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In this work, dual-gate enhancement-mode (E-mode) device based NAND circuit (DG-NAND) and the NAND block with double E-mode devices (DD-NAND) are developed and fabricated based on the GaN MIS-HEMTs (metal-insulator-semiconductor-high-electron-mobility-transistors) platform. The DG-NAND circuit has an area of 0.118 mm2 with the probe pad, which is 24% lower than the area of the DD-NAND circuit. Both static and dynamic experimental results validate the advantages of performance improvement of NAND circuits designed by dual-gate technology at an input voltage of 9 V. This paper demonstrates the design potential of dual-gate NAND in an all-GaN MIS-HEMTs platform through compact design.

Abstract Curved tip extensions are among the rotor innovation concepts that can contribute to the higher performance and lower cost of horizontal axis wind turbines. One of the key drivers to exploit their advantages is the use of accurate and efficient computational aerodynamic models during the design stage. The present work gives an overview of the performance of different state‐of‐the‐art models. The following tools were employed, in descending order of complexity: (i) a blade‐resolved Navier Stokes solver, (ii) a lifting line model, (iii) a vortex‐based method coupling a near‐wake model with a far‐wake model, and (iv) two implementations of the widely used blade element momentum method (BEM), with and without radial induction. The predictions of the codes were compared when simulating the baseline geometry of a reference wind turbine and different tip extension designs with relatively large sweep angle and/or dihedral angle. Four load cases were selected for this comparison, to cover several aspects of the aerodynamic modeling: steady power curve, pitch step, extreme operating gust impact, and standstill in deep stall. The present study highlighted the limitations of the BEM‐based formulations to capture the trends attributed to the introduction of curvature at the tip. This was true even when using the radial induction submodel. The rest of the computational methods showed relatively good agreement in most of the studied load cases. An exception to this was the standstill configuration, as the blade‐resolved Navier‐Stokes solver was the only code able to capture the highly unsteady effects of deep stall.

Abstract Objective The study aimed to investigate the attitudes of people with diabetes mellitus (DM) on COVID-19 vaccination and its influence on the glycemic control. Methods Data were collected from a consecutive series of adults (age > 18 years) with type 2 diabetes under regular follow-ups in the Integrated Care Diabetes Outpatient Clinic of Peking University First Hospital from December 1st to December 31st 2021. An online interview questionnaire was conducted, and demographic data including age, sex category, history of drug allergy, history of hypertension, the duration of diabetes, reasons for vaccine hesitancy (VH) and adverse reactions after each injection of vaccines was collected. Glucose levels were collected from medical records. Results Thirty-nine (22.9%) subjects experienced VH and 131 (77.1%) people living with diabetes received inactivated vaccine against COVID-19. Hesitant individuals had a higher proportion of female gender (vaccinated group vs. VH group, 62/131 vs. 26/39, p = 0.044), higher baseline glycosylated hemoglobin A1c (HbA1c) (vaccinated group vs. VH group, 6.56 ± 0.95% vs. 7.54 ± 2.01%, p

Abstract Background RpoN, also known as σ54, first reported in Escherichia coli, is a subunit of RNA polymerase that strictly controls the expression of different genes by identifying specific promoter elements. RpoN has an important regulatory function in carbon and nitrogen metabolism and participates in the regulation of flagellar synthesis, bacterial motility and virulence. However, little is known about the effect of RpoN in Plesiomonas shigelloides. Results To identify pathways controlled by RpoN, RNA sequencing (RNA-Seq) of the WT and the rpoN deletion strain was carried out for comparison. The RNA-seq results showed that RpoN regulates ~ 13.2% of the P. shigelloides transcriptome, involves amino acid transport and metabolism, glycerophospholipid metabolism, pantothenate and CoA biosynthesis, ribosome biosynthesis, flagellar assembly and bacterial secretion system. Furthermore, we verified the results of RNA-seq using quantitative real-time reverse transcription PCR, which indicated that the absence of rpoN caused downregulation of more than half of the polar and lateral flagella genes in P. shigelloides, and the ΔrpoN mutant was also non-motile and lacked flagella. In the present study, the ability of the ΔrpoN mutant to kill E. coli MG1655 was reduced by 54.6% compared with that of the WT, which was consistent with results in RNA-seq, which showed that the type II secretion system (T2SS-2) genes and the type VI secretion system (T6SS) genes were repressed. By contrast, the expression of type III secretion system genes was largely unchanged in the ΔrpoN mutant transcriptome and the ability of the ΔrpoN mutant to infect Caco-2 cells was also not significantly different compared with the WT. Conclusions We showed that RpoN is required for the motility and contributes to the killing ability of P. shigelloides and positively regulates the T6SS and T2SS-2 genes.

Abstract The aim of this study was to identify miRNAs in plasma exosomes as noninvasive biomarkers for the early diagnosis of lung adenocarcinoma (LUAD). First, exosomal miRNA profiling of three patients with early LUAD and three patients with benign lung disease were screened by next‐generation sequencing (NGS) method. Sequencing results showed that 154 exosomal miRNAs were differentially expressed in the plasma of LUAD patients, among which 68 miRNAs were up‐regulated and 86 miRNAs were down‐regulated. GSE137140 is a GEO database containing serum miRNAs sequencing data from 1566 lung cancer patients and 1774 non‐cancer patients controls. When comparing the sequencing data, it was found that most miRNAs (37/68) up‐regulated in our LUAD group were also significantly up‐regulated in GSE137140, suggesting that circulating miRNAs in lung cancer patients may be enriched in plasma exosomes. In GSE137140, the AUC of the combination of hsa‐miR‐103b, hsa‐miR‐29c‐5p and hsa‐miR‐877‐5p was 0.873, showing great potential as new tumor markers. To our knowledge, these three exosomal miRNAs have not been reported in lung cancer research. Furthermore, bioinformatics tools were used to analyze the target genes of three candidate miRNAs, which were indeed closely related to the occurrence and development of lung cancer. Bioinformatics algorithms deduced a highly conserved sequence in the 3’‐UTR of SFRP4, FOXM1 and TMEM98 that could be bound with miR‐103b/877‐5p/29c‐5p. A luciferase assay indicated that miR‐103b/877‐5p/29c‐5p directly targeted the 3’‐UTR of SFRP4, FOXM1 and TMEM98, respectively. Finally, three candidate miRNAs were validated by qRT‐PCR in 17 early LUAD samples and 17 control plasma samples. Integration of bioinformatics analysis and experimental validation identifies, this study provides novel insights into miRNA‐related networks in LUAD. Hsa‐miR‐103b, hsa‐miR‐29c‐5p, and hsa‐miR‐877‐5p may be used as diagnostic biomarkers for early LUAD.

Abstract High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB.

Epidemiological and mechanistic studies suggest that some US Food and Drug Administration (FDA)-approved drugs can reduce the incidence of cancer and inhibit tumor growth. Therefore, investigating FDA-approved drugs for cancer chemoprevention is a promising strategy. In this study, we screened FDA-approved drugs and found that azelnidipine, a Ca channel blocker widely used in the treatment of hypertension, inhibits the growth of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. We identified that MEK1/2 were direct targets of azelnidipine through pull-down assay and cellular thermal shift assay. Azelnidipine could suppress kinase activity of MEK1/2 through in vitro kinase assay. Hypophosphorylation of ERK1/2 decreased the levels of Cyclin D1/CDK6 in ESCC cells after azelnidipine treatment. More importantly, azelnidipine, like trametinib, inhibited the growth of ESCC in vivo. In conclusion, azelnidipine, a novel dual MEK1/2 inhibitor, exerted antitumor effects against ESCC cell lines and patient-derived xenograft in ESCC.

Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in the liver. AAV-CRISPR nearly completely eliminated apo(a) from the circulation within a week. We performed genome-wide off-target assays to determine the specificity of CRISPR-Cas9 editing within the context of the human genome. Interestingly, we identified intrachromosomal rearrangements within the LPA cDNA in the transgenic mice as well as in the LPA gene in HEK293T cells, due to the repetitive sequences within LPA itself and neighboring pseudogenes. This proof-of-concept study establishes the feasibility of using CRISPR-Cas9 to disrupt LPA in vivo, and highlights the importance of examining the diverse consequences of CRISPR cutting within repetitive loci and in the genome globally.

Abstract Studies suggest that the scaffolding protein, postsynaptic density protein-95 (PSD-95), is involved in multiple neurological dysfunctions. However, the role of PSD-95 in the anterior cingulate cortex (ACC) in neuropathic pain (NP) has not been investigated. The current study addressed the role of PSD-95 in the ACC in NP and its modulating profile with NMDA receptor subunit 2B (NR2B). The NP model was established by chronic constriction injury (CCI) of the sciatic nerve, and mechanical and thermal tests were used to evaluate behavioral hyperalgesia. Protein expression and distribution were evaluated using immunohistochemistry and western blotting. The results showed that PSD-95 and NR2B were co-localized in neurons in the ACC. After CCI, both PSD-95 and NR2B were upregulated in the ACC. Inhibiting NR2B with Ro 25-6981 attenuated pain hypersensitivity and decreased the over-expression of PSD-95 induced by CCI. Furthermore, intra-ACC administration of PSD-95 antisense oligonucleotide not only attenuated pain hypersensitivity but also downregulated the NR2B level and the phosphorylation of cyclic AMP response element-binding protein. These results demonstrated that PSD-95 in the ACC contributes to NP by interdependent activation of NR2B.

With the global trend of pursuing clean energy and decarbonization, power systems have been evolving in a fast pace that we have never seen in the history of electrification. This evolution makes the power system more dynamic and more distributed, with higher uncertainty. These new power system behaviors bring significant challenges in power system modeling and simulation as more data need to be analyzed for larger systems and more complex models to be solved in a shorter time period. The conventional computing approaches will not be sufficient for future power systems. This paper provides a historical review of computing for power system operation and planning, discusses technology advancements in high performance computing (HPC), and describes the drivers for employing HPC techniques. Some high performance computing application examples with different HPC techniques, including the latest quantum computing, are also presented to show how HPC techniques can help us be well prepared to meet the requirements of power system computing in a clean energy future.

Abstract Traumatic brain injury (TBI) contributes to the key causative elements of neurological deficits. However, no effective therapeutics have been developed yet. In our previous work, extracellular vesicles (EVs) secreted by stem cells from human exfoliated deciduous teeth (SHED) offered new insights as potential strategies for functional recovery of TBI. The current study aims to elucidate the mechanism of action, providing novel therapeutic targets for future clinical interventions. With the miRNA array performed and Real-time PCR validated, we revealed the crucial function of miR-330-5p transferred by SHED-derived EVs (SHED-EVs) in regulating microglia, the critical immune modulator in central nervous system. MiR-330-5p targeted Ehmt2 and mediated the transcription of CXCL14 to promote M2 microglia polarization and inhibit M1 polarization. Identified in our in vivo data, SHED-EVs and their effector miR-330-5p alleviated the secretion of inflammatory cytokines and resumed the motor functional recovery of TBI rats. In summary, by transferring miR-330-5p, SHED-EVs favored anti-inflammatory microglia polarization through Ehmt2 mediated CXCL14 transcription in treating traumatic brain injury.

BackgroundAmnestic mild cognitive impairment (aMCI) is an early stage of Alzheimer’s disease (AD). Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) are employed to explore spontaneous brain function in patients with aMCI. This study applied ALFF and ReHo indicators to analyze the neural mechanism of aMCI by resting-state functional magnetic resonance imaging (rs-fMRI).MethodsTwenty-six patients with aMCI were included and assigned to the aMCI group. The other 26 healthy subjects were included as a healthy control (HC) group. Rs-fMRI was performed for all participants in both groups. Between-group comparisons of demographic data and neuropsychological scores were analyzed using SPSS 25.0. Functional imaging data were analyzed using DPARSF and SPM12 software based on MATLAB 2017a. Gender, age, and years of education were used as covariates to obtain ALFF and ReHo indices.ResultsCompared with HC group, ALFF decreased in the left fusiform gyrus, left superior temporal gyrus, and increased in the left cerebellum 8, left inferior temporal gyrus, left superior frontal gyrus (BA11), and right inferior temporal gyrus (BA20) in the aMCI group (p

Background: Using epigenetic markers and fragmentomics of cell-free DNA for cancer detection has been proven applicable. Methods: We further investigated the diagnostic potential of combining two features (epigenetic markers and fragmentomic information) of cell-free DNA for detecting various types of cancers. To do this, we extracted cfDNA fragmentomic features from 191 whole-genome sequencing data and studied them in 396 low-pass 5hmC sequencing data, which included four common cancer types and control samples. Results: In our analysis of 5hmC sequencing data from cancer samples, we observed aberrant ultra-long fragments (220–500 bp) that differed from normal samples in terms of both size and coverage profile. These fragments played a significant role in predicting cancer. Leveraging the ability to detect cfDNA hydroxymethylation and fragmentomic markers simultaneously in low-pass 5hmC sequencing data, we developed an integrated model that incorporated 63 features representing both fragmentomic features and hydroxymethylation signatures. This model achieved high sensitivity and specificity for pan-cancer detection (88.52% and 82.35%, respectively). Conclusion: We showed that fragmentomic information in 5hmC sequencing data is an ideal marker for cancer detection and that it shows high performance in low-pass sequencing data.

Summary: Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and leads to progressive motor dysfunction. While studies have focused on the basal ganglia network, recent evidence suggests neuronal systems outside the basal ganglia are also related to PD pathogenesis. The zona incerta (ZI) is a predominantly inhibitory subthalamic region for global behavioral modulation. This study investigates the role of GABAergic neurons in the ZI in a mouse model of 6-hydroxydopamine (6-OHDA)-induced PD. First, we found a decrease in GABA-positive neurons in the ZI, and then the mice used chemogenetic/optogenetic stimulation to activate or inhibit GABAergic neurons. The motor performance of PD mice was significantly improved by chemogenetic/optogenetic activation of GABAergic neurons, and repeated chemogenetic activation of ZI GABAergic neurons increased the dopamine content in the striatum. Our work identifies the role of ZI GABAergic neurons in regulating motor behaviors in 6-OHDA-lesioned PD model mice.

Abstract Cardiomyopathies comprise a group of disorders wherein the primary defect is in cardiac myocytes. The common forms of pediatric cardiomyopathies, classified according to their morphological and functional manifestations, include dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and others. Cardiac gene mutations caused abnormal myofibril Ca2+ sensitivity may be involved in the underlying molecular mechanisms of cardiomyopathies. Thus far, no effective treatment for cardiomyopathies has been developed, especially for HCM and RCM in which diastolic dysfunction occurs early and followed by diastolic heart failure. Our laboratory is among the first in the field to investigate the mechanisms underlying various cardiomyopathies and search for the treatment for these disorders. In the past, we and other researchers have found that (−)‐epigallocatechin‐3‐gallate (EGCg), the major biomedical polyphenol extracted from green tea, possess multiple therapeutic effects on protecting cardiac function and correcting impaired relaxation. Given its therapeutic effects, EGCg might be a potential drug candidate for administration to patients with cardiomyopathy and heart failure. In this review, we will discuss the molecular mechanisms associated with the pathogenesis of diastolic dysfunction and summarize the pharmacological effects of EGCg on experimental animals and pediatric patients with cardiomyopathies and diastolic dysfunction.

Abstract Submarine methane seepage can potentially be promoted by the dissociation of the marine hydrates surrounding the continental margins due to oceanic warming since the Last Glacial Maximum. This seepage could be archived by authigenic carbonates at seeping sites, but the time lag caused by heat transmission through the sediment column leads to an inconsistency between the ages of the carbonate and the period of bottom water warming. Here we present the records of the authigenic carbonate crust from drilling site D1 in the Mid‐Okinawa Trough. Uranium–thorium dating results show that the carbonate crust mainly grew downwards during 14–6 ka. Gas hydrates hosted in the relatively thin stability zone dissociated in a rapid response to bottom water warming and intensified the methane seepage. Our study better supports the hypothesis that a considerable amount of methane can be released from marine hydrates due to global climatic changes.

BackgroundVaccination is considered an effective approach to deter the spread of coronavirus disease (COVID-19). However, vaccine hesitancy is a common issue that makes immunization programs more challenging. To promote vaccination in a targeted and efficient way, this study aims to develop and validate a measurement tool for evaluating the importance of influencing factors related to COVID-19 vaccination intention in China, and to examine the demographic differences.MethodsIn study 1, we developed a Factor Importance Evaluation Questionnaire (FIEQ) based on semi-structured interview results and used exploratory factor analysis (EFA) to explore its factor structure. In study 2, we verified the four-factor structure of FIEQ by confirmatory factor analysis (CFA). We then administered FIEQ to Chinese participants and conducted a student t-test and analysis of variance to examine the differences in the importance evaluation of factors based on gender and educational level.ResultsIn study 1, we developed a four-factor construct and retained 20 items after EFA (N = 577), with acceptable reliability (alpha = 0.87) and validity. In study 2, we found that the model fit was good (χ2 = 748.03 (162), p

IntroductionThe conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchestrate the immune system to target and eradicate cancers.MethodsHere, we performed single-cell RNA sequencing (scRNA-seq) and computational analysis of 35786 unselected single cells from 3 human HCC tumour and 3 matched adjacent samples to elucidate the heterogeneity and intercellular communication network of the TME. The specific lysis of HCC cell lines was examined in vitro using cytotoxicity assays. Granzyme B concentration in supernatants of cytotoxicity assays was measured by ELISA.ResultsWe found that VCAN+ tumour-associated macrophages (TAMs) might undergo M2-like polarization and differentiate in the tumour region. Regulatory dendritic cells (DCs) exhibited immune regulatory and tolerogenic phenotypes in the TME. Furthermore, we observed intensive potential intercellular crosstalk among C1QC+ TAMs, regulatory DCs, regulator T (Treg) cells, and exhausted CD8+ T cells that fostered an immunosuppressive niche in the HCC TME. Moreover, we identified that the TIGIT-PVR/PVRL2 axis provides a prominent coinhibitory signal in the immunosuppressive TME. In vitro, antibody blockade of PVR or PVRL2 on HCC cell lines or TIGIT blockade on immune cells increased immune cell-mediated lysis of tumour cell. This enhanced immune response is paralleled by the increased secretion of Granzyme B by immune cells.DiscussionCollectively, our study revealed the functional state, clinical significance, and intercellular communication of immunosuppressive cells in HCC at single-cell resolution. Moreover, PVR/PVRL2, interact with TIGIT act as prominent coinhibitory signals and might represent a promising, efficacious immunotherapy strategy in HCC.

Lipidemic effect of air pollutants are still inconsistent and their joint effects are neglected. Meanwhile, identified inflammation pathways in animal have not been applied in epidemiological studies, and beneficial effect of residential greenness remained unclear. Therefore, we used data from typically air-polluted Chinese cities to answer these questions. Particulate matter (PM) with a diameter of ≤ 1 µm (PM1), PM with a diameter of ≤ 2.5 µm (PM2.5), PM with a diameter of ≤ 10 µm (PM10), sulphur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) were predicted by space–time extremely randomized trees model. Residential greenness was reflected by Normalized Difference Vegetation Index (NDVI). Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured, and atherogenic coefficient (AC) and TG/HDL-C (TGH) ratio were calculated to indicate lipid metabolism. Generalized additive mixed model and quantile g-computation were respectively conducted to investigate individual and joint lipidemic effect of air pollutants. Covariates including demographical characteristics, living habits, meteorological factors, time trends, and disease information were considered to avoid confounding our results. Complement C3 and high-sensitivity C-reactive protein (hsCRP) were analyzed as potential mediators. Finally, association between NDVI and lipid markers were explored. We found that long-term air pollutants exposure were positively associated with lipid markers. Complement C3 mediated 54.72% (95% CI: 0.30, 63.10) and 72.53% (95% CI: 0.65, 77.61) of the association between PM1 and TC and LDL-C, respectively. We found some significant associations of lipid markers with NDVI1000 m rather than NDVI500 m. BMI, disease status, smoke/drink habits are important effect modifiers. Results are robust in sensitive analysis. Our study indicated that air pollutants exposure may detriment lipid metabolism and inflammation may be the potential triggering pathways, while greenness may exert beneficial effects. This study provided insights for the lipidemic effects of air pollution and greenness.

Microenvironment biophysical factors such as matrix stiffness can noticeably affect the differentiation of mesenchymal stem cells (MSCs). In this mechanobiology transduction process, mitochondria are shown to be an active participant. The present study aims to systematically elucidate the phenotypic and functional changes of mitochondria during the stiffness-mediated osteogenic differentiation. Additionally, the effect of mitochondria transfer on the osteogenesis of impaired MSCs caused by stiffness was investigated. Human periodontal ligament stem cells (PDLSCs) were used as model cells in the current study. Low stiffness restrained the cell spreading and significantly inhibited the proliferation and osteogenic differentiation of PDLSCs. Mitochondria of PDLSCs cultured on low stiffness exhibited shorter length, rounded shape, fusion/fission imbalance, ROS and mitophagy level increase, and ATP production reduction. The inhibited mitochondria function and osteogenic differentiation capacity were recovered to near-normal levels after transferring the mitochondria of PDLSCs cultured on the high stiffness. This study indicated that low matrix stiffness altered the mitochondrial morphology and induced systematical mitochondrial dysfunction during the osteogenic differentiation of MSCs. Mitochondria transfer was proved to be a feasible technique for maintaining MSCs function in vitro by reversing the osteogenesis ability.

Large uncertainties in the determinations of the equation of state of dense stellar matter allow for the intriguing possibility that the bulk quark matter in beta equilibrium might be the true ground state of the matter at zero pressure. Also, quarks will form Cooper pairs very readily since the dominant interaction between quarks is attractive in some channels. As a result, quark matter will generically exhibit color superconductivity, with the favored pairing pattern at intermediately high densities being two-flavor pairing. In the light of several possible candidates for such self-bound quark stars, including the very low-mass central compact object in supernova remnant HESS J1731-347 reported recently, we carry out a one-field theoretic model, the Nambu–Jona–Lasinio model, to investigate the stability of the beta-stable two-flavor color superconducting (2SC) phase of quark matter, but find no physically allowed parameter space for the existence of 2SC quark stars.

The investigation of the phase state of dense matter is hindered by complications of first-principle nonperturbative quantum chromodynamics. By performing the first consistent general-relativistic calculations of tidal-excited g-mode of neutron stars with a first-order strong interaction phase transition in the high-density core, we demonstrate that the gravitational-wave signal during binary neutron star inspiral probes their innermost hadron-quark transition and provides potent constraints from present and future gravitational-wave detectors.

Spin period distribution provides important clues to understand the formation of millisecond pulsars (MSPs). To uncover the intrinsic period distribution, we analyze three samples of radio MSPs in the Galactic field and globular clusters. The selection bias due to pulse broadening has been corrected but turns out to be negligible. We find that all the samples can be well described by a Weibull distribution of spin frequencies. Considering MSPs in the Galactic field or globular clusters and in isolation or binary systems, we find no significant difference in the spin distribution among these subpopulations. Based on the current known population of MSPs, we find that submillisecond pulsars are unlikely to be discovered by the Square Kilometre Array, although up to ∼10 discoveries of pulsars that spin faster than the current record holder of P = 1.4 ms are expected.

The storage of peach fruits at 4–5 °C can easily lead to chilling injury and greatly reduce the quality and commercial value of peach fruits. In this study, two kinds of peach fruits (CX and CM) were selected to analyze the mechanisms of chilling injury in fruits with different chilling sensitivity by means of their lipidomic, transcriptome, and dynamic changes in plant hormones. We found that the ethylene, abscisic acid (ABA), and lipid contents changed differently between CX and CM. The ABA and dilactosyl diacylglycerol (DGDG) contents significantly increased after refrigeration in CM fruit, leading to strong cold resistance. However, low temperatures induced a greater accumulation of ethylene, phospholipids, and ABA-GE in CX fruit than in CM fruit, eventually leading to more severe CI symptoms in CX fruit. Additionally, a transcriptional regulatory network for CM and CX fruits during cold storage was constructed, providing a new theoretical reference for the cultivation of cold-resistant peach cultivars and the development of postharvest preservation technology.

In order to break through the speed bottleneck, researchers envision using tubes to cover high-speed maglev trains and extract some of the air inside the tubes, creating a low-density environment on the ground, greatly reducing the aerodynamic drag of the trains, and in a relatively economical and feasible way, making high subsonic (600 km/h and above) and even supersonic ground transportation possible. The faster the running speed of high-speed trains, the greater the impact of aerodynamic drag on their energy consumption. Studying the aerodynamic characteristics of trains with a speed of 600 km/h can help optimize the aerodynamic shape of the train, reduce aerodynamic drag, and reduce energy consumption. This has positive implications for improving train energy efficiency, reducing energy consumption, and environmental impact. This paper adopts the numerical simulation method to study the drag reduction effect of the plasma arrangement and different excitation speeds on the train set in four positions when the incoming wind speed is 600 km/h, to analyze the mechanism of drag reduction, and then to analyze the combination of working conditions in order to investigate the drag reduction effect of plasma on the vacuum tube train set with an ambient pressure of 10,000 Pa. The findings demonstrate that the plasma induces the directional flow of the gas close to the wall to move the flow separation point backward and delay the separation of the flow, thereby reducing the front and rear differential pressure drag of the train set and lowering the aerodynamic drag coefficient of the entire train. The plasma arrangement is located at the rear of the flow separation point and in close proximity to the flow separation point. The pneumatic drag reduction effect peaks when the excitation speed reaches 0.2 times the train speed and the pneumatic drag reduction ratio is around 0.88%; the pneumatic drag reduction ratio of the rear car peaks when the excitation speed reaches 0.25 times the train speed and the pneumatic drag reduction ratio is 1.62%. The SDBD (Surface Dielectric Barrier Discharge) device is installed at the flow separation point around the nose tip of the rear car.

In this paper, an ammonia–urea system was developed to induce the shedding of carboxymethylcellulose carbon aerogels to form defects, and the specific surface area of the aerogels was significantly increased after carbonization, and the three-dimensional disordered pore structure of cellulose was preserved. The material showed the selective adsorption of gadolinium ions using the carboxylate active sites provided by carboxymethylation and the microporous or mesoporous structures formed after carbon burning. The successful synthesis of the material was demonstrated by relevant characterization, and the results of static adsorption experiments showed that the material was more consistent with the quasi second-order kinetic model at pH = 5.0. The maximum adsorption capacity was 99.65 mg g−1. The material showed a high adsorption capacity for gadolinium ions in the presence of competing ions and maintained 84.07% of the adsorption performance after five adsorption cycles. The simple use of urea ensured that the cellulose maintained its pore structure, and the specific surface area was greatly increased after carbonization, which provided a feasible direction for the industrial adsorption and recycling of rare-earth elements for reuse.

Bone mineralization is a sophisticated regulated process composed of crystalline calcium phosphate and collagen fibril. Autophagy, an evolutionarily conserved degradation system, whereby double-membrane vesicles deliver intracellular macromolecules and organelles to lysosomes for degradation, has recently been shown to play an essential role in mineralization. However, the formation of autophagosomes in mineralization remains to be determined. Here, we show that Coat Protein Complex I (COPI), responsible for Golgi-to-ER transport, plays a pivotal role in autophagosome formation in mineralization. COPI vesicles were increased after osteoinduction, and COPI vesicle disruption impaired osteogenesis. Mechanistically, COPI regulates autophagy activity via the mTOR complex 1 (mTORC1) pathway, a key regulator of autophagy. Inhibition of mTOR1 rescues the impaired osteogenesis by activating autophagy. Collectively, our study highlights the functional importance of COPI in mineralization and identifies COPI as a potential therapeutic target for treating bone-related diseases.

Base editing is promising for gene therapy, but in vivo delivery has been limiting. Here the authors perform structure-based rational engineering of the cytosine base editing system Target-AID to minimise off-target effects and decrease its size.

Kleiner and co-workers profile RNA 5-methylcytidine (m5C) dioxygenase enzymes using an activity-based metabolic probing strategy. They reveal ALKBH1 as the major 5-formylcytidine (f5C) writer and characterize modification sites across mRNA and tRNA.

Bringing enzymes and substrates together in confined compartments within porous systems can offer enhanced catalytic efficiency and increased lifetimes for the encapsulated enzymes. Here, the authors construct enzymatic compartments by spatiotemporal control of the self-assembly of catalytic peptide TPE-Q18H in hollow glucan particles, and demonstrate enhanced substrate-binding affinity and reaction kinetics as well as increased thermostability and resistance to hydrolysis.

Objectives:It is well known that multimodal services containing audio,video and haptics such as mixed reality,digital twin and metaverse are bound to become killer applications in the 6G era,however,the large amount of multimodal data generated by such services is highly likely to burden the signal processing, transmission and storage of existing communication systems. Therefore, a cross-modal signal reconstruction scheme is urgently needed to reduce the amount of transmitted data to support 6G immersive multimodal services in order to meet the user's immersive experience requirements and guarantee low latency,high reliability and high capacity communication quality. Methods:Firstly,by controlling the robot to touch various materials,a dataset containing audio, visual and touch signals, VisTouch, is constructed to lay the foundation for subsequent research on various cross-modal problems; secondly, by exploiting the semantic correlation between multimodal signals, a universal and robust end-to-end cross-modal signal reconstruction architecture is designed, comprising three parts: a feature extraction module, a reconstruction module and an evaluation module. The feature extraction module maps the source modal signals into a semantic feature vector in the common semantic space, and the reconstruction module inverse transforms this semantic feature vector into the target modal signal.The evaluation module evaluates the reconstruction quality in semantic and spatio-temporal dimensions, and feeds the optimization information to the feature extraction module and the reconstruction module during the training process of the framework, forming a closed-loop loop to achieve accurate signal reconstruction through continuous iteration. Further, a teleoperated platform is designed to deploy the constructed haptic reconstruction model into the codec to actually verify the operational efficiency of the model; finally, the reliability of the cross-modal signal reconstruction architecture and the accuracy of the haptic reconstruction model are verified by experimental results. Results: The constructed VisTouch dataset involves three modalities: audio, video and haptics, and contains 47 common slices of life samples. The average absolute error and accuracy of the constructed video-assisted haptic reconstruction model on the VisTouch dataset reached 0.0135 and 0.78 respectively. In order to implement the proposed cross-modal signal reconstruction framework into practical application scenarios, a teleoperation platform was further built using the robot and Nvidia development board for the industrial scenario of The results of running on this platform show that the actual mean absolute error is 0.0126,the total end-to-end delay is 127ms and the reconstruction model delay is 98ms.A questionnaire was also used to assess user satisfaction,where the mean value of haptic realism satisfaction is 4.43 with a variance of 0.72 and the mean value of time delay satisfaction is 3.87 with a variance of 1.07. Conclusions: The results of the dataset runs fully demonstrate the practicality of the constructed VisTouch dataset and the accuracy of the video-assisted haptic reconstruction model, while the actual test results of the teleoperated platform indicate that users consider the haptic signals generated by the model to be closer to the actual signals,but are generally satisfied with the running time of the algorithm, i.e. the complexity of this modality needs further optimization.

Abstract. Background:. The dermoscopic features of rosacea have already been reported. However, the current findings are incomplete, and little is known about phymatous rosacea. Hence, this study aimed to summarize and compare the dermoscopic features and patterns of three rosacea subtypes (erythematotelangiectatic [ETR], papulopustular [PPR], and phymatous [PHR]) in the Chinese Han population and to evaluate whether these features differ with patients’ genders, ages, and durations. Methods:. Dermoscopic images of 87 rosacea patients were collected in non-polarized and polarized dermoscopy contact modes at 20-fold magnification. Dermoscopic features, including vessels, scales, follicular findings, and other structures, were summarized and evaluated. Results:. The reticular linear vessels and red diffuse structureless areas of ETR were distinctive. For PPR, red diffuse structureless areas, reticular linear vessels, yellow scales, follicular plugs, and follicular pustules were typical dermoscopic criteria. The common dermoscopic features of PHR were: orange diffuse structureless areas, linear vessels with branches, perifollicular white color, orange focal structureless areas, and white lines. The following features statistically differed among the three rosacea subtypes: reticular linear vessels (P

Abstract The proliferation of Internet-of-Things has promoted a wide variety of emerging applications that require compact, lightweight, and low-cost optical spectrometers. While substantial progresses have been made in the miniaturization of spectrometers, most of them are with a major focus on the technical side but tend to feature a lower technology readiness level for manufacturability. More importantly, in spite of the advancement in miniaturized spectrometers, their performance and the metrics of real-life applications have seldomly been connected but are highly important. This review paper shows the market trend for chip-scale spectrometers and analyzes the key metrics that are required to adopt miniaturized spectrometers in real-life applications. Recent progress addressing the challenges of miniaturization of spectrometers is summarized, paying a special attention to the CMOS-compatible fabrication platform that shows a clear pathway to massive production. Insights for ways forward are also presented.

BackgroundAlzheimer's disease (AD) is a common, progressive, irreversible, and fatal neurodegenerative disorder with rapidly increasing worldwide incidence. Although much research on magnetic resonance imaging (MRI) of the white matter (WM) in AD has been published, no bibliometric analysis study has investigated this issue. Thus, this study aimed to provide an overview of the current status, hotspots, and trends in MRI of WM in AD.MethodsWe searched for records related to MRI studies of WM in AD from 1990 to 2022 in the Web of Science Core Collection (WOSCC) database. CiteSpace (version 5.1.R8) and VOSviewer (version 1.6.19) software were used for bibliometric analyses.ResultsA total of 2,199 articles were obtained from this study. From 1990 to 2022, the number of published articles showed exponential growth of y = 4.1374e0.1294x, with an average of 17.9 articles per year. The top country and institutions were the United States and the University of California Davis, accounting for 44.52 and 5.32% of the total studies, respectively. The most productive journal was Neurology, and the most co-cited journal was Lancet Neurology. Decarli C was the most productive author. The current research frontier trend focuses on the association between small vessel disease and AD, the clinical application and exploration of diffusion MRI, and related markers.ConclusionThis study provides an in-depth overview of publications on MRI of WM in AD, identifying the current research status, hotspots, and frontier trends in the field.

Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial reactive oxygen species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1β secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.

In patients with liver failure complicated by acute kidney injury, renal replacement therapy (RRT) is often required to improve the internal environment. The use of anticoagulants for RRT in patients with liver failure remains controversial. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies. The methodological quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies. A meta-analysis was performed using R software (version 3.5.1) and Review Manager (version 5.3.5). During RRT, 348 patients from 9 studies received regional citrate anticoagulation (RCA), and 127 patients from 5 studies received heparin anticoagulation (including heparin and LMWH). Among patients who received RCA, the incidence of citrate accumulation, metabolic acidosis, and metabolic alkalosis were 5.3% (95% confidence interval [CI]: 0%–25.3%), 26.4% (95% CI: 0–76.9), and 1.8% (95% CI: 0–6.8), respectively. The potassium, phosphorus, total bilirubin (TBIL), and creatinine levels were lower, whereas the serum pH, bicarbonate, base excess levels, and total calcium/ionized calcium ratio were higher after treatment than before treatment. Among patients who received heparin anticoagulation, the TBIL levels were lower, whereas the activated partial thromboplastin clotting time and D-dimer levels were higher after treatment than before treatment. The mortality rates in the RCA and heparin anticoagulation groups were 58.9% (95% CI: 39.2–77.3) and 47.4% (95% CI: 31.1–63.7), respectively. No statistical difference in mortality was observed between the 2 groups. For patients with liver failure, the administration of RCA or heparin for anticoagulation during RRT under strict monitoring may be safe and effective.

Introduction: Lung cancer has long been at the forefront of all cancers in terms of incidence and mortality. Lung adenocarcinoma is the most common type of lung cancer, accounting for 40% of all lung cancer types. Exosomes can act as biomarkers of tumors and thus play an important role.Methods: In this article, high-throughput sequencing of miRNAs in plasma exosomes from lung adenocarcinoma patients and healthy individuals was performed to obtain 87 upregulated miRNAs, which were then combined with data from the GSE137140 database uploaded by others for screening. The database included 1566 preoperative lung cancer patients, 180 postoperative patients, and 1774 non-cancerous controls. We overlapped the miRNAs upregulated in the serum of lung cancer patients in the database relative to those of non-cancer controls and post-operative patients with the upregulated miRNAs obtained from our next-generation sequencing to obtain nine miRNAs. Two miRNAs that were not reported as tumor markers in lung cancer, hsa-miR-4454 and hsa-miR-619-5p, were selected from them and then validated by qRT-PCR, and further analysis of miRNAs was performed using bioinformatics.Results: Real-time quantitative PCR showed that the expression levels of hsa-miR-4454 and hsa-miR-619-5p in plasma exosomes of patients with lung adenocarcinoma were significantly up-regulated. The AUC values of hsa-miR-619-5p and hsa-miR-4454 were 0.906 and 0.975, respectively, both greater than 0.5, showing good performance. The target genes of miRNAs were screened by bioinformatics methods, and the regulatory network between miRNAs and lncRNAs and mRNAs was studied.Discussion: Our work demonstrated that hsa-miR-4454 and hsa-miR-619-5p have the potential to be used as biomarkers for the early diagnosis of lung adenocarcinoma.

With the continuous development of 5G, big data, the Internet of Things (IOT) and other technologies, the smart park will realize data sharing, information processing and transmission, and finally tend to be smart city. There are some problems such as unclear design dimensions, poor interactivity of subsystems and high expansion costs in the development of smart park. In the face of these problems, an application-oriented comprehensive management platform system of intelligent park is designed. It is built on a digital twin software-defined campus which is scalability and flexibility with wisdom in the cloud and application at the end as the core service concept. The overall system architecture and management platform module composition are introduced in which the software defined network (SDN) technology is used to separate the control plane and data plane and the four dimensions of people, things, affairs and space are digitalization in the smart Park. One application carries a variety of park services such as production, official business handling, property administration and so on to realize the effective application of the underlying network facilities. The project of high-tech information intelligent park of the Chinese Sixth Design and Research Institute of Machinery Industry Company Limited has been implemented. As an engineering case the platform system can provide personalized design for the park and carry out multi-professional and multi-terminal integrated management, application and display so as to improve the intelligent management level and the service experience to create greater economic and social value.

IntroductionNeuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects.MethodsWe performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail.ResultsOur results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases.DiscussionThis work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.

Over the past two decades, biodegradable metals (BMs) have emerged as promising materials to fabricate temporary biomedical devices, with the purpose of avoiding potential side effects of permanent implants. In this review, we first surveyed the current status of BMs in neuroscience, and briefly summarized the representative stents for treating vascular stenosis. Then, inspired by the convincing clinical evidence on the in vivo safety of Mg alloys as cardiovascular stents, we analyzed the possibility of producing biodegradable cerebrovascular Mg alloy stents for treating ischemic stroke. For these novel applications, some key factors should also be considered in designing BM brain stents, including the anatomic features of the cerebral vasculature, hemodynamic influences, neuro-cytocompatibility and selection of alloying elements. This work may provide insights into the future design and fabrication of BM neurological devices, especially for brain stents.

Abstract Background Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. Methods This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6–8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. Discussion To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. Trial registration Name of the registry: ClinicalTrials.gov. Trial registration number: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1 .

Abstract Background Oxidative stress mediated by hyperglycemia damages cell-reparative processes such as mitophagy. Down-regulation of mitophagy is considered to be a susceptible factor for diabetes mellitus (DM) and its complications. However, the role of mitophagy in DM-associated periodontitis has not been fully elucidated. Apoptosis of human gingival epithelial cells (hGECs) is one of the representative events of DM-associated periodontitis. Thus, this study aimed to investigate PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy activated in the process of high glucose (HG)-induced hGECs apoptosis. Methods For dose–response studies, hGECs were incubated in different concentrations of glucose (5.5, 15, 25, and 50 mmol/L) for 48 h. Then, hGECs were challenged with 25 mmol/L glucose for 12 h and 48 h, respectively. Apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL), caspase 9 and mitochondrial membrane potential (MMP). Subsequently, autophagy was evaluated by estimating P62, LC3 II mRNA levels, LC3 fluorescent puncta and LC3-II/I ratio. Meanwhile, the involvement of PINK1-mediated mitophagy was assessed by qRT-PCR, western blotting and immunofluorescence. Finally, hGECs were transfected with shPINK1 and analyzed by MMP, caspase 9 and annexin V-FITC apoptosis. Results The number of TUNEL-positive cells and caspase 9 protein were significantly increased in cells challenged with HG (25 mmol/L) for 48 h (HG 48 h). MMP was impaired both at HG 12 h and HG 48 h, but the degree of depolarization was more serious at HG 48 h. The autophagy improved as the amount of LC3 II increased and p62 decreased in HG 12 h. During this process, HG 12 h treatment induced PINK1-mediated mitophagy. PINK1 silencing with HG 12 h resulted in MMP depolarization and cell apoptosis. Conclusions These results suggested that loss of the PINK1 gene may cause mitochondrial dysfunction and increase sensitivity to HG-induced apoptosis of hGECs at the early stage. PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.

The acquisition speed of two-photon fiberscopes is currently suboptimal. Here the authors report advances, including a high-speed scanner and down-sampling scheme as well as a two-stage deep learning (DL) algorithm, to allow high-speed, high-resolution imaging in freely moving mice.

As one of the hallmarks of cancer, metabolic reprogramming leads to cancer progression, and targeting glycolytic enzymes could be useful strategies for cancer therapy. By screening a small molecule library consisting of 1320 FDA-approved drugs, we found that penfluridol, an antipsychotic drug used to treat schizophrenia, could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma (ESCC). Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol. By using drug affinity responsive target stability (DARTS) technology and proteomics, we identified phosphofructokinase, liver type (PFKL), a key enzyme in glycolysis, as a direct target of penfluridol. Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells, illustrating that PFKL is essential for the bioactivity of penfluridol. High PFKL expression is correlated with advanced stages and poor survival of ESCC patients, and silencing of PFKL significantly suppressed tumor growth. Mechanistically, direct binding of penfluridol and PFKL inhibits glucose consumption, lactate and ATP production, leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner. Taken together, PFKL is a potential prognostic biomarker and therapeutic target in ESCC, and penfluridol may be a new therapeutic option for management of this lethal disease.

With the reliance on ocean resources, the nuclear power powers have set their sights on marine nuclear power plants to break through the bottleneck of energy supply for the development of ocean resources. In this paper, the computational fluid dynamics software ANSYS CFX 2021 is used to simulate the TOSQAN benchmark experiment. Three different turbulence models, the k−ε model, RNG k−ε model, and SST model, are selected to analyze the adaptability of the turbulence model. The simulation results are compared with the benchmark experimental results, and the selected numerical calculation model is used to analyze the influence of vapor on the pressure, temperature, hydrogen distribution, and hydrogen risk in the containment space when a hypothetical serious accident occurs in a marine nuclear power plant. The results show that the results simulated with the k−ε turbulence model are closer to the benchmark experimental results. Vapor has no obvious effect on the response speed of pressure balance at each position in the closed containment space, and the condensation of the vapor wall can effectively reduce the pressure peak in the closed containment space. The existence of vapor and the increase in vapor concentration will increase the temperature in the closed containment space. The condensation of vapor on the wall surface will cause the temperature in the containment space to have a peak value, which can effectively reduce the temperature in the containment space. Vapor will promote the mixing of gas in the containment space and make the hydrogen distribution tend to be uniform. The presence of vapor and the increase in vapor concentration can reduce the hydrogen risk in the containment space, but the condensation of vapor may increase the hydrogen risk in the containment space.

In the Multi-Axis Differential Absorption Spectroscopy (MAX-DOAS) trace gas and aerosol profile inversion algorithm, the vertical resolution and the observation information obtained through a series of continuous observations with multiple elevation angles (EAs) can affect the accuracy of an aerosol profile, thus further affecting the results of the gas profile. Therefore, this study examined the effect of the vertical resolution of an aerosol profile and EAs on the NO2 profile retrieval by combining simulations and measurements. Aerosol profiles were retrieved from MAX-DOAS observations and co-observed using light detection and ranging (Lidar). Three aerosol profile shapes (Boltzmann, Gaussian, and exponential) with vertical resolutions of 100 and 200 m were used in the atmospheric radiative transfer model. Firstly, the effect of the vertical resolution of the input aerosol profile on the retrieved aerosol profile with a resolution of 200 m was studied. The retrieved aerosol profiles from the two vertical resolution aerosol profiles as input were similar. The aerosol profile retrieved from a 100 m resolution profile as input was slightly overestimated compared to the input value, whereas that from a 200 m resolution input was slightly underestimated. The relative deviation of the aerosol profile retrieved from the 100 m resolution as input was higher than that of the 200 m. MAX-DOAS observations in Hefei city on 4 September 2020 were selected to verify the simulation results. The aerosol profiles retrieved from the oxygen collision complex (O4) differential slant column density derived from MAX-DOAS observations and Lidar simulation were compared with the input Lidar aerosol profiles. The correlation between the retrieved and input aerosol profiles was high, with a correlation coefficient R > 0.99. The aerosol profiles retrieved from the Lidar profile at 100 and 200 m resolutions as input closely matched the Lidar aerosol profiles, consistent with the simulation result. However, aerosol profiles retrieved from MAX-DOAS measurements differed from the Lidar profiles due to the influence of the averaging kernel matrix smoothing, the different location and viewing geometry, and uncertainties associated with the Lidar profiles. Next, NO2 profiles of different vertical resolutions were used as input profiles to retrieve the NO2 profiles under a single aerosol profile scenario. The effect of the vertical resolution on the retrieval of NO2 profiles was found to be less significant compared to aerosol retrievals. Using the Lidar aerosol profile as the a priori aerosol information had little effect on NO2 profile retrieval. Additionally, the retrieved aerosol profiles and aerosol optical depths varied under different EAs. Ten EAs (i.e., 1, 2, 3, 4, 5, 6, 8, 15, 30, and 90°) were found to obtain more information from observations.