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Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

ObjectiveThe association between autoimmune diseases and chronic rhinosinusitis in observational studies remains unclear. This study aimed to explore the genetic correlation between chronic rhinosinusitis and autoimmune diseases.MethodsWe employed Mendelian randomization (MR) analysis and linkage disequilibrium score regression (LDSC) to investigate causal relationships and genetic correlations between autoimmune phenotypes and chronic rhinosinusitis. Additionally, transcriptome-wide association (TWAS) analysis was conducted to identify the shared genes between the two conditions to demonstrate their relationship. The CRS GWAS (genome-wide association study) data and other autoimmune diseases were retrieved from ieuOpenGWAS (https://gwas.mrcieu.ac.uk/), the FinnGen alliance (https://r8.finngen.fi/), the UK Biobank (https://www.ukbiobank.ac.uk/), and the EBI database (https://www.ebi.ac.uk/).ResultsUtilizing a bivariate two-sample Mendelian randomization approach, our findings suggest a significant association of chronic rhinosinusitis with various autoimmune diseases, including allergic rhinitis (p = 9.55E-10, Odds Ratio [OR] = 2,711.019, 95% confidence interval [CI] = 261.83391–28,069.8), asthma (p = 1.81E-23, OR = 33.99643, 95%CI = 17.52439–65.95137), rheumatoid arthritis (p = 9.55E-10, OR = 1.115526, 95%CI = 1.0799484–1.1522758), hypothyroidism (p = 2.08828E-2, OR = 4.849254, 95%CI = 1.7154455–13.707962), and type 1 diabetes (p = 2.08828E-2, OR = 01.04849, 95%CI = 1.0162932–1.0817062). LDSC analysis revealed a genetic correlation between the positive autoimmune phenotypes mentioned above and chronic rhinosinusitis: AR (rg = 0.344724754, p = 3.94E-8), asthma (rg = 0.43703672, p = 1.86E-10), rheumatoid arthritis (rg = 0.27834931, p = 3.5376E-2), and hypothyroidism (rg = −0.213201473, p = 3.83093E-4). Utilizing the Transcriptome-Wide Association Studies (TWAS) approach, we identified several genes commonly associated with both chronic rhinosinusitis and autoimmune diseases. Genes such as TSLP/WDR36 (Chromosome 5, top SNP: rs1837253), ORMDL3 (Chromosome 13, top SNP: rs11557467), and IL1RL1/IL18R1 (Chromosome 2, top SNP: rs12905) exhibited a higher degree of consistency in their shared involvement across atopic dermatitis (AT), allergic rhinitis (AR), and chronic rhinosinusitis (CRS).ConclusionCurrent evidence suggests a genetic correlation between chronic rhinosinusitis and autoimmune diseases like allergic rhinitis, asthma, rheumatoid arthritis, hypothyroidism, and type 1 diabetes. Further research is required to elucidate the mechanisms underlying these associations.

Allergic rhinitis is a common non-infectious inflammatory disease that affects approximately 15 % of people worldwide and has a complex and unclear aetiology. In recent years, pyroptosis has been found to play a role in the development of allergic rhinitis. IL-9, pyroptosis, serum and glucocorticoid-induced protein kinase 1 (SGK1), NOD-like receptor 3 (NLRP3), and nuclear factor kappa B (NF-κB) have been shown to influence each other. Herein, we aimed to explore the role of IL-9 neutralising antibody in pyroptosis involving IL-9, SGK1, NF-κB, and NLRP3 in allergic rhinitis. We observed a decrease in cytokines involved in pyroptosis and gasdermin D (GSDMD) compared with those in mice with allergic rhinitis. Further, phosphorylation of NF-κB/p65 decreased compared with that in mice with allergic rhinitis; NLRP3 and ASC also decreased, although the levels were higher than those in controls. SGK1 levels decreased compared with that in mice with allergic rhinitis and increased after using IL-9 neutralising antibodies, thus demonstrating its negative regulatory effects. The IL-9 neutralising antibody reduced the inflammatory and pyroptosis responses via SGK1 and NF-κB/NLRP3/GSDMD pathway. Our research results indicate that IL-9 regulates allergic rhinitis via the influence of SGK1 and NF-κB/NLRP3/GSDMD signalling pathway, providing new insights for developing novel drugs to treat allergic rhinitis.

Abstract The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum-neutralizing activity against diverse coronaviruses. Through single B-cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, PW5-570 potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1, and SARS-CoV viral challenge in golden Syrian hamsters, respectively. Importantly, post-exposure treatment with PW5-5 and PW5-535 also markedly protects against XBB.1 challenge in these models. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.

Abstract Bone regeneration for large, critical-sized bone defects remains a clinical challenge nowadays. Guided bone regeneration (GBR) is a promising technique for the repair of multiple bone defects, which is widely used in oral and maxillofacial bone defects but is still unsatisfied in the treatment of long bone defects. Here, we successfully fabricated a bilayer mineralized collagen/collagen (MC/Col)-GBR membrane with excellent osteoinductive and barrier function by coating the MC particles prepared via in situ biomimetic mineralization process on one side of a sheet-like pure collagen layer. The aim of the present study was to investigate the physicochemical properties and biological functions of the MC/Col film, and to further evaluate its bone regeneration efficiency in large bone defect repair. Fourier-transform infrared spectra and X-ray diffraction patterns confirmed the presence of both hydroxyapatite and collagen phase in the MC/Col film, as well as the chemical interaction between them. stereo microscope, scanning electron microscopy and atomic force microscope showed the uniform distribution of MC particles in the MC/Col film, resulting in a rougher surface compared to the pure Col film. The quantitative analysis of surface contact angle, light transmittance and tensile strength demonstrated that the MC/Col film have better hydrophilicity, mechanical properties, light-barrier properties, respectively. In vitro macrophage co-culture experiments showed that the MC/Col film can effectively inhibit macrophage proliferation and fusion, reducing fibrous capsule formation. In vivo bone repair assessment of a rabbit critical segmental radial defect proved that the MC/Col film performed better than other groups in promoting bone repair and regeneration due to their unique dual osteoinductive/barrier function. These findings provided evidence that MC/Col film has a great clinical potential for effective bone defect repair. Graphic abstract

Although PFOS has been banned as a persistent organic pollutant, it still exists in large quantities within the environment, thus impacting the health of aquatic ecosystems. Previous studies focused solely on high PFOS concentrations, disregarding the connection with environmental factors. To gain a more comprehensive understanding of the PFOS effects on aquatic ecosystems amidst changing environmental conditions, this study investigated the cellular responses of Microcystis aeruginosa to varying PFOS concentrations under heatwave and nutrient stress conditions. The results showed that PFOS concentrations exceeding 5.0 µg/L had obvious effects on multiple physiological responses of M. aeruginosa, resulting in the suppression of algal cell growth and the induction of oxidative damage. However, PFOS concentration at levels below 20.0 µg/L has been found to enhance the growth of algal cells and trigger significant oxidative damage under heatwave conditions. Heatwave conditions could enhance the uptake of PFOS in algal cells, potentially leading to heightened algal growth when PFOS concentration was equal to or less than 5.0 µg/L. Conversely, deficiency or limitation of nitrogen and phosphorus significantly decreased algal abundance and chlorophyll content, inducing severe oxidative stress that could be mitigated by exposure to PFOS. This study holds significance in managing the impact of PFOS on algal growth across diverse environmental conditions.

Background/purpose: Temporomandibular joint (TMJ) osteoarthritis (TMJOA) is a chronic disease with progressive destruction of articular cartilage. This study aimed to explore the therapeutic effects of kartogenin on TMJOA via promoting the binding of core binding factor β (CBFβ) and runt-related transcription factor 1 (RUNX1). Materials and methods: Type II collagenase was injected into 35 8-week-old male Sprague Dawley rat TMJs to establish the TMJOA model. Kartogenin, or the CBFβ-RUNX1 complex inhibitor (Ro5-3335), was also delivered via intra-articular injection. Subchondral bone was analyzed by MicroCT. The hematoxylin-eosin, Safranin O, and toluidine blue O staining were used to observe histopathology. Immunohistochemical staining of proliferating cell nuclear antigen (PCNA), caspase-3 (CASP3), interleukin-1β (IL-1β), and collagen II (COL2) was performed. Results: TMJOA was established in rats by intra-articular injection of type II collagenase. The condylar cartilage and subchondral bone were damaged, with decreased PCNA and COL2 and increased CASP3 and IL-1 (P

To determine the influence of pig type (Landrace, Wujin, or Tibetan fragrant) on the quality of Xuanwei ham, we measured the ham pH, color, fat content, and moisture content; used an E-nose (a device intended to detect odors or flavors); and analyzed flavoring substances using headspace solid-phase microextraction–gas chromatography, free amino acids using high-performance liquid chromatography, and microbial diversity using high-throughput sequencing. The ham types differed from each other in these attributes. The moisture and fat contents of Landrace pig ham were significantly lower than those of the other pig types, the brightness values of the Tibetan fragrant pig ham were significantly lower than those of the other pig types, and the redness values of the Landrace and Wujin pig hams were significantly higher than those of the Tibetan fragrant pig ham. The essential amino acid contents, e-wind odor response values, and volatile flavor substances of Wujin pig hams were significantly higher than those of the Tibetan fragrant pig ham, and the relative aldehyde contents of Wujin pig ham were significantly higher than those of the other pig types. The dominant microbial phyla in each ham type were assessed based on the species commonness, composition, and diversity and included taxa such as Actinobacteria and Ascomycetes and thick-walled bacteria such as Orphanomyces, Grass Spirochaetes, and Pseudoalteromonas. The microbial diversity and richness were the greatest in the Wujin pig ham. Of the three pigs, we conclude that the Wujin pig produces the best Xuanwei ham.

Safety is essential when building a strong transportation system. As a key development direction in the global railway system, the intelligent railway has safety at its core, making safety a top priority while pursuing the goals of efficiency, convenience, economy, and environmental friendliness. This paper describes the state of the art and proposes a system architecture for intelligent railway systems. It also focuses on the development of railway safety technology at home and abroad, and proposes the active safety method and technology system based on advanced theoretical methods such as the in-depth integration of cyber–physical systems (CPS), data-driven models, and intelligent computing. Finally, several typical applications are demonstrated to verify the advancement and feasibility of active safety technology in intelligent railway systems.

Abstract Background and Aims We sought to identify novel molecular subtypes of ulcerative colitis (UC) based on large-scale cohorts and establish a clinically applicable subtyping system for the precision treatment of the disease. Methods Eight microarray profiles containing colon samples from 357 patients were utilized. Expression heterogeneity was screened out and stable subtypes were identified among UC patients. Immune infiltration pattern and biological agent response were compared among subtypes to assess the value in guiding treatment. The relationship between PRLR and TNFSF13B genes with the highest predictive value was further validated by functional experiments. Results Three stable molecular subtypes were successfully identified. Immune cell infiltration analysis defined three subtypes as innate immune activated UC (IIA), whole immune activated UC (WIA), and immune homeostasis like UC (IHL). Notably, the response rate towards biological agents (infliximab/vedolizumab) in WIA patients was the lowest (less than 10%), while the response rate in IHL patients was the highest, ranging from 42 to 60%. Among the featured genes of subtypes, the ratio of PRLR to TNFSF13B could effectively screen for IHL UC subtype suitable for biological agent therapies (Area under curve: 0.961–0.986). Furthermore, we demonstrated that PRLR expressed in epithelial cells could inhibit the expression of TNFSF13B in monocyte-derived macrophages through the CXCL1-NF-κB pathway. Conclusions We identified three stable UC subtypes with a heterogeneous immune pattern and different response rates towards biological agents for the first time. We also established a precise molecular subtyping system and classifier to predict clinical drug response and provide individualized treatment strategies for UC patients.

Abstract Quality and stability are the basic characteristics of ecosystems, reflecting their structure, process, functional integrity, ability to resist disturbance, self‐regulation, and dynamic balance. The quantitative description of ecosystem quality and stability is an indispensable and important task to promote the ecological protection and high‐quality development of the Yellow River Basin as a major national strategy. In this study, an index evaluation system was constructed from the perspective of system governance, considering the special characteristics of the Yellow River Basin, and an entropy weight model was used to establish a multi‐indicator long time series ecosystem quality evaluation index (EQI) to quantitatively describe the ecological quality changes in the Yellow River Basin over 40 years. The dissipative structure theory and Brussels apparatus model were used to establish quantitative indicators and methods, and provide ideas for the study of ecosystem homeostasis transformation in the Yellow River basin. This study found that: (1) the average EQI value of the Yellow River Basin ecosystem for 40 years was 63.96, the maximum and minimum values were 69.65 and 59.45, respectively; the overall quality showed an oscillating trend of improvement, with an annual increase of 0.03, and the spatial distribution was better in the downstream than in the midstream, and in the midstream than in the upstream; (2) The key factors influencing the system changed gradually from the total water consumption and total annual precipitation in the basin in the early stage to the average income of residents in the last 10 years. (3) The system steady‐state transition force values from 1980 to 2019 were all

Abstract A latest coding scheme named polarization‐adjusted convolutional (PAC) codes is shown to approach the dispersion bound for the code (128,64) under list decoding. However, to achieve the near‐bound performance, the list size of list decoding needs to be excessively large, which leads to insufferable time complexity. In this paper, to improve the speed of list decoding, fast list decoders for PAC codes are proposed. Four types of constituent nodes are defined and fast list decoding algorithms are provided for each of them. Simulation results present that fast list decoding with three types of constituent nodes can yield exactly the same error‐correction performance as list decoding, and reduce more than 50% time steps for the code (128,64). Moreover, fast list decoding with four types of constituent nodes can further reduce decoding complexity with negligible performance degradation.

[Objective] The effects of fertilization and mixed sowing on soil nutrients and pasture yield of degraded grassland in the Songnen Plain, Western Heilongjiang Province were studied, in order to provide a scientific basis for restoration of natural degraded grassland in local area. [Methods] The study was conducted on a natural lightly degraded grassland in the Songnen Plain of Western Heilongjiang Province. Astragalus adsurgens and Elymus dahuricus were used as reseeding grasses. Treatments consisted of two interrow mixed sowing ratios 〔legume:grass ratio 2∶2 (B1) and 1∶2 (B2)〕,and six nitrogen, phosphorus, and potassium application rate combinations: N50 P40 K45 (A1), N100 P240 K225 (A2), N150 P0K180 (A3), N200 P120 K0(A4), N250 P80 K270 (A5), and N300 P200 K90 (A6), where subscripts after each element indicated the application rate given as kg/hm2 N, P2O5, and K2O, respectively. [Results] Fertilization significantly improved available nutrients and pasture yield based on the ratio of mixed sowing. Soil nutrient changes in the surface soil layer (0—10 cm) were more affected by fertilization and mixed sowing than in the deeper layer (20—30 cm). Fertilization, mixed sowing, and their interaction had significant effects on the content of available soil nitrogen (p

IntroductionMind wandering is generally considered an endogenous mental state that arises spontaneously, which is one of the most common experiences of consciousness and typically occurs at a significant cost to mental health and behavioral performance. Previous studies have shown that mind wandering appears to be a stable trait and can be assessed reliably in adults. Surprisingly little, however, is known about how to measure the frequency of mind wandering in children, given that children can accurately introspect their experiences. The present studies aimed to develop the Frequency of Children's Mind Wandering Scale (CMWS-F) and the Context of Children's Mind Wandering Scale (CMWS-C) to assess the frequency of mind wandering and contexts in which mind wandering occurs for children aged 8 to 11 years.MethodsThe exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to develop the CMWS-F and CMWS-C. To further assess the validity of the scales, we compared the scores in CMWS-F/CMWS-C and the frequencies of probe-caught mind wandering in the typical tasks.ResultsIn study 1a, the EFA (n = 292) and CFA (n = 346) showed that attentional failure and spontaneous thinking were the two main dimensions of CMWS-F. In study 1b, contexts about mind wandering in children could be divided into high-demand and low-demand contexts using EFA (n = 258) and CFA (n = 347). Study 2 showed moderate positive correlations between the frequencies of probe-caught mind wandering in the tasks and the scores in the scales.DiscussionThe results showed that scores on the two scales could predict the performance on the experimental tasks and further demonstrated empirical validity of the CMWS-F and CMWS-C scales. Taken together, the results of the current studies provided preliminary evidence for the validity and reliability of CMWS-F and CMWS-C in children, which can be used as a reference to balance its downsides and productive aspects of mind wandering.

Abstract Joint operation of the Longyangxia and Liujiaxia reservoirs (Long-Liu operation) is of great significance for water and sediment regulation in the Yellow River. The water–sediment–electricity coupling system is a giant system with complex nonlinear relationships. A reliable Long-Liu operation scheme facilitates maximization of the benefits of the water–sediment–electricity system. Based on systems thinking, this paper quantitatively evaluated the reliability of different Long-Liu operation schemes and coordination of the water–sediment–electricity coupling system through the entropy weight method and dissipative structure model. The results indicated that the current operation scheme is more reliable than the adjusted scheme at the inter-annual scale and during the summer-autumn flood season and ice flood season within a year. However, the operation scheme should be improved during the spring irrigation period. The key factors influencing the quality of the water–sediment–electricity system include the outflow of the Liujiaxia reservoir, incoming sediment load into the Yellow River at Toudaoguai, sediment inflow-outflow difference in the Ningxia-Inner Mongolia Reach, water flow at Lanzhou and power generation upstream of Toudaoguai. The water–sediment–electricity system under the current Long-Liu operation scheme is more coordinated than that in the adjusted state, but the overall coordinated development of the system remains at a low activity level.

Abstract Puncturing and shortening are two common ways to achieve rate‐compatible non‐systematic polar codes (NSPCs). Systematic polar codes (SPCs) have been shown to outperform NSPCs with the same encoding and decoding complexity. However, rate‐compatible SPCs have never been comprehensively studied in previous work. In this paper, two rate‐compatible algorithms for SPCs are first proposed: uniform puncturing (UP) algorithm and uniform shortening (US) algorithm, which are referred to as SPC‐UP and SPC‐US, respectively. In order to effectively estimate the maximum likelihood decoding performance of punctured and shortened polar codes, subsequently, a distance spectrum calculation algorithm based on successive cancellation list (SCL) decoder for rate‐compatible polar codes is proposed. Simulation results show that rate‐compatible SPCs yield better bit error rate performance than rate‐compatible NSPCs while they have the same frame error rate performance under different code rates and decoding algorithms. Eventually, union bounds that are obtained by the distance spectrum to provide the theoretical explanation for the superiority of rate‐compatible SPCs are utilised.

Allergic rhinitis is mainly mediated by IgE after specific individuals are exposed to allergens. It is a common nasal mucosa disease of non-infectious chronic inflammatory disease and is often accompanied by asthma and conjunctivitis. In the study of allergic asthma, it was found that IL-9 participates in the pathogenic development of asthma. Because asthma and allergic rhinitis have the same airway and the same disease, it is inferred that IL-9 may also play an important role in allergic rhinitis. BALB/c mice received intranasal stimulation of ovalbumin (OVA) treatment at different times. The nasal mucosa of the mice were then sliced and stained with Sirius red and Toluidine blue, and eosinophils and mast cells in the mucosa were counted. ELISA was used to detect the expression of OVA-IgE in peripheral blood. The Th2 cell fraction in the mouse spleen was detected by flow cytometry. The expressions of IL-4, IL-5, IL-9, and IL-13 and their mRNA in mucosa were detected by real-time PCR and flow cytometry bead array analysis. Finally, the expression changes of Thymic stromal lymphopoietin related proteins and its mRNA, JAK1/2, and STAT5 proteins were detected by real-time PCR and Western blot. After the intervention with the IL-9 neutralizing antibody, the symptoms of allergic rhinitis in mice were significantly reduced. The expression of OVA-IgE in the peripheral blood of mice was inhibited, the fraction of Th2 cells in the spleen decreased, the related cytokines (IL-4, IL-5, and IL-13) were inhibited, and their functions decreased. The TSLP-OX40/OX40L signal pathway and JAK1/2-STAT5 signal are inhibited. IL-9 neutralizing antibody has a good therapeutic effect on the mouse model of allergic rhinitis, which may be related to the TSLP-OX40/OX40L pathway and JAK1/2-STAT5 signaling.

Nonylphenol (NP) can be widely used as a plasticizer, surfactant, antioxidant, textile printing, dyeing additive, and pesticide emulsifier. Animal studies have shown that NP aggravates ovalbumin (OVA)-induced allergic rhinitis (AR); however, the exact mechanism underlying its action has not yet been detailed. This study aimed to explore the aggravation of the AR inflammatory response following NP exposure and its possible mechanism. The AR mouse model was constructed using OVA. Under NP exposure, allergic nasal symptoms were observed, eosinophil infiltration was assessed by Sirius red staining, and the levels of IL-4, IL-5, and IL-13 in nasal mucosa samples were detected using cytometric bead array. The mRNA levels of OX40/OX40L and GATA3 in nasal mucosa were detected by qPCR, and the expression levels of the TSLP and JAK1/2-STAT3 signaling pathway components were also identified. Our results suggest that NP exposure exacerbated allergic nasal symptoms and that eosinophils accumulated in nasal mucosa after OVA challenge. The levels of the typical T helper 2 cytokines, as well as the mRNA levels of OX40/OX40L and GATA3, were elevated in the nasal mucosa of OVA-challenged mice exposed to NP. In addition, NP exposure elevated the TSLP, TSLPR, IL-7R, p-JAK1, p-JAK2, and p-STAT3 levels in the nasal mucosa after OVA stimulation. Overall, the present study suggests NP can exacerbate OVA-induced AR inflammatory responses; furthermore, this aggravating effect of NP may be related to the TSLP-TSLPR/IL-7R and JAK1/2-STAT3 signaling pathways.

BackgroundThe overall 5-year survival of lung cancer was reported to be only ~15%, with lung adenocarcinoma (LUAD) as the main pathological subtype. Before developing into invasive stages, LUAD undergoes pre-invasive stages of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), where surgical resection gives an excellent 5-year survival rate. Given the dramatic decline of prognosis from pre-invasive to invasive stages, a deeper understanding of key molecular changes driving the progression of LUAD is highly needed.MethodsIn this study, we performed whole-exome sequencing and RNA sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens, and their adjacent paired normal tissues. Survival data were obtained by follow-up after surgery. Key molecular events were found by comparing the gene expression profiles of tumors with different stages. Finally, to measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment, a tumor progressive (TP) index was developed to predict tumor progression and patients’ survival outcome and validated by external datasets.ResultsAs tumors progressed to more invasive stages, they acquired higher growth potential, mutational frequency of tumor suppressor genes, somatic copy number alterations, and tumor mutation burden, along with suppressed immune function. To better predict tumor progression and patients’ outcome, TP index were built to measure the imbalance between tumor intrinsic growth potential and immune microenvironment. Patients with a higher TP index had significantly worse recurrence-free survival [Hazard ratio (HR), 10.47; 95% CI, 3.21–34.14; p < 0.0001] and overall survival (OS) [Hazard ratio (HR), 4.83e8; 95% CI, 0–Inf; p = 0.0013]. We used The Cancer Genome Atlas (TCGA)-LUAD dataset for validation and found that patients with a higher TP index had significantly worse OS (HR, 1.10; 95% CI, 0.83–1.45; p = 0.048), demonstrating the prognostic value of the TP index for patients with LUAD.ConclusionsThe imbalance of tumor intrinsic growth potential and immune function orchestrate the progression of LUAD, which can be measured by TP index. Our study provided new insights into predicting survival of patients with LUAD and new target discovery for LUAD through assessing the imbalance between tumor intrinsic growth potential and immune function.

Background: Bisphenol A (BPA) is found in many plastics widely used in everyday life and affects the immune system. Previous studies found that the selective G protein coupled estrogen receptor (GPER) agonist G-1 can reduce the inflammation associated with asthma and allergic rhinitis (AR). BPA also interferes with the protective effect of estradiol against myocardial ischemia-reperfusion injury. Objective: We explored whether BPA attenuates the effect of G-1 on inflammation in a mouse AR model. Methods: The AR model was established by sensitizing and stimulating female BALB/c mice with ovalbumin (OVA) and G-1/BPA. Eosinophils, neutrophils, and lymphocyte subsets (including T and B cells) in nasal mucosa and Th2 and Treg cells in the spleen were detected by flow cytometry. Cytokines and transcription factors characteristic of Th2 and Treg cells in nasal mucosa were detected using cytometric bead arrays and quantitative PCR, respectively. Results: G-1 reduced OVA-induced nasal mucosal inflammation in mice. The proportions of eosinophils, neutrophils, Siglec-F+ neutrophils, lymphocytes, and T cell subsets were reduced by G-1, and this effect was attenuated by BPA. G-1 significantly decreased the Th2 population and levels of IL-4, IL-5, IL-13 and GATA-3; these effects were attenuated by BPA. The enhanced Treg response (as evidenced by an increased Treg population and higher IL-10 and Foxp3 levels) mediated by G-1 tended to be reduced by BPA. Discussion: We found that G-1 reduced OVA-induced nasal mucosal inflammation and significantly decreased the Th2 response, while increasing the Treg response. These effects were attenuated by BPA.

Abstract Background The maxillary anterior teeth play a crucial role in smile aesthetics. Previous studies regarding the importance of maxillary lateral incisors for smile aesthetics concentrated on their size, incisor edge level, and inclination, etc. However, the aesthetic effect of lateral incisor movement in the spatial position has not been studied yet. Therefore, the purpose of this study was to explore the influence of the labiolingual position of maxillary lateral incisors on the aesthetic perception of smiles by orthodontists and laypersons, as well as analyze differences in this perception between male and female raters. Methods A three-dimensional (3D) dental model was generated from the photograph of a man’s smile using iOrtho7.0 software (Time Angel, Wuxi, China). Based on this model, seven images were generated with different labiolingual positions of the maxillary lateral incisors in 0.5 mm increments (+ indicating labial translation, and—indicating lingual translation). The images were evaluated by 86 orthodontists and 161 laypersons using a visual analog scale, with lower scores indicating less attractiveness. Data were analyzed using Student’s t test and one-way analysis of variance with post hoc test. Results There was no significant difference in smile ratings by males and females. Orthodontists assigned lower scores to all images than laypersons. The smile at + 1.5 mm was considered the least attractive by orthodontists, while smiles at + 1.5 mm and − 1.5 mm were regarded as the least attractive by laypersons. The smile at 0 mm was evaluated as the most attractive by all raters. Laypersons gave different scores to smiles at 0 or − 0.5 mm, but orthodontists did not. Conclusions The labiolingual position of maxillary lateral incisors does affect the perception of smile aesthetics. Orthodontists may rate smile aesthetics more critically than laypersons. Therefore, communication and discussion between orthodontists and patients is needed to achieve better therapeutic and aesthetic outcomes.

Network intrusion discovery aims to detect the network attacks and abnormal network intrusion efficiently, that is an important protection implement in the field of cyber security. However, the traditional network intrusion discovery method are difficult to extract high-order features (such as spatial-temporal information) from network traffic data. In this paper, we proposed an improved method of network intrusion discovery based on convolutional long-short term memory network. This method implements the convolution operation in deep learning into the network structure of long-short term memory and improves the accuracy of network intrusion discovery. In the experimental section, we compared with other similar methods, the result shows that the proposed method has some advantages in the aspects of overall network intrusion discovery index, detection index of different types, and AUC evaluation index. In addition, we applied our method to the network intrusion discovery scenarios of video surveillance system (VSS). The result shows that the proposed method has advantages in accuracy, recall, precision, and other similar methods.

Natural compounds (NCs) undergo complicated biotransformation in vivo to produce diverse forms of metabolites dynamically, many of which are of high medicinal value. Predicting the profiles of chemical products may help to narrow down possible candidates, yet current computational methods for predicting biotransformation largely focus on synthetic compounds. Here, we proposed a method of MetNC, a tailor-made method for NC biotransformation prediction, after exploring the overall patterns of NC in vivo metabolism. Based on 850 pairs of the biotransformation dataset validated by comprehensive in vivo experiments with sourcing compounds from medicinal plants, MetNC was designed to produce a list of potential metabolites through simulating in vivo biotransformation and then prioritize true metabolites into the top list according to the functional groups in compound structures and steric hindrance around the reaction sites. Among the well-known peers of GLORYx and BioTransformer, MetNC gave the highest performance in both the metabolite coverage and the ability to short-list true products. More importantly, MetNC seemed to display an extra advantage in recommending the microbiota-transformed metabolites, suggesting its potential usefulness in the overall metabolism estimation. In summary, complemented to those techniques focusing on synthetic compounds, MetNC may help to fill the gap of natural compound metabolism and narrow down those products likely to be identified in vivo.

Bone exhibits remarkable self-repair ability without fibrous scars. It is believed that the robust regenerative capacity comes from tissue-resident stem cells, such as skeletal stem cells (SSCs). Roughly, SSC has two niches: bone marrow (BM) and periosteum. BM-SSCs have been extensively studied for years. In contrast, our knowledge about periosteal SSCs (P-SSCs) is quite limited. There is abundant clinical evidence for the presence of stem cell populations within the periosteum. Researchers have even successfully cultured “stem-like” cells from the periosteum in vitro. However, due to the lack of effective markers, it is difficult to evaluate the stemness of real P-SSCs in vivo. Recently, several research teams have developed strategies for the successful identification of P-SSCs. For the first time, we can assess the stemness of P-SSCs from visual evidence. BM-SSCs and P-SSCs not only have much in common but also share distinct properties. Here, we provide an updated review of P-SSCs and their particular responses to bone injury.

Abstract Background Nasopharyngeal carcinoma (NPC) is a common malignant tumor. Ten-eleven translocation (TET) protein 2 (TET2), an evolutionarily conserved dioxygenases, is reported to be involved in various malignant tumor developments. Here, we aim to investigate the effect of TET2 on NPC progress in vitro and in vivo, and its detailed underlying mechanism. Methods Real-time PCR and western blotting were used to determine the expression levels of TET1/2/3 in NPC cell lines. The effects of TET2 on NPC progression were evaluated using CCK8 and invasion assays in vitro. Proteins interacted with TET2 in NPC cells were detected by immunoprecipitation and mass spectrometry. The effects of TET2 or pyruvate kinase, muscle (PKM) on glycolysis in NPC cells were examined by detecting glucose uptake and lactate production. The effects of TET2 on NPC progression were evaluated using xenograft tumor model in vivo. Results TET2 expression was decreased in NPC cells, and TET2 overexpression inhibited proliferation and invasion of NPC cells, which is independent on TET2’s catalytic activity. In mechanism, TET2 N-terminal domain interacts with PKM in cytoplasm to prevent PKM dimers from translocating into nucleus, suppressing glycolysis in NPC cells, thereby inhibiting proliferation and invasion of NPC cells. Moreover, using xenograft tumor model, we found that TET2 knockout promoted NPC progression and decreased survival rate. However, administration with the inhibitor of PKM, shikonin, decreased the tumor volume of TET2-cas9 group, and increased the survival rate. Conclusion TET2 suppresses NPC development through interacting with PKM to inhibit glycolysis.

Chimeric antigen receptor (CAR) T cells targeting CD19 antigen have produced remarkable clinical outcomes for cancer patients. However, identifying measures to enhance effector function remains one of the most challenging issues in CD19-targeted immunotherapy. Here, we report a novel approach in which a microRNA (miRNA) or short-hairpin RNA (shRNA) cassette was integrated into CAR-expressing retroviral vectors. Using this system, we generated anti-CD19 CAR-T cells co-expressing miR155 or LSD1 shRNA and found that anti-CD19 CAR-T cells with miR155 upregulation or LSD1 downregulation exhibited increased anti-tumor functions in vitro and in vivo. Transcriptional profiling analysis by RNA sequencing revealed the targets of miR155 and LSD1 in anti-CD19 CAR-T cells. Our experiments indicated that introduction of miRNA or shRNA expression into anti-CD19 CAR T-cells might be an effective strategy to improve the anti-tumor effects of CAR-T cell therapy.

Esophageal and tracheal foreign body ingestion trigger common pediatric emergencies. In this case report, we describe a pediatric patient with simultaneous tracheal and esophageal obstruction caused by foreign bodies. A child aged 2 years and 1 month swallowed a pair of metallic magnetic beads at the same time; one bead entered the trachea and the other bead entered the esophagus. We suspected that the two magnetic beads were mutually attracted and thus became trapped in their respective lumina. The tracheal foreign body was uneventfully removed; this dislodged the esophageal foreign body, which was then excreted. There were no serious complications in the present case, but parents and medical personnel should be mindful of the potential hazards associated with ingestion of multiple magnetic foreign bodies. A high index of suspicion is appropriate. Investigations must be carefully planned. Treatment should not be delayed; the consequences of delay may be serious.

Introduction Nerve block technology is widely used in clinical practice for pain management. Conventional nerve localization methods, which only rely on palpation to identify anatomical landmarks, require experienced surgeons and can be risky. Visualization technologies like ultrasound guidance can help prevent complications by helping surgeons locate anatomical structures in the surgical area and by guiding the operation using different kinds of images. There are several important and complex anatomical structures in the oral and maxillofacial regions. The current article reviews the application of ultrasound guidance in oral and maxillofacial nerve blocks. Methods We searched the literature on the use of ultrasound guidance for the main nerve block techniques in the oral and maxillofacial regions using both PubMed and MEDLINE and summarized the findings. Results and Discussion A review of the literature showed that ultrasound guidance improves the safety and effectiveness of several kinds of puncture procedures, including nerve blocks. There are two approaches to blocking the mandibular nerve: intraoral and extraoral. This review found that the role of ultrasound guidance is more important in the extraoral approach. There are also two approaches to the blocking of the maxillary nerve and the trigeminal ganglion under ultrasound guidance: the superazygomatic approach and the infrazygomatic approach. The infrazygomatic approach can be further divided into the anterior approach and the posterior approach. It is generally believed that the anterior approach is safer and more effective. This review found that the effectiveness and safety of most oral and maxillofacial nerve block operations can be improved through the use of ultrasound guidance.

Since the outbreak of SARS-CoV-2, antigenicity concerns continue to linger with emerging mutants. As recent variants have shown decreased reactivity to previously determined monoclonal antibodies (mAbs) or sera, monitoring the antigenicity change of circulating mutants is urgently needed for vaccine effectiveness. Currently, antigenic comparison is mainly carried out by immuno-binding assays. Yet, an online predicting system is highly desirable to complement the targeted experimental tests from the perspective of time and cost. Here, we provided a platform of SAS (Spike protein Antigenicity for SARS-CoV-2), enabling predicting the resistant effect of emerging variants and the dynamic coverage of SARS-CoV-2 antibodies among circulating strains. When being compared to experimental results, SAS prediction obtained the consistency of 100% on 8 mAb-binding tests with detailed epitope covering mutational sites, and 80.3% on 223 anti-serum tests. Moreover, on the latest South Africa escaping strain (B.1.351), SAS predicted a significant resistance to reference strain at multiple mutated epitopes, agreeing well with the vaccine evaluation results. SAS enables auto-updating from GISAID, and the current version collects 867K GISAID strains, 15.4K unique spike (S) variants, and 28 validated and predicted epitope regions that include 339 antigenic sites. Together with the targeted immune-binding experiments, SAS may be helpful to reduce the experimental searching space, indicate the emergence and expansion of antigenic variants, and suggest the dynamic coverage of representative mAbs/vaccines among the latest circulating strains. SAS can be accessed at https://www.biosino.org/sas.

BackgroundDesigning combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects.MethodsWe here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective coinhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic antiproliferation activity.ResultsConsistent with in vivo experiments of zebrafish, coinhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In an analysis of 365 HCC individuals, the low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67 to 213%, compared to the rest of the groups.ConclusionTogether, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malignant cancers.

Background: A ganglioglioma (GG), a tumor with both neuronal and astrocytic components, rarely occurs outside the central nervous system.Case Summary: We present the first reported case of a 1-month-old male with a congenital nasopharyngeal GG, nasal congestion, and dyspnea; we include the operative video. Magnetic resonance imaging was used to explore whether the tumor communicated with the intracranial space. We used an endoscopic plasma technique to ensure complete tumor resection. This afforded a good visual field, endoscopic magnification, and good hemostasis.Conclusions: We report a rare case of a nasopharyngeal GG triggering nasal congestion and dyspnea in a 1-month-old male, and report our experience with the treatment of nasopharyngeal GG and similar diseases.

Abstract Background Functional antibody genes are often assembled by VDJ recombination and then diversified by somatic hypermutation. Identifying the combination of sourcing germline genes is critical to understand the process of antibody maturation, which may facilitate the diagnostics and rapid generation of human monoclonal antibodies in therapeutics. Despite of successful efforts in V and J fragment assignment, method in D segment tracing remains weak for immunoglobulin heavy diversity (IGHD). Results In this paper, we presented a D-sensitive mapping method called DSab-origin with accuracies around 90% in human monoclonal antibody data and average 95.8% in mouse data. Besides, DSab-origin achieved the best performance in holistic prediction of VDJ segments assignment comparing with other methods commonly used in simulation data. After that, an application example was explored on the antibody response based on a time-series antibody sequencing data after influenza vaccination. The result indicated that, despite the personal response among different donors, IGHV3–7 and IGHD4–17 were likely to be dominated gene segments in these three donors. Conclusions This work filled in a computational gap in D segment assignment for VDJ germline gene identification in antibody research. And it offered an application example of DSab-origin for studying the antibody maturation process after influenza vaccination.

An automatic region proposal network (ARPN) is proposed to generate bounding boxes with confidence scores for far-infrared (FIR) pedestrian detection. The model consists of two parts: first, the bounding boxes are predicted by the L2 loss function and a module is designed based on a convolutional neural network. This module is simple and only has two layers, each with a 1Ã-1 kernel. Second, a score map is obtained through FIR pedestrian segmentation based on a feature pyramid network. The scores are taken as the confidence levels for the predicted bounding boxes. To obtain the scores, a new labelling method is also introduced in this paper for FIR image segmentation. We can obtain the bounding boxes per pixel directly and efficiently without any manually designed hyper parameters related to the anchor boxes. To validate the model, this paper uses the LSI, CVC09, CVC14 and SCUT FIR pedestrian detection datasets in the experiments. The datasets consist of different sizes of FIR images collected from several different cameras. The datasets contain different outdoor urban scenes collected at different times, from day to night. The recall vs number of proposals, average recall and recall at IoU 0.5 are used to evaluate the proposed method and log-average miss rate is used to evaluate final detection results. Compared with other algorithms, experiments on most of the data sets also show better performance.

Introduction and ObjectiveNeoantigen-based immunotherapy is one of the breakthroughs in cancer immunotherapy. Benefit from the Cancer Genome Atlas database, we intended to identify mutant peptides with neoantigen property in bladder cancer (BC). Correlations between the immunoreactivity of candidate neoantigens and clinical manifestations were further analyzed.MethodsHLA-A*02:01 restricted mutant (MT) and wildtype (WT) peptides were predicted by using whole exome sequencing data of 412 BC patients in the TCGA database. Binding affinity to HLA-A2 molecules was determined by using T2 cell-based binding assay. The immunoreactivity to WT and MT peptides in HLA-A2+ BC patients was determined by using an ELISPOT assay upon in vitro stimulation with MT and WT peptides individually. Clinical relevance to peptide-specific immunoreactivity was analyzed by Pearson correlation analysis. The disease free survival (DFS) curves were plotted using the Kaplan–Meier method in BC patients with or without mutations and compared using the log-rank test online.ResultsFifty-seven HLA-A*02:01 restricted WT and MT peptides were selected based on predicted high affinity and expression frequency, among which 12 MT peptides from 12 individual genes exhibited strong affinity to HLA-A2 molecules when compared to WT counterparts. MT peptides induced more peptide-specific IFNγ spot forming units (SFUs) than WT counterparts in HLA-A2+ BC patients upon in vitro stimulation. They were negatively correlated to the counts of peripheral leukocytes and platelets. Patients with higher C-reactive protein level exhibited lower immunoreactivity to MT peptides. Combination of MT peptides from 6 genes, including CDKN1AG61V, RHOBP75L, DDB1S25L, AHNAKD4855Y, ANP32AS56L and MKI67H84L covered 47.5% of the patients under investigation. Patients harboring combinational mutations in these genes were associated with a longer DFS according to the cBioportal online analysis.ConclusionTwelve HLA-A*02:01 restricted MT peptides have been identified exhibiting higher binding affinity to HLA-A2 molecules and stronger immunoreactivity than WT counterparts in BC patients. Combination of MT peptides from six genes might be potential as neoantigen candidates in cancer immunotherapy against BC in the future. Inflammatory modulation is inclined to be a strategy to enhance the efficacy of neoantigen-based immunotherapy.

While T cells are considered to play a primary role in IgE-mediated atopic diseases, little is known about the systemic variations of T cell subsets from patients with allergic rhinitis (AR). To elucidate the characteristics of peripheral T cells, we analyzed natural killer, B cell, and T cell populations, performed T cell subset construction, and assessed chemokine receptor and associated serum cytokine expression in 25 AR patients and 20 healthy controls. Our results revealed increased levels of CD4+T cells, serum interleukin (IL)-10, IL-6, and interferon (IFN)-γ, and reduced Th1 and Th17 subsets, identified by their chemokine receptors, in AR patients. These results suggest a systemic activation of T cell responses in AR. We further demonstrated that AR patients exhibit significantly reduced CD4+T cell CXCR3 expression, especially in patients with moderate-severe disease severity, demonstrating that CXCR3 is a potential key molecule that hinders the Th1/Th2 balance in AR pathology. Overall, systemic T cell activation occurred in AR patients and CXCR3 dramatically decreased in CD4+T cells, which may ultimately be used as a potential disease and/or therapeutic target.

BackgroundColon cancer is one of the most common health threats for humans since its high morbidity and mortality. Detecting potential prognosis risk biomarkers (PRBs) is essential for the improvement of therapeutic strategies and drug development. Currently, although an integrated prognostic analysis of multi-omics for colon cancer is insufficient, it has been reported to be valuable for improving PRBs’ detection in other cancer types.AimThis study aims to detect potential PRBs for colon adenocarcinoma (COAD) samples through the cancer genome atlas (TCGA) by integrating muti-omics.Materials and MethodsThe multi-omics-based prognostic analysis (MPA) model was first constructed to systemically analyze the prognosis of colon cancer based on four-omics data of gene expression, exon expression, DNA methylation and somatic mutations on COAD samples. Then, the essential features related to prognosis were functionally annotated through protein–protein interaction (PPI) network and cancer-related pathways. Moreover, the significance of those essential prognostic features were further confirmed by the target regulation simulation (TRS) model. Finally, an independent testing dataset, as well as the single cell-based expression dataset were utilized to validate the generality and repeatability of PRBs detected in this study.ResultsBy integrating the result of MPA modeling, as well the PPI network, integrated pathway and TRS modeling, essential features with gene symbols such as EPB41, PSMA1, FGFR3, MRAS, LEP, C7orf46, LOC285000, LBP, ZNF35, SLC30A3, LECT2, RNF7, and DYNC1I1 were identified as PRBs which provide high potential as drug targets for COAD treatment. Validation on the independent testing dataset demonstrated that these PRBs could be applied to distinguish the prognosis of COAD patients. Moreover, the prognosis of patients with different clinical conditions could also be distinguished by the above PRBs.ConclusionsThe MPA and TRS models constructed in this paper, as well as the PPI network and integrated pathway analysis, could not only help detect PRBs as potential therapeutic targets for COAD patients but also make it a paradigm for the prognostic analysis of other cancers.

BackgroundThe dysregulation of non-coding RNAs (ncRNAs) such as miRNAs and lncRNAs are associated with the pathogenesis and progression in multiple cancers including solid tumors. Comprehensive investigations of prognosis-related ncRNA markers could promote the development of therapeutic strategies for solid tumors, but rarely reported.MethodsBy taking advantage of The Cancer Genome Atlas (TCGA), pan-cancer prognosis analysis (PCPA) models were firstly constructed based on miRNA and lncRNA expression profiles of 8,450 samples in 19 solid tumors. Further, the co-occurrence and exclusivity among ncRNA markers were systematically analyzed for different cancers.ResultsIn identified ncRNA makers, 71% of the miRNA markers were shared in multiple cancers, whereas 96% of the lncRNA markers were cancer-specific. Moreover, to analyze the regulation patterns of prognosis-related ncRNAs at the pan-cancer level, miRNA markers were further annotated into eight carcinogenic pathways. Results represented that approximately 86% of these miRNA markers could regulate the PI3K-Akt signaling pathway, while only 48% for the Notch signaling pathway. Finally, among 126 common genes that participated in eight carcinogenic pathways, BCL2, CSNK2A1, EGFR, PDGFRA, and VEGFA were proposed as potential drug targets for multiple cancers.ConclusionThe prognosis analysis and regulation characteristics of ncRNAs presented in this study may help to facilitate the discovery of anti-cancer drugs for multiple solid tumors.

Purpose. Bisphenol A (BPA) is found in many plastic products and is thus a common environmental endocrine disruptor. Plastic-related health problems, including allergic diseases, are attracting increasing attention. However, few experimental studies have explored the effect of BPA on allergic rhinitis (AR). We explore whether BPA was directly related to the allergic inflammation induced by ovalbumin (OVA) in AR mice. Methods. We first constructed OVA-induced mouse model, and after BPA administration, we evaluated nasal symptoms and measured the serum OVA-specific IgE levels by ELISA. Th2 and Treg-related cytokines of nasal mucosa were measured by cytometric bead array. Th2 and Treg-specific transcription factor levels were assayed by PCR. The proportions of CD3+CD4+IL-4+Th2 and CD4+Helios+Foxp3+ T cells (Tregs) in spleen tissue were determined by flow cytometry. Results. Compared to OVA-only-induced mice, BPA addition increased nasal symptoms and serum OVA-specific IgE levels. OVA and BPA coexposure significantly increased IL-4 and IL-13 protein levels compared to those after OVA exposure alone. BPA plus OVA tended to decrease the IL-10 protein levels compared to those after OVA alone. Coexposure to OVA and BPA significantly increased the GATA-3-encoding mRNA level, and decreased the levels of mRNAs encoding Foxp3 and Helios, compared to those after OVA exposure alone. BPA increased the Th2 cell proportion, and decreased that of Tregs, compared to the levels with OVA alone. Conclusion. BPA exerted negative effects by exacerbating AR allergic symptoms, increasing serum OVA-specific IgE levels, and compromising Th2 and Treg responses.

Sparse immune-binding data for emerging pathogens limits the ability of existing in silico antigenicity prediction methods to aid vaccine design. Here, the authors introduce a computational method that estimates antigenic pathogen similarity based on epitope structure.

Abstract Nuclear receptors (NR) are a class of proteins that are responsible for sensing steroid and thyroid hormones and certain other molecules. In that case, NR have the ability to regulate the expression of specific genes and associated with various diseases, which make it essential drug targets. Approaches which can predict the inhibition ability of compounds for different NR target should be particularly helpful for drug development. In this study, proteochemometric modelling was introduced to analysis the bioactivity between chemical compounds and NR targets. Results illustrated the ability of our PCM model for high-throughput NR-inhibitor screening after evaluated on both internal (AUC > 0.870) and external (AUC > 0.746) validation set. Moreover, in-silico predicted bioactive compounds were clustered according to structure similarity and a series of representative molecular scaffolds can be derived for five major NR targets. Through scaffolds analysis, those essential bioactive scaffolds of different NR target can be detected and compared. Generally, the methods and molecular scaffolds proposed in this article can not only help the screening of potential therapeutic NR-inhibitors but also able to guide the future NR-related drug discovery.

Multispectral pedestrian detection, which consists of a color stream and thermal stream, is essential under conditions of insufficient illumination because the fusion of the two streams can provide complementary information for detecting pedestrians based on deep convolutional neural networks (CNNs). In this paper, we introduced and adapted a simple and efficient one-stage YOLOv4 to replace the current state-of-the-art two-stage fast-RCNN for multispectral pedestrian detection and to directly predict bounding boxes with confidence scores. To further improve the detection performance, we analyzed the existing multispectral fusion methods and proposed a novel multispectral channel feature fusion (MCFF) module for integrating the features from the color and thermal streams according to the illumination conditions. Moreover, several fusion architectures, such as Early Fusion, Halfway Fusion, Late Fusion, and Direct Fusion, were carefully designed based on the MCFF to transfer the feature information from the bottom to the top at different stages. Finally, the experimental results on the KAIST and Utokyo pedestrian benchmarks showed that Halfway Fusion was used to obtain the best performance of all architectures and the MCFF could adapt fused features in the two modalities. The log-average miss rate (MR) for the two modalities with reasonable settings were 4.91% and 23.14%, respectively.

Chronic liver disease (CLD) has become a major global health problem while herb prescriptions are clinically observed with significant efficacy. Three classical Traditional Chinese Medicine (TCM) formulae, Yinchenhao Decoction (YCHT), Huangqi Decoction (HQT), and Yiguanjian (YGJ) have been widely applied in China to treat CLD, but no systematic study has yet been published to investigate their common and different mechanism of action (MOA). Partial limitation may own to deficiency of effective bioinformatics methods. Here, a computational framework of comparative network pharmacology is firstly proposed and then applied to herbal recipes for CLD disease. The analysis showed that, the three formulae modulate CLD mainly through functional modules of immune response, inflammation, energy metabolism, oxidative stress, and others. On top of that, each formula can target additional unique modules. Typically, YGJ ingredients can uniquely target the ATP synthesis and neurotransmitter release cycle. Interestingly, different formulae may regulate the same functional module in different modes. For instance, YCHT and YGJ can activate oxidative stress-related genes of SOD family while HQT are found to inhibit SOD1 gene. Overall, our framework of comparative network pharmacology proposed in our work may not only explain the MOA of different formulae treating CLD, but also provide hints to further investigate the biological basis of CLD subtypes.

Insomnia is a common and widespread sleeping disorder caused by various risk factors. Though beneficial, conventional treatments of insomnia have significant limitations. As an alternative treatment, Chinese herbal formula Suanzaoren prescription (SZRP), composed of Suanzaoren [seeds of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow] and four additional herbs, has been reported with significant anti-insomnia effects. Yet the anti-insomnia mechanism of the herb formulae remains unknown. In this study, we attempted to extrapolate the holistic anti-insomnia mechanism of SZRP through herbal targeting and network pharmacology. The results indicated that the ingredients of Suanzaoren can target multi-neurotransmitter receptors at synapse interface, which was reported to be associated with sedative and hypnotic effects, while the four additional herbs can hit multiple pathways downstream of membrane neurotransmitters. Furthermore, the four additional herbs showed highly cooperative targeting patterns in the paralleled and cross-talked pathways related to inflammatory regulation and endocrine system, which may contribute to the additional relief of insomnia caused by inflammation, anxiety, or endocrine disorder. The interesting complementary mechanism we found among the herbal groups of SZRP may provide an example to study Chinese herbal formula and offers clues to future design of anti-insomnia strategy.

Nasopharyngeal carcinoma (NPC) is the most common type of malignancy of the neck and head in Southeast Asia and North Africa. Long noncoding RNA (LncRNA) Differentiation antagonizing nonprotein coding RNA (DANCR) has been reported to exert oncogenic functions in various malignant tumors. However, whether DANCR is involved in NPC tumorgenesis and its underlying mechanisms are still unknown. In the current study, we investigated the expression and biological functions of DANCR in NPC cells and found that DANCR is highly expressed in NPC cells and IL-6 stimulation upregulates DANCR expression through an STAT3-dependent manner. Besides, DANCR knockdown attenuates IL-6-induced proliferation and invasion of NPC cells. Furthermore, DANCR specifically interacts with STAT3 to promote STAT3 activation in NPC cells. Moreover, DANCR knockdown evidently decreases IL-6 induced the association between STAT3 and JAK1 in NPC cells. In addition, we also found that DANCR also indirectly binds to JAK1 through interacting with STAT3 under IL-6 stimulation in NPC cells. Taken together, the present study for the first time demonstrates that DANCR, acting as an oncogene in NPC, promotes NPC progression by interacting with STAT3 and enhancing JAK1 binding to STAT3 to strengthen IL-6/JAK1/STAT3 signaling, suggesting that it may be a potential target to be used as a novel strategy to develop NPC therapeutics.

To explore the feasibility of cemented paste backfill with phosphogypsum (PG), bleeding water and rheological tests (slump and on-site pipeline loop tests) were performed with PG backfill slurry (PGBS). In the bleeding water test, the PGBS concentration with minimal bleeding water was measured between 60.87 and 67.61%; in the rheological slump test, values of 61 to 68% were determined for the on-site pipeline loop test. The rheological pipeline loop test demonstrated that the resistance coefficient is lowest when the concentration is no higher than 65%. Through industrial experiments, PG slurry with a concentration of 64%–65% backfill was successfully applied to the goaf. The experimental results demonstrate that PGBS with characteristics of “less bleeding water” and “improved pumpability” is obtained when its concentration is between 61 and 65%. Paste-like PG slurry was proven to be optimal for cemented PG backfilling technology.

Trains shuttle in semiopen environments, and the surrounding environment plays an important role in the safety of train operation. The weather is one of the factors that affect the surrounding environment of railways. Under haze conditions, railway monitoring and staff vision could be blurred, threatening railway safety. This paper tackles image dehazing for railways. The contributions of this paper for railway video image dehazing are as follows: (1) this paper proposes an end-to-end residual block-based haze removal method that consists of two subnetworks, namely fine-grained and coarse-grained network can directly generate the clean image from input hazy image, called RID-Net (Railway Image Dehazing Network). (2) The combined loss function (per-pixel loss and perceptual loss functions) is proposed to achieve both low-level features and high-level features so to generate the high-quality restored images. (3) We take the full-reference criterion (PSNR&SSIM), object detection, running time, and sensory vision to evaluate the proposed dehazing method. Experimental results on railway synthesized dataset, benchmark indoor dataset, and real-world dataset demonstrate our method has superior performance compared to the state-of-the-art methods.

Flavonoids are the largest class of plant polyphenols, with common structure of diphenylpropanes, consisting of two aromatic rings linked through three carbons and are abundant in both daily diets and medicinal plants. Fueled by the recognition of consuming flavonoids to get better health, researchers became interested in deciphering how flavonoids alter the functions of human body. Here, systematic studies were performed on 679 flavonoid compounds and 481 corresponding targets through bioinformatics analysis. Multiple human diseases related pathways including cancers, neuro-disease, diabetes, and infectious diseases were significantly regulated by flavonoids. Specific functions of each flavonoid subclass were further analyzed in both target and pathway level. Flavones and isoflavones were significantly enriched in multi-cancer related pathways, flavan-3-ols were found focusing on cellular processing and lymphocyte regulation, flavones preferred to act on cardiovascular related activities and isoflavones were closely related with cell multisystem disorders. Relationship between chemical constitution fragment and biological effects indicated that different side chain could significantly affect the biological functions of flavonoids subclasses. Results will highlight the common and preference functions of flavonoids and their subclasses, which concerning their pharmacological and biological properties.

Recent development has enabled synergistic drugs in treating a wide range of cancers. Being highly context-dependent, however, identification of successful ones often requires screening of combinational dose on different testing platforms in order to gain the best anticancer effects. To facilitate the development of effective computational models, we reviewed the latest strategy in searching optimal dose combination from three perspectives: (1) mainly experimental-based approach; (2) Computational-guided experimental approach; and (3) mainly computational-based approach. In addition to the introduction of each strategy, critical discussion of their advantages and disadvantages were also included, with a strong focus on the current applications and future improvements.

Temperature, nutrients, and salinity are among the important factors constraining the distribution and abundance of microorganisms in the ocean. Marine Group II (MGII) belonging to Euryarchaeota commonly dominates the planktonic archaeal community in shallow water and Marine Group I (MGI, now is called Thaumarchaeota) in deeper water in global oceans. Results of quantitative PCR (qPCR) and 454 sequencing in our study, however, showed the dominance of MGII in planktonic archaea throughout the water column of the northeastern South China Sea (SCS) that is characterized by strong water mixing. The abundance of ammonia-oxidizing archaea (AOA) representing the main group of Thaumarchaeota in deeper water in the northeastern SCS was significantly lower than in other oceanic regions. Phylogenetic analysis showed that the top operational taxonomic units (OTUs) of the MGII occurring predominantly below 200 m depth may be unique in the northeastern SCS based on the observation that they are distantly related to known sequences (identity ranging from 90–94%). The abundance of MGII was also significantly correlated with total bacteria in the whole column, which may indicate that MGII and bacteria may have similar physiological or biochemical properties or responses to environmental variation. This study provides valuable information about the dominance of MGII over AOA in both shallow and deep water in the northeastern SCS and highlights the need for comprehensive studies integrating physical, chemical, and microbial oceanography.