Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

New wheat straw fermentation feed: recombinant Schizosaccharomyces pombe efficient degradation of lignocellulose and increase feed protein.

Wheat straw contains a high amount of lignin, hindering the action of cellulase and hemicellulase enzymes, leading to difficulties in nutrient absorption by animals from straw feed. However, currently, the biological treatment of straw relies primarily on fungal degradation and cannot be directly utilized for the preparation of livestock feed. This study focuses on enzymatic co-fermentation of wheat straw to produce high-protein, low-cellulose biological feed, integrating lignin degradation with feed manufacturing, thereby simplifying the feed production process. After the optimization using Box-Behnken Design for the feed formulation, with a glucose oxidase addition of 2.46%, laccase addition of 3.4%, and malonic acid addition of 0.6%, the wheat straw feed prepared in this experiment exhibited a true protein content of 9.35%. This represented a fourfold increase compared to the non-fermented state, and the lignocellulose degradation rate of wheat straw reached 45.42%. These results not only highlight the substantial enhancement in protein content but also underscore the significant advancement in lignocellulose breakdown. This formulation significantly enhanced the palatability and nutritional value of the straw feed, contributing to the industrial development of straw feed.

Visualization and Analysis of Mapping Knowledge Domain of Fluid Flow Related to Microfluidic Chip.

Microfluidic chips are important tools to study the microscopic flow of fluid. To better understand the research clues and development trends related to microfluidic chips, a bibliometric analysis of microfluidic chips was conducted based on 1115 paper records retrieved from the Web of Science Core Collection database. CiteSpace and VOSviewer software were used to analyze the distribution of annual paper quantity, country/region distribution, subject distribution, institution distribution, major source journals distribution, highly cited papers, coauthor cooperation relationship, research knowledge domain, research focuses, and research frontiers, and a knowledge domain map was drawn. The results show that the number of papers published on microfluidic chips increased from 2010 to 2023, among which China, the United States, Iran, Canada, and Japan were the most active countries in this field. The United States was the most influential country. Nanoscience, energy, and chemical industry and multidisciplinary materials science were the main fields of microfluidic chip research. Lab on a Chip, Microfluidics and Nanofluidics, and Journal of Petroleum Science and Engineering were the main sources of papers published. The fabrication of chips, as well as their applications in porous media flow and multiphase flow, is the main knowledge domain of microfluidic chips. Micromodeling, fluid displacement, wettability, and multiphase flow are the research focuses in this field currently. The research frontiers in this field are enhanced oil recovery, interfacial tension, and stability.

Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Identity, pathogenicity and genetic diversity of Lasiodiplodia associated with stem-end rot of avocado in China.

Stem-end rot (SER) causes brown necrotic lesions in the pulp near the base of the fruit pedicel and is one of the most devastating postharvest diseases of avocados in all avocado growing regions of the world. China's avocado industry is growing very rapidly, and the planting area is expanding, but little is known about the pathogens and genetic diversity of avocado SER. To determine the causal agents of SER, avocado fruits were sampled from the main avocado-producing areas in China during 2020 and 2021. Fungal isolates were obtained from SER symptomatic avocado fruits and identified by morphology combined with phylogenetic analysis of internal transcribed spacer (ITS), translation elongation factor 1-α (EF1-α) and ß-tubulin (TUB2) gene sequences. All 101 isolates belonged to Lasiodiplodia spp., and four Lasiodiplodia species were identified, namely L. pseudotheobromae (59.41%), L. theobromae (24.75%), L. mahajangana (7.92%), L. euphorbiaceicola (1.98%), and six others are classified as Lasiodiplodia sp. (5.94%). There were only slight morphological differences in colonies and conidia of these four species of Lasiodiplodia. The pathogenicity tests showed symptoms of SER, and the 92.08% of the isolates exhibited a high level of virulence on avocado (disease index > 70), related to the disease severity on avocado fruit. All tested isolates grew well under conditions from 23 to 33℃. There was a significant difference in mycelial growth between the four species of Lasiodiplodia after treatment with high temperature or low temperature. L. pseudotheobromae growth was the fastest at 13 to 18℃, but was the lowest at 38℃ (P < 0.05). Red pigment could be produced by all tested isolates after culturing for 7 days at 38℃. The mycelial growth rate was the fastest on PDA medium, and the slowest on OMA medium but promoted spore formation (P < 0.05). In addition, was determined the genetic diversity of Lasiodiplodia pathogenic species associated with SER collected from avocado, mango, guava and soursop fruits was determined. A total of 74 isolates were clustered into 4 main ISSR groups by unweighted pair-group method with arithmetic mean (UPGMA) analysis, and the classification of this group was related to the host. Extensive diversity was detected in the Lasiodiplodia populations. The diverse geographical origins and host species significantly influenced the population differentiation, and most of the genetic variation occurred within populations (P < 0.001). This is the first study to identify the major pathogens of avocado SER in China and to survey their occurrence, pathogenicity and include a comparative analysis of genetic diversity with Lasiodiplodia spp. causing SER on other fruit hosts. Collectively, the Lasiodiplodia species complex affecting avocado showed high pathogenicity and diversity, while L. pseudotheobromae was the most frequently isolated species in China. The results of this study provide insights into the aspects of epidemic of SER disease caused by Lasiodiplodia species, which will help in developing strategies for the management and control of stem end-rot in avocado.

DNA methylation-based telomere length is associated with HIV infection, physical frailty, cancer, and all-cause mortality.

Telomere length (TL) is an important indicator of cellular aging. Shorter TL is associated with several age-related diseases including coronary heart disease, heart failure, diabetes, osteoporosis, and cancer. Recently, a DNA methylation-based TL (DNAmTL) estimator has been developed as an alternative method for directly measuring TL. In this study, we examined the association of DNAmTL with cancer prevalence and mortality risk among people with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort (VACS, N = 1917) and Women's Interagency HIV Study Cohort (WIHS, N = 481). We profiled DNAm in whole blood (VACS) or in peripheral blood mononuclear cells (WIHS) using an array-based method. Cancer prevalence was estimated from electronic medical records and cancer registry data. The VACS Index was used as a measure of physiologic frailty. Models were adjusted for self-reported race and ethnicity, batch, smoking status, alcohol consumption, and five cell types (CD4, CD8, NK, B cell, and monocyte). We found that people with HIV had shorter average DNAmTL than those without HIV infection [beta = -0.25, 95% confidence interval (-0.32, -0.18), p = 1.48E-12]. Greater value of VACS Index [beta = -0.002 (-0.003, -0.001), p = 2.82E-05] and higher cancer prevalence [beta = -0.07 (-0.10, -0.03), p = 1.37E-04 without adjusting age] were associated with shortened DNAmTL. In addition, one kilobase decrease in DNAmTL was associated with a 40% increase in mortality risk [hazard ratio: 0.60 (0.44, 0.82), p = 1.42E-03]. In summary, HIV infection, physiologic frailty, and cancer are associated with shortening DNAmTL, contributing to an increased risk of all-cause mortality.

A Multivariate analysis on evoked components of Chinese semantic congruity: an OP-MEG study with EEG.

The application of wearable magnetoencephalography using optically-pumped magnetometers has drawn extensive attention in the field of neuroscience. Electroencephalogram system can cover the whole head and reflect the overall activity of a large number of neurons. The efficacy of optically-pumped magnetometer in detecting event-related components can be validated through electroencephalogram results. Multivariate pattern analysis is capable of tracking the evolution of neurocognitive processes over time. In this paper, we adopted a classical Chinese semantic congruity paradigm and separately collected electroencephalogram and optically-pumped magnetometer signals. Then, we verified the consistency of optically-pumped magnetometer and electroencephalogram in detecting N400 using mutual information index. Multivariate pattern analysis revealed the difference in decoding performance of these two modalities, which can be further validated by dynamic/stable coding analysis on the temporal generalization matrix. The results from searchlight analysis provided a neural basis for this dissimilarity at the magnetoencephalography source level and the electroencephalogram sensor level. This study opens a new avenue for investigating the brain's coding patterns using wearable magnetoencephalography and reveals the differences in sensitivity between the two modalities in reflecting neuron representation patterns.

IL6/adiponectin/HMGB1 feedback loop mediates adipocyte and macrophage crosstalk and M2 polarization after myocardial infarction.

Background: Differences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone. Methods: The LVA, MI, and SHAM mouse models were used. Echocardiography, Masson's trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN. Results: A novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment. Conclusion: The IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

Upgrading CO2 to sustainable aromatics via perovskite-mediated tandem catalysis.

The directional transformation of carbon dioxide (CO2) with renewable hydrogen into specific carbon-heavy products (C6+) of high value presents a sustainable route for net-zero chemical manufacture. However, it is still challenging to simultaneously achieve high activity and selectivity due to the unbalanced CO2 hydrogenation and C-C coupling rates on complementary active sites in a bifunctional catalyst, thus causing unexpected secondary reaction. Here we report LaFeO3 perovskite-mediated directional tandem conversion of CO2 towards heavy aromatics with high CO2 conversion (> 60%), exceptional aromatics selectivity among hydrocarbons (> 85%), and no obvious deactivation for 1000 hours. This is enabled by disentangling the CO2 hydrogenation domain from the C-C coupling domain in the tandem system for Iron-based catalyst. Unlike other active Fe oxides showing wide hydrocarbon product distribution due to carbide formation, LaFeO3 by design is endowed with superior resistance to carburization, therefore inhibiting uncontrolled C-C coupling on oxide and isolating aromatics formation in the zeolite. In-situ spectroscopic evidence and theoretical calculations reveal an oxygenate-rich surface chemistry of LaFeO3, that easily escape from the oxide surface for further precise C-C coupling inside zeolites, thus steering CO2-HCOOH/H2CO-Aromatics reaction pathway to enable a high yield of aromatics.

Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

Genome editing of PAR2 through targeted delivery of CRISPR-Cas9 system for alleviating acute lung inflammation via ERK/NLRP3/IL-1ß and NO/iNOS signalling.

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases, immune cell infiltration and protease-driven tissue damages. It is an urgent need to explore potential drug strategies for mitigating lung inflammation. Protease-activated receptor 2 (PAR2) as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction. However, it has been rarely reported about the role of PAR2 in lung inflammation. This study applied CRISPR-Cas9 system encoding Cas9 and sgRNA (pCas9-PAR2) for PAR2 knockout and fabricated an anionic human serum albumin-based nanoparticles to deliver pCas9-PAR2 with superior inflammation-targeting efficiency and stability (TAP/pCas9-PAR2). TAP/pCas9-PAR2 robustly facilitated pCas9-PAR2 to enter and transfect inflammatory cells, eliciting precise gene editing of PAR2 in vitro and in vivo. Importantly, PAR2 deficiency by TAP/pCas9-PAR2 effectively and safely promoted macrophage polarization, suppressed pro-inflammatory cytokine releases and alleviated acute lung inflammation, uncovering a novel value of PAR2. It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/pCas9-PAR2 was mainly dependent on ERK-mediated NLRP3/IL-1ß and NO/iNOS signalling. Therefore, this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.

OPM-MEG Measuring Phase Synchronization on Source Time Series: Application in Rhythmic Median Nerve Stimulation.

The magnetoencephalogram (MEG) based on array optically pumped magnetometers (OPMs) has the potential of replacing conventional cryogenic superconducting quantum interference device. Phase synchronization is a common method for measuring brain oscillations and functional connectivity. Verifying the feasibility and fidelity of OPM-MEG in measuring phase synchronization will help its widespread application in the study of aforementioned neural mechanisms. The analysis method on source-level time series can weaken the influence of instantaneous field spread effect. In this paper, the OPM-MEG was used for measuring the evoked responses of 20Hz rhythmic and arrhythmic median nerve stimulation, and the inter-trial phase synchronization (ITPS) and inter-reginal phase synchronization (IRPS) of primary somatosensory cortex (SI) and secondary somatosensory cortex (SII) were analysed. The results find that under rhythmic condition, the evoked responses of SI and SII show continuous oscillations and the effect of resetting phase. The values of ITPS and IRPS significantly increase at the stimulation frequency of 20Hz and its harmonic of 40Hz, whereas the arrhythmic stimulation does not exhibit this phenomenon. Moreover, in the initial stage of stimulation, the ITPS and IRPS values are significantly higher at Mu rhythm in the rhythmic condition compared to arrhythmic. In conclusion, the results demonstrate the ability of OPM-MEG in measuring phase pattern and functional connectivity on source-level, and may also prove beneficial for the study on the mechanism of rhythmic stimulation therapy for rehabilitation.

Daily natural gas load prediction method based on APSO optimization and Attention-BiLSTM.

As the economy continues to develop and technology advances, there is an increasing societal need for an environmentally friendly ecosystem. Consequently, natural gas, known for its minimal greenhouse gas emissions, has been widely adopted as a clean energy alternative. The accurate prediction of short-term natural gas demand poses a significant challenge within this context, as precise forecasts have important implications for gas dispatch and pipeline safety. The incorporation of intelligent algorithms into prediction methodologies has resulted in notable progress in recent times. Nevertheless, certain limitations persist. However, there exist certain limitations, including the tendency to easily fall into local optimization and inadequate search capability. To address the challenge of accurately predicting daily natural gas loads, we propose a novel methodology that integrates the adaptive particle swarm optimization algorithm, attention mechanism, and bidirectional long short-term memory (BiLSTM) neural networks. The initial step involves utilizing the BiLSTM network to conduct bidirectional data learning. Following this, the attention mechanism is employed to calculate the weights of the hidden layer in the BiLSTM, with a specific focus on weight distribution. Lastly, the adaptive particle swarm optimization algorithm is utilized to comprehensively optimize and design the network structure, initial learning rate, and learning rounds of the BiLSTM network model, thereby enhancing the accuracy of the model. The findings revealed that the combined model achieved a mean absolute percentage error (MAPE) of 0.90% and a coefficient of determination (R2) of 0.99. These results surpassed those of the other comparative models, demonstrating superior prediction accuracy, as well as exhibiting favorable generalization and prediction stability.

Development towards high-resolution kHz-speed rotation-free volumetric imaging.

X-ray multi-projection imaging (XMPI) has the potential to provide rotation-free 3D movies of optically opaque samples. The absence of rotation enables superior imaging speed and preserves fragile sample dynamics by avoiding the centrifugal forces introduced by conventional rotary tomography. Here, we present our XMPI observations at the ID19 beamline (ESRF, France) of 3D dynamics in melted aluminum with 1000 frames per second and 8 µm resolution per projection using the full dynamical range of our detectors. Since XMPI is a method under development, we also provide different tests for the instrumentation of up to 3000 frames per second. As the high-brilliance of 4th generation light-sources becomes more available, XMPI is a promising technique for current and future X-ray imaging instruments.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.

[Review of Comprehensive Evaluation System of Vehicle Pollution and Carbon Synergistic Reduction].

Vehicle emissions have become one of the most important air pollution sources in China. Promoting vehicle synergistic reduction of pollution and carbon is the key to improving regional environmental quality and achieving the carbon peaking and carbon neutrality goals. Building a collaborative evaluation system and comprehensive quantitative method is an important prerequisite for scientific and effective implementation of vehicle pollution and carbon synergistic reduction. Therefore, it is significant to extensively review existing synergistic evaluation methods and comprehensive environmental benefit accounting methods of atmospheric pollution and carbon reduction. On this basis, we focused on vehicle emission characteristics, systematically organized the key indicators of vehicle collaborative reduction evaluation, and summarized quantitative methods of policy effects from three aspects (health exposure cost, climate change cost, and pollutant control cost), to provide theoretical support for policy formulation, schemes selection, and their effect evaluation. For the future, the assessment of vehicle coordinated emission reduction is proposed to accelerate unified index system establishment, deeply analyze the spatial distribution of environmental benefits, focus on the pollution transfer caused by vehicle electrification, and explore the quantitative methods of climate change cost due to extreme weather.

Engineering M2-type macrophages with a metal polyphenol network for peripheral artery disease treatment.

Functional cell treatment for critical limb ischemia is limited by cell viability loss and dysfunction resulting from a harmful ischemic microenvironment. Metal-polyphenol networks have emerged as novel cell delivery vehicles for protecting cells from the detrimental ischemic microenvironment and prolonging the survival rate of cells in the ischemic microenvironment. M2 macrophages are closely related to tissue repair, and they secrete anti-inflammatory factors that contribute to lesion repair. However, these cells are easily metabolized in the body with low efficiency. Herein, M2 macrophages were decorated with a metal‒polyphenol network that contains copper ions and epigallocatechin gallate (Cu-EGCG@M2) to increase cell survival and therapeutic potential. Cu-EGCG@M2 synergistically promoted angiogenesis through the inherent angiogenesis effect of M2 macrophages and copper ions. We found that Cu-EGCG@M2 increased in vitro viability and strengthened the in vivo therapeutic effect on the ischemic hindlimbs of mice, which promoted the recovery of blood and muscle regeneration, resulting in superior limb salvage. These therapeutic effects were ascribed to the increased survival rate and therapeutic period of M2 macrophages, as well as the ameliorated microenvironment at the ischemic site. Additionally, Cu-EGCG exhibited antioxidant, anti-inflammatory, and proangiogenic effects. Our findings provide a feasible option for cell-based treatment of CLI.

Aucubin protects against myocardial ischemia-reperfusion injury by regulating STAT3/NF-κB/HMGB-1 pathway.

The main characteristics of the myocardial ischemia/reperfusion injury (MI/RI) are oxidative stress, apoptosis, and an inflammatory response. Aucubin (AU) is an iridoid glycoside that possesses various biological properties and has been discovered to demonstrate antioxidant and anti-inflammatory impacts in pathological processes, such as ischemia-reperfusion. The objective of this research was to investigate if AU treatment could mitigate myocardial inflammation and apoptosis caused by ischemia/reperfusion (I/R) in both laboratory and animal models, and to elucidate its underlying mechanism. By ligating the coronary artery on the left anterior descending side, a successful MI/RI rat model was created. Additionally, H9C2 cells were subjected to hypoxia/reoxygenation (H/R) in order to imitate the injury caused by ischemia/reperfusion (I/R). Furthermore, various concentrations of AU were administered to H9C2 cells or rats before H/R stimulation or myocardial I/R surgery, respectively. In vitro, the assessment was conducted on cardiac function, inflammatory markers, and myocardial pathology. In vivo, we examined the viability of cells, as well as factors related to apoptosis and oxidative stress. Furthermore, the presence of proteins belonging to the STAT3/NF-κB/HMGB1 signaling pathway was observed both in vivo and in vitro. AU effectively improved cardiomyocyte injury caused by H/R and myocardial injury caused by I/R. Furthermore, AU suppressed the production of reactive oxygen species and inflammatory molecules (TNF-alpha, IL-1ß, and IL-6) and proteins associated with cell death (caspase-3 and Bax), while enhancing the levels of anti-inflammatory agents (IL-10) and the anti-apoptotic protein Bcl-2.AU mechanistically affected the phosphorylation of STAT3 at the Ser727 site and Tyr705 following H/R by modulating the signaling pathway involving signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB)/high mobility group box 1 (HMGB1), while also suppressing the nuclear translocation of NF-κB p65 and HMGB1 exonucleation. In conclusion, the use of AU treatment might offer protection against myocardial infarction and injury by reducing oxidative stress, suppressing apoptosis, and mitigating inflammation. The regulation of the STAT3/NF-κB/HMGB-1 pathway may contribute to this phenomenon by affecting STAT3 phosphorylation and controlling NF-κB and HMGB-1 translocation. Contributes to identifying possible objectives for myocardial ischemia/reperfusion damage.

Glycyrrhizic acid alleviated MI/R-induced injuries by inhibiting Hippo/YAP signaling pathways.

BACKGROUND: Previous research has demonstrated that glycyrrhizic acid (GA) exhibits antioxidant, anti-inflammatory, and antiapoptotic characteristics. Using myocardial ischemia/reperfusion injury as a case study, this study aims to clarify the functional significance of GA and to elucidate the mechanisms involved. MATERIALS AND METHODS: In this study, an MI/R injury model was established both in vivo and in vitro to investigate the impact of GA on MI/R injury. The viability of H9c2 cells was evaluated using the Cell Counting Kit-8. Myocardial damage was assessed through the measurement of creatine kinase myocardial band (CK-MB) levels and lactate dehydrogenase (LDH), HE staining, and MASSON staining. Inflammatory cytokine levels (IL-6, IL-1ß, IL-10, and TNF-α) were measured to determine the presence of inflammation. Cellular oxidative stress was evaluated by measuring ROS and MMP levels, while cardiac function was assessed using cardiac color Doppler ultrasound. Immunofluorescence staining to determine the nuclear translocation of YAP, TUNEL to determine apoptosis, and western blotting to determine gene expression. RESULTS: GA treatment effectively alleviated myocardial injury induced by MI/R, as evidenced by reduced levels of inflammatory cytokines (IL-1ß, IL-6, IL-10, and TNF-α) and cardiac biomarkers (CK-MB, LDH) in MI/R rats. Moreover, There was a significant increase in cell viability in vitro after GA treatment and inhibited reactive oxygen species (ROS) during oxidative stress, while also increasing mitochondrial membrane potential (MMP) in vitro. The Western blot findings indicate that GA treatment effectively suppressed apoptosis in both in vivo and in vitro settings. Additionally, GA demonstrated inhibitory effects on the activation of the Hippo/YAP signaling pathway triggered by MI/R and facilitated YAP nuclear translocation both in vitro and in vivo. It has been found, however, in vitro, that silencing the YAP gene negates GA's protective effect against hypoxia/reoxygenation-induced myocardial injury. CONCLUSION: This study suggests that GA regulates YAP nuclear translocation by inhibiting the Hippo/YAP signaling pathway, which protects ists against MI/R injury. This finding may present a novel therapeutic approach for the treatment of MI/R.

Investigation of FRMPD4 variants associated with X-linked epilepsy.

BACKGROUND: The etiology of unexplained epilepsy in most patients remains unclear. Variants of FRMPD4 are suggested to be associated with neurodevelopmental disorders. Therefore, we screened for disease-causing FRMPD4 variants in patients with epilepsy. METHODS: Trios-based whole-exome sequencing was conducted on a cohort of 85 patients with unexplained epilepsy, their parents, and extended family members. Additional cases with FRMPD4 variants were identified from the China Epilepsy Gene Matching Platform V.1.0. The frequency of variants was analyzed, and their subregional effects were predicted using in silico tools. The genotype-phenotype correlation of the newly defined causative genes and protein stability were analyzed using I-Mutant V.3.0 and Grantham scores. RESULTS: Two novel missense variants of FRMPD4 were identified in two families. Using the gene matching platform, we identified three additional novel missense variants. These variants presented at low or no allele frequencies in the gnomAD database. All the variants were located outside the three FRMPD4 main domains (WW, PDZ, and FERM). In silico analyses revealed that the variants were damaging and were predicted to be the least stable. All patients eventually became seizure-free. Eight of the 21 patients with FRMPD4 variants had epilepsy, of which five (63%) had missense variants located outside the domains, two had deletions involving exon 2, and one had a frameshift variant located outside the domains. Patients with epilepsy caused by missense variants were often free of intellectual disabilities (4/5), whereas patients with epilepsy caused by truncated variants had intellectual disabilities and structural brain abnormalities (3/3). CONCLUSIONS: The FRMPD4 gene is potentially associated with epilepsy. The genotype-phenotype correlation of FRMPD4 variants indicated that differences in variant types and locations of FRMPD4 may explain their phenotypic variation.