONS FOR CAUTION: The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province, China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

A DNA Damage Response Related Signature to Predict Prognosis in Patients with Acute Myeloid Leukemia.

The prognosis of acute myeloid leukemia (AML) is disappointing in most subtypes and varies widely. DNA damage response (DDR) is associated with prognosis and immunotherapy in multiple cancers. Here, we identify a signature of eight DDR-related genes associated with overall survival, which stratifies AML patients into high- and low-risk groups. Patients in low-risk group were more likely to respond to sorafenib. The signature could be an independent prognostic predictor for patients treated with ADE and ADE plus gemtuzumab ozogamicin. Therefore, this DDR prognostic signature might be applied to prognostic stratification and treatment selection in AML patients, which warrants further studies.

PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.

Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrate that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses reveal key residues that govern the interaction between PTP-MEG2 and its substrate, a peptide containing the phosphorylated NSF-pY83 site, specify PTP-MEG2 substrate selectivity, and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface reveals that PTP-MEG2 controls the fusion pore opening through NSF independent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we uncover that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY125 and MUNC18-1-pY145 sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies thus provide mechanistic insights in complex exocytosis processes.

Insights into an Amorphous NiCoB Nanoparticle-Catalyzed MgH2 System for Hydrogen Storage.

In the paper, we synthesized amorphous NiCoB nanoparticles by a simple chemical reduction method and employed them as high-activity catalysts to considerably improve the hydrogen storage properties of MgH2. The MgH2-NiCoB composite quickly absorbed 3.6 wt % H2 at a low temperature of 85 °C and released 5.5 wt % H2 below 270 °C within 600 s. It is worth noting that the hydrogenation activation energy was reduced to 33.0 kJ·mol-1. Detailed microstructure analysis reveals that MgB2, Mg2Ni/Mg2NiH4, and Mg2Co/Mg2CoH5 were in situ generated during the first de/absorption cycle and dispersed at the surface of NiCoB. These active ingredients created lots of boundary interfaces to facilitate the hydrogen diffusion and destabilize the Mg-H bonds, thus decreasing the kinetic barriers. This work provides support for a promising catalytic effect of amorphous NiCoB on de/absorption reactions of MgH2, showing new ways for designing Mg-based hydrogen storage systems toward practical application.

Computational Study of the Fe(II) and α-Ketoglutarate-Dependent Aryloxyalkanoate Dioxygenase (AAD-1) in the Degradation of the Herbicide 2,4-Dichlorophenoxyacetic Acid.

The AAD-1 enzyme belongs to the Fe(II) and α-ketoglutarate (Fe/αKG)-dependent nonheme aryloxyalkanoate dioxygenase family (AADs), which catalyzes the breakdown of 2,4-dichlorophenoxyacetic acid (2,4-D, an active ingredient of thousands of commercial herbicides) by using the highly active Fe(IV)═O complex. Multiple species of bacteria degrade 2,4-D via a pathway initiated by AADs; however, the detail of how they promote the cleavage of the ether C-O bond to generate 2,4-dichlorophenol (2,4-DCP) and glyoxylate is still unclear, which is the prerequisite for the further degradation of these halogenated aromatics. In this work, based on the crystal structure of AAD-1, the computational models were constructed, and a series of QM/MM and QM-only calculations were performed to explore the cleavage of the ether bond in 2,4-D with the catalysis of AAD-1. Our calculations reveal that AAD-1 may be only responsible for the hydroxylation of the substrate to generate the intermediate hemiacetal, which corresponds to an overall energy barrier of 14.2 kcal/mol on the quintet state surface, and the decomposition of the hemiacetal in the active site center of AAD-1 was calculated to be rather slow, corresponding to an energy barrier of 24.5 kcal/mol. In contrast, the decomposition of the free hemiacetal molecule in a solvent was calculated to be quite easy. Whether the decomposition of the hemiacetal occurs inside or outside the activation site is still worthy of experimental verification.

Bone Marrow Stromal Cell-Secreted Extracellular Vesicles Containing miR-34c-5p Alleviate Lung Injury and Inflammation in Bronchopulmonary Dysplasia Through Promotion of PTEN Degradation by Targeting OTUD3.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the predominant chronic disorder in preterm neonates. This study explored impacts of miR-34c-5p carried by bone marrow stromal cells-secreted extracellular vesicles (BMSC-EVs) on BPD progression. METHODS: A BPD mouse model was established, followed by measurement of miR-34c-5p, OTUD3, and PTEN expression. EVs were isolated from BMSCs transfected with miR-34c-5p mimic or mimic NC and intratracheally injected into mice. CD31 and Ki67 expression was detected and the pathological changes of lung tissues and lung function indexes were observed for mice. A neonatal human pulmonary microvascular endothelial cell (HPMEC) model was developed with hyperoxia, followed by co-culture with extracted EVs and ectopic experiments for measurement of cell viability, migration, and angiogenesis. IL-4, IL-13, IL-1ß, and IL-6 levels were measured in cell supernatants and lung tissues. Dual-luciferase reporter, ubiquitination, Co-IP, and RIP assays were adopted to determine the relationship among miR-34c-5p, OTUD3, and PTEN. RESULTS: Lung tissues of BPD mice had downregulated miR-34c-5p expression and upregulated OTUD3 and PTEN expression. BMSC-EVs and BMSC-EVs-miR-34c-5p treatment improved lung injury and alveolar structure, decreased lung resistance and IL-4, IL-13, IL-1ß, and IL-6 levels, and elevated dynamic lung compliance in BPD mice, as well as enhanced proliferation, angiogenesis, and migration and restrained inflammation in HPMECs. Mechanistically, miR-34c-5p negatively targeted OTUD3 which restrained ubiquitination to promote PTEN protein stabilization. Upregulation of OTUD3 or PTEN negated the changes in the proliferation, angiogenesis, migration, and inflammation of hyperoxia-treated HPMECs induced by BMSC-EVs-miR-34c-5p. CONCLUSION: BMSC-EVs-miR-34c-5p alleviated lung injury and inflammation in hyperoxia-induced BPD by blocking the OTUD3/PTEN axis.

Therapeutic Role and Potential Mechanism of Resveratrol in Atherosclerosis: TLR4/NF-κB/HIF-1α.

Atherosclerosis, the main pathological basis of cardiovascular disease, is a chronic inflammatory disease that severely affects the quality of human life. Resveratrol (Res) is a natural polyphenol that is a major component of many herbs and foods. The present study analyzed resveratrol from the perspective of visualization and bibliometric analysis and found that resveratrol is closely related to the inflammatory response in cardiovascular diseases (associated with atherosclerosis). To explore the specific molecular mechanism of resveratrol, network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used, in which HIF-1α signaling may be a key pathway in the treatment of AS. Furthermore, we induced the polarization of macrophage RAW264.7 to M1 type to generate inflammatory response by the combination of lipopolysaccharide (LPS) (200 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL). LPS and IFN-γ increased the inflammatory factor levels of IL-1ß, TNF-α, and IL-6 in RAW264.7, and the proportion of M1-type macrophages also increased, but the expression of inflammatory factors decreased after resveratrol administration, which confirmed the anti-inflammatory effect of resveratrol in AS. In addition, we found that resveratrol downregulated the protein expression of toll-like receptor 4 (TLR4)/NF-κB/hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, resveratrol has a significant anti-inflammatory effect, alleviates HIF-1α-mediated angiogenesis, and prevents the progression of AS through the TLR4/NF-κB signaling pathway.

DDIT4 is essential for DINP-induced autophagy of ovarian granulosa cells.

As one of the most important phthalates, di-isononyl phthalate (DINP) has been widely used as a common plasticizer in the food and personal care products sectors. In our previous study, we found that DINP can induce autophagy of ovarian granulosa cells; while the underlying mechanism is unclear. In the study, we showed that DINP exposure could induce autophagy of ovarian granulosa cells and KGN cells, accompanied with the increase in the mRNA and protein level of DDIT4. Furthermore, overexpression of DDIT4 were shown to induce autophagy of KGN cells; while knockdown of DDIT4 inhibited DINP-induced autophagy, implying that DDIT4 played an important role in DINP-induced autophagy of ovarian granulosa cells. There were three putative binding sites of transcription factor ATF4 in the promoter region of DDIT4 gene, suggesting that DDIT4 might be regulated by ATF4. Herein, we found that overexpression of ATF4 could upregulate the expression of DDIT4 in KGN cells, while knockdown of ATF4 inhibited its expression. Subsequently, ATF4 was identified to bind to the promoter region of DDIT4 gene and promote its transcription. The expression of ATF4 was also increased in the DINP-exposed granulosa cells, and ATF4 overexpression promoted autophagy of KGN cells; whereas knockdown of ATF4 alleviated DINP-induced upregulation of DDIT4 and autophagy of the cells. Taken together, DINP triggered autophagy of ovarian granulosa cells through activating ATF4/DDIT4 signals.