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Abstract The digitization of operation and maintenance in the intelligent power grid equipment relies on a diverse array of information for smart decision-making. In the domain of intelligent decision generation, proficiency is contingent upon extensive learning from copious amounts of text. This necessitates not only robust processing capabilities but also a high level of specialization. In addressing situations where authorization is lacking, pre-trained language models (PLMs) have already provided ideas when confronted with specialized domains or tasks. In consideration of the complexity of textual content in the field of the power grid, which encompasses a multitude of specialized knowledge and involves an abundance of proprietary terminology, we have undertaken an exploration of pre-trained model specialization using the power grid domain as an example, specifically for the task of generating maintenance strategies. A two-stage fine-tuning approach (P2FT) is employed, utilizing a large-scale pre-training model specifically designed for natural language processing. The efficacy and practical value of this method were evaluated through multiple metrics, juxtaposed with other advanced approaches involving low-parameter or parameter-free fine-tuning methods. Through a meticulous analysis and validation of experimental outcomes, we have corroborated the feasibility and practical application value of employing this approach for pre-trained model specialization. Additionally, it has furnished valuable guidance for text generation within both the Chinese language domain and the power grid domain.

Abstract Background Interstitial lung disease (ILD) is a serious complication in systemic juvenile idiopathic arthritis (SJIA). This study aimed to identify the clinical characteristics and prognosis of SJIA-ILD. Methods A two-center retrospective cohort study was conducted on patients newly diagnosed with SJIA in China from October 2010 to December 2021. Clinical characteristics, laboratory parameters, outcomes, and relapse rates were compared between ILD and non-ILD groups. Results A total of 176 children with SJIA were included, including 35 in ILD group and 141 in non-ILD group. The median age at onset of SJIA was 5.8 years (range 4.4–9.5) in patients with SJIA-ILD. It exhibited higher incidences of cervical spine (28.6%) and hip involvement (40.0%) in ILD group (P = 0.031 and P = 0.029, respectively). The incidence of macrophage activation syndrome (MAS) in ILD group reached up to 40%, significantly elevated than that in non-ILD group (P = 0.047). Children with ILD demonstrated a stronger inflammatory response and were more prone to developing lymphopenia (P = 0.009), requiring more combination therapy (P = 0.006) to control disease activity. 54.3% of patients received biologic therapies, with only three patient receiving biologics (one with IL-6 blockade, two with TNF inhibitor) prior to ILD onset and none receiving IL-1 blockade. The median follow-up duration was 6.0 years (range 3.9–9.5). The proportions of patients with SJIA-ILD achieving clinical inactive disease without glucocorticoids within 6 to 12 months of the treatment were significantly lower than control group (45.7% vs. 70.2%, P = 0.006). In ILD group, only 54.3% of patients achieved complete remission, and 17.1% were in a non-remission state, among whom two deaths from respiratory failure. There was no significant difference in disease relapse rates between the two groups (P > 0.05). Conclusions Patients with SJIA-ILD exhibited heightened inflammation, increased hip joint and cervical spine involvement, and were more susceptible to developing lymphopenia and MAS, suggesting a relatively poor prognosis. They required a prolonged time to control inflammation and more aggressive treatment strategies to achieve inactive status. The unsatisfactory rate of complete remission highlighted an urgent need for focused clinical strategies.

Abstract TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.

Abstract Accurate identification and classification of equipment defects are essential for assessing the health of power equipment and making informed maintenance decisions. Traditional defect classification methods, which rely on subjective manual records and intricate defect descriptions, have proven to be inefficient. Existing approaches often evaluate equipment status solely based on defect grade. To enhance the precision of power equipment defect identification, we developed a multi-label classification dataset by compiling historical defect records. Furthermore, we assessed the performance of 11 established multi-label classification methods on this dataset, encompassing both traditional machine learning and deep learning methods. Experimental results reveal that methods considering label correlations exhibit significant performance advantages. By employing balanced loss functions, we effectively address the challenge of sample imbalance across various categories, thereby enhancing classification accuracy. Additionally, segmenting the power equipment defect classification task, which involves numerous labels, into label recall and ranking stages can substantially improve classification performance. The dataset we have created is available for further research by other scholars in the field.

Abstract Background Inflammatory diseases are often initiated by the activation of inflammasomes triggered by pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), which mediate pyroptosis. Although pyroptosis resulting from aberrant inflammasome triggering in thyroid follicular cells (TFCs) has been observed in Hashimoto's thyroiditis (HT) patients, the underlying mechanisms remain largely unknown. Given the extensive involvement of protein ubiquitination and deubiquitination in inflammatory diseases, we aimed to investigate how deubiquitinating enzymes regulate thyroid follicular cell pyroptosis and HT pathogenesis. Methods Our study specifically investigated the role of Ubiquitin-specific peptidase 1 (USP1), a deubiquitinase (DUB), in regulating the inflammasome components NLRP3 and AIM2, which are crucial in pyroptosis. We conducted a series of experiments to elucidate the function of USP1 in promoting pyroptosis associated with inflammasomes and the progression of HT. These experiments involved techniques such as USP1 knockdown or inhibition, measurement of key pyroptosis indicators including caspase-1, caspase-1 p20, and GSDMD-N, and examination of the effects of USP1 abrogation on HT using a mouse model. Furthermore, we explored the impact of USP1 on NLRP3 transcription and its potential interaction with p65 nuclear transportation. Results Our findings provide compelling evidence indicating that USP1 plays a pivotal role in promoting inflammasome-mediated pyroptosis and HT progression by stabilizing NLRP3 and AIM2 through deubiquitination. Furthermore, we discovered that USP1 modulates the transcription of NLRP3 by facilitating p65 nuclear transportation. Knockdown or inhibition of USP1 resulted in weakened cell pyroptosis, as evidenced by reduced levels of caspase-1 p20 and GSDMD-N, which could be restored upon AIM2 overexpression. Remarkably, USP1 abrogation significantly ameliorated HT in the mice model, likely to that treating mice with pyroptosis inhibitors VX-765 and disulfiram. Conclusions Our study highlights a regulatory mechanism of USP1 on inflammasome activation and pyroptosis in TFCs during HT pathogenesis. These findings expand our understanding of HT and suggest that inhibiting USP1 may be a potential treatment strategy for managing HT.

Abstract Tyrannosaurids were the most derived group of Tyrannosauroidea and are characterized by having two body plans: gracile, long-snouted and robust, deep-snouted skulls. Both groups lived sympatrically in central Asia. Here, we report a new deep-snouted tyrannosaurid, Asiatyrannus xui gen. et sp. nov., from the Upper Cretaceous of Ganzhou City, southeastern China, which has produced the large-bodied and long-snouted Qianzhousaurus. Based on histological analysis, the holotype of Asiatyrannus xui is not a somatically mature adult, but it already passed through the most rapid growth stages. Asiatyrannus is a small to medium-sized tyrannosaurine, with a skull length of 47.5 cm and an estimated total body length of 3.5–4 m; or around half the size of Qianzhousaurus and other large-bodied tyrannosaurines in similar growth stages. Asiatyrannus and Qianzhousaurus are sympatric tyrannosaurid genera in the Maastrichtian of southeastern China. Asiatyrannus differs from Qianzhousaurus in that it has a proportionally deeper snout, longer premaxilla, deeper maxilla, and deeper dentary, and the cornual process of the lacrimal is inflated without developing a discrete horn. The different skull proportions and body sizes suggest that Asiatyrannus and Qianzhousaurus likely had different feeding strategies and occupied different ecological niches.

Abstract Protein induced by vitamin K absence or antagonist II (PIVKA-II) plays a critical role in the diagnosis of hepatocellular carcinoma (HCC), however, studies on its efficacy in diagnosing recurrent HCC were rarely found. A multicenter, retrospective, and observational study was conducted. During the overall follow-up of 5 years, HCC patients who had curative resection were monitored every 3 months in the first year post-surgery and every 6 months thereafter if no recurrence occurred. Tumor markers were collected at the diagnosis of recurrence for those with recurrence and at the last follow-up for those without recurrence. The median serum levels of PIVKA-II and AFP in the recurrence group were significantly higher than those in the non-recurrence group (PIVKA-II: 84.62 vs. 18.76 mAU/ml, p

To tackle the challenges associated with variability and uncertainty in distributed power generation, as well as the complexities of solving high-dimensional energy management mathematical models in mi-crogrid energy optimization, a microgrid energy optimization management method is proposed based on an improved soft actor-critic algorithm. In the proposed method, the improved soft actor-critic algorithm employs an entropy-based objective function to encourage target exploration without assigning signifi-cantly higher probabilities to any part of the action space, which can simplify the analysis process of distributed power generation variability and uncertainty while effectively mitigating the convergence fragility issues in solving the high-dimensional mathematical model of microgrid energy management. The effectiveness of the proposed method is validated through a case study analysis of microgrid energy op-timization management. The results revealed an increase of 51.20%, 52.38%, 13.43%, 16.50%, 58.26%, and 36.33% in the total profits of a microgrid compared with the Deep Q-network algorithm, the state-action-reward-state-action algorithm, the proximal policy optimization algorithm, the ant-colony based algorithm, a microgrid energy optimization management strategy based on the genetic algorithm and the fuzzy inference system, and the theoretical retailer stragety, respectively. Additionally, com-pared with other methods and strategies, the proposed method can learn more optimal microgrid energy management behaviors and anticipate fluctuations in electricity prices and demand.

This study examines the impact of communication and group size on bank run games, with a strategic focus on three-player games. In the baseline treatment group, communication is not allowed in two-player and three-player games. The main treatment consists of costless communication, cheap communication, and costly communication. The sender's action becomes more predictable with the increasing communication costs due to a lack of incentives to deceive. We find that in the non-cooperative, two-player bank run game, communication fosters cooperative behavior with the learning effect in the repeated interaction. However, coordination is far more difficult to achieve with Nash Pareto dominant equilibrium in three-player games due to its complexity in decision-making in larger groups. The ultimate result presents the limitation of communication as an efficiency-enhancing mechanism. A public recommendation is that policymakers should increase public transparency and ensure public confidence in banking systems to mitigate the risks and uncertainty of bank runs. In sum, the study presents the following: • In a three-player bank run game, communication is less effective than in a two-player scenario. • Policymakers should ensure public confidence and increase public transparency of banking systems.

Abstract Background Hypertrophic cranial pachymeningitis (HCP) is uncommon but a poorly understood complication of granulomatosis with polyangiitis (GPA). Objectives We conducted this retrospective study to elucidate the clinical characteristics and factors independently associated with granulomatosis with polyangiitis (GPA) complicated by hypertrophic cranial pachymeningitis (HCP) in China. Methods We collected the medical records of 78 patients diagnosed with GPA who were admitted to the inpatient department of Peking Union Medical College Hospital between January 2003 and September 2021. Clinical features, laboratory and radiological findings, and Birmingham Vasculitis Activity Scores (excluding meningitis score) were recorded. A binary logistic regression analysis was performed to analyze factors independently associated with GPA-related HCP. Results Headache (100%) and cranial nerve palsy (61.5%) were common manifestations of HCP. Compared to 52 GPA patients without HCP, 26 patients with HCP required more time from initial symptoms to diagnosis, with a lower ratio of pulmonary and renal involvement, a higher ratio of myeloperoxidase–antineutrophil cytoplasmic antibody (MPO-ANCA) positivity, conductive or sensorineural hearing loss, mastoiditis, and decreased vision or sudden visual loss. Binary logistic regression analysis indicated that proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) negativity (OR 10.698, p = 0.001), conductive or sensorineural hearing loss (OR 10.855, p = 0.005), and decreased vision or sudden visual loss (OR 8.647, p = 0.015) were significantly associated with GPA-related HCP. Of the 26 patients, 18 received methylprednisolone pulse treatment, and 18 received intrathecal injections of dexamethasone and methotrexate. Conclusions HCP was a severe manifestation of GPA in our study. Independent factors associated with the occurrence of HCP in patients with GPA included PR3-ANCA negativity, conductive or sensorineural hearing loss, and decreased vision or sudden visual loss. Furthermore, GPA-related HCP was associated with higher disease activity, requiring more intensive treatments.

In response to the growing demand for sustainable and efficient energy management, this paper introduces an innovative approach aimed at enhancing grid-connected multi-microgrid systems. The study proposes a strategy that involves the leasing of shared energy storage (SES) to establish a collaborative micro-grid coalition (MGCO), enabling active participation in the dispatching operations of active distribution networks (ADNs). A hierarchical framework wherein the ADN assumes the role of the central orchestrator is developed, while the MGCO and SES operators (SESO) function as responsive entities within a single-leader multi-follower game optimization model. The ADN leader implements time-of-use (TOU) pricing mechanisms as a strategic incentive to encourage active engagement from the MGCO and SESO followers in peak regulation dispatch activities. In response to these TOU policies, the followers implement a two-stage dispatch optimization strategy. The first stage is dedicated to optimizing energy storage utilization. Within this phase, each microgrid meticulously fine-tunes its energy storage charging and discharging strategies with the primary objectives of mitigating power fluctuations, reducing load variance, minimizing energy storage costs, and facilitating on-demand leasing of energy storage resources. Subsequently, energy storage resources are pooled and shared to harness collective benefits and enhance alliance-wide energy utilization. Emphasis is placed on prioritizing the integration of renewable energy sources, promptly responding to peak demand regulation and scheduling, maximizing overall benefits, and equitably distributing cooperative advantages among alliance members. To substantiate the effectiveness of this comprehensive methodology, the paper presents illustrative results that provide compelling evidence of its potential to facilitate the seamless integration of microgrids, shared energy storage, and active distribution networks.

A bridge hybrid isolation system, integrating both active and passive control strategies, is proposed and investigated to enhance seismic performance. The system is modeled as a two-layer structure, with the upper layer subjected to active control via a Proportional–Integral–Derivative (PID) controller, and the lower layer employing a conventional passive base isolation system. The displacement response of the superstructure is minimized by the control forces generated by the PID controller, which also accounts for the reaction forces transmitted to the lower isolation layer. To optimize the controller’s performance, a genetic algorithm is implemented for real-time tuning of the PID parameters. Numerical simulations, conducted using the Newmark method, are employed to assess the influence of active control on the lower isolation system. The results reveal that, while active control increases the peak displacement of the superstructure to some extent, it significantly prolongs the structural period, thus enhancing the system’s overall seismic resilience and stability.

BackgroundAcute rejection (AR) after liver transplantation (LT) remains an important factor affecting the prognosis of patients. CD8+ T cells are considered to be important regulatory T lymphocytes involved in AR after LT. Our previous study confirmed that autophagy mediated AR by promoting activation and proliferation of CD8+ T cells. However, the underlying mechanisms regulating autophagy in CD8+ T cells during AR remain unclear.MethodsHuman liver biopsy specimens of AR after orthotopic LT were collected to assess the relationship between JNK and CD8+ T cells autophagy. The effect of JNK inhibition on CD8+ T cells autophagy and its role in AR were further examined in rats. Besides, the underlying mechanisms how JNK regulated the autophagy of CD8+ T cells were further explored.ResultsThe expression of JNK is positive correlated with the autophagy level of CD8+ T cells in AR patients. And similar findings were obtained in rats after LT. Further, JNK inhibitor remarkably inhibited the autophagy of CD8+ T cells in rat LT recipients. In addition, administration of JNK inhibitor significantly attenuated AR injury by promoting the apoptosis and downregulating the function of CD8+ T cells. Mechanistically, JNK may activate the autophagy of CD8+ T cells through upregulating BECN1 by inhibiting the formation of Bcl-2/BECN1 complex.ConclusionJNK signaling promoted CD8+ T cells autophagy to mediate AR after LT, providing a theoretical basis for finding new drug targets for the prevention and treatment of AR after LT.

Abstract Background Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. Methods The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-β1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. Results TGF-β1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-β1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). Conclusion Pd-MSCs-EVs ameliorated TGF-β1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.

Purpose. NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Methods. Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Results. Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Conclusions. Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.

Panax notoginseng is a traditional Chinese medicinal herb. With its wide applications in medicine, food products, health care, cosmetics and other industries, identification and detection of P. notoginseng have become critical. In this study, we developed a real-time polymerase chain reaction (qPCR) assay with specific and internal control probes based on chloroplast psbA-trnH gene and 18S rDNA to identify and detect P. notoginseng in different products. A specific primer and probe set was designed by comparing psbA-trnH sequence among P. notoginseng, Panax ginseng, Panax quinquefolius and Panax japonicus. Besides, the 18S rDNA gene was used as an internal control. The qPCR condition was optimized with the sensitivity to be 0.005 ng/μL and high specificity. There was no cross-reaction among 18 closely related common Chinese herbs. Detection results of 28 commercially available P. notoginseng products were consistent with the standardized sequencing results. This study provides a rapid, specific and sensitive assay for detection of P. notoginseng in different products.

Abstract Background An immune-related gene signature (IGS) was established for discriminating prognosis, predicting benefit of immunotherapy, and exploring therapeutic options in hepatocellular carcinoma (HCC). Methods Based on Immune-related hub genes and The Cancer Genome Atlas (TCGA) LIHC dataset (n = 363), an immune-related gene signature (IGS) was established by least absolute shrinkage and selection operator (LASSO) analysis. The prognostic significance and clinical implications of IGS were verified in International Cancer Genome Consortium (ICGC) and Chinese HCC (CHCC) cohorts. The molecular and immune characteristics and the benefit of immune checkpoint inhibitor (ICI) therapy in IGS-defined subgroups were analyzed. In addition, by leveraging the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing datasets, we determined the potential therapeutic agents for high IGS-risk patients. Results The IGS was constructed based on 8 immune-related hub genes with individual coefficients. The IGS risk model could robustly predict the survival of HCC patients in TCGA, ICGC, and CHCC cohorts. Compared with 4 previous established immune genes-based signatures, IGS exhibited superior performance in survival prediction. Additionally, for immunological characteristics and enriched pathways, a low-IGS score was correlated with IL-6/JAK/STAT3 signaling, inflammatory response and interferon α/γ response pathways, low TP53 mutation rate, high infiltration level, and more benefit from ICI therapy. In contrast, high IGS score manifested an immunosuppressive microenvironment and activated aggressive pathways. Finally, by in silico screening potential compounds, vindesine, ispinesib and dasatinib were identified as potential therapeutic agents for high-IGS risk patients. Conclusions This study developed a robust IGS model for survival prediction of HCC patients, providing new insights into integrating tailored risk stratification with precise immunotherapy and screening potentially targeted agents.

Abstract Background Globally, millions of patients suffer from regenerative deficiencies, such as refractory wound healing, which is characterized by excessive inflammation and abnormal angiogenesis. Growth factors and stem cells are currently employed to accelerate tissue repair and regeneration; however, they are complex and costly. Thus, the exploration of new regeneration accelerators is of considerable medical interest. This study developed a plain nanoparticle that accelerates tissue regeneration with the involvement of angiogenesis and inflammatory regulation. Methods Grey selenium and sublimed sulphur were thermalized in PEG-200 and isothermally recrystallised to composite nanoparticles (Nano-Se@S). The tissue regeneration accelerating activities of Nano-Se@S were evaluated in mice, zebrafish, chick embryos, and human cells. Transcriptomic analysis was performed to investigate the potential mechanisms involved during tissue regeneration. Results Through the cooperation of sulphur, which is inert to tissue regeneration, Nano-Se@S demonstrated improved tissue regeneration acceleration activity compared to Nano-Se. Transcriptome analysis revealed that Nano-Se@S improved biosynthesis and ROS scavenging but suppressed inflammation. The ROS scavenging and angiogenesis-promoting activities of Nano-Se@S were further confirmed in transgenic zebrafish and chick embryos. Interestingly, we found that Nano-Se@S recruits leukocytes to the wound surface at the early stage of regeneration, which contributes to sterilization during regeneration. Conclusion Our study highlights Nano-Se@S as a tissue regeneration accelerator, and Nano-Se@S may provide new inspiration for therapeutics for regenerative-deficient diseases. Graphical Abstract

Non-intrusive load monitoring is a novel and cost-effective technology for monitoring details of electricity consumption and identifying the operating status of appliances. It supports the construction of the energy internet and big data on electricity consumption in smart cities. However, one of the most challenging problems in this area is that machine learning algorithms often require large amounts of labeled data. In this paper, a non-intrusive load monitoring model based on the Self-supervised Regularization is proposed. The model reduces the pre-processing stage compared to the traditional methods. We make full use of the unlabeled data by using them to generate proxy labels to participate in the model training together with the true labels. We performed experiments on the common data set PLAID to compare performance with the existing method Mean Teacher and CoMatch. The experimental results show that: 1) when using all labeled data, the model with self-supervised regularization significantly improves the traditional supervised classifier with a recognition accuracy of 0.965; 2) when coupled with unlabeled data, our model produces good semi-supervised performance. It is highly competitive with current state-of-the-art Mean Teacher and Contrastive Learning.

Abstract Background RNA methylation (RM) is a crucial post-translational modification (PTM) that directs epigenetic regulation. It mostly consists of N1-methyladenosine (m1A), 5-methylcytosine (m5C), N3-methylcytidine (m3C), N6-methyladenosine (m6A), and 2′-O-methylation (Nm). The “writers” mainly act as intermediaries between these modifications and associated biological processes. However, little is known about the interactions and potential functions of these RM writers in hepatocellular carcinoma (HCC). Methods The expression properties and genetic alterations of 38 RM writers were assessed in HCC samples from five bioinformatic datasets. Two patterns associated with RM writers were identified using consensus clustering. Then, utilizing differentially expressed genes (DEGs) from different RM subtypes, we built a risk model called RM_Score. Additionally, we investigated the correlation of RM_Score with clinical characteristics, tumor microenvironment (TME) infiltration, molecular subtypes, therapeutic response, immunotherapy effectiveness, and competing endogenous RNA (ceRNA) network. Results RM writers were correlated with TME cell infiltration and prognosis. Cluster_1/2 and gene.cluster_A/B were shown to be capable of distinguishing the HCC patients with poor prognosis after consensus and unsupervised clustering of RNA methylation writers. Additionally, we constructed RNA modification pattern-specific risk model and subdivided the cases into RM_Score high and RM_Score low subgroups. In individual cohorts or merged datasets, the high RM_Score was related to a worse overall survival of HCC patients. RM_Score also exhibited correlations with immune and proliferation related pathways. In response to anti-cancer treatments, the RM_Score had a negative correlation (drug sensitive) with drugs that focused on the MAPK/ERK and metabolism signaling, and a positive correlation (drug resistant) with compounds targeting RKT and PI3K/mTOR signaling pathway. Notably, the RM_Score was connected to the therapeutic effectiveness of PD-L1 blockage, implying that RM writers may be the target of immunotherapy to optimize clinical outcomes. Additionally, a ceRNA network was generated including 2 lncRNAs, 4 miRNAs, and 7 mRNAs that was connected to RM writers. Conclusions We thoroughly investigated the potential functions of RNA methylation writers and established an RM_patterns-based risk model for HCC patients. This study emphasized the critical functions of RM modification in TME infiltration, targeted therapy, and immunotherapy, providing potential targets for HCC.

Abstract Purpose A variety of studies have connected circadian rhythm to the initiation and progression of hepatocellular carcinoma (HCC). The purpose of this study was to figure out about the circadian genes' profile characteristics, prognostic significance, and targeted values in HCC. Methods The expression profiles and prognostic significance of circadian genes in the cancer genome atlas liver hepatocellular carcinoma (TCGA-LIHC) database were investigated using bioinformatics analysis. The expression features of Casein Kinase 1 Delta (CSNK1D), a robust signature gene, was further detected by immunohistochemistry, western blotting and Real-time quantitative PCR (RT-qPCR) in a local HCC cohort. The effect of CSNK1D on corresponding phenotypes of HCC cells was evaluated using Cell Counting Kit-8 (CCK8), flowcytometry, clone assay, Transwell assay, and xenograft assay. In addition, the underlying mechanisms of CSNK1D in the Wnt/β-catenin signaling were validated by multiple molecular experiments. Results Abnormal expression of the Circadian genome was associated with the malignant clinicopathological characteristics of HCC patients. A 10 circadian gene-based signature with substantial prognostic significance was developed using Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. Of them, CSNK1D, significantly elevated in a local HCC cohort, was chosen for further investigation. Silencing or overexpression of CSNK1D significantly reduced or increased proliferation, invasion, sorafenib resistance, xenograft development, and epithelial-mesenchymal transformation (EMT) of HCC cells, respectively. Mechanically, CSNK1D exacerbated the aggressiveness of HCC cells by activating Wnt/β-catenin signaling through interacting with Dishevelled Segment Polarity Protein 3 (DVL3). Conclusions The Circadian gene CSNK1D was found to contribute to HCC progression by boosting the Wnt/β-catenin pathway, hinting that it could be a prospective therapeutic target for HCC.

Abstract Background Macrophages are key innate immune cells implicated in the pathogenesis of Behçet’s disease (BD), and macrophage polarization plays a pivotal role in inflammatory response. This study aimed to investigate the role of BD serum on the phenotypes and functions of macrophage polarization. Methods BD or HC serum-treated human monocyte-derived macrophages (HMDMs) were examined M1/M2 phenotypes using flow cytometry and ELISA. The phagocytic capacity of HMDMs and CD4+T cell differentiation facilitated by HMDMs were measured by flow cytometry. Transcriptome analysis of BD and HC serum-stimulated HMDMs was conducted to identify differentially expressed genes. NF-κB signaling was examined using western blot to explore the mechanism of macrophage polarization induced by BD serum. Results BD serum-treated macrophages expressed a higher level of CD86, IL-12, and TNF-α and a lower level of CD163, which were compatible with the M1-like phenotype. Furthermore, BD serum-treated macrophages showed enhanced phagocytic capacity and promoted more Th1 cell differentiation. Sixty-one differentially expressed genes were identified between BD and HC serum-treated macrophages and were enriched in NF-κB signaling. BD serum-treated macrophages showed upregulated p-p65 and downregulated IκBα, and NF-κB inhibitor attenuated BD serum-stimulated M1-like phenotype. Conclusions BD serum promoted macrophage polarization toward a proinflammatory M1-like phenotype through NF-κB signaling and potentially facilitated inflammation in BD. M1 polarized macrophages may be a potential therapeutic target for BD.

Selenium (Se) is an essential trace element involved in nearly all human physiological processes but suffers from a narrow margin between benefit and toxicity. The nanoform of selenium has been proven shown to be more bioavailable and less toxic, yet significant challenges remain regarding the efficient and feasible synthesis of biologically active nanoselenium. In addition, although nanoselenium has shown a variety of biological activities, more interesting nanoselenium features are expected. In this work, hydrosoluble nanoselenium termed Nano-Se in the zero oxidation state was synthesized between gray Se and PEG. A zebrafish screen was carried out in zebrafish larvae cocultured with Nano-Se. Excitingly, Nano-Se promoted the action of the FGFR, Wnt, and VEGF signaling pathways, which play crucial roles in tissue regeneration. As expected, Nano-Se not only achieved the regeneration of zebrafish tail fins and mouse skin but also promoted the repair of skin in diabetic mice while maintaining a profitable safe profile. In brief, the Nano-Se reported here provided an efficient and feasible method for bioactive nanoselenium synthesis and not only expanded the application of nanoselenium to regenerative medicine but also likely reinvigorated efforts for discovering more peculiarunique biofunctions of nanoselenium in a great variety of human diseases.

Voltage-induced heating defect is a type of defect that may occur in transformation substation equipment. Although this type of defect is less common compared to current-induced heating defects, it is crucial to identify it due to its association with severe insulation degradation problems that require prompt intervention. However, the temperature variations caused by these defects may be relatively subtle, making it challenging to distinguish them in thermal images. In this work, considering the characteristics of voltage-induced heating defects and the scarcity of defect data, we propose a two-stage method for defect detection. In the first stage, we employ oriented R-CNN to detect oriented parts of the equipment, accurately localizing the centerline of each part. In the second stage, we extract the temperature distribution along the centerline of specific parts and discretize them as features. Subsequently, we train one-class support vector machines based on the features extracted from normal images for defect diagnosis. Experimental results demonstrate that the proposed method is capable of accurately detecting defects while maintaining a low false positive rate.

Efficient electro-thermal coupling calculation is of great significance to the monitoring and structural design of power equipment. Finite element method (FEM) is one of the powerful tools of electro-thermal analysis and is widely used in various fields. However, the finite element method itself cannot solve the first-order discontinuity, which causes the deterioration of accuracy. For example, in the electro-thermal coupling calculation, Joule heat is often used as the only heat source of the thermal field, and the calculation of Joule heat depends on the first-order variable field strength of the electric field. The calculation error of is further amplified in the thermal field solution, and the performance is more obvious in strong electromagnetic environment. Therefore, this paper proposes a finite element (RFEM) electrothermal coupling method based on the radial point interpolation method (RPIM). The idea of this method is to use the first-order continuous RPIM method to interpolate the variables in the overall solution domain to obtain continuous and smooth solution results. Examples show that RFEM has a higher solution efficiency than FEM, and it is better at capturing local high gradient changes in an electromagnetic environment.

Abstract Background Bullous systemic lupus erythematosus (BSLE) is a rare subtype of systemic lupus erythematosus (SLE) that is clinically characterized by subepidermal tense vesicles or bullae. We aimed to investigate the clinical and laboratory features of patients with BSLE. Methods We retrospectively reviewed all patients who fulfilled the diagnostic criteria for BSLE in our institution from 2015 to 2021. Cutaneous lesions, systemic manifestations, treatment options, and outcomes were evaluated. For each case of BSLE, four controls were randomly selected from patients with single SLE. Major clinical and laboratory characteristics were compared between the two groups. Results Among 4221 patients with SLE, 12 developed BSLE. Vesiculobullous lesions were the first sign in five of the BSLE patients (5/12, 41.7%) and appeared after SLE diagnosis in the remaining seven patients (7/12, 58.3%), with a median duration from SLE onset of 36 months (4–115 months). The most common BSLE-affected sites were the head and neck (10/12, 83.3%), extremities (9/12, 75.0%), trunk (7/12, 58.3%), and mucosae (6/12, 50.0%). All patients with BSLE had extra-cutaneous involvement. The SLE disease activity index score exceeded 5 in 10/12 (83.3%) patients, which indicated high disease activity. Patients in the BSLE group had significantly higher incidences of proteinuria (83.3% vs. 47.9%, P = 0.027), hematuria (75% vs. 31.3%, P = 0.006), hemolytic anemia (33.3% vs. 0%, P = 0.000), and leukopenia (66.7% vs. 25.0%, P = 0.006) than those in the control group. The use of systemic corticosteroids, immunosuppressants, dapsone, and skin care was effective in controlling disease. Conclusions Vesiculobullous lesions may be the first manifestation and indicate a high disease activity in patients with BSLE. Early diagnosis using clinical, histopathological, and immunological evaluations can lead to appropriate treatment of this progressive disease and improve prognosis.

The safe and stable operation of power transmission and transformation equipment is the foundation of power grid safety, so the prediction of power transmission and transformation equipment fault is particularly important, and the prediction of the characteristic parameters that affect the equipment fault is the core of fault prediction. In this paper, a method for predicting the characteristic parameters of power transmission and transformation equipment based on combination prediction is presented. According to the correlation analysis results of various parameters, the key prediction input data with high correlation degree with the predicted parameters are extracted automatically, and the method library including multiple single-factor prediction models, multi-factor prediction models and combined prediction models is established. The error checking method is used to automatically select the optimal prediction method, and then the characteristic parameters of the parameter are automatically predicted. The test results show that the multi-factor power transmission and transformation equipment fault feature parameter prediction method can improve the accuracy of prediction, and is of great significance to improve the scientific evaluation of equipment health status and the prediction of equipment fault.

Duplex stainless steel (DSS) exhibits good mechanical properties and corrosion resistance, and has attracted more and more attention within the fields of both science and technology. However, the increasing levels of N and of Cr, Mo, etc., as alloying elements in DSS increase production difficulty. In particular, the N element increases the risk of Cr2N precipitation, which can seriously deteriorate the thermal plasticity of DSS, while increasing its strength. For this reason, a low-N-content 25Cr-type DSS was designed in order to adapt additive manufacturing processes. With regard to the nano-inclusions of oxide precipitation and effective grain refinement, and considering the benefits of selective laser melting fabrication, a low-N 25Cr-type duplex stainless steel with a 0.09 wt.% N content achieved high mechanical properties, with a yield strength of 712 MPa and an elongation of 27.5%, while the V-notch impact toughness was 160 J/cm2. The microstructure evolution and the reasons behind the improvement in mechanical properties will be discussed in detail.

BackgroundEtanercept biosimilar recombinant human TNF-α receptor II: IgG Fc fusion protein (rhTNFR-Fc) has showed its efficacy and safety in Chinese patients with rheumatoid arthritis. However, data on rhTNFR-Fc's application in juvenile idiopathic arthritis (JIA) is limited.MethodsA prospective, observational, multicenter study was performed at 6 institutes in China from July 2020 to December 2021. In a 24-week follow-up, patients with JIA including polyarticular JIA and enthesitis related arthritis received rhTNFR-Fc plus methotrexate (MTX) treatment. The primary outcome parameters were improvements of cJADAS-10 (clinical Juvenile Arthritis Disease Activity Score), and the secondary outcome parameter was an inactive disease.Results60 patients completed at least 12-week follow-up, and 57 completed 24-week follow-up. They had high C reactive protein values (11.6 mg/L) and cJADAS-10 (14.6) at baseline. Thirteen patients had morning stiffness. 33 patients showed synovial thickening, and 34 showed bone marrow edemas on MRI. Ultrasonography demonstrated significant joint effusions in 43 patients. The cJADAS-10 sharply decreased from 14.66 at the baseline to 2.4 at 24 weeks of rhTNFR-Fc therapy, respectively (P

PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)–associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disease caused by heterozygous gain-of-function mutation in PSTPIP1. As one of the PSTPIP1-associated inflammatory diseases (PAIDs), neutropenia is a distinct manifestation to separate PAMI syndrome from other PAIDs. This study aimed to investigate the potential role of neutrophils and inflammatory signatures in the pathogenesis of PAMI. PAMI neutrophils displayed markedly increased production of interleukin-1β (IL-1β) and IL-18 by enzyme linked immunosorbent assay (ELISA) assay and intracellular cytokine staining. ASC speck formation and lactic dehydrogenase (LDH) release are also increased in patient neutrophils suggesting elevated pyrin inflammasome activation followed by upregulated cell death in PAMI neutrophils. RNA sequencing result showed strong inflammatory signals in both nuclear-factor kappa B (NF-κB) pathway and interferon (IFN) pathway in patient neutrophils. This study highlighted that elevated proinflammatory cytokines IL-1β and IL-18, increased pyrin inflammasome activation, and upregulation of NF-κB and IFN signaling pathways in neutrophils play important roles in pathogenicity of PAMI syndrome.

Objective: The aim of this study was to evaluate the effectiveness and safety of low-dose interferon alpha-2a (IFNα2a) in Behçet’s syndrome (BS) patients with refractory vascular/cardiac or neurological involvement. Methods: In this retrospective cohort study, we consecutively included 25 BS patients with refractory vascular/cardiac ( n = 16) or neurological involvement ( n = 9) who received IFNα2a treatment in our center between June 2018 and September 2021. The low-dose IFNα2a (3 million IU, every other day) was used as an add-on treatment with the continuation of glucocorticoids (GCs) and immunosuppressants. Results: In total, 25 patients (20 males, 5 females) with a mean age of 31.92 ± 9.25 years were included. IFNα2a was administered for BS patients with refractory vascular/cardiac involvement ( n = 16) and neurological involvement ( n = 9). Before the initiation of IFNα2a, patients had insufficient response or intolerance to conventional therapies. After a median follow-up of 23 [interquartile range (IQR), 11–30] months, all patients achieved clinical improvement. The Behçet’s disease Current Activity Form (BDCAF) score improved significantly (5 versus 0, median, p 0.05). Decrease in erythrocyte sedimentation rate [ESR; 24 (IQR, 12–43.5) versus 5 (IQR, 2.75–10.5) mm/h, p = 0.0001] and C-reactive protein [CRP; 6.64 (IQR, 3.67–19.82) versus 1.24 (IQR, 0.24–3.12) mg/liter, p

Background & Aims: Hepatitis B virus (HBV) infection is a significant cause of liver function damage. However, previous studies on HBV mainly aimed at ordinary people, and there is a lack of consensus on the relationship between HBV infection and gestational diabetes mellitus (GDM) and whether HBV-infected pregnant women should undergo antiviral treatment. In addition, systematic studies on the impact of HBV infection on GDM have rarely been studied directly. Therefore, the overall goal of this study was to pursue the association between HBV infection, liver function, and GDM using Xiamen area gestational big data.Methods: Using the Xiamen Primary Health Information System-maternal and child health information system, the data on participants (138,867 in total) expected confinement between 2008 and 2018 were included. Using univariate and multivariate logistic regressions, we constructed models to determine the role of HBV infection and liver function status in GDM. In addition, an analysis of variance tests was performed to study whether the relationship between HBsAg and GDM differed in the normal liver function and the abnormal liver function subgroups.Results: HBsAg's positive status showed a substantial correlation with GDM onset in univariate and multivariate logistic regressions (p < 0.001). Subgroup analysis among HBsAg, liver function, and GDM suggests that both HBsAg and liver function affect the onset of GDM and have the highest prevalence of both abnormalities. Furthermore, ANOVA was used to investigate the association of HBsAg positive (p < 0.001), abnormal liver function (p < 0.001), and their interaction (p = 0.302) on the onset of GDM. This result showed that HBsAg is an independent factor of GDM pathogenesis, regardless of liver function status.Conclusion: HBsAg and liver function are independent factors in GDM. Therefore, regarding these results, while clinicians consider the traditional risk factors of GDM, it is necessary to consider the HBV infection status. Conducting a dietary intervention for HBsAg-positive pregnant women at the early stage of pregnancy is conducive to reducing the adverse effects.

Abstract Gestational diabetes mellitus (GDM) has aroused wide public concern, as it affects approximately 1.8–25.1% of pregnancies worldwide. This study aimed to examine the association of pre-pregnancy demographic parameters and early-pregnancy laboratory biomarkers with later GDM risk, and further to establish a nomogram prediction model. This study is based on the big obstetric data from 10 “AAA” hospitals in Xiamen. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria. Data are analyzed using Stata (v14.1) and R (v3.5.2). Total 187,432 gestational women free of pre-pregnancy diabetes mellitus were eligible for analysis, including 49,611 women with GDM and 137,821 women without GDM. Irrespective of confounding adjustment, eight independent factors were consistently and significantly associated with GDM, including pre-pregnancy body mass index (BMI), pre-pregnancy intake of folic acid, white cell count, platelet count, alanine transaminase, albumin, direct bilirubin, and creatinine (p

Abstract Regulatory T-cell (Treg)/T-helper 17 (Th17) cell balance plays an important role in the progression of rheumatoid arthritis (RA). Our study explored the protective effect of protectin DX (PDX), which restored Treg/Th17 cell balance in RA, and the role of the nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathway in this process. Using mass spectrometry, we discovered that level of PDX decreased in active-RA patients and increased in inactive-RA patients compared with HCs, and serum PDX was a potential biomarker in RA activity detection (area under the curve [AUC] = 0.86). In addition, a collagen-induced arthritis (CIA) mice model was constructed and PDX obviously delayed RA progression in the CIA model, upregulating Tregs and anti-inflammatory cytokines while downregulating Th17 cells and pro-inflammatory cytokines. Moreover, NLRP3 knockout and rescue experiments demonstrated that NLRP3 participated in PDX-mediated Treg/Th17 cell balance restoration, joint injury amelioration and inflammatory-response attenuation using Nlrp3 −/− mice. Furthermore, microarray and verified experiments confirmed that PDX reduced NLRP3 expression via miRNA-20a (miR-20a). In summary, we confirmed for the first time that PDX could effectively ameliorate CIA progression by restoring Treg/Th17 cell balance, which was mediated by inhibition of the NLRP3 inflammasome pathway via miR-20a.

Abstract Background Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease caused by mutations in the ADA2 gene. Few Chinese cases have been reported. We describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and non-Chinese patients. Methods Primary immunodeficiency disease panel or whole-exome sequencing was performed for suspected cases, and assays for adenosine deaminase 2 (ADA2) enzyme activity were also carried out for the patients and their parents. Case reports of Chinese and non-Chinese patients with DADA2 were searched in PubMed and Chinese national databases. Results Seven unrelated children from China with DADA2 were included in our study. Five were identified at Peking Union Medical College Hospital, and two had been reported previously (1 on PubMed and 1 in Chinese literature). Fourteen mutations in ADA2 were identified, 7 of which have not previously been reported in non-Chinese patients. Four children who underwent enzymatic analysis had lower ADA2 activity compared with their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, and neurologic involvement. Treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on phenotype and severity. Conclusion This study includes the largest number of Chinese DADA2 patients to date. We recommend the combination of enzymatic analysis with gene screening to confirm the diagnosis. Different genotypes were observed among Chinese DADA2 patients; most phenotypes were similar to those of non-Chinese DADA2 patients, except for growth retardation. Disease remission might not be achieved with anti-IL-6 therapy.

Abstract Background Behcet’s disease (BD) is a relapsing systemic vascular autoimmune/inflammatory disease. Despite much effort to investigate BD, there are virtually no unique laboratory markers identified to help in the diagnosis of BD, and the pathogenesis is largely unknown. The aim of this work is to explore interactions between different clinical variables by correlation analysis to determine associations between the functional linkages of different paired variables and potential diagnostic biomarkers of BD. Methods We measured the immunoglobulin proteome (IgG, IgG1–4, IgA, IgA1–2) and 29 clinical variables in 66 healthy controls and 63 patients with BD. We performed a comprehensive clinical variable linkage analysis and defined the physiological, pathological and pharmacological linkages based on the correlations of all variables in healthy controls and BD patients without and with immunomodulatory therapy. We further calculated relative changes between variables derived from comprehensive linkage analysis for better indications in the clinic. The potential indicators were validated in a validation set with 76 patients with BD, 30 healthy controls, 18 patients with Takayasu arteritis and 18 patients with ANCA-associated vasculitis. Results In this study, the variables identified were found to act in synergy rather than alone in BD patients under physiological, pathological and pharmacological conditions. Immunity and inflammation can be suppressed by corticosteroids and immunosuppressants, and integrative analysis of granulocytes, platelets and related variables is likely to provide a more comprehensive understanding of disease activity, thrombotic potential and ultimately potential tissue damage. We determined that total protein/mean corpuscular hemoglobin and total protein/mean corpuscular hemoglobin levels, total protein/mean corpuscular volume, and plateletcrit/monocyte counts were significantly increased in BD compared with controls (P

Abstract Background DNA primase subunit 1 (PRIM1) has been reported as a novel oncogene in several cancer types. However, its roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate underlying mechanisms of PRIM1 and identify it as a potential molecular target for HCC. Methods Hub genes were screened between HCC tissues and normal liver tissues in 3 gene expression omnibus (GEO) datasets and the cancer genome atlas (TCGA). The expression features and prognostic value of one of the hub genes PRIM1 were analyzed by bioinformatic analyses and immunohistochemistry. Loss-of-function and gain-of-function studies were used to investigate the regulatory role of PRIM1 in HCC cells. Real-time (RT)-qPCR, western blotting, and ubiquitin immunoprecipitation assays were performed to explore the underlying mechanisms. The xenograft model was employed to detect the roles of PRIM1 in tumor growth in vivo. Finally, the 3D spheroid model was conducted to validate the role of PRIM1 in tumor growth and sorafenib resistance. Results The hub genes of HCC were screened in multiple bioinformatic datasets. PRIM1, as one of the hub genes, was significantly overexpressed in HCC tissues in mRNA and protein levels. In addition, high expression of PRIM1 indicated poor prognosis of HCC patients in TCGA, ICGC, and Nantong cohorts. Overexpression of PRIM1 promoted the proliferation, migration/invasion, and sorafenib resistance of HCC cells, with the decrease in apoptosis and cell cycle arrest. Mechanically, PRIM1 facilitated epithelial-mesenchymal transition (EMT) process and the activity of PI3K/AKT/mTOR signaling of HCC cells. Additionally, PRIM1 could cause the ubiquitination and degradation of P53 by upregulating Ubiquitin Conjugating Enzyme E2 C (UBE2C). Furthermore, knockdown of PRIM1 significantly inhibited the growth of xenograft tumors and HCC cells-derived spheroids with enhanced sorafenib resistance. Conclusion This study implies that PRIM1 may play a key role in the progression of HCC and may serve as a potential target for HCC treatment.

Evidence of active tuberculosis (ATB) in patients with rheumatic diseases are research priorities but limited data from China have been reported. Research targeting patients not taking anti-TNF biologics are especially insufficient. We aimed to investigate the prevalence and risk factors of ATB in this at-risk population. We conducted a tertiary hospital-based, multi-center, cross-sectional study by using stratified multi-stage cluster sampling strategy to screen ATB in patients with rheumatic diseases. We estimated the prevalence of ATB in patients with rheumatic diseases and identified risk factors among those who were not taking anti-TNF biologic. A total of 13,550 eligible patients were enrolled, and the result showed the standardized prevalence of ATB according to the composition ratio of various types of rheumatic disease was 882/100000 (95% confidence interval (CI): 706-1057). Multivariable logistic regression analysis in patients not taking anti-TNF biologics showed that the independent risk factors of ATB were having systemic lupus erythematosus (SLE) (OR=2.722, 95% CI: 1.437-5.159, p=0.002), having Behcet’s disease (BD) (OR= 5.261, 95% CI: 2.071-13.365, p

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1+ plasma cells, CD8+ T cells, CD103+ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen–specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8+ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1+ memory B cells in tumors could improve immunotherapy outcomes.

Abstract The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs’ precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.

Abstract Background Recent studies have suggested that the gut microbiota is altered in children with juvenile idiopathic arthritis (JIA). However, age, sex, and body mass index (BMI) were not matched in the previous studies, and the results are inconsistent. We conducted an age-, sex-, and BMI-matched cross-sectional study to characterize the gut microbiota in children with JIA, and evaluate its potential in clinical prediction. Methods A total of 40 patients with JIA and 42 healthy controls, ranging from 1 to 16 years, were enrolled in this study. Fecal samples were collected for 16S rDNA sequencing. The data were analyzed using QIIME software and R packages. Specifically, the random forest model was used to identify biomarkers, and the receiver operating characteristic curve and the decision curve analysis were used to evaluate model performance. Results A total of 39 fecal samples from patients with JIA, and 42 fecal samples from healthy controls were sequenced successfully. The Chao 1 and Shannon–Wiener index in the JIA group were significantly lower than those in the control group, and the Bray-Curtis dissimilarity also differed significantly between the two groups. The relative abundance of 4 genera, Anaerostipes, Dialister, Lachnospira, and Roseburia, decreased significantly in the JIA group compared to those in the control group. The 4 genera included microbes that produce short-chain fatty acids (SCFAs) and were negatively correlated with some rheumatic indices. Moreover, 12 genera were identified as potential biomarkers by using the nested cross-validation function of the random forest. A random forest model constructed using these genera was able to differentiate the patients with JIA from the healthy controls, and the area under the receiver operating characteristic curve was 0.7975. The decision curve analysis indicated that the model had usefulness in clinical practice. Conclusions The gut microbiota in patients with JIA is altered and characterized by a decreased abundance of 4 SCFA-producing genera. The decreases in the 4 genera correlated with more serious clinical indices. Twelve genera could be used as biomarkers and predictors in clinical practice. Trial registration The study is registered online at the Chinese Clinical Trial Registry on 11 May 2018 (registration number: ChiCTR1800016110).

Abstract Background To explore the modulatory effects and mechanism of secretory clusterin (sCLU) on cancer stem cell (CSC) properties in hepatocellular carcinoma (HCC). Methods The effects of sCLU repression or overexpression on chemoresistance, migration, invasion, and tumor growth were detected by MTT, wound healing, transwell assays, and xenograft assay, respectively. The tumor sphere assay was performed to evaluate the self-renewal ability of HCC cells. In addition, the molecular regulation between sCLU and AKT/GSK-3β/β-catenin axis in HCC cells were discovered by western blotting, quantitative real-time PCR (qRT-PCR), and immunofluorescence. The expression status of sCLU and β-catenin in HCC tissues were investigated by immunohistochemistry. Results Knockdown or overexpressing sCLU remarkably inhibited or promoted the chemoresistance against sorafenib/doxorubicin, metastasis, and tumor growth of HCC cells, respectively. HepG2 and HCCLM3-derived spheroids showed higher expression of sCLU than that in attached cells. Additionally, repressing sCLU impaired the self-renewal capacity of HCC cells and CSC-related chemoresistance while overexpression of sCLU enhanced these CSC properties. Knockdown or overexpression of sCLU inhibited or increased the expressions of β-catenin, cyclinD1, MMP-2 and MMP-9, and the phosphorylation of AKT or GSK3β signaling, respectively. However, LiCl or LY294002 abrogated the effects mediated by sCLU silencing or overexpression on chemoresistance, metastasis, and CSC phenotype. Furthermore, co-expression of sCLU and β-catenin in HCC tissues indicated poor prognosis of HCC patients. Conclusions Taken together, the oncogenic sCLU might promote CSC phenotype via activating AKT/GSK3β/β-catenin axis, suggesting that sCLU was a potential molecular-target for HCC therapy.

BackgroundBehcet’s disease (BD) is a chronic inflammatory disease that involves systemic vasculitis and mainly manifests as oral and genital ulcers, uveitis, and skin damage as the first clinical symptoms, leading to gastrointestinal, aortic, or even neural deterioration. There is an urgent need for effective gene signatures for BD’s early diagnosis and elucidation of its underlying etiology.MethodsWe identified 82 differentially expressed genes (DEGs) in BD cases compared with healthy controls (HC) after combining two Gene Expression Omnibus datasets. We performed pathway analyses on these DEGs and constructed a gene co-expression network and its correlation with clinical traits. Hub genes were identified using a protein–protein interaction network. We manually selected CCL4 as a central hub gene, and gene-set enrichment and immune cell subset analyses were applied on patients in high- and low-CCL4 expression groups. Meanwhile, we validated the diagnostic value of hub genes in differentiating BD patients from HC in peripheral blood mononuclear cells using real-time PCR.ResultsTwelve hub genes were identified, and we validated the upregulation of CCL4 and the downregulation of NPY2R mRNA expression. Higher expression of CCL4 was accompanied by larger fractions of CD8 + T cells, natural killer cells, M1 macrophages, and activated mast cells. Receiver operator characteristic curves showed good discrimination between cases and controls based on the expression of these genes.ConclusionCCL4 and NPY2R could be diagnostic biomarkers for BD that reveal inflammatory status and predict vascular involvement in BD, respectively.

The conventional PV/T and the heat pipe PV/T systems have the opposite relative magnitudes of heat loss coefficients during the day-time and night-time. In the present study, their effects on the annual effective supply days, annual heat gain, and annual electric gain are compared and discussed based on the typical meteorological year data of Shanghai city. Influences of setting temperature, photovoltaic coverage ratio, and water tank volume on the operating performance are comparatively and sensitively analysed. The results show that compared with the conventional PV/T system, the lower night-time heat loss of the heat pipe PV/T system distinctly enhances the photothermal performance but modestly weakens the photovoltaic performance. The former increases by 33.20% in annual heat gain while the latter decreases by 6.88% in annual electric gain. Increasing the setting temperature results in a maximum deterioration of 38.79% in annual heat gain but slightly weakens the photovoltaic performance. Increasing the photovoltaic coverage ratio proportionally enhances the photovoltaic performance but evidently weakens the photothermal performance of up to 37.87%. The optimum water tank volume is 60 L. Increasing the water tank volume leads to a maximum decrease of 19.74% in annual heat gain and an increase of 20.25% in heat loss.

Background: As a newly emerging technique, endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) has become an increasingly popular procedure of interest. The purpose of this study was to introduce a modified Endo-TLIF system and share our preliminary clinical experiences and outcomes in treating lumbar degenerative disease with this procedure.Methods: Ninety-six patients (thirty-seven men and fifty-nine women; mean age 55.85 ± 11.03 years) with lumbar degenerative diseases who underwent Endo-TLIF in our hospital were enrolled. The surgical time, volume of intraoperative blood loss, postoperative hospitalization time and postoperative drainage were documented. Clinical outcomes were evaluated by visual analog scale (VAS) scores, Oswestry Disability Index (ODI) scores, and modified MacNab criteria. Bone fusion was identified through computerized tomography (CT) scans or X-ray during the follow-up period.Results: All patients were followed up for at least 12 months, and the average follow-up time was 17.03 ± 3.27 months. The mean operative time was 136.79 ± 30.14 minutes, and the mean intraoperative blood loss was 53.06 ± 28.89 ml. The mean VAS scores of low back pain and leg pain were 5.05 ± 1.37 and 6.25 ± 1.03, respectively, before surgery, which improved to 2.27 ± 0.66 and 2.22 ± 0.55, respectively, after the operation (P < 0.05). The final VAS scores of low back pain and leg pain were 0.66 ± 0.60 and 0.73 ± 0.66, respectively (P < 0.05). The preoperative ODI score (49.06 ± 6.66) also improved significantly at the 3-month follow-up (13.00 ± 7.37; P < 0.05). The final ODI score was 8.03 ± 6.13 (P < 0.05). There were 10 cases of non-fusion (nine women and one man) at the 12-month follow-up, but no cases of non-union were identified by imaging at the final follow-up.Conclusions: The present study demonstrated satisfactory clinical and radiologic results among patients who received Endo-TLIF treatment from our institution. This indicates that Endo-TLIF is efficient and safe for select patients.

Background: To investigate the efficacy and safety of biologics in the perioperative management of severe aortic valve regurgitation (AR) caused by Behçet syndrome (BS). Methods: We retrospectively analyzed 20 patients with severe AR caused by BS who were all treated with biologics during the perioperative period of cardiac surgeries in our center between February 2016 and October 2020. Results: A total of 20 patients with severe AR were enrolled, including 19 males and 1 female, with a mean age of 39.1 ± 8.8 years and a median course of 8 [interquartile range (IQR) 5.25–10.00] years. Before biologic administration, 92.9% of the patients who underwent aortic valve replacement had failed conventional therapy and developed postoperative paravalvular leakage (PVL) at a median interval of 4 months. Biologics were administered with background glucocorticoids (GCs) and immunosuppressants during the perioperative period for 22 aortic valve surgeries, including preoperatively with a median interval of 3.5 (IQR 2.75–4.25) months in 13 cases and within 3 months postoperatively in 9 cases. After a median follow up of 21 (IQR 15–32) months, 2 out of 13 cases (15.4%) preoperatively, and 1 out of 9 cases (11.1%) postoperatively treated with biologics developed PVL, and the rest were event free. The Behçet’s Disease Current Activity Form score improved significantly (7 versus 0, median, p