FOSL1-mediated LINC01566 negatively regulates CD4+ T-cell activation in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined. METHODS: Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter. RESULTS: Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566. CONCLUSIONS: In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

Botulinum toxin combined with static progressive stretching improves fibrous stiffness of knee joint in rats through TGF-ß1/Smad pathway.

Joint stiffness and fibrosis are common complications that affect mobility and quality of life, necessitating effective therapeutic strategies to alleviate these issues. The study aimed to observe the therapeutic effect of static progressive stretching (SPS) combined with botulinum toxin type A (BTX-A) on knee joint stiffness in rats and its effect on the transforming growth factor beta 1 (TGF-ß1)/small mother against decapentaplegic (Smad) pathway in the development of joint capsule fibrosis. Forty Sprague Dawley rats were randomly divided into the blank control group, model control group, SPS intervention group, BTX-A intervention group, and SPS combined with BTX-A intervention group. Except for the blank control group, the right knee joints of the other rats were surgically fixed with Kirschner wire internal immobilization in full flexion for four weeks to form joint flexion contracture and cause fibrotic stiffness of the joint. The therapeutic effect of each intervention was assessed by the range of motion (ROM) of the knee joint, joint stiffness, the number of total cells, and collagen deposition in the posterior joint capsule, as well as the protein level expressions of  TGF-ß1, Smad2, Smad3, Smad4, p-Smad2/3, collagen I and III, and alpha smooth muscle actin (α-SMA) in the posterior joint capsule in the TGF-ß1/Smad pathway. SPS combined with BTX-A was more effective in relieving joint fibrosis stiffness, improving the histopathological changes in the posterior joint capsule, and suppressing the high expression of target proteins and the overactivated TGF-ß1/Smad pathway. The overactivated TGF-ß1/Smad pathway was involved in the formation of knee joint fibrosis stiffness in rats. SPS combined with BTX-A was effective in relieving joint flexion contracture and fibrosis of the joint capsule. Moreover, the inhibition of the overactivated TGF-ß1/Smad pathway may be the potential molecular mechanism for its therapeutic effect.

Metachronous multifocal carcinoma: A case report.

BACKGROUND: The incidence of multiple primary carcinomas (MPC) varies greatly, ranging from 0.73% to 11.70% in foreign countries, with duo-duplex carcinoma being the most common, trio-duplex carcinoma and above being rare, and simultaneous multigenic carcinoma being even rarer, accounting for 18.4% to 25.3% of the incidence of MPC. However, there is no report regarding patients presenting with simultaneous dual-origin carcinoma of the liver and colon and heterochronous pancreatic cancer. CASE SUMMARY: We report a special case of multifocal carcinoma, in which one patient had a medical condition of primary liver and colon cancer and pancreatic cystadenocarcinoma 2 years after surgery. Through aggressive advanced fluorescent laparoscopic techniques, standardized immunotherapy, targeting, and chemotherapy, a better prognosis and a desirable survival period were achieved for the patient. CONCLUSION: There is a need to clarify the nature of MPC through advanced surgical means to ensure better diagnosis and treatment.

Deep learning model based on contrast-enhanced ultrasound for predicting vessels encapsulating tumor clusters in hepatocellular carcinoma.

OBJECTIVES: To establish and validate a non-invasive deep learning (DL) model based on contrast-enhanced ultrasound (CEUS) to predict vessels encapsulating tumor clusters (VETC) patterns in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study included consecutive HCC patients with preoperative CEUS images and available tissue specimens. Patients were randomly allocated into the training and test cohorts. CEUS images were analyzed using the ResNet-18 convolutional neural network for the development and validation of the VETC predictive model. The predictive value for postoperative early recurrence (ER) of the proposed model was further evaluated. RESULTS: A total of 242 patients were enrolled finally, including 195 in the training cohort (54.6 ± 11.2 years, 178 males) and 47 in the test cohort (55.1 ± 10.6 years, 40 males). The DL model (DL signature) achieved favorable performance in both the training cohort (area under the receiver operating characteristics curve [AUC]: 0.92, 95% confidence interval [CI]: 0.88-0.96) and test cohort (AUC: 0.90, 95% CI: 0.82-0.99). The stratified analysis demonstrated good discrimination of DL signature regardless of tumor size. Moreover, the DL signature was found independently correlated with postoperative ER (hazard ratio [HR]: 1.99, 95% CI: 1.29-3.06, p = 0.002). C-indexes of 0.70 and 0.73 were achieved when the DL signature was used to predict ER independently and combined with clinical features. CONCLUSION: The proposed DL signature provides a non-invasive and practical method for VETC-HCC prediction, and contributes to the identification of patients with high risk of postoperative ER. CLINICAL RELEVANCE STATEMENT: This DL model based on contrast-enhanced US displayed an important role in non-invasive diagnosis and prognostication for patients with VETC-HCC, which was helpful in individualized management. KEY POINTS: Preoperative biopsy to determine VETC status in HCC patients is limited. The contrast-enhanced DL model provides a non-invasive tool for the prediction of VETC-HCC. The proposed deep-learning signature assisted in identifying patients with a high risk of postoperative ER.

Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer's Disease Models.

Background: Mitochondrial dysfunction exists in Alzheimer's disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-ß secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.

The Relationship Between the Number of Chronic Diseases and Health-Related Quality of Life Among Middle-Aged and Older Adults in Rural Areas of Yunnan Province, China: moderating Effect of Health Lifestyle.

Purpose: With population aging, individuals in underdeveloped areas may experience a higher prevalence of chronic non-communicable diseases (NCDs), a lower level of health-related quality of life (HRQoL), and distinct lifestyles. However, this triadic association remains inadequately studied, particularly regarding the role of health lifestyle. This study aims to examine the relationship between the number of NCDs and HRQoL, while considering the moderating effect of health lifestyle among middle-aged and older adults residing in resource-limited areas. Methods: This cross-sectional study was conducted in Yunnan Province from July to December 2022. Participants completed a self-report questionnaire related to socio-demographic information, NCDs conditions, health lifestyle status, and HRQoL, which was assessed using the EuroQol five-dimension five-level (EQ-5D-5L) scale. Hierarchical regression and simple slope tests were used to examine the moderating effect of health lifestyle. Results: Out of the total 2704 participants, 57.91% presented at least one NCD. The mean scores for health lifestyle and health utility value were 11.109 and 0.944 respectively. The number of NCDs was negatively associated with health utility value, while positively correlated with the health lifestyle score (P<0.001). The results of hierarchical regression indicated that health lifestyle exerted a negative moderating effect on the relationship between the number of NCDs and HRQoL (ß=0.006, P<0.001), which was also observed for specific health-related behaviors such as sleep duration (ß=0.013, P<0.001), physical examination attendance (ß=0.006, P<0.05) and physical activity (ß=0.013, P<0.001). Conclusion: These findings highlight the crucial role of a healthy lifestyle in attenuating the association between the number of NCDs and HRQoL. Recognizing the potential modulating influence of a healthy lifestyle in this relationship could be pivotal for developing effective interventions for this population, even within resource-constrained rural settings.

Activation of CTU2 expression by LXR promotes the development of hepatocellular carcinoma.

Cytosolic thiouridylase 2 (CTU2) is an enzyme modifying transfer RNAs post-transcriptionally, which has been implicated in breast cancer and melanoma development. And we found CTU2 participated in hepatocellular carcinoma (HCC) progression here. HepG2 cells as well as xenograft nude mice model were employed to investigate the role of CTU2 in HCC development in vitro and in vivo respectively. Further, we defined CTU2 as a Liver X receptor (LXR) targeted gene, with a typical LXR element in the CTU2 promoter. CTU2 expression was activated by LXR agonist and depressed by LXR knockout. Interestingly, we also found CTU2 took part in lipogenesis by directly enhancing the synthesis of lipogenic proteins, which provided a novel mechanism for LXR regulating lipid synthesis. Meanwhile, lipogenesis was active during cell proliferation, particularly in tumor cells. Reduction of CTU2 expression was related to reduced tumor burden and synergized anti-tumor effect of LXR ligands by inducing tumor cell apoptosis and inhibiting cell proliferation. Taken together, our study identified CTU2 as an LXR target gene. Inhibition of CTU2 expression could enhance the anti-tumor effect of LXR ligand in HCC, identifying CTU2 as a promising target for HCC treatment and providing a novel strategy for the application of LXR agonists in anti-tumor effect.

Laparoscopic left hemihepatectomy guided by indocyanine green fluorescence: A cranial-dorsal approach.

BACKGROUND: Advancements in laparoscopic technology and a deeper understanding of intrahepatic anatomy have led to the establishment of more precise laparoscopic hepatectomy (LH) techniques. The indocyanine green (ICG) fluorescence navigation technique has emerged as the most effective method for identifying hepatic regions, potentially overcoming the limitations of LH. While laparoscopic left hemihepatectomy (LLH) is a standardized procedure, there is a need for innovative strategies to enhance its outcomes. AIM: To investigate a standardized cranial-dorsal strategy for LLH, focusing on important anatomical markers, surgical skills, and ICG staining methods. METHODS: Thirty-seven patients who underwent ICG fluorescence-guided LLH at Qujing Second People's Hospital between January 2019 and February 2022 were retrospectively analyzed. The cranial-dorsal approach was performed which involves dissecting the left hepatic vein cephalad, isolating the Arantius ligament , exposing the middle hepatic vein, and dissecting the parenchyma from the dorsal to the foot in order to complete the anatomical LLH. The surgical methods, as well as intra- and post-surgical data, were recorded and analyzed. Our hospital's Medical Ethics Committee approved this study (Ethical review: 2022-019-01). RESULTS: Intraoperative blood loss during LLH was 335.68 ± 99.869 mL and the rates of transfusion and conversion to laparotomy were 13.5% and 0%, respectively. The overall incidence of complications throughout the follow-up (median of 18 months; range 1-36 months) was 21.6%. No mortality or severe complications (level IV) were reported. CONCLUSION: LLH has the potential to become a novel, standardized approach that can effectively, safely, and simply expose the middle hepatic vein and meet the requirements of precision surgery.

Global burden of maternal disorders attributable to malnutrition from 1990 to 2019 and predictions to 2035: worsening or improving?

Background and aims: Maternal malnutrition is a major global public health problem that can lead to serious maternal diseases. This study aimed to analyze and predict the spatio-temporal trends in the burden of maternal disorders attributable to malnutrition, and to provide a basis for scientific improvement of maternal malnutrition and targeted prevention of maternal disorders. Methods: Data on maternal disorders attributable to malnutrition, including number of deaths, disability-adjusted life years (DALYs), population attributable fractions (PAFs), age-standardized mortality rates (ASMRs), and age-standardized DALY rates (ASDRs) were obtained from the Global Burden of Disease Study 2019 to describe their epidemiological characteristics by age, region, year, and type of disease. A log-linear regression model was used to calculate the annual percentage change (AAPC) of ASMR or ASDR to reflect their temporal trends. Bayesian age-period-cohort model was used to predict the number of deaths and mortality rates to 2035. Results: Global number of deaths and DALYs for maternal disorders attributable to malnutrition declined by 42.35 and 41.61% from 1990 to 2019, with an AAPC of -3.09 (95% CI: -3.31, -2.88) and -2.98 (95% CI: -3.20, -2.77) for ASMR and ASDR, respectively. The burden was higher among younger pregnant women (20-29 years) in low and low-middle socio-demographic index (SDI) regions, whereas it was higher among older pregnant women (30-39 years) in high SDI region. Both ASMR and ASDR showed a significant decreasing trend with increasing SDI. Maternal hemorrhage had the highest burden of all diseases. Global deaths are predicted to decline from 42,350 in 2019 to 38,461 in 2035, with the ASMR declining from 1.08 (95% UI: 0.38, 1.79) to 0.89 (95% UI: 0.47, 1.31). Conclusion: Maternal malnutrition is improving globally, but in the context of the global food crisis, attention needs to be paid to malnutrition in low SDI regions, especially among young pregnant women, and corresponding measures need to be taken to effectively reduce the burden of disease.

CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20.

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.

Microorganisms uptake zero-valent sulfur via membrane lipid dissolution of octasulfur and intracellular solubilization as persulfide.

Zero-valent sulfur, commonly utilized as a fertilizer or fungicide, is prevalent in various environmental contexts. Its most stable and predominant form, octasulfur (S8), plays a crucial role in microbial sulfur metabolism, either through oxidation or reduction. However, the mechanism underlying its cellular uptake remains elusive. We presented evidence that zero-valent sulfur was adsorbed to the cell surface and then dissolved into the membrane lipid layer as lipid-soluble S8 molecules, which reacted with cellular low-molecular thiols to form persulfide, e.g., glutathione persulfide (GSSH), in the cytoplasm. The process brought extracellular zero-valent sulfur into the cells. When persulfide dioxygenase is present in the cells, GSSH will be oxidized. Otherwise, GSSH will react with another glutathione (GSH) to produce glutathione disulfide (GSSG) and hydrogen sulfide (H2S). The mechanism is different from simple diffusion, as insoluble S8 becomes soluble GSSH after crossing the cytoplasmic membrane. The uptake process is limited by physical contact of insoluble zero-valent sulfur with microbial cells and the regeneration of cellular thiols. Our findings elucidate the cellular uptake mechanism of zero-valent sulfur, which provides critical information for its application in agricultural practices and the bioremediation of sulfur contaminants and heavy metals.

Synergistic leaching process for ion-exchange ammonium from weathered crust elution deposited rare earth tailings with potassium magnesium compound eluent.

The ion-exchangeable ammonium (IE-A) that accounts for 60-90% of the total residual ammonium in rare earth tailings has great potential to pollute the surrounding environment, and much research has been done to seek an effective elution method. However, the current study mainly focused on the single salt solution, which made it hard to reach the desired elution efficiency. In this study, the efficient binary compound eluent was prepared, and the response surface experiments and dynamic elution were performed to optimize the elution condition and evaluate the practical application prospect. Batch experimental results showed that the best IE-A elution efficiency could be achieved at the K:Mg molar ratio of 8:2, the liquid-solid ratio of 26:1, and the concentration of 0.1 mol/L at the natural solution pH. Dynamic experimental results indicated that a higher concentration, flow rate, and elution temperature could all accelerate the elution process, and the highest elution efficiency could reach 99%. The fitting results by shrinking core models show that the apparent activation energy of IE-A was 4.24 kJ/mol in the temperature range of 288-328 K, and the reaction order was 0.16. XPS and FTIR revealed that IE-A was effectively eluted by a potassium and magnesium compound leaching agent via an ion-exchange reaction. Overall, the developed compound solution with potassium and magnesium is a candidate for an elution agent that could be used to remove residual ammonium in a closed field of rare earth ores.

Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis.

Type 2 diabetes (T2D) is a chronic, burdensome disease that is characterized by disordered insulin sensitivity and disturbed glucose/lipid homeostasis. Berberine (BBR) has multiple therapeutic actions on T2D, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity and energy expenditure. Recently, the function of BBR on fibroblast growth factor 21 (FGF21) has been identified. However, if BBR ameliorates T2D through FGF21, the underlying mechanisms remain unknown. Herein, we used T2D wild type (WT) and FGF21 global knockout (FKO) mice [mouse T2D model: established by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection], and hepatocyte-specific peroxisome proliferator activated receptor γ (PPARγ) deficient (PPARγHepKO) mice, and cultured human liver carcinoma cells line, HepG2 cells, to characterize the role of BBR in glucose/lipid metabolism and insulin sensitivity. We found that BBR activated FGF21 expression by up-regulating PPARγ expression at the cellular level. Meanwhile, BBR ameliorated glucosamine hydrochloride (Glcn)-induced insulin resistance and increased glucose transporter 2 (GLUT2) expression in a PPARγ/FGF21-dependent manner. In T2D mice, BBR up-regulated the expression of PPARγ, FGF21 and GLUT2 in the liver, and GLUT2 in the pancreas. BBR also reversed T2D-induced insulin resistance, liver lipid accumulation, and damage in liver and pancreas. However, FGF21 deficiency diminished these effects of BBR on diabetic mice. Altogether, our study demonstrates that the therapeutic effects of BBR on T2D were partly accomplished by activating PPARγ-FGF21-GLUT2 signaling pathway. The discovery of this new pathway provides a deeper understanding of the mechanism of BBR for T2D treatment.

LncPCD: a manually curated database of experimentally supported associations between lncRNA-mediated programmed cell death and diseases.

Programmed cell death (PCD) refers to controlled cell death that is conducted to keep the internal environment stable. Long noncoding RNAs (lncRNAs) participate in the progression of PCD in a variety of diseases. However, no specialized online repository is available to collect and store the associations between lncRNA-mediated PCD and diseases. Here, we developed LncPCD, a comprehensive database that provides information on experimentally supported associations of lncRNA-mediated PCD with diseases. The current version of LncPCD documents 6666 associations between five common types of PCD (apoptosis, autophagy, ferroptosis, necroptosis and pyroptosis) and 1222 lncRNAs in 331 diseases. We also manually curated a wealth of information: (1) 7 important lncRNA regulatory mechanisms, (2) 310 PCD-associated cell types in three species, (3) detailed information on lncRNA subcellular locations and (4) clinical applications for lncRNA-mediated PCD in diseases. Additionally, 10 single-cell sequencing datasets were integrated into LncPCD to characterize the dynamics of lncRNAs in diseases. Overall, LncPCD is an extremely useful resource for understanding the functions and mechanisms of lncRNA-mediated PCD in diseases. Database URL:  http://spare4.hospital.studio:9000/lncPCD/Home.jsp.

Predicting Infectious Complications after Percutaneous Thermal Ablation of Liver Malignancies: A 12-year Single-Center Experience.

Background Infectious complications after percutaneous thermal ablation are seldom discussed, but better understanding of risk factors and early prediction is critical. Purpose To estimate the incidence of infectious complications after percutaneous thermal ablation of liver malignancies and to develop prediction models. Materials and Methods This single-center retrospective study reviewed the data of 3167 patients who underwent 7545 percutaneous US-guided thermal ablation procedures of liver malignancies between January 2010 and January 2022. All procedures with infectious complications were included as the case group. For each case, one treatment date-matched control subject without infection was randomly selected following a nested case-control design. Independent factors of overall and hepatobiliary infection were investigated with multivariable logistic regression. Results A total of 80 patients (median age, 59 years; IQR, 51-68 years; 64 men, 16 women) developed infectious complications after 80 ablation procedures; the incidence was 1.1% (80 of 7545 procedures). Of those with infection, 18% (14 of 80 patients) were severe, and 10% (eight of 80 patients) died as a result. Independent risk factors for overall infectious complication included prior biliary intervention (odds ratio [OR], 18.6; 95% CI: 4, 86; P < .001), prior transarterial chemoembolization (TACE) (OR, 2.4; 95% CI: 1.0, 5.8; P = .045), and the largest tumor size (OR, 1.9; 95% CI: 1.3, 2.8; P = .002); on this basis, subcapsular location was an additional risk factor of hepatobiliary infection. Prediction models for overall and hepatobiliary infection had an area under the receiver operating characteristics curve (AUC) of 0.77 and 0.82, respectively, both of which showed better AUC compared with the models, including prior biliary intervention alone (AUC = 0.63 and 0.65, respectively; P = .01 and P = .005, respectively). Conclusion Infectious complications after percutaneous thermal ablation of liver malignancies were uncommon but potentially fatal. Independent predictors were prior biliary intervention, prior transarterial chemoembolization, and the largest tumor size. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Ben-Arie and Sosna in this issue.

Long-term spatiotemporal evolution and coordinated control of air pollutants in a typical mega-mountain city of Cheng-Yu region under the "dual carbon" goal.

Clarifying the spatiotemporal distribution and impact mechanism of pollution is the prerequisite for megacities to formulate relevant air pollution prevention and control measures and achieve carbon neutrality goals. Chongqing is one of the dual-core key megacities in Cheng-Yu region and as a typical mountain-city in China, environmental problems are complex and sensitive. This research aims to investigate the exceeding standard levels and spatio-temporal evolution of criteria pollutants between 2014 and 2020. The results indicated that PM10, PM2.5, CO and SO2 were decreased significantly by 45.91%, 52.86%, 38.89% and 66.67%, respectively. Conversely, the concentration of pollutant O3 present a fluctuating growth and found a "seesaw" phenomenon between it and PM. Furthermore, PM and O3 are highest in winter and summer, respectively. SO2, NO2, CO, and PM showed a "U-shaped", and O3 showed an inverted "U-shaped" seasonal variation. PM and O3 concentrations are still far behind the WHO, 2021AQGs standards. Significant spatial heterogeneity was observed in air pollution distribution. These results are of great significance for Chongqing to achieve "double control and double reduction" of PM2.5 and O3 pollution, and formulate a regional carbon peaking roadmap under climate coordination. Besides, it can provide an important platform for exploring air pollution in typical terrain around the world and provide references for related epidemiological research.Implications: Chongqing is one of the dual-core key megacities in Cheng-Yu region and as a typical mountain city, environmental problems are complex and sensitive. Under the background of the "14th Five-Year Plan", the construction of the "Cheng-Yu Dual-City Economic Circle" and the "Dual-Carbon" goal, this article comprehensively discussed the annual and seasonal excess levels and spatiotemporal evolution of pollutants under the multiple policy and the newest international standards (WHO,2021AQG) backgrounds from 2014 to 2020 in Chongqing. Furthermore, suggestions and measures related to the collaborative management of pollutants were discussed. Finally, limitations and recommendations were also put forward.Clarifying the spatiotemporal distribution and impact mechanism of pollution is the prerequisite for cities to formulate relevant air pollution control measures and achieve carbon neutrality goals. This study is of great significance for Chongqing to achieve "double control and double reduction" of PM2.5 and O3 pollution, study and formulate a regional carbon peaking roadmap under climate coordination and an action plan for sustained improvement of air quality.In addition, this research can advanced our understanding of air pollution in complex terrain. Furthermore, it also promote the construction of the China national strategic Cheng-Yu economic circle and build a beautiful west. Moreover, it provides scientific insights for local policymakers to guide smart urban planning, industrial layout, energy structure, and transportation planning to improve air quality throughout the Cheng-Yu region. Finally, this is also conducive to future scientific research in other regions of China, and even megacities with complex terrain in the world.

The Structural and Electronic Engineering of Molybdenum Disulfide Nanosheets as Carbon-Free Sulfur Hosts for Boosting Energy Density and Cycling Life of Lithium-Sulfur Batteries.

The compact sulfur cathodes with high sulfur content and high sulfur loading are crucial to promise high energy density of lithium-sulfur (Li-S) batteries. However, some daunting problems, such as low sulfur utilization efficiency, serious polysulfides shuttling, and poor rate performance, are usually accompanied during practical deployment. The sulfur hosts play key roles. Herein, the carbon-free sulfur host composed of vanadium-doped molybdenum disulfide (VMS) nanosheets is reported. Benefiting from the basal plane activation of molybdenum disulfide and structural advantage of VMS, high stacking density of sulfur cathode is allowed for high areal and volumetric capacities of the electrodes together with the effective suppression of polysulfides shuttling and the expedited redox kinetics of sulfur species during cycling. The resultant electrode with high sulfur content of 89 wt.% and high sulfur loading of 7.2 mg cm-2 achieves high gravimetric capacity of 900.9 mAh g-1 , the areal capacity of 6.48 mAh cm-2 , and volumetric capacity of 940 mAh cm-3 at 0.5 C. The electrochemical performance can rival with the state-of-the-art those in the reported Li-S batteries. This work provides methodology guidance for the development of the cathode materials to achieve high-energy-density and long-life Li-S batteries.

Molecular insights into the catalytic promiscuity of a bacterial diterpene synthase.

Diterpene synthase VenA is responsible for assembling venezuelaene A with a unique 5-5-6-7 tetracyclic skeleton from geranylgeranyl pyrophosphate. VenA also demonstrates substrate promiscuity by accepting geranyl pyrophosphate and farnesyl pyrophosphate as alternative substrates. Herein, we report the crystal structures of VenA in both apo form and holo form in complex with a trinuclear magnesium cluster and pyrophosphate group. Functional and structural investigations on the atypical 115DSFVSD120 motif of VenA, versus the canonical Asp-rich motif of DDXX(X)D/E, reveal that the absent second Asp of canonical motif is functionally replaced by Ser116 and Gln83, together with bioinformatics analysis identifying a hidden subclass of type I microbial terpene synthases. Further structural analysis, multiscale computational simulations, and structure-directed mutagenesis provide significant mechanistic insights into the substrate selectivity and catalytic promiscuity of VenA. Finally, VenA is semi-rationally engineered into a sesterterpene synthase to recognize the larger substrate geranylfarnesyl pyrophosphate.

Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice.

INTRODUCTION: Accumulation of ß-amyloid (Aß) in neurons of patients with Alzheimer's disease (AD) inhibits the activity of key enzymes in mitochondrial metabolic pathways, triggering mitochondrial dysfunction, which plays an important role in the onset and development of AD. Mitophagy is a process whereby dysfunctional or damaged mitochondria are removed from the cell. Aberrant mitochondrial metabolism may hinder mitophagy, promote autophagosome accumulation, and lead to neuronal death. OBJECTIVES: The aim of this experiment is to explore the mechanism of neuronal mitochondria damage in the hippocampus of different age APP/PS1 double transgenic AD mice, and to explore the related metabolites and metabolic pathways for further understanding of the pathogenesis, so as to provide new ideas and strategies for the treatment of AD. METHODS: In this study, 24 APP/PS1(APPswe/PSEN1dE9) mice were divided into 3, 6, 9, and 12-month-old groups, and 6-month-old wild-type C57BL/6 mice were as controls. The Morris water maze test was used to evaluate learning and memory. Levels of Aß were detected by immunohistochemistry. Electron microscopy was used to observe mitochondrial damage and autophagosome accumulation. Western blot was for measuring LC3, P62, PINK1, Parkin, Miro1, and Tom 20 protein expression levels. Gas chromatography coupled with mass spectrometry was used to screen differentially abundant metabolites. RESULTS: The results showed that with the increase of age in APP/PS1 mice, cognitive impairment, hippocampal neuron mitochondrial damage, and autophagosome accumulation all increased. Furthermore, enhanced mitophagy and impaired mitochondrial clearance leading to metabolic abnormalities were observed with ageing in APP/PS1 mouse hippocampus. Especially, abnormal accumulation of succinic acid and citric acid in the Krebs cycle was observed. CONCLUSION: This study investigated the abnormal glucose metabolism associated with age-related damage to mitochondria in the hippocampus of APP/PS1 mice. These findings provide new insights into the pathogenesis of AD.