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Abstract Real-time and accurate guidance for tumor resection has long been anticipated by surgeons. In the past decade, the flourishing material science has made impressive progress in near-infrared fluorophores that may fulfill this purpose. Fluorescence imaging-guided surgery shows great promise for clinical application and has undergone widespread evaluations, though it still requires continuous improvements to transition this technique from bench to bedside. Concurrently, the rapid progress of artificial intelligence (AI) has revolutionized medicine, aiding in the screening, diagnosis, and treatment of human doctors. Incorporating AI helps enhance fluorescence imaging and is poised to bring major innovations to surgical guidance, thereby realizing precision cancer surgery. This review provides an overview of the principles and clinical evaluations of fluorescence-guided surgery. Furthermore, recent endeavors to synergize AI with fluorescence imaging were presented, and the benefits of this interdisciplinary convergence were discussed. Finally, several implementation strategies to overcome technical hurdles were proposed to encourage and inspire future research to expedite the clinical application of these revolutionary technologies.

Abstract Objectives Exploring the value of adding correlation analysis (radiomic features (RFs) of pelvic metastatic lymph nodes and primary lesions) to screen RFs of primary lesions in the feature selection process of establishing prediction model. Methods A total of 394 prostate cancer (PCa) patients (263 in the training group, 74 in the internal validation group and 57 in the external validation group) from two tertiary hospitals were included in the study. The cases with pelvic lymph node metastasis (PLNM) positive in the training group were diagnosed by biopsy or MRI with a short-axis diameter ≥ 1.5 cm, PLNM-negative cases in the training group and all cases in validation group were underwent both radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND). The RFs of PLNM-negative lesion and PLNM-positive tissues including primary lesions and their metastatic lymph nodes (MLNs) in the training group were extracted from T2WI and apparent diffusion coefficient (ADC) map to build the following two models by fivefold cross-validation: the lesion model, established according to the primary lesion RFs selected by t tests and absolute shrinkage and selection operator (LASSO); the lesion-correlation model, established according to the primary lesion RFs selected by Pearson correlation analysis (RFs of primary lesions and their MLNs, correlation coefficient > 0.9), t test and LASSO. Finally, we compared the performance of these two models in predicting PLNM. Results The AUC and the DeLong test of AUC in the lesion model and lesion-correlation model were as follows: training groups (0.8053, 0.8466, p = 0.0002), internal validation group (0.7321, 0.8268, p = 0.0429), and external validation group (0.6445, 0.7874, p = 0.0431), respectively. Conclusion The lesion-correlation model established by features of primary tumors correlated with MLNs has more advantages than the lesion model in predicting PLNM.

Abstract Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

Abstract PTBP1 is an oncogene that regulates the splicing of precursor mRNA. However, the relationship between PTBP1 expression and gene methylation, cancer prognosis, and tumor microenvironment remains unclear. The expression profiles of PTBP1 across various cancers were derived from the TCGA, as well as the GTEx and CGGA databases. The CGGA mRNA_325, CGGA mRNA_301, and CGGA mRNA_693 datasets were utilized as validation cohorts. Immune cell infiltration scores were approximated using the TIMER 2.0 tool. Functional enrichment analysis for groups with high and low PTBP1 expression was conducted using Gene Set Enrichment Analysis (GSEA). Methylation data were predominantly sourced from the SMART and Mexpress databases. Linked-omics analysis was employed to perform functional enrichment analysis of genes related to PTBP1 methylation, as well as to conduct protein functional enrichment analysis. Single-cell transcriptome analysis and spatial transcriptome analysis were carried out using Seurat version 4.10. Compared to normal tissues, PTBP1 is significantly overexpressed and hypomethylated in various cancers. It is implicated in prognosis, immune cell infiltration, immune checkpoint expression, genomic variation, tumor neoantigen load, and tumor mutational burden across a spectrum of cancers, with particularly notable effects in low-grade gliomas. In the context of gliomas, PTBP1 expression correlates with WHO grade and IDH1 mutation status. PTBP1 expression and methylation play an important role in a variety of cancers. PTBP1 can be used as a marker of inflammation, progression and prognosis in gliomas.

Abstract Background Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. Methods The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. Conclusions Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. Trial registration ChiCTR2000031608.

Abstract As an orally effective benzimidazole anthelmintic agent, fenbendazole was not only widely used in agriculture and animal husbandry to prevent and treat parasites, but also shows anti-cancer effects against several types of cancer, exhibits anti-cancer effects in paclitaxel and doxorubicin-resistant cancer cells. However, fenbendazole’s poor in water solubility (0.3 µg/mL), limits its clinical applications. Even great efforts were made toward increasing its water solubility, the results were not significant to reach anti-cancer drug delivery requirement (5–10 mg/mL). Through single factor and orthogonal strategy, many complex conditions were designed and used to prepare the complexes, the inclusion complex with methyl-β-cyclodextrin with 29.2 % of inclusion rate and 89.5% of inclusion yield can increase drug’s water solubility to 20.21 mg/mL, which is the best result so far. Its structure was confirmed by differential scanning calorimetry, scanning electron microscopic image, 1D and 2D NMR spectra in D2O. In its in vitro pharmacokinetic study, fenbendazole was 75% released in 15 min., in its in vivo pharmacokinetic study, the bio-availabilities of fenbendazole, its major metabolic anthelmintic agent oxfendazole and its minor metabolic anthelmintic agent oxfendazole were increased to 138%, 149% and 169% respectively, which would allow for fewer drug doses to achieve the same therapeutic effect and suggest that the complex can be used as a potential anticancer agent.

Abstract Saturation characteristics of water and capillary pressure are important for hydrofracturing or water flooding, which is widely adopted in dust suppression, methane displacement, and gas and coal outburst elimination. In this paper, we have studied the water saturation characteristics of coal samples with different coal ranks and their effect on capillary pressure. It was found that the isothermal adsorption of water vapor from coal samples can be divided into three processes: monolayer adsorption, multilayer adsorption, and capillary condensation. The dent isothermal adsorption model can well describe water vapor adsorption of coal samples, indicating water molecules were first adsorbed on the first‐order adsorption site of pore surfaces at low relative humidity and then on the second‐order adsorption site with increasing relative humidity. An obvious hysteresis occurred in the process of water imbibition and drainage. A capillary pressure of ~325 MPa or even larger was required to displace the water from the coal. Besides, micro‐ and mesopores play a more important role in capillary pressure. The capillary pressure of coal samples was positively correlated with wettability at lower water saturation, but it is not significant at higher capillary pressures. Therefore, the article's results provide a new direction for solving the water‐locking effect in coal seams.

IntroductionThe increasing penetration of distributed generation (e.g., solar power and wind power) in the energy market has caused unpredictable disturbances in power systems and accelerated the application of intelligent control, such as reinforcement learning (RL), in automatic generation control (AGC). However, traditional RL cannot ensure constraint safety during training and frequently violates the constraints (e.g., frequency limitations), further threatening the safety and stability of grid operation.MethodsTo address the safety issue, we propose a novel safe RL framework that combines expert experiences with the RL controller to achieve imitation-based RL. This method allows an initialized safe policy by imitating expert experiences to prevent random explorations at the beginning. Specifically, we first formulate the AGC problem mathematically as a Markov decision process. Then, the imitation mechanism is developed atop a soft actor–critic RL algorithm.Results and discussionFinally, numerical studies are conducted with an IEEE 39-bus network, which show that the proposed method satisfies the frequency control performance standard better and improves the RL training efficiency.

IntroductionThe precise forecasting of Significant wave height(SWH) is vital to ensure the safety and efficiency of aquatic activities such as ocean engineering, shipping, and fishing.MethodsThis paper proposes a deep learning model named SAC-ConvLSTM to perform 24-hour prediction with the SWH in the South China Sea. The long-term prediction capability of the model is enhanced by using the attention mechanism and context vectors. The prediction ability of the model is evaluated by mean absolute error (MAE), root mean square error (RMSE), mean square error (MSE), and Pearson correlation coefficient (PCC).ResultsThe experimental results show that the optimal input sequence length for the model is 12. Starting from 12 hours, the SAC-ConvLSTM model consistently outperforms other models in predictive performance. For the 24-hour prediction, this model achieves RMSE, MAE, and PCC values of 0.2117 m, 0.1083 m, and 0.9630, respectively. In addition, the introduction of wind can improve the accuracy of wave prediction. The SAC-ConvLSTM model also has good prediction performance compared to the ConvLSTM model during extreme weather, especially in coastal areas.DiscussionThis paper presents a 24-hour prediction of SWH in the South China Sea. Through comparative validation, the SAC-ConvLSTM model outperforms other models. The inclusion of wind data enhances the model's predictive capability. This model also performs well under extreme weather conditions. In physical oceanography, variables related to SWH include not only wind but also other factors such as mean wave period and sea surface air pressure. In the future, additional variables can be incorporated to further improve the model's predictive performance.

Bacterial biofilms are organized heterogeneous assemblages of microbial cells encased within a self-produced matrix of exopolysaccharides, extracellular DNA and proteins. Over the last decade, more and more biofilm-associated proteins have been discovered and investigated. Furthermore, omics techniques such as transcriptomes, proteomes also play important roles in identifying new biofilm-associated genes or proteins. However, those important data have been uploaded separately to various databases, which creates obstacles for biofilm researchers to have a comprehensive access to these data. In this work, we constructed BBSdb, a state-of-the-art open resource of bacterial biofilm-associated protein. It includes 48 different bacteria species, 105 transcriptome datasets, 21 proteome datasets, 1205 experimental samples, 57,823 differentially expressed genes (DEGs), 13,605 differentially expressed proteins (DEPs), 1,930 ‘Top 5% differentially expressed genes’, 444 ‘Threshold-based DEGs’ and a predictor for prediction of biofilm-associated protein. In addition, 1,781 biofilm-associated proteins, including annotation and sequences, were extracted from 942 articles and public databases via text-mining analysis. We used E. coli as an example to represent how to explore potential biofilm-associated proteins in bacteria. We believe that this study will be of broad interest to researchers in field of bacteria, especially biofilms, which are involved in bacterial growth, pathogenicity, and drug resistance.Availability and implementation: The BBSdb is freely available at http://124.222.145.44/#!/.

Primary graft dysfunction (PGD) is a severe form of acute lung injury resulting from lung ischemia/reperfusion injury (I/R) in lung transplantation (LTx), associated with elevated post-transplant morbidity and mortality rates. Neutrophils infiltrating during reperfusion are identified as pivotal contributors to lung I/R injury by releasing excessive neutrophil extracellular traps (NETs) via NETosis. While alveolar macrophages (AMs) are involved in regulating neutrophil chemotaxis and infiltration, their role in NETosis during lung I/R remains inadequately elucidated. Extracellular histones constitute the main structure of NETs and can activate AMs. In this study, we confirmed the significant involvement of extracellular histone-induced M1 phenotype of AMs (M1-AMs) in driving NETosis during lung I/R. Using secretome analysis, public protein databases, and transwell co-culture models of AMs and neutrophils, we identified Cathepsin C (CTSC) derived from AMs as a major mediator in NETosis. Further elucidating the molecular mechanisms, we found that CTSC induced NETosis through a pathway dependent on NADPH oxidase-mediated production of reactive oxygen species (ROS). CTSC could significantly activate p38 MAPK, resulting in the phosphorylation of the NADPH oxidase subunit p47phox, thereby facilitating the trafficking of cytoplasmic subunits to the cell membrane and activating NADPH oxidase. Moreover, CTSC up-regulated and activated its substrate membrane proteinase 3 (mPR3), resulting in an increased release of NETosis-related inflammatory factors. Inhibiting CTSC revealed great potential in mitigating NETosis-related injury during lung I/R. These findings suggests that CTSC from AMs may be a crucial factor in mediating NETosis during lung I/R, and targeting CTSC inhition may represent a novel intervention for PGD in LTx.

Objective Apart from the role of the retinoblastoma gene, the genomic events associated with poor outcomes in patients with ophthalmic tumors are poorly understood. Methods We retrospectively analyzed 48 patients with six types of ophthalmic tumors. We searched for high-frequency mutated genes and susceptibility genes in these patients using combined exome and transcriptome analysis. Results We identified four clearly causative genes ( TP53, PTCH1, SMO, BAP1 ). Susceptibility gene analysis identified hotspot genes, including RUNX1, APC, IDH2 , and BRCA2 , and high-frequency gene analysis identified several genes, including TP53, TTN , and MUC16 . Transcriptome analysis identified 5868 differentially expressed genes, of which TOP2A and ZWINT were upregulated in all samples, while CFD , ELANE , HBA1 , and HBB were downregulated. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the phosphoinositide 3-kinase (PI3K)-Akt and Transcriptional misregulation in cancer signaling pathways may be involved in ophthalmic tumorigenesis. Conclusions TP53 is clearly involved in ophthalmic tumorigenesis, especially in basal cell carcinoma, and the PI3K-Akt signaling pathway may be an essential pathway involved in ophthalmic tumorigenesis. RUNX1, SMO, TOP2A , and ZWINT are also highly likely to be involved in ophthalmic tumorigenesis, but further functional experiments are needed to verify the mechanisms of these genes in regulating tumorigenesis.

Speculative out-of-order execution is a strategy of masking execution latency by allowing younger instructions to execute before older instructions. While originally considered to be innocuous, speculative out-of-order execution was brought into the spotlight with the 2018 publication of the Spectre and Meltdown attacks. These attacks demonstrated that microarchitectural side channels can leak sensitive data accessed by speculatively executed instructions that are not part of the normal program execution. Since then, a significant effort has been vested in investigating how microarchitectural side channels can leak data from speculatively executed instructions and how to control this leakage. However, much less is known about how speculative out-of-order execution affects microarchitectural side-channel attacks. In this paper, we investigate how speculative out-of-order execution affects the Evict+Time cache attack. Evict+Time is based on the observation that cache misses are slower than cache hits, hence by measuring the execution time of code, an attacker can determine if a cache miss occurred during the execution. We demonstrate that, due to limited resources for tracking out-of-order execution, under certain conditions an attacker can gain more fine-grained information and determine whether a cache miss occurred in part of the executed code. Based on the observation, we design the Evict+Spec+Time attack, a variant of Evict+Time that can learn not only whether a cache miss occurred, but also in which part of the victim code it occurred. We demonstrate that Evict+Spec+Time is an order of magnitude more efficient than Evict+Time when attacking a T-tables-based implementation of AES. We further show an Evict+Spec+Time attack on an S-boxbased implementation of AES, recovering the key with as little as 14 815 decryptions. To the best of our knowledge, ours is the first successful Evict+Time attack on such a victim.

Summary: Neutrophils play an important role in antiviral immunity, but the underlying mechanisms remain unclear. Here, we found that SIRT2 deficiency inhibited the infiltration of neutrophils, as well as the secretion of inflammatory cytokines and the formation of neutrophil extracellular traps (NETs), ameliorating disease symptoms during acute respiratory virus infection. Mechanistically, SIRT2 deficiency upregulates quinolinic acid (QA)-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) and leads to expression of quinolinate phosphoribosyltransferase (QPRT), which promotes the synthesis of QA for NAD+ and limits viral infection when de novo NAD+ synthesis is blocked. Tryptophan-2,3-oxygenase expressed in epithelial cells metabolizes tryptophan to produce kynurenine and 3-hydroxyaminobenzoic acid, which is a source of intracellular QA in neutrophils. Thus, our findings reveal a previously unrecognized QPRT-mediated switch in NAD+ metabolism by exploiting neutrophil-derived QA as an alternative source of replenishing intracellular NAD+ pools induced by SIRT2 to regulate neutrophil functions during virus infection, with implications for future immunotherapy approaches.

Abstract SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

Abstract Developing highly efficient catalysts is significant for Li-CO2 batteries. However, understanding the exact structure of catalysts during battery operation remains a challenge, which hampers knowledge-driven optimization. Here we use X-ray absorption spectroscopy to probe the reconstruction of CoSx (x = 8/9, 1.097, and 2) pre-catalysts and identify the local geometric ligand environment of cobalt during cycling in the Li-CO2 batteries. We find that different oxidized states after reconstruction are decisive to battery performance. Specifically, complete oxidation on CoS1.097 and Co9S8 leads to electrochemical performance deterioration, while oxidation on CoS2 terminates with Co-S4-O2 motifs, leading to improved activity. Density functional theory calculations show that partial oxidation contributes to charge redistributions on cobalt and thus facilitates the catalytic ability. Together, the spectroscopic and electrochemical results provide valuable insight into the structural evolution during cycling and the structure-activity relationship in the electrocatalyst study of Li-CO2 batteries.

Abstract Macrophages and tumour stroma cells account for the main cellular components in the tumour microenvironment (TME). Current advancements in single-cell analysis have revolutionized our understanding of macrophage diversity and macrophage–stroma interactions. Accordingly, this review describes new insight into tumour-associated macrophage (TAM) heterogeneity in terms of tumour type, phenotype, metabolism, and spatial distribution and presents the association between these factors and TAM functional states. Meanwhile, we focus on the immunomodulatory feature of TAMs and highlight the tumour-promoting effect of macrophage–tumour stroma interactions in the immunosuppressive TME. Finally, we summarize recent studies investigating macrophage-targeted therapy and discuss their therapeutic potential in improving immunotherapy by alleviating immunosuppression.

The arc ignition system based on charring polymers has advantages of simple structure, low ignition power consumption and multiple ignitions, which bringing it broadly application prospect in hybrid propulsion system of micro/nano satellite. However, charring polymers alone need a relatively high input voltage to achieve pyrolysis and ignition, which increases the burden and cost of the power system of micro/nano satellite in practical application. Adding conductive substance into charring polymers can effectively decrease the conducting voltage which can realize low voltage and low power consumption repeated ignition of arc ignition system. In this paper, a charring conductive polymer ignition grain with a cavity geometry in precombustion chamber, which is composed of PLA and multiwall carbon nanotubes (MWCNT) was proposed. The detailed ignition processes were analyzed and two different ignition mechanisms in the cavity of charring conductive polymers were revealed. The ignition characteristics of charring conductive polymers were also investigated at different input voltages, ignition grain structures, ignition locations and injection schemes in a visual ignition combustor. The results demonstrated that the ignition delay and external energy required for ignition were inversely correlated with the voltages applied to ignition grain. Moreover, the incremental depth of cavity shortened the ignition delay and external energy required for ignition while accelerated the propagation of flame. As the depth of cavity increased from 2 to 6 mm (at 50 V), the time of flame propagating out of ignition grain changed from 235.6 to 108 ms, and values of mean ignition delay time and mean external energy required for ignition decreased from 462.8 to 320 ms and 16.2 to 10.75 J, respectively. The rear side of the cavity was the ideal ignition position which had a shorter ignition delay and a faster flame propagation speed in comparison to other ignition positions. Compared to direct injection scheme, swirling injection provided a more favorable flow field environment in the cavity, which was beneficial to ignition and initial flame propagation, but the ignition position needed to be away from the outlet of swirling injector. At last, the repeated ignition characteristic of charring conductive polymers was also investigated. The ignition delay time and external energy required for ignition decreased with repeated ignition times but the variation was decreasing gradually.

In order to characterize the local damage and fatigue strength of 5754 and 5052 aluminum alloy cross-welded joints containing pre-cracks under impact loading, an interval fatigue life prediction approach is presented based on the continuum damage mechanics and the uncertain interval analysis technique. The impact test is carried out on the cruciform welded joints of dissimilar lightweight metals with U-type pre-crack located at the middle edge of specimen. In consideration of uncertain factors caused by the welding process, the interval fatigue damage model under the coupling effect of fatigue and impact load is established. Then, the interval fatigue parameters and interval curve between stress amplitudes and fatigue life are determined. The impact process is simulated by using the finite element dynamic analysis to obtain the stress and plastic strain fields. Based on the suggested model, the predicted results agree well with the experimental data.

Abstract Aims Assessing the global burden and health inequalities of Hypertension Heart Disease (HHD) during the period from 1990 to 2019. Methods Secondary analysis of the Global Burden of Disease (GBD) study in 2019, focusing on the burden of diseases, injuries, and risk factors worldwide. Disability-Adjusted Life Years (DALYs) data related to HHD are extracted from the 2019 GBD. Inequality Slope Index (SII) and Concentration Index are calculated to assess health inequalities across regions and countries. Results The total DALYs for HHD reached 21.51 million, demonstrating a substantial increase of 54.25% compared to the figures recorded in 1990, while the age-standardized DALY rates per 100,000 population for HHD in 2019 showed a notable decline to 268.19 (95% UI 204.57, 298.07), reflecting a significant decrease of 26.4% compared to the rates observed in 1990. The DALYs rate of hypertensive heart disease increases with age. Countries with moderate SDI accounted for 38.72% of the global burden of HHD in terms of DALYs. The highest age-standardized DALY rates (per 100,000) are predominantly concentrated in underdeveloped areas. In 1990 and 2019, the SII (per 100,000 population) for DALYs were − 121.6398 (95% CI -187.3729 to -55.90684) and − 1.592634 (95% CI -53.11027 to 49.925) respectively. The significant decline suggests a reduction in the inequality of age-standardized burden of HHD between high-income and low-income countries during this period. Conclusion The unequal prevalence of HHD across different populations can hinder the achievement of the “health for all” objective. Persistent disparities in HHD have been observed globally over the past thirty years. It is crucial to prioritize efforts towards reducing avoidable health inequalities associated with hypertension-related heart disease, particularly in low-income and middle-income countries.

Abstract Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

Background Carotid-femoral pulse wave velocity has been identified as an autonomous predictor of cardiovascular mortality and kidney injury. This important clinical parameter can be non-invasively estimated using the calculated pulse wave velocity (ePWV). The objective of this study was to examine the correlation between ePWV and in-hospital as well as one-year mortality among critically ill patients with chronic kidney disease (CKD) and atherosclerotic heart disease (ASHD).Methods This study included a cohort of 1173 patients diagnosed with both CKD and ASHD, sourced from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The four groups divided into quartiles according to ePWV were compared using a Kaplan-Meier survival curve to assess variations in survival rates. Cox proportional hazards models were employed to analyze the correlation between ePWV and in-hospital as well as one-year mortality among critically ill patients with both CKD and ASHD. To further investigate the dose-response relationship, a restricted cubic splines (RCS) model was utilized. Additionally, stratification analyses were performed to examine the impact of ePWV on hospital and one-year mortality across different subgroups.Results The survival analysis results revealed a negative correlation between higher ePWV and survival rate. After adjusting for confounding factors, higher ePWV level (ePWV > 11.90 m/s) exhibited a statistically significant association with an increased risk of both in-hospital and one-year mortality among patients diagnosed with both CKD and ASHD (HR = 4.72, 95% CI = 3.01–7.39, p

Background Estimated pulse wave velocity (ePWV) has been found to be an independent predictor of cardiovascular mortality and kidney injury, which can be estimated noninvasively. This study aimed to investigate the association between ePWV and in-hospital mortality in critically ill patients with acute kidney injury (AKI).Methods This study included 5960 patients with AKI from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The low and high ePWV groups were compared using a Kaplan-Meier survival curve to evaluate the differences in survival status. Cox proportional hazards models were used to explore the association between ePWV and in-hospital mortality in critically ill patients with AKI. To further examine the dose-response relationship, we used a restricted cubic spline (RCS) model. Stratification analyses were conducted to investigate the effect of ePWV on hospital mortality across various subgroups.Results Survival analysis indicated that patients with high ePWV had a lower survival rate than those with low ePWV. Following adjustment, high ePWV demonstrated a statistically significant association with an increased risk of in-hospital mortality among AKI patients (HR = 1.53, 95% CI = 1.36-1.71, p

Abstract Background Undetermined lung nodules are common in locally advanced rectal cancer (LARC) and lack precise risk stratification. This study aimed to develop a radiomic‐based score (Rad‐score) to distinguish metastasis and predict overall survival (OS) in patients with LARC and lung nodules. Methods Retrospective data from two institutions (July 10, 2006—September 24, 2015) was used to develop and validate the Rad‐score for distinguishing lung nodule malignancy. The prognostic value of the Rad‐score was investigated in LARC cohorts, leading to the construction and validation of a clinical and radiomic score (Cli‐Rad‐score) that incorporates both clinical and radiomic information for the purpose of improving personalized clinical prognosis prediction. Descriptive statistics, survival analysis, and model comparison were performed to assess the results. Results The Rad‐score demonstrated great performance in distinguishing malignancy, with C‐index values of 0.793 [95% CI: 0.729–0.856] in the training set and 0.730 [95% CI: 0.666–0.874] in the validation set. In independent LARC cohorts, Rad‐score validation achieved C‐index values of 0.794 [95% CI: 0.737–0.851] and 0.747 [95% CI: 0.615–0.879]. Regarding prognostic prediction, Rad‐score effectively stratified patients. Cli‐Rad‐score outperformed the clinicopathological information alone in risk stratification, as evidenced by significantly higher C‐index values (0.735 vs. 0.695 in the internal set and 0.618 vs. 0.595 in the external set). Conclusions CT‐based radiomics could serve as a reliable and powerful tool for lung nodule malignancy distinction and prognostic prediction in LARC patients. Rad‐score predicts prognosis independently. Incorporation of Cli‐Rad‐score significantly enhances the persionalized clinical prognostic capacity in LARC patients with lung nodules.

Studies show that inflammation induced by cancer is a key factor in carcinogenesis. Here, we sought to assess the relationship between patients with locally advanced rectal cancer (LARC) and the lymphocyte to neutrophil granulocyte ratio (LGR) prior to neoadjuvant chemoradiotherapy (nCRT) and distant metastasis-free survival (DMFS). Using a receiver operating characteristic (ROC) analysis of 326 LARC patients who underwent total mesorectal excision (TME) surgery and neoadjuvant chemoradiotherapy, we were able to determine the ideal LGR cutoff value. We used the Kaplan-Meier method and univariate and multivariate Cox regression to study the clinical characteristics of LARC patients in comparison between the low LGR group and the high LGR group. DMFS analysis was one of the primary clinical variables examined. We discovered that the low LGR group of LARC patients had a longer DMFS than the high LGR group. The median duration of follow-up for LARC patients was 89.4 months, with a significantly lower DMFS observed in the high LGR group compared to the low LGR group. Multivariate Cox regression analysis revealed that LARC patients with low LGR levels, early ypTNM stages, and BRAF wild had longer DMFS. LGR prior to nCRT was a critical prognostic indicator that contributed extra predictive value beyond conventional clinicopathological characteristics to predict the outcome of LARC patients receiving neoadjuvant chemoradiotherapy followed by TME surgery.

Abstract With the development of distributed generation and power electronics technology, DC microgrids have made certain progress with their advantages of simple structure, economic efficiency, and easy control. Considering factors such as the geographical location of some residential areas, microgrids with fuel cells that can operate independently are also receiving increasing attention. In this paper, an online control method named virtual hydrogen consumption is proposed based on an independent DC microgrid which solves the problem of electro‐hydrogen conversion successfully. By solving the overall consumption function, the analytical solution is further obtained to realize the online control. Based on the results of RT‐LAB platform, the proposed method can maintain the output of fuel cell system in its high efficiency range with a lower volatility.

Members of the Malvaceae family, including Corchorus spp., Gossypium spp., Bombax spp., and Ceiba spp., are important sources of natural fibers. In the past decade, the genomes of several Malvaceae species have been assembled; however, the evolutionary history of Malvaceae species and the differences in their fiber development remain to be clarified. Here, we report the genome assembly and annotation of two natural fiber plants from the Malvaceae, Bombax ceiba and Ceiba pentandra, whose assembled genome sizes are 783.56 Mb and 1575.47 Mb, respectively. Comparative analysis revealed that whole-genome duplication and Gypsy long terminal repeat retroelements have been the major causes of differences in chromosome number (2n = 14 to 2n = 96) and genome size (234 Mb to 2676 Mb) among Malvaceae species. We also used comparative genomic analyses to reconstruct the ancestral Malvaceae karyotype with 11 proto-chromosomes, providing new insights into the evolutionary trajectories of Malvaceae species. MYB-MIXTA-like 3 is relatively conserved among the Malvaceae and functions in fiber cell-fate determination in the epidermis. It appears to perform this function in any tissue where it is expressed, i.e. in fibers on the endocarp of B. ceiba and in ovule fibers of cotton. We identified a structural variation in a cellulose synthase gene and a higher copy number of cellulose synthase-like genes as possible causes of the finer, less spinnable, weaker fibers of B. ceiba. Our study provides two high-quality genomes of natural fiber plants and offers insights into the evolution of Malvaceae species and differences in their natural fiber formation and development through multi-omics analysis.

BackgroundSmilax glabra Roxb. (named tufuling in Chinese, SGR) has both medicinal and edible value. SGR has obvious pharmacological activity, especially in anti-inflammation and treating immune system diseases. This study investigated differential protein expression and its relationship with immune infiltration in hypertension treated with SGR using proteomics and bioinformatics.MethodsN-Nitro L-arginine methyl ester (L-NAME) was used to replicate the hypertension model, with SGR administered by gavage for 4 weeks, and the systolic and diastolic blood pressure in each group of rats was measured using the tail-cuff method every 7 days. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to determine the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) expressions in each group, followed by the detection of protein expression in rat liver samples using the tandem mass tag (TMT) technique. Additionally, hub targets were output using Cytoscape 3.9.1 software, and ALDH2 expression in the liver and serum in each group of rats was detected by ELISA. Moreover, R4.3.0 software was used to evaluate the relationship between acetaldehyde dehydrogenase 2 (ALDH2) and immune cells, and ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) was performed to identify the components of SGR. Furthermore, the association between components of SGR and ALDH2 was analyzed with molecular docking and LigPlot1.4.5 software.ResultsCompared with the model group (L-NAME), SGR at high and medium doses reduced systolic and diastolic blood pressure while reducing TC, TG, and LDL-C levels and increasing HDL-C levels in hypertensive rats (p < 0.05). Moreover, 92 differentially expressed proteins (DEPs) were identified using TMT. These DEPs participated in peroxisome functioning, fatty acid degradation, and other signaling pathways, with ALDH2 being the core target and correlated with various immune cells. In addition, 18 components were determined in SGR, with 8 compounds binding to ALDH2. Molecular docking was performed to confirm that SGR played a role in hypertension based on the combined action of multiple components.ConclusionIn conclusion, SGR has an antihypertensive effect on L-NAME-induced hypertension, with ALDH2 as its hub target. SGR may regulate neutrophil, regulatory T cell, and other cells’ infiltration by targeting ALDH2, thereby contributing to the treatment of hypertension.

Gliosarcoma is a rare subtype of glioblastoma (GBM) with a shorter medical history and a worse prognosis compared to other Grade 4 gliomas. Most gliosarcomas are sporadic, but it is undeniable that a small percentage are linked to germline mutations and several inherited cancer susceptibility syndromes, including Lynch Syndrome (LS). The authors present a case of a primary mismatch repair-deficient gliosarcoma in LS. A 54-year-old Chinese male patient was admitted to the hospital with a history of facial asymmetry for over 1 month and right temporo-occipital pain for 5 days. Head MRI revealed a complex mass lesion in the right frontoparietal region, consisting of cystic and solid components. The patient’s history of colon malignancy and family history of rectal carcinoma were noteworthy. Postoperative pathology indicated the presence of gliosarcoma with high-frequency microsatellite instability (MSI-H) and mismatch repair deficiency (MMRD). Further genetic testing results confirmed a germline heterozygous mutation in MSH2, which is considered the gold standard for diagnosing LS. This case report enriches the existing literature on germline MSH2 mutations and gliosarcomas. It highlights the importance for neurosurgeons to consider possible hereditary disorders when treating patients with a history of concurrent tumors outside the nervous system. Genetic testing is crucial for further identification of such disorders.

BackgroundPrimary dysmenorrhea (PD) is one of the most common reasons that affect the life quality of women during childbearing age. This research aims to explore the efficacy and curative effect characteristics of oral contraceptives and low-power visible-light-activated photodynamic therapy (PDT). Besides investigating the possible mechanism of PDT, we expected to find a treatment model with better efficacy and fewer side effects.MethodIt was a multicenter, randomized, parallel-controlled study. Eligible participants were randomly assigned to three groups: placebo group, oral contraceptive (Marvelon) group, and the PDT group. They were treated continuously for three menstrual cycles and followed up for two cycles after treatment. The scores of the visual analog scale (VAS) and the concentration of pain-related small molecules in blood before and after treatment were recorded in each group, which can evaluate the therapeutic characteristics of different treatments.ResultBoth Marvelon and PDT were effective. The effect of Marvelon appears quickly which can significantly relieve symptoms at the beginning, while PDT shows a relatively slow role. There was no significant difference in the final efficacy two cycles after treatment. The therapeutic effect was achieved by reducing the concentrations of prostaglandin 2 (PGE2) and endothelin (ET) in the blood.ConclusionMarvelon and PDT are effective methods for the treatment of PD. The long-term efficacy of the two is similar, while the therapeutic characteristics and the side effects are different. Patients can choose the suitable way according to their individual needs.

Abstract Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus‐induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage‐released apoEVs, which bound iron‐containing proteins and neutralized α‐toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti‐inflammatory agents (microRNA‐146a). These engineered apoEVs can capture iron and neutralize α‐toxin with their natural membrane while also regulating inflammation by releasing microRNA‐146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes‐driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron‐loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.

ABSTRACT: The economic losses incurred due to reduced muscle pigmentation highlight the crucial role of melanin-based coloration in the meat of black-bone chickens. Melanogenesis in the breast muscle of black-bone chickens is currently poorly understood in terms of molecular mechanisms. This study employed whole-transcriptome sequencing to analyze black and white breast muscle samples from black-bone chickens, leading to the identification of 367 differentially expressed (DE) mRNAs, 48 DElncRNAs, 104 DEcircRNAs, and 112 DEmiRNAs involved in melanin deposition. Based on these findings, a competitive endogenous RNA (ceRNA) network was developed to better understand the complex mechanisms of melanin deposition. Furthermore, our analysis revealed key DEmRNAs (TYR, DCT, EDNRB, MLPH and OCA2) regulated by DEmiRNAs (gga-miR-140-5p, gga-miR-1682, gga-miR-3529, gga-miR-499-3p, novel-m0012-3p, gga-miR-200b-5p, gga-miR-203a, gga-miR-6651-5p, gga-miR-7455-3p, gga-miR-31-5p, miR-140-x, miR-455-x, novel-m0065-3p, gga-miR-29b-1-5p, miR-455-y, novel-m0085-3p, and gga-miR-196-1-3p). These DEmiRNAs competitively interacted with DElncRNAs including MSTRG.2609.2, MSTRG.4185.1, LOC112530666, LOC112533366, LOC771030, LOC107054724, LOC121107411, LOC100859072, LOC101750037, LOC121108550, LOC121109224, LOC121110876, and LOC101749016, as well as DEcircRNAs, such as novel_circ_000158, novel_circ_000623, novel_001518, and novel_circ_003596. The findings from this study provide insight into the mechanisms that regulate lncRNA, circRNA, miRNA, and mRNA expression in chicken melanin deposition.

Abstract Background Peripheral lung lesions can be sampled using various techniques, including computer tomography-guided transthoracic needle aspiration, electromagnetic navigation bronchoscopy, virtual navigation bronchoscopy, and radial probe endobronchial ultrasound transbronchial lung biopsy. Mediastinal lesions can be sampled using techniques like convex probe endobronchial ultrasound-guided transbronchial needle aspiration (CEBUS-TBNA) and endoscopic ultrasound-fine-needle aspiration. However, effective, safe techniques for lesions adjacent to the segmental or subsegmental bronchi are lacking. Herein, we retrospectively evaluated the diagnostic yield and safety of radial probe endobronchial ultrasound-assisted transbronchial needle aspiration (REBUS-TBNA) for lesions adjacent to the segmental bronchi, and explored the factors related to diagnostic yield. Methods We retrospectively analyzed the diagnostic yield and safety of REBUS-TBNA cases performed in our department from January 2019 to December 2022. Observation group patients had undergone REBUS-TBNA for lesions adjacent to the segmental bronchi; control group patients had undergone CEBUS-TBNA for mediastinal or hilar lesions. Patient characteristics and lesion sizes, diagnostic yield, adverse events, and relations between diagnostic yield and clinical characteristics were analyzed. Results There were not statistically significant between-group differences in sex, age, diagnostic yield, or rate of adverse events. The observation group (n = 25; 17 male, 8 female) had a mean age of 64.76 ± 10.75 years. The average lesion size was 4.66 ± 1.07 cm, and lesions were predominantly in the upper lobes (80%). REBUS-TBNA diagnostic yield was 84%, with no adverse events reported. Diagnostic yield was not associated with lesion size or extent of bronchial stenosis; however, it was positively correlated with number of punctures. Patients with > 3 punctures had a significantly higher diagnostic yield than those with ≤ 3 punctures. Conclusions REBUS-TBNA is a safe, effective diagnostic technique, particularly for lesions adjacent to the segmental or subsegmental bronchi of the upper lobe. Performing more than three punctures during the procedure improves the diagnostic yield. Larger-scale studies are warranted to confirm these results, and to further explore the clinical value of REBUS-TBNA.

Pepper (Capsicum annuum L.) is an economically important crop containing capsaicinoids in the seed and placenta, which has various culinary, medical, and industrial applications. Late embryogenesis abundant (LEA) proteins are a large group of hydrophilic proteins participating in the plant stress response and seed development. However, to date there have been no genome‐wide analyses of the LEA gene family in pepper. In the present study, 82 LEA genes were identified in the C. annuum genome and classified into nine subfamilies. Most CaLEA genes contain few introns (≤ 2) and are unevenly distributed across 10 chromosomes. Eight pairs of tandem duplication genes and two pairs of segmental duplication genes were identified in the LEA gene family; these duplicated genes were highly conserved and may have performed similar functions during evolution. Expression profile analysis indicated that CaLEA genes exhibited different tissue expression patterns, especially during embryonic development and stress response, particularly in cold stress. Three out of five CaLEA genes showed induced expression upon cold treatment. In summary, we have comprehensively reviewed the LEA gene family in pepper, offering a new perspective on the evolution of this family.

Abstract Crystalline porous materials such as covalent organic frameworks (COFs), metal-organic frameworks (MOFs) and porous organic cages (POCs) have been widely applied in various fields with outstanding performances. However, the lack of general and effective methodology for large-scale production limits their further industrial applications. In this work, we developed a general approach comprising high pressure homogenization (HPH), which can realize large-scale synthesis of crystalline porous materials including COFs, MOFs, and POCs under benign conditions. This universal strategy, as illustrated in the proof of principle studies, has prepared 4 COFs, 4 MOFs, and 2 POCs. It can circumvent some drawbacks of existing approaches including low yield, high energy consumption, low efficiency, weak mass/thermal transfer, tedious procedures, poor reproducibility, and high cost. On the basis of this approach, an industrial homogenizer can produce 0.96 ~ 580.48 ton of high-performance COFs, MOFs, and POCs per day, which is unachievable via other methods.

Abstract Background The incidence and mortality of clear cell carcinoma of the kidney increases yearly. There are limited screening methods and advances in treating kidney renal clear cell carcinoma (KIRC). It is important to find new biomarkers to screen, diagnose and predict the prognosis of KIRC. Some studies have shown that CD72 influences the development and progression of colorectal cancer, nasopharyngeal cancer, and acute lymphoid leukemia. However, there is a lack of research on the role of CD72 in the pathogenesis of KIRC. This study aimed to determine whether CD72 is associated with the prognosis and immune infiltration of KIRC, providing an essential molecular basis for the early non-invasive diagnosis and immunotherapy of KIRC. Methods Using TCGA, GTE, GEO, and ImmPort databases, we obtained the differentially expressed mRNA (DEmRNA) associated with the prognosis and immunity of KIRC patients. We used the Kruskal–Wallis test to identify clinicopathological parameters associated with target gene expression. We performed univariate and multivariate COX regression analyses to determine the effect of target gene expression and clinicopathological parameters on survival. We analyzed the target genes' relevant functions and signaling pathways through enrichment analysis. Finally, the correlation of target genes with tumor immune infiltration was explored by ssGSEA and Spearman correlation analysis. Results The results revealed that patients with KIRC with higher expression of CD72 have a poorer prognosis. CD72 was associated with the Pathologic T stage, Pathologic stage, Pathologic M stage, Pathologic N stage, Histologic grade in KIRC patients, Laterality, and OS event. It was an independent predictor of the overall survival of KIRC patients. Functional enrichment analysis showed that CD72 was significantly enriched in oncogenic and immune-related pathways. According to ssGSEA and Spearman correlation analysis, CD72 expression was significantly associated with tumor immune cells and immune checkpoints. Conclusion Our study suggests that CD72 is associated with tumor immunity and may be a biomarker relevant to the diagnosis and prognosis of KIRC patients.

Core–shell nanostructures are powerful platforms for the development of novel nanoscale drug delivery systems with sustained drug release profiles. Coaxial electrospinning is facile and convenient for creating medicated core–shell nanostructures with elaborate designs with which the sustained-release behaviors of drug molecules can be intentionally adjusted. With resveratrol (RES) as a model for a poorly water-soluble drug and cellulose acetate (CA) and PVP as polymeric carriers, a brand-new electrospun core–shell nanostructure was fabricated in this study. The guest RES and the host CA molecules were designed to have a reverse gradient distribution within the core–shell nanostructures. Scanning electron microscope and transmission electron microscope evaluations verified that these nanofibers had linear morphologies, without beads or spindles, and an obvious core–shell double-chamber structure. The X-ray diffraction patterns and Fourier transform infrared spectroscopic results indicated that the involved components were highly compatible and presented in an amorphous molecular distribution state. In vitro dissolution tests verified that the new core–shell structures were able to prevent the initial burst release, extend the continuous-release time period, and reduce the negative tailing-off release effect, thus ensuring a better sustained-release profile than the traditional blended drug-loaded nanofibers. The mechanism underlying the influence of the new core–shell structure with an RES/CA reverse gradient distribution on the behaviors of RES release is proposed. Based on this proof-of-concept demonstration, a series of advanced functional nanomaterials can be similarly developed based on the gradient distributions of functional molecules within electrospun multi-chamber nanostructures.

Alginate is a natural polymer with good biocompatible properties and is a potential polymeric material for the sustainable development and replacement of petroleum derivatives. However, the non-spinnability of pure alginate solutions has hindered the expansion of alginate applications. With the continuous development of electrospinning technology, synthetic polymers, such as PEO and PVA, are used as co-spinning agents to increase the spinnability of alginate. Moreover, the coaxial, parallel Janus, tertiary and other diverse and novel electrospun fiber structures prepared by multi-fluid electrospinning have found a new breakthrough for the problem of poor spinning of natural polymers. Meanwhile, the diverse electrospun fiber structures effectively achieve multiple release modes of drugs. The powerful combination of alginate and electrostatic spinning is widely used in many biomedical fields, such as tissue engineering, regenerative engineering, bioscaffolds, and drug delivery, and the research fever continues to climb. This is particularly true for the controlled delivery aspect of drugs. This review provides a brief overview of alginate, introduces new advances in electrostatic spinning, and highlights the research progress of alginate-based electrospun nanofibers in achieving various controlled release modes, such as pulsed release, sustained release, biphasic release, responsive release, and targeted release.

ABSTRACTBovine enterovirus (BEV) consisting of enterovirus species E (EV-E) and F (EV-F) is the causative agent associated with respiratory and gastrointestinal diseases in cattle. Here, we reported the characterization, genetic diversity, and recombination of novel BEV strains isolated from the major cattle-raising regions in China during 2012–2018. Twenty-seven BEV strains were successfully isolated and characterized. Molecular characterization demonstrated that the majority of these novel BEV strains (24/27) were EV-E, while only few strains (3/27) were EV-F. Sequence analysis revealed the diversity of the circulating BEV strains such as species and subtypes where different species or subtype coinfections were detected in the same regions and even in the same cattle herds. For the EV-E, two novel subtypes, designated as EV-E6 and EV-E7, were revealed in addition to the currently reported EV-E1–EV-E5. Comparative genomic analysis revealed the intraspecies and interspecies genetic exchanges among BEV isolates. The representative strain HeN-B62 was probably from AN12 (EV-F7) and PS-87-Belfast (EV-F3) strains. The interspecies recombination between EV-E and EV-F was also discovered, where the EV-F7-AN12 might be from EV-E5 and EV-F1, and EV-E5-MexKSU/5 may be recombined from EV-F7 and EV-E1. The aforementioned results revealed the genetic diversity and recombination of novel BEV strains and unveiled the different BEV species or subtype infections in the same cattle herd, which will broaden the understanding of enterovirus genetic diversity, recombination, pathogenesis, and prevention of disease outbreaks.IMPORTANCEBovine enterovirus (BEV) infection is an emerging disease in China that is characterized by digestive, respiratory, and reproductive disorders. In this study, we first reported two novel EV-E subtypes detected in cattle herds in China, unveiled the coinfection of two enterovirus species (EV-E/EV-F) and different subtypes (EV-E2/EV-E7, EV-E1/EV-E7, and EV-E3/EV-E6) in the same cattle herds, and revealed the enterovirus genetic exchange in intraspecies and interspecies recombination. These results provide an important update of enterovirus prevalence and epidemiological aspects and contribute to a better understanding of enterovirus genetic diversity, evolution, and pathogenesis.

Abstract Background Human papillomavirus (HPV) integration into the host genome is an important factor in HPV(+)OPSCC carcinogenesis, in conjunction with HPV oncoproteins E6/E7. However, a well‐studied investigation about virus–host interaction still needs to be completed. Our objective is to characterise HPV integration to investigate potential mechanisms of tumourigenesis independent of E6/E7 oncoproteins. Materials and methods High‐throughput viral integration detection was performed on 109 HPV(+)OPSCC tumours with relevant clinicopathological information. Of these tumours, 38 tumours underwent targeted gene sequencing, 29 underwent whole exome sequencing and 26 underwent RNA sequencing. Results HPV integration was detected in 94% of tumours (with a mean integration count of 337). Tumours occurring at the tonsil/oropharyngeal wall that exhibit higher PD‐L1 expression demonstrated increased integration sites (p = .024). HPV exhibited a propensity for integration at genomic sites located within specific fragile sites (FRA19A) or genes associated with functional roles such as cell proliferation and differentiation (PTEN, AR), immune evasion (CD274) and glycoprotein biosynthesis process (FUT8). The viral oncogenes E2, E4, E6 and E7 tended to remain intact. HPV fragments displayed enrichment within host copy number variation (CNV) regions. However, insertions into genes related to altered homologous recombination repair were infrequent. Genes with integration had distinct expression levels. Fifty‐nine genes whose expression level was affected by viral integration were identified, for example, EPHB1, which was reported to be involved in cellular protein metabolic process. Conclusions HPV can promote oncogenesis through recurrent integration into functional host genome regions, leading to subsequent genomic aberrations and gene expression disruption. This study characterises viral integrations and virus–host interactions, enhancing our understanding of HPV‐related carcinogenesis mechanisms.

BackgroundThe gut microbiota (GM) is believed to be closely associated with symptomatic carotid atherosclerosis (SCAS), yet more evidence is needed to substantiate the significant role of GM in SCAS. This study, based on the detection of bacterial DNA in carotid plaques, explores the characteristics of GM in SCAS patients with plaque bacterial genetic material positivity, aiming to provide a reference for subsequent research.MethodsWe enrolled 27 healthy individuals (NHF group) and 23 SCAS patients (PFBS group). We utilized 16S rDNA V3-V4 region gene sequencing to analyze the microbiota in fecal samples from both groups, as well as in plaque samples from the carotid bifurcation extending to the origin of the internal carotid artery in all patients.ResultsOur results indicate significant differences in the gut microbiota (GM) between SCAS patients and healthy individuals. The detection rate of bacterial DNA in plaque samples was approximately 26%. Compared to patients with negative plaques (PRSOPWNP group), those with positive plaques (PRSOPWPP group) exhibited significant alterations in their GM, particularly an upregulation of 11 bacterial genera (such as Klebsiella and Streptococcus) in the gut, which were also present in the plaques. In terms of microbial gene function prediction, pathways such as Fluorobenzoate degradation were significantly upregulated in the GM of patients with positive plaques.ConclusionIn summary, our study is the first to identify significant alterations in the gut microbiota of patients with positive plaques, providing crucial microbial evidence for further exploration of the pathogenesis of SCAS.

Phellinus spp. have historically been used as traditional medicines to treat various diseases owing to their antioxidant, antitumor, and antidiabetic activities. Polysaccharides exhibit antidiabetic activity. In the present study, the polysaccharide contents of four Phellinus strains were compared. Phellinus igniarius QB72 possessed higher polysaccharide production, stronger 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and α-amylase inhibitory activity. The three polysaccharides were sequentially extracted and partially purified from the fermentation mycelia using hot water, 1 % (NH4)2C2O4, and 1.25 M NaOH. Hot water extract polysaccharides exhibited higher DPPH radical scavenging and strong inhibitory activity against α-amylase with an IC50 value of 6.84 ± 0.37 mg/mL. The carbohydrate content of A1 (approximately 17457 Da) was approximately 88.28 %. The α-amylase inhibitory activity IC50 was decreased (3.178 ± 0.187 mg/mL) after DEAE water elution. P. igniarius QB72 hot-water extracts of partially purified polysaccharides have great potential as α-amylase inhibitors in food and medication-assisted additives.

Background: The skeletal muscle index (SMI) can serve as a surrogate for a patient’s nutritional status, which is associated with treatment toxicity. This study aims to investigate the potential of baseline skeletal muscle radiomics features to predict gastrointestinal toxicity of neoadjuvant chemoradiotherapy for rectal cancer. Methods: A total of 214 rectal cancer patients (115, 49 and 50 in the training, internal and external validation set, respectively) who underwent neoadjuvant pelvic radiotherapy with capecitabine and irinotecan were retrospectively identified. The skeletal muscle at the level of the third lumber vertebra was contoured, and the radiomics features were extracted from computed tomography scans. In the training set, the least absolute shrinkage and selection operator (LASSO) regression algorithm was applied to select features that were most significantly associated with grade 3–4 gastrointestinal toxicity (diarrhea, nausea, vomiting and proctitis). The predictive performance and clinical utility were estimated using the area under the receiver operator characteristic curve (AUC), F1-score and decision curve analysis (DCA). Results: Nine features, including the SMI and eight radiomics features, were associated with grade 3–4 gastrointestinal toxicity and included in the logistic regression. This combined predictive model, which incorporated the SMI and radiomics features, showed better discrimination than the SMI alone, with an AUC of 0.856 (95 % CI: 0.782–0.929) in the training cohort, 0.812 (95 % CI: 0.667–0.956) in the internal validation cohort and 0.745 (95 % CI: 0.600–0.890) in the external validation cohort. DCA further verified the clinical utility of the combined predictive model. Conclusion: Radiomics features of skeletal muscle were significantly associated with gastrointestinal toxicity. The predictive model incorporating the SMI and radiomics features exhibits favorable discrimination and may be highly informative for clinical decision-makings.

As one of the best electrocatalysts for the hydrogen evolution reaction, platinum catalysts are a benchmark for the performance evaluation of new catalysts. However, platinum catalysts reported in the literature show diverse electrocatalytic performances, resulting in the lack of a common reference standard. In this study, we investigated several factors that affect the performance of platinum catalysts by performing experimental measurements and data processing. These factors included the solution resistance, electrolyte temperature, loading quantity, catalyst microstructure, and normalization method of the current density. Finally, we recommended criteria for the performance evaluation of electrocatalysts.

Abstract Background Cancer-associated fibroblasts (CAFs) are critically involved in tumor progression by maintaining extracellular mesenchyma (ECM) production and improving tumor development. Cyclooxygenase-2 (COX-2) has been proved to promote ECM formation and tumor progression. However, the mechanisms of COX-2 mediated CAFs activation have not yet been elucidated. Therefore, we conducted this study to identify the effects and mechanisms of COX-2 underlying CAFs activation by tumor-derived exosomal miRNAs in lung adenocarcinoma (LUAD) progression. Methods As measures of CAFs activation, the expressions of fibroblasts activated protein-1 (FAP-1) and α-smooth muscle actin (α-SMA), the main CAFs markers, were detected by Western blotting and Immunohistochemistry. And the expression of Fibronectin (FN1) was used to analyze ECM production by CAFs. The exosomes were extracted by ultracentrifugation and exo-miRNAs were detected by qRT-PCR. Herein, we further elucidated the implicated mechanisms using online prediction software, luciferase reporter assays, co-immunoprecipitation, and experimental animal models. Results In vivo, a positive correlation was observed between the COX-2 expression levels in parenchyma and α-SMA/FN1 expression levels in mesenchyma in LUAD. However, PGE2, one of major product of COX-2, did not affect CAFs activation directly. COX-2 overexpression increased exo-miR-1290 expression, which promoted CAFs activation. Furthermore, Cullin3 (CUL3), a potential target of miR-1290, was found to suppress COX-2/exo-miR-1290-mediated CAFs activation and ECM production, consequently impeding tumor progression. CUL3 is identified to induce the Nuclear Factor Erythroid 2–Related Factor 2 (NFE2L2, Nrf2) ubiquitination and degradation, while exo-miR-1290 can prevent Nrf2 ubiquitination and increase its protein stability by targeting CUL3. Additionally, we identified that Nrf2 is direcctly bound with promoters of FAP-1 and FN1, which enhanced CAFs activation by promoting FAP-1 and FN1 transcription. Conclusions Our data identify a new CAFs activation mechanism by exosomes derived from cancer cells that overexpress COX-2. Specifically, COX-2/exo-miR-1290/CUL3 is suggested as a novel signaling pathway for mediating CAFs activation and tumor progression in LUAD. Consequently, this finding suggests a novel strategy for cancer treatment that may tackle tumor progression in the future. Video Abstract

To improve the effect of curcumin microcapsules, single-factor variables and orthogonal tests were used to elevate the embedding rate of microcapsules, and a mice model of diarrhea induced by senna leaf were applied to test the effect of microcapsules. Results showed that, after optimization, the optimal combination was determined as the concentration of sodium alginate, polysaccharide from Scorias spongiosa, curcumin, Tween 80, and CaCl2 of 2.5%, 0.15%, 0.4%, 0.3%, and 2.0%, respectively. In addition, the optimal embedding time was 1.5 h. The embedding rate of curcumin microcapsules reached 92.26%. The experimental results showed that the optimized curcumin microcapsules could enhance the oxidative stress ability through the TRL4/NF-κB pathway by reducing the concentrations of pro-inflammatory factors IL-1β, TNF-α, and IL-6, and promoting the release of anti-inflammatory factor IL-10. Through the Nrf2 signaling pathway the intestinal antioxidant activity of mice could be improved by promoting the formation of superoxide dismutase and inhibiting the formation of malondialdehyde. As a result, curcumin microcapsules could maintain the intestinal barrier of mice under the combined action of antioxidant and anti-inflammatory agents, thus achieving the purpose of effective intervention in mice diarrhea. The research lays a theoretical foundation for the popularization and application of curcumin microcapsule intervention in diarrhea.

Abstract Background Long non-coding RNA (lncRNA) plays a vital role in tumor proliferation, migration, and treatment. Since it is challenging to standardize the gene expression levels detected by different platforms, the signatures composed of many immune-related single lncRNAs are still inaccurate. Utilizing a gene pair formed of two immune-related lncRNAs and strategically assigning values can effectively meet the demand for a higher-accuracy dual biomarker combination. Methods Co-expression and differential expression analyses were performed on immune genes and lncRNAs data from The Cancer Genome Atlas and the ImmPort database to obtain differentially expressed immune-related lncRNAs for pairwise pairing. The prognostic-related differentially expressed immune-related lncRNAs (PR-DE-irlncRNAs) pairs were then identified by univariate Cox regression and used for lasso regression to construct a prognostic model. Various methods were used to validate the predictive prognostic performance of the model. Additionally, we explored the potential guiding value of the model in immunotherapy and chemotherapy and constructed a nomogram suitable for efficient prognosis prediction. Mechanistic exploration of anti-tumor immunity and mutational perspectives are also included. We also analyzed the correlation between the model and immune checkpoint inhibitors (ICIs)-related, N6-methyadenosine (m6A)-related, and multidrug resistance genes. Results We used a total of 20 pairs of PR-DE-irlncRNAs to create a prognosis model. Quantitative real-time polymerase chain reaction experiments further verified the abnormal expression of 11 lncRNAs in HNSCC cells. Various methods have confirmed the excellent performance of the model in predicting patient prognosis. We reasoned that lncRNAs/TP53 mutation might play a positive/negative anti-tumor role through the immune system by multi-perspective analyses. Finally, it was found that the prognostic model was closely related to immunotherapy and chemotherapy as well as the expression of ICIs/m6A/multidrug resistance-related genes. Conclusion The prognostic model performs excellently in predicting the prognosis of patients and provides the potential value of practical guidance for treatment.