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Abstract Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.

BackgroundImpaired sensitivity to thyroid hormones (TH) was associated with metabolic syndrome. The study aimed to explore the association between central TH sensitivity indices and insulin resistance (IR) in euthyroid adults with obesity.MethodsThis cross-sectional study enrolled 293 euthyroid outpatients with obesity in Beijing Chao-Yang Hospital. We used the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotrophic T4 resistance index (TT4RI) to indicate central TH sensitivity. IR was assessed by homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin resistance index (hepatic-IR), the Matsuda index, and the adipose tissue insulin resistance index (Adipo-IR). Participants were categorized according to tertiles of TH sensitivity indices. We used multiple linear regressions to explore the associations.ResultsThere was a significant stepwise increase in HOMA-IR and Adipo-IR from the lowest to the highest tertiles of TH sensitivity indices (all P

Background Bleeding risk brought by intensive lipid‐lowering therapy and low low‐density lipoprotein cholesterol is concerning, while evidence regarding the relationship between remnant cholesterol and bleeding is frightening. This study aimed to investigate the association between remnant cholesterol at admission and an in‐hospital bleeding event after acute ischemic stroke or transient ischemic attack (TIA). Methods and Results A total of 3222 eligible patients admitted to Shanghai Huashan Hospital between 2015 and 2021 with complete lipid data were analyzed. Patients were classified into low (

In response to local sudden disasters, e.g., high-rise office or residential building fire disasters, road occupation can cause conflicts, and traffic directions may be opposite between evacuation vehicles and rescue vehicles; moreover, lane contraflow can be adopted to meet these surge traffic demands. However, lane contraflow that provides more roads for rescue vehicles reduces the traffic supply in the evacuation direction. It is unclear how to control the number of contraflow roads used by rescue vehicles to coordinate evacuation and rescue traffic operations. Here, we adjust the critical rescue traffic volume of reversing the normal road traffic direction to control rescue contraflow. Additionally, we propose a multiobjective mixed integer linear programming formulation for evacuation and rescue traffic optimization. Additionally, considering that the upper limit of the critical rescue traffic volume is unknown and that the proposed formulation includes multiple objectives and multi-priority vehicle classes, a three-stage solving algorithm is developed. Next, a large-scale evacuation and rescue traffic optimization result dataset is obtained for the Nguyen–Dupuis road network, and the impact of different rescue contraflow control plans on evacuation and rescue traffic is studied based on data-driven statistical analysis. The results show that by adjusting the optimal rescue traffic route, the critical rescue traffic volume for reversing the normal road traffic direction can reduce the interference of rescue traffic to evacuation traffic operation performance without reducing rescue traffic operation performance, and can be used to coordinate evacuation and rescue traffic operation under rescue contraflow.

Abstract Purpose This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus. Methods Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose). Results The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43). Conclusions CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.

Abstract Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. Conclusions DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Social memory is the ability to discriminate between familiar and unknown conspecifics. It is an important component of social cognition and is therefore essential for the establishment of social relationships. Although the neural circuit mechanisms underlying social memory encoding have been well investigated, little focus has been placed on the regulatory mechanisms of social memory processing. The dopaminergic system, originating from the midbrain ventral tegmental area (VTA), is a key modulator of cognitive function. This study aimed to illustrate its role in modulating social memory and explore the possible molecular mechanisms. Here, we show that the activation of VTA dopamine (DA) neurons is required for the formation, but not the retrieval, of social memory. Inhibition of VTA DA neurons before social interaction, but not 24 h after social interaction, significantly impaired social discrimination the following day. In addition, we showed that the activation of VTA DA neurons was regulated by the serine/threonine protein kinase liver kinase B1 (Lkb1). Deletion of Lkb1 in VTA DA neurons reduced the frequency of burst firing of dopaminergic neurons. Furthermore, Lkb1 plays an important role in regulating social behaviors. Both genetic and virus-mediated deletions of Lkb1 in the VTA of adult mice impaired social memory and subsequently attenuated social familiarization. Altogether, our results provide direct evidence linking social memory formation to the activation of VTA DA neurons in mice and illustrate the crucial role of Lkb1 in regulating VTA DA neuron function.

Abstract China contributed nearly one-fifth of the world maize production over the past few years. Mapping the distributions of maize cropland in China is crucial to ensure global food security. Nonetheless, 10 m maize cropland maps in China are still unavailable, restricting the promotion of sustainable agriculture. In this paper, we collect numerous samples to produce annual 10-m maize cropland maps in China from 2017 to 2021 with a machine learning based classification framework. To overcome the temporal variations of plants, the proposed framework takes Sentinel-2 sequence images as input and utilizes deep neural networks and random forest as classifiers to map maize in a zone-specific way. The generated maps have an overall accuracy (OA) spanning from 0.87 to 0.95 and the maize-cultivated areas estimated by the maps are highly consistent with the records in statistical yearbooks (R 2 varying from 0.83 to 0.95). To the best of our knowledge, this is the first annual 10-m maize maps across China, which largely facilitates the sustainable agriculture development in China dominated by smallholder farmlands.

Abstract Background The Mitogen-activated protein kinase 1 (MAPK1) has both independent functions of phosphorylating histones as a kinase and directly binding the promoter regions of genes to regulate gene expression as a transcription factor. Previous studies have identified elevated expression of MAPK1 in human gastric cancer, which is associated with its role as a kinase, facilitating the migration and invasion of gastric cancer cells. However, how MAPK1 binds to its target genes as a transcription factor and whether it modulates related gene expressions in gastric cancer remains unclear. Results Here, we integrated biochemical assays (protein interactions and chromatin immunoprecipitation (ChIP)), cellular analysis assays (cell proliferation and migration), RNA sequencing, ChIP sequencing, and clinical analysis to investigate the potential genomic recognition patterns of MAPK1 in a human gastric adenocarcinoma cell-line (AGS) and to uncover its regulatory effect on gastric cancer progression. We confirmed that MAPK1 promotes AGS cells invasion and migration by regulating the target genes in different directions, up-regulating seven target genes (KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, and TMEM267) and down-regulating one gene (FGG). Among them, five genes (FGG, MYH15, STARD4, SYTL4, and TMEM267) were first associated with cancer procession, while the other three (KRT81, KRT6A, and KRT13) have previously been confirmed to be related to cancer metastasis and migration. Conclusion Our data showed that MAPK1 can bind to the promoter regions of these target genes to control their transcription as a bidirectional transcription factor, promoting AGS cell motility and invasion. Our research has expanded the understanding of the regulatory roles of MAPK1, enriched our knowledge of transcription factors, and provided novel candidates for cancer therapeutics.

A superior cultivar of dried jujube in China is ‘Huizao’ (HZ) jujube. Nonetheless, detailed evaluations of the texture quality of HZ fruit have been the subject of few studies. Texture is a significant indicator of the sensory and processed quality of a fruit. Here, we differentiate and characterize the texture quality of HZ fruit from the four primary producing regions in southern Xinjiang, as well as develop a system for assessing the texture quality of HZ fruit. Correlation investigation indicated strong relationships between the springiness, chewiness, cohesiveness, gumminess, and hardness of HZ fruit. Furthermore, according to the factor molecules, the texture quality of HZ fruit in the four production areas was evaluated as Bazhou (1.24) > Hotan (0.773) > Kashi (−0.577) > Aksu (−0.852). RDA analysis of six texture quality parameters and 24 climate conditions identified higher mean temperature (TEM) and lower relative humidity (RHU) as the primary factors contributing to the improved texture quality of HZ fruit in Xinjiang. This study identified the variations in the texture of HZ fruit in the four primary producing regions of Southern Xinjiang. The HZ fruit in Hotan and Bazhou exhibit superior springiness and stickiness, while the fruit in Aksu and Kashi exhibit greater hardness. The texture of HZ fruit is significantly influenced by springiness, hardness, and adhesiveness, and a comprehensive evaluation model has been established through this research. This will provide a theoretical foundation for optimizing the dominant producing areas and regional production of HZ varieties in Xinjiang.

Abstract There is an urgent need for novel diagnostic and therapeutic strategies for patients with Glioblastoma multiforme (GBM). Previous studies have shown that BCL2 like 13 (BCL2L13) is a member of the BCL2 family regulating cell growth and apoptosis in different types of tumors. However, the clinical significance, biological role, and potential mechanism in GBM remain unexplored. In this study, we showed that BCL2L13 expression is significantly upregulated in GBM cell lines and clinical GBM tissue samples. Mechanistically, BCL2L13 targeted DNM1L at the Ser616 site, leading to mitochondrial fission and high mitophagy flux. Functionally, these alterations significantly promoted the proliferation and invasion of GBM cells both in vitro and in vivo. Overall, our findings demonstrated that BCL2L13 plays a significant role in promoting mitophagy via DNM1L-mediated mitochondrial fission in GBM. Therefore, the regulation and biological function of BCL2L13 render it a candidate molecular target for treating GBM.

Abstract Background Both elevated inflammation and atherogenic dyslipidemia are prominent in young-onset diabetes and are increasingly identified as biologically intertwined processes that contribute to diabetogenesis. We aimed to investigate the age-specific risks of type 2 diabetes (T2D) upon concomitant chronic inflammation and atherogenic dyslipidemia. Methods Age-stratified Cox regression analysis of the risk of incident diabetes upon co-exposure to time-averaged cumulative high-sensitivity C-reactive protein (CumCRP) and atherogenic index of plasma (CumAIP) among 42,925 nondiabetic participants from a real-world, prospective cohort (Kailuan Study). Results During a median 6.41 years of follow-up, 3987 T2D developed. Isolated CumAIP and CumCRP were significantly associated with incident T2D in the entire cohort and across all age subgroups. Both CumAIP and CumCRP were jointly associated with an increased risk of diabetes (P-interaction = 0.0126). Compared to CumAIP

Abstracts As the major maize-cultivated areas, the one-season cropland of China is increasingly threatened by rapid urbanization and soybean rejuvenation. Quantifying the area changes of maize cropland is crucial for both food and energy security. Nonetheless, due to the lack of survey data related to planting types, long-term and fine-grained maize cropland maps in China dominated by small-scale farmlands are still unavailable. In this paper, we collect 75,657 samples based on field surveys and propose a deep learning-based method according to the phenology information of maize. With the generalization capability, the proposed method produces maize cropland maps with a resolution of 30 m from 2013 to 2021 in the one-season planting areas of China. The maize-cultivated areas derived from the maps are highly consistent with the data recorded by statistical yearbooks (R 2 = 0.85 on average), which indicates that the produced maps are reliable to facilitate the research on food and energy security.

Biocontrol agents play a crucial role in agricultural production by reducing the use of pesticides and chemical fertilizers, controlling pests and diseases, and enhancing crop yield and quality. While extensive research has focused on the growth-promoting and yield-increasing effects of biocontrol agents on herbaceous plants, their impact on woody crops such as trees and shrubs has not been reported. This study investigates the effects of the actinomycete strain Act12, applied via root drenching and foliar spraying, on the flowering and fruit set rates, leaf physiology and enzyme activity, and fruit characteristics and yield of the jujube tree (Ziziphus jujuba Mill.). Additionally, this study analyzes the physicochemical properties of the soil and the diversity and community structure of its microorganisms. The results indicate that treatment with Act12 significantly altered the α and β diversity of soil microorganisms and enhanced the interaction networks among them. This led to increased levels of available nitrogen, phosphorus, and potassium in the soil, significantly improving nutrient availability. Consequently, there was an improvement in the number of flower buds and fruits, as well as an increase in the longitudinal diameter and individual fruit weight of the jujube. These effects significantly enhanced the yield and total sugar content of the winter jujube. Given these findings, Act12 can be considered an effective microbial agent for enhancing the yield and quality of winter jujube when applied to the soil.

Abstract Background Solute carrier family 25 member 32 (SLC25A32) is an important member of SLC25A family and plays a role in folate transport metabolism. However, the mechanism and function of SLC25A32 in the progression of human glioblastoma (GBM) remain unclear. Methods In this study, folate related gene analysis was performed to explore gene expression profiles in low-grade glioma (LGG) and GBM. Western blotting, real-time quantitative PCR (qRT-PCR), and immunohistochemistry (IHC) were used to confirm the expression levels of SLC25A32 in GBM tissues and cell lines. CCK-8 assays, colony formation assays, and Edu assays were performed to assess the role of SLC25A32 on proliferation in GBM in vitro. A 3D sphere invasion assay and an ex vivo co-culture invasion model were performed to assess the effects of SLC25A32 on invasion in GBM. Results Elevated expression of SLC25A32 was observed in GBM, and high SLC25A32 expression was associated with a high glioma grade and poorer prognosis. Immunohistochemistry performed with anti-SLC25A32 on samples from an independent cohort of patients confirmed these results. Knockdown of SLC25A32 inhibited the proliferation and invasion of GBM cells, but overexpression of SLC25A32 significantly promoted cell growth and invasion. These effects were mainly due to the activation of the PI3K-AKT-mTOR signaling pathway. Conclusion Our study demonstrated that SLC25A32 plays a significant role in promoting the malignant phenotype of GBM. Therefore, SLC25A32 can be used as an independent prognostic factor in patients with GBM, providing a new target for the comprehensive treatment of GBM.

Abstract The dentate gyrus (DG) of the hippocampus encodes contextual information associated with fear, and cell activity in the DG is required for acquisition and extinction of contextual fear. However, the underlying molecular mechanisms are not fully understood. Here we show that mice deficient for peroxisome proliferator-activated receptor-α (PPARα) exhibited a slower rate of contextual fear extinction. Furthermore, selective deletion of PPARα in the DG attenuated, while activation of PPARα in the DG by local infusion of aspirin facilitated extinction of contextual fear. The intrinsic excitability of DG granule neurons was reduced by PPARα deficiency but increased by activation of PPARα with aspirin. Using RNA-Seq transcriptome we found that the transcription level of neuropeptide S receptor 1 (Npsr1) was tightly correlated with PPARα activation. Our results provide evidence that PPARα plays an important role in regulating DG neuronal excitability and contextual fear extinction.

BackgroundThe bioinformatics analysis on glioma has been a hot point recently. The purpose of this study was to provide an overview of the research in this field using a bibliometric method.MethodsThe Web of Science Core Collection (WOSCC) database was used to search for literature related to the bioinformatics analysis of gliomas. Countries, institutions, authors, references, and keywords were analyzed using VOSviewer, CiteSpace, and Microsoft Excel software.ResultChina was the most productive country, while the USA was the most cited. Capital Medical University had the largest number of publications and citations. Institutions tend to collaborate more with other institutions in their countries rather than foreign ones. The most productive and most cited author was Jiang Tao. Two citation paths were identified, with literature in basic research journals often cited in clinical journals. Immune-related vocabularies appeared frequently in recent studies.ConclusionGlioma bioinformatics analyses spanned a wide range of fields. The international communication in this field urgently needs to be strengthened. Glioma bioinformatics approaches are developing from basic research to clinical applications. Recently, immune-related research has become a focus.

Abstract Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late‐stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour‐host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR‐146a‐5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR‐146a‐5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour‐promoting cytokines (IL‐6, IL‐8, MCP‐1 and CXCL1). Brain metastases were significantly reduced following miR‐146a‐5p knockdown. Corroborating these findings, miR‐146a‐5p inhibition led to a reduction of IL‐6, IL‐8, MCP‐1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR‐146a‐5p inhibitor, both in vitro and in vivo. Our results highlight the pro‐metastatic function of miR‐146a‐5p in EVs and identifies deserpidine for targeted adjuvant treatment.

Abstract Background Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. Methods GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. Results Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. Conclusions Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.

Abstract Background Concurrent atherogenic dyslipidemia and elevated inflammation are commonly observed in overt hyperglycemia and have long been proposed to contribute to diabetogenesis. However, the temporal relationship between them and the effect of their cumulative co-exposure on future incident type 2 diabetes (T2D) remains unclear. Methods Longitudinal analysis of data on 52,224 participants from a real-world, prospective cohort study (Kailuan Study) was performed to address the temporal relationship between high-sensitivity C-reactive protein (hsCRP) and the atherogenic index of plasma (AIP, calculated as triglyceride/high-density lipoprotein) in an approximately 4-year exposure period (2006/2007 to 2010/2011). After excluding 8824 participants with known diabetes, 43,360 nondiabetic participants were included for further analysis of the T2D outcome. Cox regression models were used to examine the adjusted hazard ratios (aHRs) upon the cumulative hsCRP (CumCRP) and AIP (CumAIP) in the exposure period. Results In temporal analysis, the adjusted standardized correlation coefficient (β1) of hsCRP_2006/2007 and AIP_2010/2011 was 0.0740 (95% CI, 0.0659 to 0.0820; P < 0.001), whereas the standardized correlation coefficient (β2) of AIP_2006/2007 and hsCRP_2010/2011 was − 0.0293 (95% CI, − 0.0385 to − 0.0201; P < 0.001), which was significantly less than β1 (P < 0.001). During a median follow-up of 7.9 years, 5,118 T2D cases occurred. Isolated exposure to CumAIP or CumCRP was dose-dependently associated with T2D risks, independent of traditional risk factors. Significant interactions were observed between the median CumAIP (− 0.0701) and CumCRP thresholds (1, 3 mg/L) (P = 0.0308). Compared to CumAIP < − 0.0701 and CumCRP < 1 mg/L, those in the same CumAIP stratum but with increasing CumCRP levels had an approximately 1.5-fold higher T2D risk; those in higher CumAIP stratum had significantly higher aHRs (95% CIs): 1.64 (1.45–1.86), 1.87 (1.68–2.09), and 2.04 (1.81–2.30), respectively, in the CumCRP < 1, 1 ≤ CumCRP < 3, CumCRP ≥ 3 mg/L strata. Additionally, the T2D risks in the co-exposure were more prominent in nonhypertensive, nondyslipidemic, nonprediabetic, or female participants. Conclusions These findings suggest a stronger association between elevated hsCRP and future AIP changes than vice versa and highlight the urgent need for combined assessment and management of chronic inflammation and atherogenic dyslipidemia in primary prevention, particularly for those with subclinical risks of T2D.

IntroductionSafranal is an active component of the traditional Tibetan medicine (TTM) saffron, which has potential anticancer activity.Methods and resultsHere, we studied the therapeutic effect and mechanism of safranal on GBM. CCK-8, GBM-brain organoid coculture experiments and 3D tumour spheroid invasion assays showed that safranal inhibited GBM cell proliferation and invasion in vitro. Network pharmacology, RNA-seq, molecular docking analysis, western blotting, apoptosis, and cell cycle assays predicted and verified that safranal could promote GBM cell apoptosis and G2/M phase arrest and inhibit the PI3K/AKT/mTOR axis. In vivo experiments showed that safranal could inhibit GBM cell growth alone and in combination with TMZ.ConclusionThis study revealed that safranal inhibits GBM cell growth in vivo and in vitro, promotes GBM cell apoptosis and G2/M phase arrest, inhibits the PI3K/AKT/mTOR axis and cooperate with TMZ.

ObjectiveA surgical simulation of an endoscope-dominated side-to-end hypoglossal-facial anastomosis was performed to evaluate the feasibility.MethodsEight anatomical cadaver heads (16 sides) were recruited. The steps in conventional procedures were abbreviated or omitted. A facial nerve was first harvested near its external genu and was used for a side-to-end hypoglossal-facial anastomosis. The stump of the used facial nerve was truncated and recycled immediately caudal to the facial recess in another anastomosis and then recycled again at the stylomastoid foramen. As a recycled stump becomes too short to ensure a side-to-end anastomosis, the hypoglossal nerve was transected in situ, and an endoscopic end-to-end hypoglossal-facial anastomosis was attempted. Surgical simulation and quantitative measurement methods were used to analyze the anastomosis effects of different harvested sites of the facial nerve.ResultsSeveral steps in the conventional procedures provide little benefit in endoscopic surgery. A facial nerve stump recycled at the stylomastoid foramen is too short to ensure a tensionless side-to-end anastomosis. An endoscopic end-to-end hypoglossal-facial anastomosis was feasible, although it required more time than the classical microsurgical anastomosis. The greater agility of an endoscope enables the conventional surgical steps to be overlapped or interweaved into the procedure.ConclusionsThe multiple surgical fields and ability to manipulate the viewpoint provided by an endoscope have brought about breakthroughs in classical surgical paradigms. In addition, it is best to choose the sites of the facial nerve harvested near the external genu. If unavailable, an alternative section site could be selected immediately caudal to the facial recess, but cannot be distal to the stylomastoid foramen. The length of the stump should be individualized and preferably optimized with a nerve stimulator.

Abstract Background Metabolic syndrome (MetS) has been proposed as a clinically identifiable high-risk state for the prediction and prevention of cardiovascular diseases and type 2 diabetes mellitus. As a promising “omics” technology, metabolomics provides an innovative strategy to gain a deeper understanding of the pathophysiology of MetS. The study aimed to systematically investigate the metabolic alterations in MetS and identify biomarker panels for the identification of MetS using machine learning methods. Methods Nuclear magnetic resonance-based untargeted metabolomics analysis was performed on 1011 plasma samples (205 MetS patients and 806 healthy controls). Univariate and multivariate analyses were applied to identify metabolic biomarkers for MetS. Metabolic pathway enrichment analysis was performed to reveal the disturbed metabolic pathways related to MetS. Four machine learning algorithms, including support vector machine (SVM), random forest (RF), k-nearest neighbor (KNN), and logistic regression were used to build diagnostic models for MetS. Results Thirteen significantly differential metabolites were identified and pathway enrichment revealed that arginine, proline, and glutathione metabolism are disturbed metabolic pathways related to MetS. The protein-metabolite-disease interaction network identified 38 proteins and 23 diseases are associated with 10 MetS-related metabolites. The areas under the receiver operating characteristic curve of the SVM, RF, KNN, and logistic regression models based on metabolic biomarkers were 0.887, 0.993, 0.914, and 0.755, respectively. Conclusions The plasma metabolome provides a promising resource of biomarkers for the predictive diagnosis and targeted prevention of MetS. Alterations in amino acid metabolism play significant roles in the pathophysiology of MetS. The biomarker panels and metabolic pathways could be used as preventive targets in dealing with cardiometabolic diseases related to MetS.

Abstract Background The tripartite motif (TRIM) family of proteins plays a key role in the developmental growth and therapeutic resistance of many tumors. However, the regulatory mechanisms and biological functions of TRIM proteins in human glioblastoma (GBM) are not yet fully understood. In this study, we focused on TRIM56, which emerged as the most differentially expressed TRIM family member with increased expression in GBM. Methods Western blot, real-time quantitative PCR (qRT-PCR), immunofluorescence (IF) and immunohistochemistry (IHC) were used to study the expression levels of TRIM56 and cIAP1 in GBM cell lines. Co-immunoprecipitation (co-IP) was used to explore the specific binding between target proteins and TRIM56. A xenograft animal model was used to verify the tumor promoting effect of TRIM56 on glioma in vivo. Results We observed elevated expression of TRIM56 in malignant gliomas and revealed that TRIM56 promoted glioma progression in vitro and in a GBM xenograft model in nude mice. Analysis of the Human Ubiquitin Array and co-IPs showed that cIAP1 is a protein downstream of TRIM56. TRIM56 deubiquitinated cIAP1, mainly through the zinc finger domain (amino acids 21–205) of TRIM56, thereby reducing the degradation of cIAP1 and thus increasing its expression. TRIM56 also showed prognostic significance in overall survival of glioma patients. Conclusions TRIM56-regulated post-translational modifications may contribute to glioma development through stabilization of cIAP1. Furthermore, TRIM56 may serve as a novel prognostic indicator and therapeutic molecular target for GBM.

Abstract Background Plant-specific BURP domain-containing genes are involved in plant development and stress responses. However, the role of BURP family in jujube (Ziziphus jujuba Mill.) has not been investigated. Results In this study, 17 BURP genes belonging to four subfamilies were identified in jujube based on homology analysis, gene structures, and conserved motif confirmation. Gene duplication analysis indicated both tandem duplication and segmental duplication had contributed to ZjBURP expansion. The ZjBURPs were extensively expressed in flowers, young fruits, and jujube leaves. Transcriptomic data and qRT-PCR analysis further revealed that ZjBURPs also significantly influence fruit development, and most genes could be induced by low temperature, salinity, and drought stresses. Notably, several BURP genes significantly altered expression in response to low temperature (ZjPG1) and drought stresses (ZjBNM7, ZjBNM8, and ZjBNM9). Conclusions These results provided insights into the possible roles of ZjBURPs in jujube development and stress response. These findings would help selecting candidate ZjBURP genes for cold- and drought-tolerant jujube breeding.

Abstract Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.

This paper focuses on the bus evacuation problem with pedestrians’ short-distance walking ability between bus stations during no-notice disasters in downtown areas. A mixed-integer linear programming model is proposed to solve this problem. The objective function is to minimize the evacuation time and number of casualties. The model obtains the flow of evacuees and buses on each arc to the route of buses in the process of evacuation. Furthermore, a real-time bus evacuation demand estimation method is proposed based on smart card data. Finally, the example of Zhongguancun area in Beijing is used to verify the practicality and validity of the model. The results show that pedestrian short-distance walking can effectively reduce casualties and improve the utilization rate of buses.

Abstract The development trend of Fischer–Tropsch (F–T) technology is to develop high value-added products. The separation of linear α-olefins with low cost is an effective method. Nevertheless, the lack of thermodynamic data and the huge energy consumption are the two main problems restricting the development of the separation process. The thermodynamic data of the key components (1-dodecene and n-dodecane) in the F–T product were measured. The Wilson binary interaction parameters of the key components were obtained. Next, one traditional distillation column sequence and two dividing wall column (DWC) sequences were designed to separate the F–T heavy oil to obtain narrow fractions with different carbon numbers. Then, the obtained fractions of C10 and C12 were simulated to obtain 1-decene and 1-dodecene, respectively. There was a traditional distillation and a differential pressure thermal coupling distillation process. When separating 95.0% purity 1-decene and 1-octene, the direct DWC process and differential pressure thermal coupled distillation are an excellent combination, which can reduce the energy by 33.1% (i.e., 11,286 kW) and total annual cost by 15.9% (i.e., 3.96 × 106 $) compared with traditional distillation.

Jujube fruit is rich in linoleic acid and other bioactive components and has great potential to be used for the development of functional foods. However, the roles of FAD2 genes in linoleic acid biosynthesis in jujube fruit remain unclear. Here, we identified 15 major components in jujube and found that linoleic acid was the main unsaturated fatty acid; major differences in the content and distribution of linoleic acid in the pulp and seeds were observed, and levels of linoleic acid decreased during fruit maturation. Analysis of the fatty acid metabolome, genome, and gene expression patterns of cultivated and wild-type jujube revealed five ZjFAD2 family members highly related to linoleic acid biosynthesis. The heterologous expression of these five ZjFAD2 family members in tobacco revealed that all five of these genes increased the content of linoleic acid. Additionally, transient expression of these genes in jujube fruit and the virus-induced gene silencing (VIGS) test further confirmed the key roles of ZjFAD2-11 and ZjFAD2-1 in the biosynthesis of linoleic acid. The results of this research provide valuable insights into the molecular mechanism underlying linoleic acid synthesis in jujube and will aid the development of quality-oriented breeding strategies.

Abstract Ethylene response factor (ERF) transcription factors constitute a subfamily of the AP2/ERF superfamily in plants and play multiple roles in plant growth and development as well as in stress responses. In this study, the GsERF1 gene from the wild soybean BW69 line (an Al-resistant Glycine soja line) was rapidly induced in response to aluminum stress. Quantitative real-time PCR (qRT–PCR) analysis showed that the GsERF1 gene maintained a constitutive expression pattern and was induced in soybean in response to aluminum stress, with increased amounts of transcripts detected in the roots. The putative GsERF1 protein, which contains an AP2 domain, was located in the nucleus and maintained transactivation activity. In addition, under AlCl3 treatment, GsERF1 overexpression increased the relative growth rate of the roots of Arabidopsis and weakened the hematoxylin staining of hairy roots. Ethylene synthesis-related genes such as ACS4, ACS5 and ACS6 were upregulated in GsERF1 transgenic lines compared with the wild type under AlCl3 treatment. Furthermore, the expression levels of stress/ABA-responsive marker genes, including ABI1, ABI2, ABI4, ABI5 and RD29B, in the GsERF1 transgenic lines were affected by AlCl3 treatment, unlike those in the wild type. Taken together, the results indicated that overexpression of GsERF1 may enhance aluminum tolerance of Arabidopsis through an ethylene-mediated pathway and/or ABA signaling pathway, the findings of which lay a foundation for breeding soybean plants tolerant to aluminum stress.

Data-driven generative design (DDGD) methods utilize deep neural networks to create novel designs based on existing data. The structure-aware DDGD method can handle complex geometries and automate the assembly of separate components into systems, showing promise in facilitating creative designs. However, determining the appropriate vectorized design representation (VDR) to evaluate 3D shapes generated from the structure-aware DDGD model remains largely unexplored. To that end, we conducted a comparative analysis of surrogate models’ performance in predicting the engineering performance of 3D shapes using VDRs from two sources: the trained latent space of structure-aware DDGD models encoding structural and geometric information and an embedding method encoding only geometric information. We conducted two case studies: one involving 3D car models focusing on drag coefficients and the other involving 3D aircraft models considering both drag and lift coefficients. Our results demonstrate that using latent vectors as VDRs can significantly deteriorate surrogate models’ predictions. Moreover, increasing the dimensionality of the VDRs in the embedding method may not necessarily improve the prediction, especially when the VDRs contain more information irrelevant to the engineering performance. Therefore, when selecting VDRs for surrogate modeling, the latent vectors obtained from training structure-aware DDGD models must be used with caution, although they are more accessible once training is complete. The underlying physics associated with the engineering performance should be paid attention. This paper provides empirical evidence for the effectiveness of different types of VDRs of structure-aware DDGD for surrogate modeling, thus facilitating the construction of better surrogate models for AI-generated designs.

In the heavy petroleum industry, the development of efficient demulsifiers for the effective breaking of interfacially active asphaltenes (IAA)-stabilized water-in-heavy oil (W/HO) emulsions is a highly attractive but challenging goal. Herein, a novel nitrogen and oxygen containing demulsifier (JXGZ) with strong hydrogen bonding has been successfully synthesized through combining esterification, polymerization and amidation. Bottle tests indicated that JXGZ is effectual in quickly demulsifying the IAA-stabilized W/HO emulsions; complete dehydration (100%) to the emulsions could be achieved in 4 min at 55 °C using 400 ppm of JXGZ. In addition, the effects of demulsifier concentration, temperature and time on the demulsification performance of JXGZ are systematically analyzed. Demulsification mechanisms reveal that the excellent demulsification performance of JXGZ is attributed to the strong hydrogen bonding between JXGZ and water molecules (dual swords synergistic effect under hydrogen bond reconstruction). The interaction of the “dual swords synergistic effect” generated by two types of hydrogen bonds can quickly break the non-covalent interaction force (π-π stacking, Van der Waals force, hydrogen bonds) of IAA at the heavy oil–water interface, quickly promote the aggregation and coalescence of water molecules and finally achieve the demulsification of W/HO emulsions. These findings indicate that the JXGZ demulsifier shows engineering application prospects in the demulsification of heavy oil–water emulsions, and this work provides the key information for developing more efficient chemical demulsifiers suitable for large-scale industrial applications.

Vanadium dioxide (VO2) thin films of different thicknesses were prepared by regulating the deposition time (2, 2.5, 3, and 3.5 h). The impact of deposition time on the microstructure, surface morphology, and cross-section morphology was investigated. The results showed that the grain size increased with the film thickness. Meanwhile, the influence of film thickness on the residual stress was evaluated by X-ray diffraction. The phenomenon of “compressive-to-tensile stress transition” was illustrated as the thickness increased. The change of dominant mechanism for residual stress was used for explaining this situation. First, the composition of residual stress indicates that growth stress play a key role. Then, the effect of “atomic shot peening” can be used to explain the compressive stress. Lastly, the increased grain size, lower grain boundary density, and “tight effect” in the progress of film growth cause tensile stress.

ObjectiveChronic internal carotid artery occlusion (CICAO) can cause transient ischemic attack (TIA) and ischemic stroke. Carotid artery stenting (CAS) with embolic protection devices and hybrid surgery combining carotid endarterectomy and endovascular treatment are effective methods for carotid revascularization. The objective of this study was to evaluate and compare the effect and safety of the two surgical procedures.MethodsThis was a single-center retrospective study. In this study, 44 patients who underwent hybrid surgery and 35 who underwent endovascular intervention (EI) at our center were enrolled consecutively between May 2016 and March 2022. All patients were classified into four groups (A-D), as described by Hasan et al. We recorded and analyzed clinical data, angiographic characteristics, technical success rate, perioperative complications, and follow-up data.ResultsThere was no significant difference in baseline characteristics between hybrid surgery group and EI group, except for plasma high density lipoproteins (HDL) levels (median [interquartile range]: hybrid surgery, 0.99 [0.88–1.18] vs. EI, 0.85 [0.78–0.98] mmol/L, P = 0.001). The technical success rate of hybrid surgery was higher than that of EI (37/44 [84.1%] vs. 18/35 [51.4%], P = 0.002; type A: 15/16 [93.8%] vs. 10/11 [90.9%], P = 1.000; type B: 9/10 [90.0%] vs. 5/7 [71.4%], P = 0.537; type C: 12/15 [80.0%] vs. 3/12 [25.0%], P = 0.004; type D: 1/3 [33.3%] vs. 0/5 [0%], P = 0.375). No significant difference was observed in the incidence of perioperative complications between the two procedures (hybrid surgery: 7/44 [15.9%] vs. EI: 6/35 [17.1%], P = 0.883). In addition, there were no significant differences in the rates of stroke and restenosis during follow-up.ConclusionsFor patients with symptomatic CICAO, hybrid surgery may have an advantage over EI in successfully recanalizing occluded segments. There was no significant difference in safety and restenosis between hybrid surgery and EI.

Neural tissue is an important soft tissue; for instance, craniofacial nerves govern several aspects of human behavior, including the expression of speech, emotion transmission, sensation, and motor function. Therefore, nerve repair to promote functional recovery after craniofacial soft tissue injuries is indispensable. However, the repair and regeneration of craniofacial nerves are challenging due to their intricate anatomical and physiological characteristics. Currently, nerve transplantation is an irreplaceable treatment for segmental nerve defects. With the development of emerging technologies, transplantation donors have become more diverse. The present article reviews the traditional and emerging alternative materials aimed at advancing cutting-edge research on craniofacial nerve repair and facilitating the transition from the laboratory to the clinic. It also provides a reference for donor selection for nerve repair after clinical craniofacial soft tissue injuries. We found that autografts are still widely accepted as the first options for segmental nerve defects. However, allogeneic composite functional units have a strong advantage for nerve transplantation for nerve defects accompanied by several tissue damages or loss. As an alternative to autografts, decellularized tissue has attracted increasing attention because of its low immunogenicity. Nerve conduits have been developed from traditional autologous tissue to composite conduits based on various synthetic materials, with developments in tissue engineering technology. Nerve conduits have great potential to replace traditional donors because their structures are more consistent with the physiological microenvironment and show self-regulation performance with improvements in 3D technology. New materials, such as hydrogels and nanomaterials, have attracted increasing attention in the biomedical field. Their biocompatibility and stimuli-responsiveness have been gradually explored by researchers in the regeneration and regulation of neural networks.

Rigorous molecular analysis of the immune cell environment and immune response of human tumors has led to immune checkpoint inhibitors as one of the most promising strategies for the treatment of human cancer. However, in human glioblastoma multiforme (GBM) which develops in part by attracting immune cell types intrinsic to the human brain (microglia), standard immunotherapy has yielded inconsistent results in experimental models and patients. Here, we analyzed publicly available expression datasets to identify molecules possibly associated with immune response originating from or influencing the tumor microenvironment in primary tumor samples. Using three glioma datasets (GSE16011, Rembrandt-glioma and TCGA-glioma), we first analyzed the data to distinguish between GBMs of high and low tumor cell purity, a reflection of the cellular composition of the tumor microenvironment, and second, to identify differentially expressed genes (DEGs) between these two groups using GSEA and other analyses. Tumor purity was negatively correlated with patient prognosis. The interferon gamma-related gene BST2 emerged as a DEG that was highly expressed in GBM and negatively correlated with tumor purity. BST2high tumors also tended to harbor PTEN mutations (31 vs. 9%, BST2high versus BST2low) while BST2low tumors more often had sustained TP53 mutations (8 versus 36%, BST2high versus BST2low). Prognosis of patients with BST2high tumors was also poor relative to patients with BST2low tumors. Further molecular in silico analysis demonstrated that high expression of BST2 was negatively correlated with CD8+ T cells but positively correlated with macrophages with an M2 phenotype. Further functional analysis demonstrated that BST2 was associated with multiple immune checkpoints and cytokines, and may promote tumorigenesis and progression through interferon gamma, IL6/JAK/STAT3 signaling, IL2/STAT5 signaling and the TNF-α signaling via NF-kB pathway. Finally, a series of experiments confirmed that the expression of BST2 can be significantly increased by IFN induction, and knockdown of BST2 can significantly inhibit the growth and invasion of GBM cells, and may affect the phenotype of tumor-associated macrophages. In conclusion, BST2 may promote the progression of GBM and may be a target for treatment.

Atherosclerosis is a chronic inflammatory disease closely associated with immunological activity. Lymph nodes (LNs) are essential secondary lymphoid organs, in which complex immune responses occur. Enlarged LNs are commonly observed around inflamed tissues or tumors; however, their role in atherosclerosis is not well understood. We hypothesized that enlarged pericarotid LNs would be present in symptomatic patients with carotid atherosclerosis. Therefore, we recorded the size of LNs around the carotid artery during surgery in patients undergoing carotid endarterectomy (CEA) for carotid atherosclerotic stenosis. Patients were stratified by enlarged LNs, defined as a diameter ≥ 10mm in the transverse diameters. Demographic and clinical data of participants were measured and analyzed. Hematoxylin and eosin (H&E), Sirius red, DAB-enhanced Perls’ Prussian blue, alizarin red, and immunohistochemistry (IHC) staining were performed for composition identification of plaques or LNs. Symptomatic patients were defined as those presenting with an ipsilateral cerebral ischemic event. Compared with patients with non-enlarged LNs, patients with enlarged LNs were more likely to be symptomatic (22/32, 68.8% versus 9/40, 22.5%, P < 0.001) and use calcium channel blocker drugs (17/32, 53.1% versus 10/40, 25%, P=0.014). In addition, they showed lower body mass index (mean ± SD: 24.00 ± 2.66 versus 25.34 ± 2.56 kg/m2, P=0.034), lower weight (median [interquartile range]: 64 [60.00-76.00] versus 72.5 [65.00-77.50] Kg, P = 0.046) and higher diastolic blood pressure (mean ± SD: 78.94 ± 9.30 versus 73.93 ± 8.84 mmHg, P = 0.022). The plague from patients with enlarged LNs exhibited a lower relative percentage of fibrous tissue (29.49 ± 10.73% versus 34.62 ± 10.33%, P = 0.041). The enlarged LNs remained oval-shaped by visual inspection. Compared to non-enlarged LNs, the predominant changes in enlarged LNs were atrophic lymphatic sinuses and dilated LNs parenchyma. Enlarged LNs contained more germinal centers and lymphocytes. In conclusion, symptomatic patients with carotid atherosclerosis have enlarged pericarotid LNs. The current study supports the conclusion that enlarged LNs with an activated and enhanced adaptive immune response may indicate plaque instability. Pericarotid LNs will be a promising marker of plaque stability and may be a potential therapeutic target in patients with carotid atherosclerosis.

Ionic liquids (ILs) have shown excellent performance in the separation of binary azeotropes through extractive distillation [1]. But the role of the ionic liquid in azeotropic system is not well understood. In this paper, COSMO-RS model was applied to screen an appropriate IL to separate the binary azeotrope of ethyl acetate (EA) and ethanol and 1-octyl-3-methylimidazolium tetrafluoroborate ([OMIM][BF4]) was selected. The Quantum Mechanics (QM) calculations and molecular dynamics (MD) simulation are performed to study the interactions between the solvent molecules and [OMIM][BF4], in order to investigate the separation mechanism at the molecular level. The nature of the interactions is studied through the reduced density gradient (RDG) function and quantum theory of Atom in Molecule (QTAIM). Hydrogen bonds and van der Waals interactions are the key interactions in the complexes. The results of MD simulations indicate that the introduction of ILs has a prominent effect on the interaction between the solvent molecules, especially on reducing the number of hydrogen bonds among the solvent molecules. The radial distribution function (RDF) reveals that the interaction between the cation and solvent molecules will increase while the concentration of ILs increases. This paper provides important information for understanding the role of ILs in the separation of the azeotropic system, which is valuable to the development of new entrainers.

Accurate yield estimation at the regional scale has always been a persistent challenge in the agricultural sector. With the vigorous emergence of remote sensing land surface observations in recent decades, data assimilation methodology has become an effective means to promote the accuracy and efficiency of yield estimation by integrating regional data and point-scale crop models. This paper focuses on the black soil area of Northeast China, a national strategic grain production base, applying the AquaCrop crop growth model to simulate the fractional vegetation cover (FVC) and maize yield from 2000 to 2020 and then forming a reliable FVC optimization dataset based on an ensemble Kalman filter (EnKF) assimilation algorithm with remote sensing products. Using the random forest model, the regression relationship between FVC and yield was established from the long-term time series data, which is crucial to achieve better yield estimation through the optimized FVC. The major findings include the following: (1) The R2 of the assimilated FVC and maize yield can reach 0.557. (2) When compared with the local statistical yield, our method reduced the mean absolute error (MAE) from 1.164 ton/ha (based on GLASS FVC products) to 1.004 ton/ha (based on the calibrated AquaCrop model) and then to 0.888 ton/ha (the result after assimilation). The above results show that we have proposed a yield estimation method to provide accurate yield estimations by combining data assimilation and machine learning. This study provided deep insights into understanding the variations in FVC and revealed the spatially explicit yield prediction ability from the time series land surface parameters, which has significant potential for optimizing water and soil resource management.

Diabetic kidney disease (DKD) is an important complication of diabetes. The prevention of DKD can effectively reduce the mortality rate of diabetic patients and improve their quality of life. The present study examined the effects of fermented and germinated foxtail millet whole grain (FG-FM) on kidney lesions in a diabetic mouse model (Db/Db mice). The results proved that the FG-FM consumption significantly alleviated the kidney tissue damage in the diabetic mouse model. The transcriptome analysis of kidney tissues demonstrated that the overactivation of signaling pathways related to inflammation and immunity in the diabetic mouse model was significantly inhibited with the FG-FM intake. Moreover, the consumption of the FG-FM diet effectively elevated the bacterial diversity, increased the relative abundance of probiotics and decreased the relative abundance of previously reported DKD-related bacteria in the gut microbiota of diabetic mice. Our study confirmed foxtail millet as a potential source of functional food for the non-pharmacological intervention of DKD.

Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172. Subsequently, we demonstrated that RB-induced G2/M phase arrest occurred through downregulation of CDC25C and upregulation of p21, which was caused by activation of the MAPK/ERK pathway, and that RB inhibited GBM invasion by elevating intercellular Ca2+ to suppress the Src/FAK/Paxillin focal adhesion pathway. Intriguingly, we confirmed that upon RB binding to ATP1A1, Na+-K+-ATPase was activated as a receptor and then triggered the intracellular MAPK/ERK pathway and Ca2+-mediated Src/FAK/Paxillin focal adhesion pathway, which led to G2/M phase arrest and inhibited the invasion of GBM cells. Taken together, our findings reveal the antitumor mechanism of RB by targeting the ATP1A1 signaling cascade and two key signaling pathways and highlight the potential of RB as a new class of promising anticancer agents.

Jujube is rich in nutrients and can be eaten fresh or made into dried fruit, candied fruit, and preserved fruit. Its slightly bitter peel affects nutritional value and commercial value, but the mechanism of the formation of bitter substances is still unclear. We dynamically analyzed the biosynthesis of jujube peel bitterness and related nutrient metabolites through the transcriptome and metabolome. The results demonstrated that flavonoids were the main bitter substances in ‘Junzao’ jujube fruit skins and a total of 11,106 differentially expressed genes and 94 differentially abundant flavonoid metabolites were identified. Expression patterns of genes in the flavonoid synthesis pathway showed that flavonol synthase (FLS) expression was significantly correlated with quercetin content. Transient overexpression and virus induced gene silencing (VIGS) of ZjFLS1 and ZjFLS2 in jujube fruits and sour jujube seedlings significantly affected flavonol accumulation, especially the content of quercetin-3-O-rutinoside. Moreover, in vitro enzymatic reactions showed that ZjFLS1 and ZjFLS2 could catalyze the formation of quercetin from dihydroquercetin. These findings indicate that ZjFLS gene is the key gene in the biosynthesis of bitter substances in jujube fruit skins and provide basis for the research on the development of functional nutrients in jujube and the synthesis mechanism of bitter compounds.

Chromium is considered one of the most severe toxic elements affecting agriculture. Soybean seedlings under chromium stress were treated with glutathione and buthionine sulfoximine. The effects of exogenous glutathione on the physiological effects of two different chromium-resistant soybean seedlings and the expression levels of expression levels related genes were studied. This study tested the seedling weight and SPAD values, detected enzymatic antioxidants (i.e., superoxide dismutase, peroxidase, catalase, catalase, ascorbate peroxidase), and non-enzymatic antioxidants (i.e., glutathione, proline, soluble sugars, and soluble phenols) that attenuate chromium-induced reactive oxygen species, and quantified several genes associated with glutathione-mediated chromium stress. The results showed that exogenous glutathione could improve the physiological adaptability of soybean seedlings by regulating photosynthesis, antioxidant, and related enzyme activities, osmotic system, the compartmentalization of ion chelation, and regulating the transcription level of related genes, thereby increasing the chromium accumulation of soybean seedlings, enhancing the tolerance of chromium stress, and reducing the toxicity of chromium. Overall, the application of glutathione alleviates chromium toxicity in soybeans, and this strategy may be a potential farming option for soybean bioremediation in chromium-contaminated soils.

The COVID-19 pandemic caused by SARS-CoV-2 infection has placed health systems under excessive pressure and especially elderly people with cancer. Glioblastoma multiforme (GBM) is a malignant brain tumor with an increasing incidence in elderly individuals, and thereby GBM patients are a vulnerable population during the COVID-19 outbreak. Accumulating studies have implied that SARS-CoV-2 might invade the brain directly via coronavirus receptors. However, little is known about SARS-CoV-2 infection in the clinical development of GBM. Here, we explored the oncogenic roles of six coronavirus receptors (ACE2, DPP4, ANPEP, AXL, TMPRSS2, and ENPEP) in GBM using bioinformatics and experimental approaches. We found that ANPEP and ENPEP were significantly increased at both the mRNA and protein levels in GBM compared with normal brain tissue. Kaplan–Meier survival curves and Cox regression analysis demonstrated that high expressions of ANPEP and ENPEP are associated with poor prognosis and survival. Moreover, all receptors are positively correlated with the immune infiltration levels of monocyte. Furthermore, we identified 245 genes between COVID-19 and coronavirus receptors–correlated genes in GBM and performed a thorough analysis of their protein–protein interaction network, functional signaling pathway and molecular process. Our work explores for the first time the association of coronavirus receptors with GBM and suggests ANPEP and ENPEP as potential therapeutic targets of GBM irrespective of COVID-19.

Salt stress has a detrimental impact on crop yield, quality, and profitability. The tau-like glutathione transferases (GSTs) represent a significant group of enzymes that play a crucial role in plant stress responses, including salt stress. In this study, we identified a tau-like glutathione transferase family gene from soybean named GmGSTU23. Expression pattern analysis revealed that GmGSTU23 was predominantly expressed in the roots and flowers and exhibited a concentration–time-specific pattern in response to salt stress. Transgenic lines were generated and subjected to phenotypic characterization under salt stress. The transgenic lines exhibited increased salt tolerance, root length, and fresh weight compared to the wild type. Antioxidant enzyme activity and malondialdehyde content were subsequently measured, and the data revealed no significant differences between the transgenic and wild-type plants in the absence of salt stress. However, under salt stress, the wild-type plants exhibited significantly lower activities of SOD, POD, and CAT than the three transgenic lines, whereas the activity of APX and the content of MDA showed the opposite trend. We identified changes in glutathione pools and associated enzyme activity to gain insights into the underlying mechanisms of the observed phenotypic differences. Notably, under salt stress, the transgenic Arabidopsis’s GST activity, GR activity, and GSH content were significantly higher than those of the wild type. In summary, our findings suggest that GmGSTU23 mediates the scavenging of reactive oxygen species and glutathione by enhancing the activity of glutathione transferase, thereby conferring enhanced tolerance to salt stress in plants.

The present work reported the intrinsic mechanical behavior of vanadium dioxide (VO2) thin film deposited on a SiO2 substrate using a combination of nanoindentation tests and a theoretical model. The effect of phase transition on mechanical parameters was studied by adjusting the test temperature. A new model that can simultaneously extract the elastic modulus and hardness was derived by introducing a dimensional analysis. The results showed that the thin film exhibits a hardness of 9.43 GPa and a Young’s modulus of about 138.5 GPa at room temperature, compared with the values of 5.71 GPa and 126.9 GPa at a high temperature, respectively. It can be seen that the intrinsic mechanical parameters decrease to a certain extent after a phase transition. Finally, the numerical simulation results were consistent with those of the experiments, which verified the effectiveness of the new method. In addition, this study also provided useful guidance for mechanical tests on other ultra-thin films.

Triterpenoids are important, pharmacologically active substances in jujube (Ziziphus jujuba Mill.), and play an important role in the plant’s resistance to abiotic stress. However, regulation of their biosynthesis, and the underlying mechanism of their balance with stress resistance, remain poorly understood. In this study, we screened and functionally characterized the ZjWRKY18 transcription factor, which is associated with triterpenoid accumulation. The transcription factor is induced by methyl jasmonate and salicylic acid, and its activity was observed by gene overexpression and silencing experiments, combined with analyses of transcripts and metabolites. ZjWRKY18 gene silencing decreased the transcription of triterpenoid synthesis pathway genes and the corresponding triterpenoid content. Overexpression of the gene promoted the biosynthesis of jujube triterpenoids, as well as triterpenoids in tobacco and Arabidopsis thaliana. In addition, ZjWRKY18 binds to W-box sequences to activate promoters of 3-hydroxy-3-methyl glutaryl coenzyme A reductase and farnesyl pyrophosphate synthase, suggesting that ZjWRKY18 positively regulates the triterpenoid synthesis pathway. Overexpression of ZjWRKY18 also increased tolerance to salt stress in tobacco and Arabidopsis thaliana. These results highlight the potential use of ZjWRKY18 to improve triterpenoid biosynthesis and salt stress tolerance in plants, and provide a strong basis for metabolic engineering to improve the content of triterpenoids and breeding of jujube varieties that are resistant to stress.