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Abstract Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2+; HCN4+ cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.

Abstract Background Time-restricted eating (TRE), a popular form of intermittent fasting, has shown benefits for improving metabolic diseases and cardiometabolic health. However, the effect of TRE in the regulation of blood pressure in primary hypertension remains unclear. Methods A 6-week randomized controlled trial was conducted, in which a total of 74 stage 1 primary hypertensive patients without high-risk were randomly assigned to Dietary Approaches to Stop Hypertension (DASH) group (n = 37) or DASH + TRE group (n = 37). Participants in the DASH + TRE group were instructed to consume their food within an 8-h window. Scientific research platform in We Chat application was used to track participants. The primary outcome was blood pressure. The secondary outcomes included body composition, cardiometabolic risk factors, inflammation-related parameters, urinary Na+ excretion, other clinical variables and safety outcomes. Results The reduction of systolic blood pressure and diastolic blood pressure were 5.595 ± 4.072 and 5.351 ± 5.643 mm Hg in the DASH group and 8.459 ± 4.260 and 9.459 ± 4.375 mm Hg in the DASH + TRE group. DASH + TRE group improved blood pressure diurnal rhythm. Subjects in DASH + TRE group had decreased extracellular water and increased urinary Na+ excretion. Furthermore, the decrease in blood pressure was associated with a reduction of extracellular water or increase in urinary Na+ excretion. In addition, safety outcomes such as nighttime hunger were also reported. Conclusion Our study demonstrated that 8-h TRE + DASH diet caused a greater decrease in blood pressure in stage 1 primary hypertensive patients than DASH diet. This study may provide novel insights into the benefits of lifestyle modification in the treatment of primary hypertension. Trial registration https://www.chictr.org.cn/ (ChiCTR2300069393, registered on March 15, 2023).

Abstract A novel method based on machine learning is proposed to estimate the electromagnetic radiation level at the ground plane near fifth‐generation (5G) base stations. The machine learning model was trained using data from various 5G base stations, enabling it to estimate the electric field intensity at any arbitrary radiation point when the base station provides service to different numbers of 5G terminals which are in different service modes. The inputs required for the model include the transmit power of the antenna, the antenna gain, the distance between the 5G base station and 5G terminals, terminal service modes, the number of 5G terminals and the environmental complexity around the 5G base station. Experimental results demonstrate the feasibility and effectiveness of the estimation method, with the mean absolute percentage error of the machine learning model being approximately 5.98%. This level of accuracy showcases the reliability of the approach. Moreover, the proposed method offers low costs when compared with on‐site measurements. The estimated results can be utilised to reduce test costs and provide valuable guidance for optimal site selection, thereby facilitating radio wave coverage or electromagnetic radiation regulation of 5G base stations.

Abstract Objective To develop a nomogram based on tumor and peritumoral edema (PE) radiomics features extracted from preoperative multiparameter MRI for predicting brain invasion (BI) in atypical meningioma (AM). Methods In this retrospective study, according to the 2021 WHO classification criteria, a total of 469 patients with pathologically confirmed AM from three medical centres were enrolled and divided into training (n = 273), internal validation (n = 117) and external validation (n = 79) cohorts. BI was diagnosed based on the histopathological examination. Preoperative contrast-enhanced T1-weighted MR images (T1C) and T2-weighted MR images (T2) for extracting meningioma features and T2-fluid attenuated inversion recovery (FLAIR) sequences for extracting meningioma and PE features were obtained. The multiple logistic regression was applied to develop separate multiparameter radiomics models for comparison. A nomogram was developed by combining radiomics features and clinical risk factors, and the clinical usefulness of the nomogram was verified using decision curve analysis. Results Among the clinical factors, PE volume and PE/tumor volume ratio are the risk of BI in AM. The combined nomogram based on multiparameter MRI radiomics features of meningioma and PE and clinical indicators achieved the best performance in predicting BI in AM, with area under the curve values of 0.862 (95% CI, 0.819–0.905) in the training cohort, 0.834 (95% CI, 0.780–0.908) in the internal validation cohort and 0.867 (95% CI, 0.785–0.950) in the external validation cohort, respectively. Conclusions The nomogram based on tumor and PE radiomics features extracted from preoperative multiparameter MRI and clinical factors can predict the risk of BI in patients with AM.

Active Magnetic Bearing (AMB) is a kind of electromagnetic support that makes the rotor movement frictionless and can suppress rotor vibration by controlling the magnetic force. The most common approach to restrain the rotor vibration in AMBs is to adopt a notch filter or adaptive filter in the AMB controller. However, these methods cannot obtain the precise amplitude and phase of the compensation current. Thus, they are not so effective in terms of suppressing the vibrations of the fundamental and other harmonic orders over the whole speed range. To improve the vibration suppression performance of AMBs, an adaptive filter based on Least Mean Square (LMS) is applied to extract the vibration signals from the rotor displacement signal. An Iterative Search Algorithm (ISA) is proposed in this paper to obtain the corresponding relationship between the compensation current and vibration signals. The ISA is responsible for searching the compensating amplitude and shifting phase online for the LMS filter, enabling the AMB controller to generate the corresponding compensation force for vibration suppression. The results of ISA are recorded to suppress vibration using the Look-Up Table (LUT) in variable speed range. Comprehensive simulations and experimental validations are carried out in fixed and variable speed range, and the results demonstrate that by employing the ISA, vibrations of the fundamental and other harmonic orders are suppressed effectively.

Abstract Background Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). Results CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. Conclusions CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine. Graphical Abstract

Abstract Background Transcription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1/2 result in severe cardiac defects. However, the function and mechanism of HAND1/2 in regulating human early cardiac lineage commitment and differentiation are still unclear. Methods With NKX2.5 eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2, respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP+ cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data. Results Either HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1/2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1/2-deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1/2-deficient hESCs. Conclusions HAND1/2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1/2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.

Abstract Objective To investigate the association of timing, frequency, and food quality of night eating with all-cause, cancer, and diabetes mortality. Methods This study included 41,744 participants from the US National Health and Nutrition Examination Survey (2002–2018). Night eating information was collected by 24-h dietary recall and the exposures were timing, frequency, and food quality of night eating. Food quality was assessed by latent class analysis. The outcomes were all-cause, cancer, and diabetes mortality, which were identified by the National Death Index and the International Classification of Diseases 10th Revision. Adjusted hazard ratios [aHR] with 95% confidence intervals [CI] were computed by Cox regression. Results During a median follow-up of 8.7 years, 6066 deaths were documented, including 1381 from cancer and 206 from diabetes. Compared with no night eating (eating before 22:00), the later timing of night eating was associated with higher risk of all-cause and diabetes mortality (each P-trend

Abstract The transforming growth factor‐β (TGF‐β) superfamily, including Nodal and Activin, plays a critical role in various cellular processes. Understanding the intricate regulation and gene expression dynamics of TGF‐β signalling is of interest due to its diverse biological roles. A machine learning approach is used to predict gene expression patterns induced by Activin using features, such as histone modifications, RNA polymerase II binding, SMAD2‐binding, and mRNA half‐life. RNA sequencing and ChIP sequencing datasets were analysed and differentially expressed SMAD2‐binding genes were identified. These genes were classified into activated and repressed categories based on their expression patterns. The predictive power of different features and combinations was evaluated using logistic regression models and their performances were assessed. Results showed that RNA polymerase II binding was the most informative feature for predicting the expression patterns of SMAD2‐binding genes. The authors provide insights into the interplay between transcriptional regulation and Activin signalling and offers a computational framework for predicting gene expression patterns in response to cell signalling.

Abstract Background Accumulating evidence has suggested an oncogenic effect of diurnal disruption on cancer progression. To test whether targeting circadian rhythm by dietary strategy suppressed lung cancer progression, we adopted 6-h time-restricted feeding (TRF) paradigm to elucidate whether and how TRF impacts lung cancer progression. Methods This study used multiple lung cancer cell lines, two xenograft mouse models, and a chemical-treated mouse lung cancer model. Stable TIM-knockdown and TIM-overexpressing A549 cells were constructed. Cancer behaviors in vitro were determined by colony formation, EdU proliferation, wound healing, transwell migration, flow cytometer, and CCK8 assays. Immunofluorescence, pathology examinations, and targeted metabolomics were also used in tumor cells and tissues. mCherry-GFP-LC3 plasmid was used to detect autophagic flux. Results We found for the first time that compared to normal ad libitum feeding, 6-h TRF inhibited lung cancer progression and reprogrammed the rhythms of metabolites or genes involved in glycolysis and the circadian rhythm in tumors. After TRF intervention, only timeless (TIM) gene among five lung cancer-associated clock genes was found to consistently align rhythm of tumor cells to that of tumor tissues. Further, we demonstrated that the anti-tumor effect upon TRF was partially mediated by the rhythmic downregulation of the TIM and the subsequent activation of autophagy. Combining TRF with TIM inhibition further enhanced the anti-tumor effect, comparable to treatment efficacy of chemotherapy in xenograft model. Conclusions Six-hour TRF inhibits lung cancer progression and reshapes circadian metabolism, which is partially mediated by the rhythmic downregulation of the TIM and the subsequent upregulation of autophagy.

BackgroundAcanthopanax senticosus (AS) can improve sleep, enhance memory, and reduce fatigue and is considered as an effective drug for Alzheimer’s disease (AD). The therapeutic effect and mechanism need to be further investigated.MethodsTo confirm the AS play efficacy in alleviating memory impairment in mice, 5×FAD transgenic mice were subjected to an open-field experiment and a novelty recognition experiment. Network pharmacology technique was used to analyze the information of key compounds and potential key targets of AS for the treatment of AD, molecular docking technique was applied to predict the binding ability of targets and compounds, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed on the targets to derive the possible metabolic processes and pathway mechanisms of AS in treating AD. Quantitative real-time PCR (qRT-PCR) and western blot technique were carried out to validate the candidate genes and pathways.ResultsIn the open-field experiment, compared with the wild-type (WT) group, the number of times the mice in the AD group crossed the central zone was significantly reduced (P< 0.01). Compared with the AD group, the number of times the mice in the AS group crossed the central zone was significantly increased (P< 0.001). In the new object recognition experiment, compared with the WT group, the percentage of times the AD group explored new objects was significantly reduced (P< 0.05). Compared with the AD group, the AS group had an increase in the percentage of time spent exploring new things and the number of times it was explored (P< 0.05). At the same time, the donepezil group had a significantly higher percentage of times exploring new things (P< 0.01). By using network pharmacology technology, 395 common targets of AS and AD were retrieved. The Cytoscape software was used to construct the protein–protein interaction (PPI) network of common targets. Using the algorithm, nine key targets were retrieved: APP, NTRK1, ESR1, CFTR, CSNK2A1, EGFR, ESR2, GSK3B, and PAK1. The results of molecular docking indicate that 11 pairs of compounds and their corresponding targets have a significant binding ability, as the molecular binding energies were less than -7.0. In comparison to the AD group, the mRNA expression of the key target genes was significantly decreased in the AS treatment group (P< 0.001). The KEGG analysis showed that the MAPK signaling pathway was significantly enriched, and Western blot confirmed that the TRAF6 protein decreased significantly (P< 0.0001). Meanwhile, the levels of MAP3K7 and P38 phosphorylation increased, and there was also an increase in the expression of HSP27 proteins.ConclusionOur study indicates that the multi-component and multi-target properties of AS play an important role in the alleviation of anxiety and memory impairment caused by AD, and the mechanism is involved in the phosphorylation and activation of the MAPK signaling pathway. The results of this study could provide a novel perspective for the clinical treatment of AD.

Abstract Background Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes. Methods To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma. Results The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data. Conclusions Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.

Abstract Background Identifying reliable biomarkers could effectively predict esophagus carcinoma (EC) patients with poor prognosis. In this work, we constructed an immune-related gene pairs (IRGP) signature to evaluate the prognosis of EC. Results The IRGP signature was trained by the TCGA cohort and validated by three GEO datasets, respectively. Cox regression model together with LASSO was applied to construct the overall survival (OS) associated IRGP. 21 IRGPs consisting of 38 immune-related genes were included in our signature, according to which patients were stratified into high- and low-risk groups. The results of Kaplan-Meier survival analyses indicated that high-risk EC patients had worse OS than low-risk group in the training set, meta-validation set and all independent validation datasets. After adjustment in multivariate Cox analyses, our signature continued to be an independent prognostic factor of EC and the signature-based nomogram could effectively predict the prognosis of EC sufferers. Besides, Gene Ontology analysis revealed this signature is related to immunity. ‘CIBERSORT’ analysis revealed the infiltration levels of plasma cells and activated CD4 memory T cells in two risk groups were significantly different. Ultimately, we validated the expression levels of six selected genes from IRGP index in KYSE-150 and KYSE-450. Conclusions This IRGP signature could be applied to select EC patients with high mortality risk, thereby improving prospects for the treatment of EC.

Abstract Background The association of the meal timing of dietary total antioxidant capacity (DAC) with mortality is unclear. We aimed to investigate the association between the meal timing of DAC and all-cause, cardiovascular disease (CVD), and cancer mortality in general adult populations. Methods A total of 56,066 adults who participated in the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were recruited for this study. Dietary intake (quantity and timing) was evaluated by nonconsecutive 24-h dietary recalls. The main exposure variables were the DAC across three meals (total, breakfast, lunch, and dinner; without coffee) and the difference between dinner and breakfast DAC (Δ = dinner-breakfast; without coffee). The outcomes were all-cause, CVD, and cancer mortality. The adjusted hazard ratios [aHRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. Results Among the 56,066 participants, there were 8566 deaths from any cause, including 2196 from CVD and 1984 from cancer causes. Compared to participants in the lowest quintiles of the total DAC, those in the highest quintiles had 34% and 27% decreased risks of all-cause and CVD mortality, respectively (all-cause mortality: aHRs 0.66 [95% CI 0.57–0.76]; CVD mortality: aHRs 0.73 [95% CI 0.57–0.94]). More importantly, participants in the highest quintiles of the dinner DAC, but not those in that of breakfast or lunch, had a 24% decrease in all-cause mortality (aHRs 0.76 [95% CI 0.67–0.87]) compared with those in the lowest quintiles. Inverse associations were further confirmed for Δ DAC (aHRs 0.84 [95% CI 0.74–0.96]). Above associations did not change when including DAC from snacks or tea. Mediation analysis showed that the total associations of total, dinner or Δ DACs with reduced all-cause mortality were 24%, 13% and 6%, respectively, mediated by serum CRP. Additionally, all-cause mortality was decreased by 7% in models replacing 10% breakfast DAC (aHRs 0.93 [95% CI 0.9–0.97]) with an equivalent proportion of dinner DAC. For cancer mortality, no statistical significance was detected in the adjusted models. Conclusions The findings emphasize the putative beneficial relationship of a diet rich in antioxidants and meal timing on serum CRP and all-cause mortality.

In this article, rotor designs utilizing assisted-poles are investigated for a high-torque density spoke-type permanent magnet synchronous machine (PMSM) with fractional slot concentrated winding (FSCW) to explore the rich air-gap magnetic field harmonics and torque generation mechanism. Due to their higher average torque output, spoke-type PMSMs with FSCW are increasingly used in high-torque density applications. However, slot harmonics generate torque ripples that are difficult to eliminate in FSCW spoke-type PMSMs. Removing slot harmonics from the stator or winding results in a large drop in torque since their winding factors are identical to those of the main harmonic. Therefore, rotor designs having assisted-poles (symmetrical and asymmetrical) are investigated in this work to mitigate slot harmonics and minimize torque ripples. Firstly, the air-gap flux density is analyzed for the machines having assisted-poles, and a model of interaction between the stator and rotor-MMF harmonics is created and validated through Finite element analysis (FEA) to analyze the torque production mechanism. In addition, an analytical relationship between the assisted-poles’ dimensions and the generated torque harmonics is proposed. Furthermore, a generalized torque ripple reduction concept for the FSCW spoke-type PMSM having asymmetrically designed assisted-poles is presented. The proposed design and optimization method are validated through analytical calculations and FEA simulations, and a brief comparative analysis is presented for the analyzed machine prototypes. It has been established that the machine designed by applying the proposed asymmetrical assisted-poles can achieve a reduction in torque ripples while also significantly lowering cogging torque in comparison to the conventional spoke-type PMSMs and other spoke-type PMSMs with rotor having symmetrical assisted-poles.

Abstract Introduction The cannabinoid receptor 2 (CB2) is mainly involved in the immune system. However, although CB2 has been reported to play an anti‐tumor function in breast cancer (BC), its specific mechanism in BC remains unclear. Methods We examined the expression and prognostic significance of CB2 in BC tissues by qPCR, second‐generation sequencing, western blot, and immunohistochemistry. We assessed the impacts of overexpression and a specific agonist of CB2 on the growth, proliferation, apoptosis, and drug resistance of BC cells in vitro and in vivo using CCK‐8, flow cytometry, TUNEL staining, immunofluorescence, tumor xenografts, western blot, and colony formation assays. Results CB2 expression was significantly lower in BC compared with paracancerous tissues. It was also highly expressed in benign tumors and ductal carcinoma in situ, and its expression was correlated with prognosis in BC patients. CB2 overexpression and treatment of BC cells with a CB2 agonist inhibited proliferation and promoted apoptosis, and these actions were achieved by suppressing the PI3K/Akt/mTOR signaling pathway. Moreover, CB2 expression was increased in MDA‐MB‐231 cell treated with cisplatin, doxorubicin, and docetaxel, and sensitivity to these anti‐tumor drugs was increased in BC cells overexpressing CB2. Conclusions These findings reveal that CB2 mediates BC via the PI3K/Akt/mTOR signaling pathway. CB2 could be a novel target for the diagnosis and treatment of BC.

Abstract China’s renewable energy innovation is essential for realizing its carbon neutrality targets and the low-carbon transition, but few studies have spatially examined its characteristics and spillover effects. To fill the research gap, this study investigates its distribution and trends from a spatiotemporal dimension and focuses on the spatial effects of the influencing factors to identify those that have a significant impact on renewable energy innovation by using China’s provincial panel data from 2006 to 2019. The results show the following findings. (1) Renewable energy innovation shows distinct spatial differences across China’s provinces such that it is high in the east and south and low in the west and north, which exhibits spatial locking and path-dependence. (2) There is a positive spatial correlation with renewable energy innovation. (3) R&D investment and GDP per capita significantly promote renewable energy innovation, but the former effect is mainly observed in the local area, whereas the latter shows spatial effects. More market-oriented policies should be taken for the improvement of renewable energy innovation and the establishment of regional coordination mechanisms are proposed.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease account for 60–80% of the total number of people with dementia, but its treatment and prevention strategies are still in a long process of exploration. It has been reported that a healthy lifestyle may be an effective non-pharmacological intervention for the prevention and treatment of AD, including increased physical activity and the consumption of polyphenol-rich foods. This study, therefore, investigated the effects of 8 weeks of moderate-intensity aerobic exercise (EX), administration of chlorogenic acid administration (GCA), and a combination of both (EX+GCA) on β-amyloid (Aβ) deposition, inflammatory factors, oxidative stress markers, neuronal damage, and cognitive performance in the brains of AD model mice (APP/PS1) and which signaling pathways may be responsible for these effects. The study used Western blot to detect the expression of signaling pathway-related proteins, enzyme-linked immunosorbent assay to detect the expression of inflammatory factors, hematoxylin–eosin staining to detect hippocampal neuronal morphology, immunohistochemistry to detect changes in Aβ deposition in the hippocampus, an oxidative stress marker kit to detect oxidative stress status and the Morris water maze to detect changes in cognitive performance. This study showed that an 8-week intervention (EX/GCA/EX+GCA) activating the SIRT1/PGC-1α signaling pathway improved oxidative stress, neuroinflammation, Aβ deposition, and cognitive performance in mice. However, there was no obvious difference between the EX and GCA groups. In contrast, the combined EX+GCA intervention was significantly better than phase EX or GCA. Our study suggests that although relief of Aβ deposition, neuroinflammation, oxidative stress, neuronal damage, and cognitive decline could also be achieved with EX or GCA, the combined EX+GCA intervention showed better results. These relief effects on AD-related conditions may be obtained by mediating the activation of the SIRT1/PGC-1α signaling pathway. This study is the first to explore the improvement of AD-related conditions with a combined lifestyle of EX+GCA. This healthy lifestyle could be a candidate option for the treatment of AD.

The homeostasis of the gut microbiota and circadian rhythm is critical to host health, and both are inextricably intertwined with lung cancer. Although time-restricted feeding (TRF) can maintain circadian synchronization and improve metabolic disorders, the effects of TRF on the fecal microbiome, metabolome and their diurnal oscillations in lung cancer have not been discussed. We performed 16S rRNA sequencing and untargeted metabonomic sequencing of the feces prepared from models of tumor-bearing BALB/c nude mice and urethane-induced lung cancer. We demonstrated for the first time that TRF significantly delayed the growth of lung tumors. Moreover, TRF altered the abundances of the fecal microbiome, metabolome and circadian clocks, as well as their rhythmicity, in lung cancer models of tumor-bearing BALB/c nude mice and/or urethane-induced lung cancer C57BL/6J mice. The results of fecal microbiota transplantation proved that the antitumor effects of TRF occur by regulating the fecal microbiota. Notably, Lactobacillus and Bacillus were increased upon TRF and were correlated with most differential metabolites. Pathway enrichment analysis of metabolites revealed that TRF mainly affected immune and inflammatory processes, which might further explain how TRF exerted its anticancer benefits. These findings underscore the possibility that the fecal microbiome/metabolome regulates lung cancer following a TRF paradigm.

Considering the drug treatment strategy in both virus-to-cell and cell-to-cell transmissions, this paper presents an HIV model with Filippov control. Given the threshold level $ N_t $, when the total number of infected cells is less or greater than threshold level $ N_t $, the threshold dynamics of the model are studied by using the Routh-Hurwitz Criterion. When the total number of infected cells is equal to $ N_t $, the sliding mode equations are obtained by Utkin equivalent control method, and the dynamics are studied. In addition, the optimal control strategy is introduced for the case that the number of infected cells is greater than $ N_t $. By dynamic programming, the Hamilton-Jacobi-Bellman (HJB) equation is constructed, and the optimal control is obtained. Numerical simulations are presented to illustrate the validity of our results.

We aimed to examine the association of traditional Chinese herbal dietary formulas with ability of daily life and physical function in elderly patients with mild cognitive impairment. The current study included 60 cases of elderly patients with mild cognitive impairment from Yueyang Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Shanghai University of Traditional Chinese Medicine and Hongkou District, Shanghai. The participants were randomly divided into two groups: group A (herbal dietary formula group, consisting of Alpiniae Oxyphyllae Fructus, Nelumbinis plumula, Chinese Yam, Poria cocos, and Jineijin), 30 cases, and group B (vitamin E), 30 cases, treatment for 3 months. Cognitive function was measured using the Montreal Cognitive Assessment (MOCA) and Mini-Mental State Examination (MMSE); body function was measured using the Chinese Simplified Physical Performance Test (CMPPT), including stand static balance, sitting-up timing, squat timing, and six-meter walk timing. Daily life based on ability was measured by grip strength and the Activity of Daily Living Scale (ADL). The lower the scores of the above items, the poorer the disease degree, except for ADL: the lower the score, the higher the self-care ability. After 3 months of treatment, the two-handed grip strength of both the herbal dietary formula group and vitamin E group increased; the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased after medication, being statistically significantly different (p < 0.05). The two-handed grip strength of group A increased significantly, and the ADL, sitting-up timing, squatting timing, and six-meter walking timing decreased distinctly compared with the vitamin E group. There was a statistically significant difference (p < 0.05). The scores of MMSE, MOCA, total CMPPT, and standing static balance of the herbal dietary formula group increased after medication. The difference was statistically significant (p < 0.05). The vitamin E group’s MMSE and MOCA scores, CMPPT total scores, and standing resting balance scores did not change significantly after medication (p > 0.05). In summary, a traditional Chinese herbal dietary formula can improve body and cognitive function in patients with MCI, and the curative effect is better than that of vitamin E. Traditional Chinese herbal dietary formulas can improve the daily life quality of MCI patients, which has clinical application value.

The effect of the antioxidant capacity of diet and its distribution across three meals on mortality risk among cancer patients remains unexplored. We aimed to prospectively investigate the association of dietary total antioxidant capacity (DAC) and its distribution across three meals with all-cause, cancer, and noncancer mortality among cancer survivors. We included 5,009 patients with cancer from the National Health and Nutrition Examination Survey conducted between 1999 and 2018. The adjusted hazard ratio (aHR) was estimated using the survey-weighted Cox proportional hazards model. During a median follow-up of 7.9 years, 1811 deaths, including 575 cancer-related deaths, were recorded. Among cancer survivors, compared with participants in the lowest quartile of total DAC from three meals, those in the highest quartile had a 24% decreased risk of noncancer mortality (aHR = 0.76, 95% confidence interval [CI]: 0.60–0.92), but not of all-cause and cancer mortality (each p trend >0.1). However, this association became insignificant for total DAC after excluding dinner DAC. In addition, higher dinner DAC rather than breakfast or lunch DAC was associated with a 21% lower risk of all-cause mortality (aHR = 0.79, 95% CI: 0.65–0.98) and 28% lower risk of noncancer mortality (aHR = 0.72, 95% CI: 0.57–0.90). Similar associations were found for ΔDAC (dinner DAC − breakfast DAC) with noncancer mortality (aHR = 0.56, 95% CI: 0.38–0.83), but DAC was not associated with cancer mortality (p trend >0.3). Among cancer survivors, total DAC from three meals was associated with reduced noncancer mortality, with the primary effect attributable to increased DAC intake from dinner. Our findings emphasize that DAC consumption from dinner should be advocated to reduce mortality risk in cancer survivors.

Abstract Sepsis is a life-threatening syndrome with multi-organ dysfunction in critical care medicine. With the occurrence of sepsis-induced cardiomyopathy (SIC), characterized by reduced ventricular contractility, the mortality of sepsis is boosted to 70–90%. Pyruvate kinase M2 (PKM2) functions in a variety of biological processes and diseases other than glycolysis, and has been documented as a cardioprotective factor in several heart diseases. It is currently unknown whether PKM2 influences the development of SIC. Here, we found that PKM2 was upregulated in cardiomyocytes treated with LPS both in vitro and in vivo. Pkm2 inhibition exacerbated the LPS-induced cardiac damage to neonatal rat cardiomyocytes (NRCMs). Furthermore, cardiomyocytes lacking PKM2 aggravated LPS-induced cardiomyopathy, including myocardial damage and impaired contractility, whereas PKM2 overexpression and activation mitigated SIC. Mechanism investigation revealed that PKM2 interacted with sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), a key regulator of the excitation-contraction coupling, to maintain calcium homeostasis, and PKM2 deficiency exacerbated LPS-induced cardiac systolic dysfunction by impairing SERCA2a expression. In conclusion, these findings highlight that PKM2 plays an essential role in gram-negative sepsis-induced cardiomyopathy, which provides an attractive target for the prevention and treatment of septic cardiomyopathy.

Abstract Background The clinicopathological characteristics of solid pseudopapillary tumor (SPT) and pancreatic neuroendocrine neoplasm (pNEN) are different. We, therefore, systematically investigated the performance of the clinicopathological characteristics in distinguishing SPT from pNEN. Methods We collected the cases from the Surveillance, Epidemiology, and End Results Program. The International Classification of Diseases for Oncology, third edition (ICD-O-3) for tumors was used to identify patients with pNEN or patients with SPT. To determine the performance of age in combination with gender in distinguishing SPT from pNEN, a nomogram was developed and the performance of this nomogram was evaluated by the receiver operating characteristic curve and the area under the curve (AUC). Results In the training cohort, 563 patients with pNENs and 30 patients with SPTs were recruited. The logistic regression and receiver operating characteristic curves suggest that age, gender, T-stage, N-stage, and M-stage could discriminate SPT and pNEN. The AUC of age, gender, T-stage, N-stage, and M-stage was 0.82, 0.75, 0.65, 0.69, and 0.70, respectively. Based on the nomogram, we observed that the AUC of age and gender is significantly high than that of the T-stage, N-stage, and M-stage. Conclusions The present study proposes a non-invasive nomogram that could aid in the differential diagnosis of pNEN and SPT. This might help the clinicians to distinguish SPT from pNEN and choose the appropriate treatments for the patients.

Phosphorylation catalyzed by kinases is a key event in signaling pathways involved in cardiomyocyte hypertrophy. Here the authors show that the kinase CLK4 ameliorates cardiac hypertrophy by phosphorylating NEXN.

Pancreatic cancer (PC) is a malignant tumor of the digestive system that has a bad prognosis. N6-methyladenosine (m6A) is involved in a wide variety of biological activities due to the fact that it is the most common form of mRNA modification in mammals. Numerous research has accumulated evidence suggesting that a malfunction in the regulation of m6A RNA modification is associated with various illnesses, including cancers. However, its implications in PC remain poorly characterized. The methylation data, level 3 RNA sequencing data, and clinical information of PC patients were all retrieved from the TCGA datasets. Genes associated with m6A RNA methylation were compiled from the existing body of research and made available for download from the m6Avar database. The LASSO Cox regression method was used to construct a 4-gene methylation signature, which was then used to classify all PC patients included in the TCGA dataset into either a low- or high-risk group. In this study, based on the set criteria of cor>0.4 and p value < 0.05. A total of 3507 gene methylation were identified to be regulated by m6A regulators. Based on the univariate Cox regression analysis and identified 3507 gene methylation, 858 gene methylation was significantly associated with the patient’s prognosis. The multivariate Cox regression analysis identified four gene methylation (PCSK6, HSP90AA1, TPM3, and TTLL6) to construct a prognosis model. Survival assays indicated that the patients in the high-risk group tend to have a worse prognosis. ROC curves showed that our prognosis signature had a good prediction ability on patient survival. Immune assays suggested a different immune infiltration pattern in patients with high- and low-risk scores. Moreover, we found that two immune-related genes, CTLA4 and TIGIT, were downregulated in high-risk patients. We generated a unique methylation signature that is related to m6A regulators and is capable of accurately predicting the prognosis for patients with PC. The findings might prove useful for therapeutic customization and the process of making medical decisions.

Due to the diversity of landforms, an appropriate threshold should be selected for the simplification of different landforms. The distribution of simplified index was obtained by preprocessing the terrain data, and the distribution was used as a reference for threshold selection. In order to study the influence of terrain simplification on the prediction of complex electromagnetic environment, a visibility algorithm used in the regular model of terrain and a probability-based power propagation model are proposed. The visibility algorithm used in the regular model of terrain is based on the relationship between planes and triangular planes in three-dimensional space. The visible triangular surfaces and the corresponding visible area of the triangular surfaces in the terrain can be calculated with the visibility algorithm. The probability-based power propagation model uses the results of the visibility algorithm to calculate the propagation probability and calculates the change of receiver power in combination with the radio wave propagation characteristics. The spatial visibility algorithm and the probability-based power propagation model can be applied to the complex electromagnetic environment to analyze the influence of terrain simplification on prediction accuracy. The minimum error between the simulation result of the probability-based power propagation model and the Wireless InSite simulation result is 0.5018dB, and the average error is 1.5039dB.

Synchronous reluctance machine (SynRM) can be perceived as a special type of permanent magnet synchronous machine (PMSM), and shares similar control method, i.e. the sine-wave current drive with sinusoidal phase currents. In this paper, square-wave drive, which is employed for permanent magnet brushless (BLDC) motors, is employed for the SynRM, in order to economically reduce the cost of rotor position sensor. It is revealed that the torque density and efficiency are slightly sacrificed, whereas torque ripple is deteriorated, proving the SynRM with square-wave drive still promising for the cost-sensitive application if torque ripple is not considered as a critical issue. To further investigate the additional pulsating torque under square-wave drive, mathematical model based on a-b-c phase inductance and d-q axis inductance are established, together with the time-stepping FE calculated currents. It is concluded that the harmonics in the currents tend to cause non-sinusoidal variation of the magnetic reluctance, which can be represented as additional inductance harmonics. The harmonics of the current and inductance interact with each other, thus undesirable torque ripple components are produced.

Electron radiation damage to macromolecules is an inevitable resolution limit factor in all major structural determination applications using cryo-electron microscopy (cryo-EM). Single particle analysis (SPA) and micro-crystal electron diffraction (MicroED) have been employed to assess radiation damage with a variety of protein complexes. Although radiation induced sidechain density loss and resolution decay were observed by both methods, the minimum dose of electron irradiation reducing high-resolution limit reported by SPA is more than ten folds higher than measured by MicroED using the conventional dose concept, and there is a gap between the attained resolutions assessed by these two methods. We compared and analyzed these two approaches side-by-side in detail from several aspects to identify some crucial determinants and to explain this discrepancy. Probability of a high energy electron being inelastically scattered by a macromolecule is proportional to number of layers of the molecules in its transmission path. As a result, the same electron dose could induce much more site-specific damage to macromolecules in 3D protein crystal than single particle samples. Major differences in data collection and processing scheme are the key factors to different levels of sensitivity to radiation damage at high resolution between the two methods. High resolution electron diffraction in MicroED dataset is very sensitive to global damage to 3D protein crystals with low dose accumulation, and its intensity attenuation rates at atomic resolution shell could be applied for estimating ratio of damaged and total selected single particles for SPA. More in-depth systematically radiation damage assessments using SPA and MicroED will benefit all applications of cryo-EM, especially cellular structure analysis by tomography.

PurposeThe ICRU/GEC-ESTRO released the ICRU Report No. 89, which introduced the concept of four-dimensional brachytherapy and ushered in a new era of brachytherapy for cervical cancer. The purpose of this study was to evaluate the local control and late toxicity of four-dimensional brachytherapy in cervical cancer through a systematic review and to reveal the dose-response relationship between the volumetric dose paraments and the local control rate via a probit model.Material and MethodsWe identified studies that reported the HR-CTV D90 and local control probabilities by searching the PubMed Database, the Web of Science Core Collection and the Cochrane Library Database through February 1st, 2022. Regression analyses were performed between the HR-CTV D90 and the local control probability using a probit model.ResultsNineteen studies enrolling 3,616 patients were included. The probit model showed a significant relationship between the HR-CTV D90 value and IR-CTV D90 Vs. the local control probability, P < 0.001 and P = 0.003, respectively. The D90 for HR-CTV and IR-CTV corresponding to a probability of 90% local control was 79.1 GyEQD2,10 (95% CI:69.8 – 83.7 GyEQD2,10) and 66.5 GyEQD2,10 (95% CI: 62.8 - 67.9 GyEQD2,10), respectively. The limits for the prescribed dose of 85 GyEQD2,10 for HR-CTV D90 theoretically warranted a 92.1% (95% CI: 90.2% - 95.3%) local control rate, and 87.2% (95% CI: 82.4% - 91.8%) local control probability was expected for 65 GyEQD2,10 to IR-CTV D90. The probit model showed no significant relationship between the D2cc to organs at risk and the probability of grade 3 and above gastrointestinal or genitourinary toxicity.ConclusionsFour-dimensional brachytherapy takes into account uncertain factors such as tumour regression, internal organ motion and organ filling, and provides a more accurate and more therapeutic ratio delivery through adaptive delineation and replanning, replacement of the applicator, and the addition of interstitial needles. The dose volume effect relationship of four-dimensional brachytherapy between the HR-CTV D90 and the local control rate provides an objective planning aim dose.

Bone marrow adipose tissue has brown fat characteristics. Several studies have demonstrated that total flavonoids of Epimedium (TFE) could prevent bone loss and reduce the white adiposity in bone marrow induced by ovariectomy (OVX) in rats. However, the effects of TFE on marrow brown fat in OVX rats remain unclear. In this word, we addressed this question expected to provide a new target for preventing and treating osteoporosis. Thirty-six 3-month-old female Sprague-Dawley rats were equally divided into Sham controls, OVX controls, and OVX treated with TFE. Chemical shift coding magnetic resonance was performed to detect marrow fat fraction at the left femur at baseline, 6 and 12 weeks post-OVX. Bone mineral density at the lumbar spine and femur was measured by dual-energy x-ray absorptiometry. Serum bone biomarkers by ELISA, trabecular bone microarchitecture at the proximal tibia by micro-CT, quantitative parameters of marrow adipocyte by hematoxylin, and eosin staining were evaluated. The marrow adipocyte gene and protein expressions profile were determined by real-time quantitative PCR and immunostaining in whole tibiae. We found that TFE treatment could decrease bone turnover rate and improved bone mineral density and trabecular microarchitecture in OVX rats. OVX resulted in marrow adipogenesis as evidenced by increased marrow fat fraction, larger marrow adipocyte size, increased adipocyte number and percentage of adipocyte area, marrow white adipocyte gene, and protein expression, including PPARγ2 and FABP4. These pathological changes induced by estrogen deficiency were restored by TFE treatment. TFE also increased brown adipocyte expressions of the transcription factor Ucp1 and Prdm16 in whole tibiae. There was no detectible protein expression of brown adipocyte markers in the proximal tibia. Taken together, TFE regulation of bone marrow adiposity in OVX rats is mediated, at least in part, via maintaining the reciprocity of white and brown adipose tissue.

Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.

ABSTRACT: This paper studies the environmental effects of technical change using a spatial model with panel data from 284 prefecture-cities over 2004–2015 in China. We find that the effects of technical change vary across different dimensions of technical change and different pollution indicators. Furthermore, we also provide robust evidence for the existence of the spatial effects of technical change on environmental pollution across cities. First, indigenous technical change displays three patterns of effects on the four pollutants: a positive effect on wastewater, a negative effect on PM2.5 concentrations, and an inverted U-shaped relationship with SO2 and soot emissions. The spatial effect of indigenous technical change promotes cleaner industrial productions (fewer emissions of SO2, soot and wastewater) but higher PM2.5 concentrations. Second, technology transfers from foreign direct investment are associated with less pollution except for wastewater, and their spatial effects are unanimously negative on all pollutants. Finally, absorptive capacity can also promote cleaner industrial production, but its spatial effects can do otherwise. Accordingly, the government should take the spatial spillover effects of technical change into account when implementing specific policies, pin down specific pollutants to make full use of the pollution-reducing effects of technical change, and improve the absorptive capacity of domestic firms.

Most companies survive the pain of cost and schedule overruns because of inaccurate project activity time settings. In order to deliver a project with a target cost and on schedule, this research proposes an inverse optimal value approach to optimize activity durations and the corresponding worker assignments synchronously to make the optimal project cost infinitely close to an ideal cost. The leader model reflects cost orientation and adjustability of activity durations, the follower model reflects the complexity of activity sequence, critical path completion time, cost pressure, skill matching, energy consumption, and other costs. Through upper-level and lower-level feedback and interaction of activity durations and worker assignments it is possible to deliver a project with an ideal cost. With considerations of the mathematical model characteristics of bi-level programming, nonlinearity, NP hard, and MAX functions, an improved genetic algorithm combining adaptive artificial fish swarms is designed. From the comparison results of random examples and an actual example, the error rate of the optimal value of the improved algorithm is acceptable. Numerical experiments show that the inverse optimal approach can deliver a project without delay and with an ideal cost. The inverse optimization method is more in line with the idea of target management, and can help managers achieve the purpose of cost control.

With the rapid development of digitalization, social interaction is becoming more and more frequent and complex, and the problem of household financial fragility is becoming more and more prominent, which brings challenges to macro financial stability. In order to explore the relationship between social interaction and household financial vulnerability, Based on the data of China Family Panel Studies(CFPS) 2018, this paper constructs an index system of social interaction, financial literacy and household financial fragility, discusses the influence mechanism of social interaction on household financial fragility, and clarifies the mechanism of social interaction affecting household financial fragility through financial literacy. The results show that social interaction significantly alleviates household financial fragility; social interaction alleviates household financial fragility by improving financial literacy ; this impact mainly exists in subgroups with higher financial literacy, urban and Internet-using households. Therefore, household financial fragility can be alleviated by improving social interaction conditions and narrowing the financial literacy gap.

Phytosterols (PS) showed anti-inflammatory activities in acute lung injury (ALI), but the mechanism needs to be further elucidated. In this study, male C57BL/6J mice were gavaged with PS (75 mg/kg or 150 mg/kg) for 7 consecutive days, mice ALI were induced by tracheal instillation of LPS (50 μL, 1 mg/mL). In vitro, RAW264.7 cells were incubated with LPS in the presence or absence of 50 μM β-sitosterol. Enzyme-linked immunosorbent assay was used to detect levels of inflammatory cytokines. Real-time quantitative PCR and western blot analysis were used to detect changes in nuclear factor-kB (NF-κB) and liver X receptors (LXRs) pathways. The results showed that PS administration activated LXRs/ABCA1 pathway and significantly ameliorated LPS-induced pulmonary inflammation of ALI. The role of phytosterols was verified in LPS-stimulated RAW264.7 cells and the protective effect was weakened by administration of LXR antagonist GSK2033. These findings suggested that PS ameliorates LPS-induced ALI partially by activating the LXRs/ABCA1 pathway.

Previous fundamental and clinical research has shown that electroacupuncture (EA) at the acupoints of Quchi (LI11) and Zusanli (ST36) can successfully alleviate motor dysfunction following stroke. Additionally, it has been discovered that gut microbiota and their metabolites play an essential role in stroke. However, the relationship between the metabolites of gut microbiota and the efficacy of EA is still unclear. Therefore, the aim of this study was to evaluate the mechanism of EA at LI11 and ST36 in the treatment of motor dysfunction after middle cerebral artery occlusion/reperfusion (MCAO/R) in model rats by comparing the differences and correlation between different short-chain fatty acids (SCFAs) and the recovery of motor function. The results indicated that EA at LI11 and ST36 acupoints enhanced the neurological function, motor function, and infarct volume of MCAO/R rats. The levels of acetic acid, propionic acid, and total SCFAs were considerably lower in the MCAO/R group than in the sham group (P

City image is the observer’s subjective impression of the city image. It is an important content of urban geography and planning research and has important guiding significance for shaping a unique urban space. Cognitive research on traditional urban imagery is mainly by means of questionnaires and image sketches. It has problems such as high cost, low update frequency, and limited data coverage, which cannot meet the needs of quantitative research on smart cities and urban economic development in the information age. With the advent of the era of big data and the development of Internet technology, there are more and more quantitative research results on smart city image cognition with the help of big data and deep learning technology. It will be a feasible way to apply it to urban image research. This article combines the development and transformation of smart cities with the transformation of urban planning and leads to an innovation in the construction of urban image cognition based on urban image, active representation data as the data source, and deep learning as the core technology. The theoretical connotation and cognitive dimension of urban imagery are expanded to establish a cognitive model of urban imagery. The city image is cognitively analyzed from three dimensions: image structure, image type, and image evaluation. Specific cities are taken as examples to verify the applicability and scientificity of the cognitive methods and models, so as to enhance the practicality and applicability of urban imagery in urban planning. At the same time, this research is used to answer the development dilemma of big data, summarize the development trend of big data, and explore the new changes that artificial intelligence brings to urban planning. The experimental results show that the model we designed efficiently evaluates the image of the city and can also effectively recognize the image of the city in the main urban area of Chongqing.

Abstract Background The infrared tympanic thermometer (IRTT) is a popular method for temperature screening in children, but it has been debated for the low accuracy and reproducibility compared with other measurements. This study was aimed to identify and quantify studies reporting the diagnostic accuracy of the new generation IRTT in children and to compare the sensitivity and specificity of IRTT under different cutoffs and give the optimal cutoff. Methods Articles were derived from a systematic search in PubMed, Web of Science Core Collection, and Embase, and were assessed for internal validity by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The figure of risk of bias was created by Review Manager 5.3 and data were synthesized by MetaDisc 1.4. Results Twelve diagnostic studies, involving 4639 pediatric patients, were included. The cut-offs varied from 37.0 °C to 38.0 °C among these studies. The cut-off 37.8 °C was with the highest sROC AUC (0.97) and Youden Index (0.83) and was deemed to be the optimal cutoff. Conclusion The optimal cutoff for infrared tympanic thermometers is 37.8 °C. New Generation Tympanic Thermometry is with high diagnostic accuracy in pediatric patients and can be an alternative for fever screening in children.

Mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB) pathways are considered to be two crucial intracellular signaling cascades in pro-inflammatory responses. In this study, we reported the coding sequences (CDS) of MAPKp38 and NF-κBp65 from yellow catfish. We also investigated the gene structure, expression patterns and functional role in yellow catfish. The CDS of MAPKp38 is 1,086 bp encoding 361 amino acids (AA). The MAPKp38 protein has a long highly conserved serine/threonine protein kinases catalytic domain. The NF-κBp65 CDS is 1,794 bp, and the gene encodes 597 AA, with a Rel homology domain (RHD) which consists of a RHD-DNA-binding domain and an Ig-like, plexins, transcription factors (IPT) domain. Moreover, MAPKp38 and NF-κBp65 protein of bony fish and other vertebrates have a single clade. Quantitative real-time PCR analysis revealed the presence of the MAPKp38 and NF-κBp65 transcript in 12 tissues of healthy yellow catfish. The highest expression levels of MAPKp38 and NF-κBp65 were detected in the heart and liver, respectively. Upon stimulation with an intraperitoneal injection of lipopolysaccharide (LPS), the expression levels of MAPKp38 and NF-κBp65 were up-regulated in the intestine. These results indicated that MAPKp38 and NF-κBp65 play important roles in mediating the response protection against LPS in yellow catfish. Keywords: Mitogen-activated protein kinases, Nuclear factor kappa B, Lipopolysaccharide, Expression pattern, Yellow catfish

Abstract Background Silk fibroin hydrogel, derived from Bombyx mori cocoons, has been shown to have potential effects on wound healing due to its excellent biocompatibility and less immunogenic and biodegradable properties. Many studies suggest silk fibroin as a promising material of wound dressing and it can support the adhesion and proliferation of a variety of human cells in vitro. However, lack of translational evidence has hampered its clinical applications for skin repair. Herein, a heparin-immobilized fibroin hydrogel was fabricated to deliver FGF1 (human acidic fibroblast growth factor 1) on top of wound in rats with full-thickness skin excision by performing comprehensive preclinical studies to fully evaluate its safety and effectiveness. The wound-healing efficiency of developed fibroin hydrogels was evaluated in full-thickness wound model of rats, compared with the chitosan used clinically. Results The water absorption, swelling ratio, accumulative FGF1 releasing rate and biodegradation ratio of fabricated hydrogels were measured. The regenerated fibroin hydrogels with good water uptake properties rapidly swelled to a 17.3-fold maximum swelling behavior over 12 h and a total amount of 40.48 ± 1.28% hydrogels was lost within 15 days. Furthermore, accumulative releasing data suggested that heparinized hydrogels possessed effective release behavior of FGF1. Then full-thickness skin excision was created in rats and left untreated or covered with heparinized fibroin hydrogels-immobilized recombinant human FGF1. The histological evaluation using hematoxylin and eosin (HE) and Masson’s trichrome (MT) staining was performed to observe the dermic formation and collagen deposition on the wound-healing site. To evaluate the wound-healing mechanisms induced by fibroin hydrogel treatment, wound-healing scratch and cell proliferation assay were performed. it was found that both fibroin hydrogels and FGF1 can facilitate the migration of fibroblast L929 cells proliferation and migration. Conclusion This study provides systematic preclinical evidence that the silk fibroin promotes wound healing as a wound-healing dressing, thereby establishing a foundation toward its further application for new treatment options of wound repair and regeneration.

Background Tumor mutation burden (TMB) is an important determinant and biomarker for response of targeted therapy and prognosis in patients with lung cancer. The present study aimed to determine whether radiomics signature could non‐invasively predict the TMB status and driver mutations in patients with resectable early stage lung adenocarcinoma (LUAD). Methods A total of 61pulmonary nodules (PNs) from 51 patients post‐operatively diagnosed LUAD were enrolled for analysis. Two datasets were divided according to two‐thirds of patients from different commercial Comprehensive Genomic Profiling (CGP) panels: a training cohort including 41 PNs and a testing cohort including rest 20PNs. We sequenced all tumor specimens and paired blood cells using next generation sequencing (NGS), so as to detect TMB status and somatic mutations. We collected 718 quantitative 3D radiomics features extracted from segmented volumes of each PNs and 78 clinical and pathological features retrieved from medical records as well. Support vector machine methods were performed to establish the predictive model. Results We established an efficient fusion‐positive tumor prediction model that predicts TMB status and EGFR/TP53 mutations of early stage LUAD. The radiomics signature yielded a median AUC value of 0.606, 0.604, and 0.586 respectively. Combining radiomics with the clinical information can further improve the prediction performance, which the median AUC values are 0.671 for TMB, 0.697 and 0.656 for EGFR/TP53 respectively. Conclusion It is feasible and effective to facilitate TMB and somatic driver mutations prediction by using the radiomics signature and NGS data in early stage LUAD.

The real-time and label-free terahertz (THz) metamaterial (MM) sensor is proposed to distinguish the normal concentration of glucose from the abnormal concentration based on the THz time-domain spectroscopy (TDS) technology. The physical mechanism of the biosensing performance is verified theoretically and experimentally. The designed sensor is composed of a couple of asymmetric thick metals on a silicon dioxide substrate and exhibits two transmission dips at 0.26 THz and 0.4 THz in the region from 0.1 THz to 0.5 THz, respectively. Four glucose samples with concentrations from 4 mmol/L to 10 mmol/L with the step of 2 mmol/L are loaded on the top side of the sensor, respectively. The measured results show that the two dips have a red-shift as the concentration of glucose increases. The proposed sensor achieves the sensitivity of 1.22 THz/(mol/L) and 0.52 THz/(mol/L) and the limit of measurement reaches 9 mg/dL. The proposed THz MM sensor has potential applications in diagnosing hyperglycemia and the related diseases.

BackgroundTo investigate characteristic clinical and imaging features and establish a scoring system for preoperative prediction of malignancy in the bulging duodenal papilla.MethodsA total of 147 patients with bulging duodenal papilla (Benign enlargement n = 67; malignant enlargement n = 80) from our hospital between 2010 and 2020 were retrospectively analyzed. We investigated meaningful clinical and CT imaging features and established the score model through logistic regression and weighted. The calibration test, the ROC, AUC, and cut-off points were performed in score model. The model was also divided into three score ranges for convenient clinical evaluation.ResultsThree clinical and CT imaging features were finally included in the score model including direct bilirubin (DBil) increase >7 umol/L (3 points), pancreatic duct (PD) dilation >5 mm (2 points), and irregular shape (2 points). The AUCs of the primary predictive model and score model were 0.896 (95% CI, 0.835–0.940) and 0.896 (95% CI, 0.835–0.940), respectively. This scoring system presented with a sensitivity of 78.8% and a specificity of 88.1% when using 2.5 points as cutoff value. Three score ranges were also proposed for convenient clinical use as follows: 0–2 points; 3–4 points; 5–7 points. The number of patients with malignant duodenal papillary enlargement increased with the increasing scores.ConclusionsWe proposed a convenient scoring system to preoperative predict malignancy in the bulging duodenal papilla.

Abstract Background Red maple (Acer rubrum L.) is one of the most common and widespread trees with colorful leaves. We found a mutant with red, yellow, and green leaf phenotypes in different branches, which provided ideal materials with the same genetic relationship, and little interference from the environment, for the study of complex metabolic networks that underly variations in the coloration of leaves. We applied a combination of NGS and SMRT sequencing to various red maple tissues. Results A total of 125,448 unigenes were obtained, of which 46 and 69 were thought to be related to the synthesis of anthocyanins and carotenoids, respectively. In addition, 88 unigenes were presumed to be involved in the chlorophyll metabolic pathway. Based on a comprehensive analysis of the pigment gene expression network, the mechanisms of leaf color were investigated. The massive accumulation of Cy led to its higher content and proportion than other pigments, which caused the redness of leaves. Yellow coloration was the result of the complete decomposition of chlorophyll pigments, the unmasking of carotenoid pigments, and a slight accumulation of Cy. Conclusions This study provides a systematic analysis of color variations in the red maple. Moreover, mass sequence data obtained by deep sequencing will provide references for the controlled breeding of red maple.

Graph-based multi-view feature learning methods learn a low-dimensional embedding of the data by modeling the affinity correlations with a graph to reduce the dimension. However, the learned low-dimensional representation relies on a fixed graph that is potentially inaccurate and unreliable. Besides, the graph construction and the projection matrix leaning are separated into two independent processes. To tackle the problems, we propose a robust unsupervised multi-view feature learning method with a dynamic graph. The dynamic graph structure is constructed adaptively and the robust projection matrix is learned simultaneously. Specifically, we adaptively learn a dynamic graph which captures the intrinsic multiple view-specific relations of samples. Robust projection matrix learning suppresses the adverse noises and preserves the intrinsic graph structure. Moreover, the assigned weights are learned automatically for each view without any extra parameter. We finally develop an efficient alternative optimization algorithm to solve the objective formulation. The extensive experiments conducted on several multi-view datasets demonstrate the effectiveness of our proposed method.

This study uses the Planned Risk Information Seeking Model (PRISM) to estimate the public's information seeking and avoidance intentions during the COVID-19 outbreak based on an online sample of 1031 Chinese adults and provides support for the applicability of PRISM framework in the situation of a novel high-level risk. The results indicate that information seeking is primarily directed by informational subjective norms (ISN) and perceived seeking control (PSC), while the main predictors of information avoidance include ISN and attitude toward seeking. Because ISN are the strongest predictor of both information seeking and avoidance, the way the public copes with COVID-19 information may be strongly affected by individuals' social environment. Furthermore, a significant relationship between risk perception and affective risk response is identified. Our results also indicate that people who perceive greater knowledge of COVID-19 are more likely to report greater knowledge insufficiency, which results in less information avoidance.

Summary: The 26S proteasome is specialized for regulated protein degradation. It is formed by a regulatory particle (RP) that recognizes ubiquitinated substrates and caps a hollow cylindrical core particle (CP) where substrates are proteolyzed. Structural heterogeneity caused by dynamics makes it challenging to observe ubiquitin chains at the RP by cryogenic electron microscopy (cryo-EM). Here, we present a cryo-EM-based protocol we applied to study the human 26S proteasome with ubiquitin chains by using non-cleavable M1-linked hexaubiquitin (M1-Ub6) unanchored to a substrate.For complete details on the use and execution of this protocol, please refer to Chen et al. (2020).

This paper proposes a new perspective of analyzing non-linear acoustic characteristics of the snore sounds. According to the ERB (Equivalent Rectangular Bandwidth) scale used in psychoacoustics, the ERB correlation dimension (ECD) of the snore sound was computed to feature different severity levels of sleep apnea hypopnea syndrome (SAHS). For the training group of 93 subjects, snore episodes were manually segmented and the ECD parameters of the snores were extracted, which established the gaussian mixture models (GMM). The nocturnal snore sound of the testing group of another 120 subjects was tested to detect SAHS snores, thus estimating the apnea hypopnea index (AHI), which is called AHIECD. Compared to the AHIPSG value of the gold standard polysomnography (PSG) diagnosis, the estimated AHIECD achieved an accuracy of 87.5% in diagnosis the SAHS severity levels. The results suggest that the ECD vectors can be effective parameters for screening SAHS.