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Abstract Background In recent years, the use of endocrine-disrupting chemicals (EDCs) has become increasingly common, leading to severe environmental pollution and harm to aquatic organisms. 17α-Methyltestosterone (MT) is a synthetic androgen that can cause immunotoxicity in aquaculture, affecting fish health. To address this issue, this study aimed to investigate the effect of Vitamin C (VC) on MT-induced immunotoxicity and determine the optimal VC supplementation. Results Carassius auratus was exposed to 50 ng/L MT and treated with 25, 50, and 150 mg/kg VC for 7, 14, and 21 d. Morphological indicators, histological characteristics, hepatic antioxidant capacity, and immune-related gene expression were analyzed. Additionally, RNA-seq was performed on the liver tissues of the control, MT, and MT + 25 mg/kg VC groups after 21 d. Results showed that, MT treatment significantly increased liver malondialdehyde content and inhibited immune-related gene expression (TNF-α, IL-8, INF-γ, IL-10, Caspase-9, and IGF-I), causing oxidative stress and immunotoxicity, leading to hepatic steatosis. However, supplementation with 25–50 mg/kg VC effectively alleviated the MT-induced damage to the hepatic structure and immune system. RNA-seq revealed significant enrichment of differentially expressed genes in multiple signaling pathways, including the mTOR, MAPK, and Wnt pathways. Conclusions In summary, 25–50 mg/kg VC alleviated inhibitory effect of MT on immune-related genes in C. auratus liver, reducing MT-induced tissue damage. VC not only alleviated inflammation, oxidative stress, and immunotoxicity induced by MT through the regulation of the mTOR, MAPK, and Wnt signaling pathways, but also indirectly enhanced cellular antioxidant defense mechanisms by regulating the NRF2 pathway. This provides a theoretical basis for VC application in aquaculture, improving fish health and increasing efficiency.

Abstract We investigate the meson-baryon interaction in coupled channels with the quantum numbers of the pentaquarks $$P_{bss}$$ P bss and $$P_{bsss}$$ P bsss . The interaction is derived from an extension of the local hidden gauge approach to the heavy quark sector, which has demonstrated accurate results compared to experiments involving $$\Omega _{b}$$ Ω b , $$\Xi _{b}$$ Ξ b states, and pentaquarks $$P_{c}$$ P c and $$P_{cs}$$ P cs . In our study, we identify several molecular states with small decay widths within the chosen set of coupled channels. The spin-parity ( $$J^P$$ J P ) of these states is as follows: $$J^P={\frac{1}{2}}^-$$ J P = 1 2 - for pseudoscalar-baryon ( $${\frac{1}{2}}^+$$ 1 2 + ) coupled channels, $$J^P={\frac{3}{2}}^-$$ J P = 3 2 - for pseudoscalar-baryon ( $${\frac{3}{2}}^+$$ 3 2 + ) coupled channels, $$J^P={\frac{1}{2}}^-$$ J P = 1 2 - and $${\frac{3}{2}}^-$$ 3 2 - for vector-baryon ( $${\frac{1}{2}}^+$$ 1 2 + ) coupled channels, and $$J^P={\frac{1}{2}}^-$$ J P = 1 2 - , $${\frac{3}{2}}^-$$ 3 2 - , $${\frac{5}{2}}^-$$ 5 2 - for vector-baryon ( $${\frac{3}{2}}^+$$ 3 2 + ) coupled channels. We search for the poles of these states and evaluate their couplings to the different channels.

Abstract We propose the reaction $$\psi (3686) \rightarrow \bar{\Xi }^+ \bar{K}^0 \Sigma ^{*-}$$ ψ ( 3686 ) → Ξ ¯ + K ¯ 0 Σ ∗ - , with the $$\Sigma ^{*-}$$ Σ ∗ - decaying to $$\pi ^- \Lambda $$ π - Λ in order to show evidence for the existence of two $$\Xi (1820)$$ Ξ ( 1820 ) states, one around 1824 MeV and narrow, and another one around 1875 MeV and wide. The phase space for $$\bar{K}^0 \Sigma ^{*-}$$ K ¯ 0 Σ ∗ - production reduces the effect of the lower mass resonance, magnifying the effect of the higher mass resonance that shows clearly over the phase space. The estimated rate of the production is bigger than the one of the $$\psi (3686) \rightarrow \bar{\Xi }^+ K^- \Lambda $$ ψ ( 3686 ) → Ξ ¯ + K - Λ reaction, where a clear peak for $$\Xi (1820)$$ Ξ ( 1820 ) was observed by the BESIII collaboration, what makes the Beijing facility ideal to carry out the reaction proposed.

Abstract WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.

BackgroundQuartz dust cannot be degraded in the lungs, and inhalation of a large amount of quartz dust in the occupational production process will lead to the occurrence of pulmonary fibrosis, and then develop into silicosis. In recent years, studies have found that exosomes may be involved in the pathogenesis of fibrotic diseases by carrying microribonucleic acid (miRNA), but the mechanism of their actions in silicosis still needs to be studied. ObjectiveTo investigate the role of exosome-derived miRNA-21-5p/mothers against decapentaplegic homolog 7 (Smad7) in quartz dust-induced pulmonary fibrosis in rats. MethodsTwenty-four healthy male SD rats were randomly divided into four groups (six rats in each group): control 4-week group, control 16-week group, quartz 4-week group, and quartz 16-week group. At the beginning of the experiment, 1 mL of quartz suspension (50 mg·mL−1) and 1 mL of normal saline were injected into the trachea of rats in the quartz group and the control group, respectively, by means of one-time non-exposure intratracheal dust staining. Alveolar lavage was performed at the 4th and 16th weeks after dust staining, the exosomes in lavage solution were extracted by polyethylene glycol (PEG) precipitation, morphological identification was conducted by transmission electron microscopy (TEM), particle size of exosomes was detected by nano-tracking analysis (NTA), and the marker proteins CD9 and CD63 of exosomes were detected by Western blotting (WB). The expression of miRNA-21-5p in exosomes was determined by reverse transcription polymerase chain reaction (RT-PCR). The degree of lung tissue injury and fibrosis was observed by hematoxylin-eosin staining (HE) and Masson staining. The collagen content of lung tissue was detected by hydroxyproline (HYP) method. The expression of Smad7 protein in lung tissue was detected by WB. ResultsThe results of pathological staining showed that compared with the control group, lung inflammatory cell infiltration, alveolar wall thickening, and collagen increase were observed after 4 weeks of dusting, and collagen deposition and silicon nodules appeared after 16 weeks of dusting. Compared with the control group, the expression level of HYP in the lung tissue of the quartz group was increased after 4 weeks and 16 weeks of dust staining (P

Abstract Background To characterize sleep disturbance in patients with established rheumatoid arthritis (RA) and explore the relationship between sleep and mechanisms of central nervous system pain regulation. Methods Forty-eight RA participants completed wrist-worn actigraphy monitoring and daily sleep diaries for 14 days to assess sleep-wake parameters. Participants underwent quantitative sensory testing to assess pressure pain thresholds, temporal summation, and conditioned pain modulation. Data were analyzed using descriptive statistics, Spearman’s correlation, and multivariable median regression analyses. Results Median actigraphy and sleep diary derived sleep duration was 7.6 h (interquartile range (IQR) 7.0, 8.2) and 7.1 h (IQR 6.7, 7.6), respectively. Actigraphy based sleep fragmentation (rho = 0.34), wake after sleep onset (rho = 0.36), and sleep efficiency (rho = -0.32) were each related to higher temporal summation values in unadjusted analyses, but these relationships did not persist after controlling for age, body mass index, disease duration, and swollen joint count. No significant relationships were observed between sleep with pressure pain thresholds and conditioned pain modulation. Conclusion Actigraphy and sleep diary monitoring are well tolerated in established RA patients. Future investigations should include both subjective and objective assessments, as they may provide information relating to different components and mechanisms.

Abstract In this work we compare the predictions for the scattering length and effective range of the channels $$K^0 \Sigma ^+, K^+ \Sigma ^0, K^+ \Lambda $$ K 0 Σ + , K + Σ 0 , K + Λ and $$\eta p$$ η p , assuming the $$N^*(1535)$$ N ∗ ( 1535 ) state as a molecular state of these channels, or an original genuine state, made for instance from three quarks. Looking at very different scenarios, what we conclude is that the predictions of these two pictures are drastically different, to the point that we advise the measurement of these magnitudes, accessible for instance by measuring correlation functions, in order to gain much valuable information concerning the nature of this state.

Abstract To understand the mechanical response pattern of the existing structure and ground due to the construction of metro tunnels underneath, the finite difference method is adopted to study the torsional deformation and stress variation of the existing structure and the effect of underground carriageway structures on the surface subsidence. The curves of the maximum differential subsidence, torsion angle, and distortion of the cross‐section of the existing structure show two peaks in succession during traversing of two metro tunnels beneath it. The torsion angle of the existing structure changes when the two tunnels traverse beneath it in opposite directions. The first traversing of the shield tunnel mainly induces the magnitude variation in torsional deformation of the existing structure, but the second traversing of the subsurface tunnel may cause a dynamic change in the magnitude and form of torsional deformation in the existing structure. The shielding effect can reduce the surface subsidence caused by metro tunnel excavation to a certain extent, and the development trend of subsidence becomes slower as the excavation continues.

Abstract Background The correlation between metals and hypertension, such as sodium, zinc, potassium, and magnesium, has been confirmed, while the relationship between aluminum and hypertension is not very clear. This study aimed to evaluate the correlation between plasma aluminum and hypertension in electrolytic aluminum workers by the Bayesian networks (BN). Methods In 2019, 476 male workers in an aluminum factory were investigated. The plasma aluminum concentration of workers was measured by inductively coupled plasma mass spectrometry. The influencing factors on the prevalence of hypertension were analyzed by the BN. Results The prevalence of hypertension was 23.9% in 476 male workers. The risk of hypertension from plasma aluminum in the Q2, Q3, and Q4 groups was 5.20 (1.90–14.25), 6.92 (2.51–19.08), and 7.33 (2.69–20.01), respectively, compared with that in the Q1 group. The risk of hypertension from the duration of exposure to aluminum of >10 years was 2.23 (1.09–4.57), compared without aluminum exposure. Area under the curve was 0.80 of plasma aluminum and the duration of exposure to aluminum was based on covariates, indicating that aluminum exposure had important predictive value in the prevalence of hypertension in the occupational population. The results of the study using the BN model showed that if the plasma aluminum of all participants was higher than Q4 (≥47.86 µg/L) and the participants were drinking, smoking, diabetes, central obesity, dyslipidemia, and aged >50 years, the proportion of hypertension was 71.2%. Conclusions The prevalence of hypertension increased significantly with the increase of plasma aluminum level.

Abstract The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single‐cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI‐to‐CKD model of unilateral ischemia‐reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co‐localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro‐repair subsets, whereas infiltrating monocyte‐derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling‐associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin‐like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI‐to‐CKD transition, which could be a potential therapeutic target for preventing CKD development.

BackgroundThe role of long non-coding RNAs (lncRNAs) in the invasion and metastasis of gastric cancer remains largely unclear.MethodsIntegrating transcriptome data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differentially expressed genes were identified in gastric cancer. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) database-curated gene set, lncRNAs associated with invasion and metastasis were identified. The Cox analyses were performed to identify prognostic lncRNAs. The competing endogenous RNA (ceRNA) regulation network was constructed to identify hub lncRNAs in gastric cancer. Functional and pathway analyses were used to investigate the function of identified lncRNAs. RT-qPCR and Transwell assays were used to investigate the expression in gastric cancer tissues and functions in gastric cancer cell lines.ResultsBased on GEO and TCGA databases, 111 differentially expressed lncRNAs were identified between gastric cancer and normal samples. A total of 43 lncRNAs were significantly correlated with hallmark genes of cancer invasion and metastasis. Among them, as a hub lncRNA in the invasion-related ceRNA regulation network, FAM87A showed potential regulation on MAPK signaling and transforming growth factor (TGF) signaling cascade, such as TGFB2, TGFBR1, and TGFBR2. Furthermore, FAM87A also showed a significant correlation with cell adhesion molecules, such as Integrin alpha 6 (ITGA6) and Contactin-1 (CNTN1). RT-qPCR experiments showed that FAM87A expression was upregulated in gastric cancer tissues compared to normal samples (n = 30). Transwell assays showed that FAM87A knockdown inhibited the migration and invasion abilities of gastric cancer cells in vitro. Notably, clinical data analysis showed that lncRNA FAM87A could be an independent factor for the overall survival of patients with gastric cancer.ConclusionLncRNA FAM87A may play a pivotal role in regulating migration and invasion of gastric cancer cells. FAM87A could be a potential biomarker for the overall survival of patients with gastric cancer.

Abstract Background The spleen plays a critical role in the immune response against malaria parasite infection, where splenic fibroblasts (SFs) are abundantly present and contribute to immune function by secreting type I collagen (collagen I). The protein family is characterized by Plasmodium vivax tryptophan-rich antigens (PvTRAgs), comprising 40 members. PvTRAg23 has been reported to bind to human SFs (HSFs) and affect collagen I levels. Given the role of type I collagen in splenic immune function, it is important to investigate the functions of the other members within the PvTRAg protein family. Methods Protein structural prediction was conducted utilizing bioinformatics analysis tools and software. A total of 23 PvTRAgs were successfully expressed and purified using an Escherichia coli prokaryotic expression system, and the purified proteins were used for co-culture with HSFs. The collagen I levels and collagen-related signaling pathway protein levels were detected by immunoblotting, and the relative expression levels of inflammatory factors were determined by quantitative real-time PCR. Results In silico analysis showed that P. vivax has 40 genes encoding the TRAg family. The C-terminal region of all PvTRAgs is characterized by the presence of a domain rich in tryptophan residues. A total of 23 recombinant PvTRAgs were successfully expressed and purified. Only five PvTRAgs (PvTRAg5, PvTRAg16, PvTRAg23, PvTRAg30, and PvTRAg32) mediated the activation of the NF-κBp65 signaling pathway, which resulted in the production of inflammatory molecules and ultimately a significant reduction in collagen I levels in HSFs. Conclusions Our research contributes to the expansion of knowledge regarding the functional role of PvTRAgs, while it also enhances our understanding of the immune evasion mechanisms utilized by parasites. Graphical Abstract

Abstract Background This study investigated the role of Galectin-3 in the degeneration of intervertebral disc cartilage. Methods The patients who underwent lumbar spine surgery due to degenerative disc disease were recruited and divided into Modic I, Modic II, and Modic III; groups. HE staining was used to detect the pathological changes in endplates. The changes of Galectin-3, MMP3, Aggrecan, CCL3, and Col II were detected by immunohistochemistry, RT-PCR, and Western blot. MTT and flow cytometry were used to detect cartilage endplate cell proliferation, cell cycle, and apoptosis. Results With the progression of degeneration (from Modic I to III), the chondrocytes and density of the cartilage endplate of the intervertebral disc decreased, and the collagen arrangement of the cartilage endplate of the intervertebral disc was broken and calcified. Meanwhile, the expressions of Aggrecan, Col II, Galectin-3, Aggrecan, and CCL3 gradually decreased. After treatment with Galectin-3 inhibitor GB1107, the proliferation of rat cartilage end plate cells was significantly reduced (P

Abstract Background Atrial fibrillation (AF) is a common cardiac arrhythmia. The ratio of red cell distribution width (RDW) to albumin has been recognized as a reliable prognostic marker for poor outcomes in a variety of diseases. However, the evidence regarding the association between RDW to albumin ratio (RAR) and in hospital mortality in patients with AF admitted to the Intensive Care Unit (ICU) currently was unclear. The purpose of this study was to explore the association between RAR and in hospital mortality in patients with AF in the ICU. Methods This retrospective cohort study used data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database for the identification of patients with atrial fibrillation (AF). The primary endpoint investigated was in-hospital mortality. Multivariable-adjusted Cox regression analysis and forest plots were utilized to evaluate the correlation between the RAR and in-hospital mortality among patients with AF admitted to ICU. Additionally, receiver operating characteristic (ROC) curves were conducted to assess and compare the predictive efficacy of RDW and the RAR. Results Our study included 4,584 patients with AF with a mean age of 75.1 ± 12.3 years, 57% of whom were male. The in-hospital mortality was 20.3%. The relationship between RAR and in-hospital mortality was linear. The Cox proportional hazard model, adjusted for potential confounders, found a high RAR independently associated with in hospital mortality. For each increase of 1 unit in RAR, there is a 12% rise in the in-hospital mortality rate (95% CI 1.06–1.19). The ROC curves revealed that the discriminatory ability of the RAR was better than that of RDW. The area under the ROC curves (AUCs) for RAR and RDW were 0.651 (95%CI: 0.631–0.671) and 0.599 (95% CI: 0.579–0.620). Conclusions RAR is independently correlated with in hospital mortality and in AF. High level of RAR is associated with increased in-hospital mortality rates.

Abstract Background The elimination of schistosomiasis remains a challenging task, with current measures primarily focused on the monitoring and control of Oncomelania hupensis (O. hupensis) snail, the sole intermediate host of Schistosome japonicum. Given the emerging, re-emerging, and persistent habitats of snails, understanding their genetic diversity might be essential for their successful monitoring and control. The aims of this study were to analyze the genetic diversity of Oncomelania hupensis robertsoni (O. h. robertsoni) using microsatellite DNA markers; and validate the applicability of previously identified microsatellite loci for O. hupensis in hilly regions. Methods A total of 17 populations of O. h. robertsoni from Yunnan Province in China were selected for analysis of genetic diversity using six microsatellite DNA polymorphic loci (P82, P84, T4-22, T5-11, T5-13, and T6-27). Results The number of alleles among populations ranged from 0 to 19, with an average of 5. The average ranges of expected (He) and observed (Ho) heterozygosity within populations were 0.506 to 0.761 and 0.443 to 0.792, respectively. The average fixation index within the population ranged from – 0.801 to 0.211. The average polymorphic information content (PIC) within the population ranged from 0.411 to 0.757, appearing to be polymorphic for all loci (all PIC > 0.5), except for P28 and P48. A total of 68 loci showed significant deviations from Hardy-Weinberg equilibrium (P < 0.05), and pairwise Fst values ranged from 0.051 to 0.379. The analysis of molecular variance indicated that 88% of the variation occurred within snail populations, whereas 12% occurred among snail populations. Phylogenetic trees and principal coordinate analysis revealed two distinct clusters within the snail population, corresponding to “Yunnan North” and “Yunnan South”. Conclusions O. h. robertsoni exhibited a relatively high level of genetic differentiation, with variation chiefly existing within snail populations. All snail in this region could be separated into two clusters. The microsatellite loci P82 and P84 might not be suitable for classification studies of O. hupensis in hilly regions. These findings provided important information for the monitoring and control of snail, and for further genetic diversity studies on snail populations. Graphical Abstract

ABSTRACTHigh-concentration protein formulation is of paramount importance in patient-centric drug product development, but it also presents challenges due to the potential for enhanced aggregation and increased viscosity. The analysis of critical quality attributes often necessitates the transfer of samples from their primary containers together with sample dilution. Therefore, there is a demand for noninvasive, in situ biophysical methods to assess protein drug products directly in primary sterile containers, such as prefilled syringes, without dilution. In this study, we introduce a novel application of water proton nuclear magnetic resonance (wNMR) to evaluate the aggregation propensity of a high-concentration drug product, Dupixent® (dupilumab), under stress conditions. wNMR results demonstrate a concentration-dependent, reversible association of dupilumab in the commercial formulation, as well as irreversible aggregation when exposed to accelerated thermal stress, but gradually reversible aggregation when exposed to freeze and thaw cycles. Importantly, these results show a strong correlation with data obtained from established biophysical analytical tools widely used in the pharmaceutical industry. The application of wNMR represents a promising approach for in situ noninvasive analysis of high-concentration protein formulations directly in their primary containers, providing valuable insights for drug development and quality assessment.

This experiment used mice as the experimental subjects to study the alleviating effect of Lactobacillus pentosus CQZC01 (LPCQZC01) on antibiotic-induced diarrhea in mice. After adaptive feeding for seven days, Kunming (KM) mice were randomly divided into the following groups: positive control group, model group, normal group, high concentration group of LPCQZC01 (H-LPCQZC01, 1×109 CFU/mL), and low concentration group of LPCQZC01 (L-LPCQZC01, 1×108 CFU/mL). Except for the normal group, mice were orally administered with lincomycin hydrochloride (120 mg/day) for 7 consecutive days. Changes in body weight, food intake, water consumption, and fecal water content of mice were observed. A histological examination of mouse colon and small intestine sections was done to find out if Lactobacillus pentosus CQZC01 may help mice with antibiotic-induced diarrhea. The findings demonstrated that, in comparison to the model group, mice in the H-LPCQZC01 and L-LPCQZC01 groups had considerably lower blood levels of nterleukin-6 (IL-6), interleukin-17A (IL-17A), 5-hydroxytryptamine (5-HT), and malondialdehyde (MDA), and other variables. In comparison to the model group, the fecal water content in the H-LPCQZC01 and L-LPCQZC01 groups was considerably lower. The H-LPCQZC01 and L-LPCQZC01 groups consumed more food and liquids than the model group did. The H-LPCQZC01 and L-LPCQZC01 groups had more intact colon walls and more compact, regular, and organized intestinal villi. H-LPCQZC01 and L-LPCQZC01 groups had the lower CFTR, EGFR expression and stronger NHE1, NHE2 expression than model group. This study reveals that Lactobacillus pentosus CQZC01 may treat inflammatory lesions in the mouse intestines and successfully treat antibiotic-induced diarrhea in mice.

Abstract Objectives To develop and validate a magnetic resonance imaging-based (MRI) deep multiple instance learning (D-MIL) model and combine it with clinical parameters for preoperative prediction of lymph node metastasis (LNM) in operable cervical cancer. Methods A total of 392 patients with cervical cancer were retrospectively enrolled. Clinical parameters were analysed by logistical regression to construct a clinical model (M1). A ResNet50 structure is applied to extract features at the instance level without using manual annotations about the tumour region and then construct a D-MIL model (M2). A hybrid model (M3) was constructed by M1 and M2 scores. The diagnostic performance of each model was evaluated by the area under the receiver operating characteristic curve (AUC) and compared using the Delong method. Disease-free survival (DFS) was evaluated by the Kaplan‒Meier method. Results SCC-Ag, maximum lymph node short diameter (LNmax), and tumour volume were found to be independent predictors of M1 model. For the diagnosis of LNM, the AUC of the training/internal/external cohort of M1 was 0.736/0.690/0.732, the AUC of the training/internal/external cohort of M2 was 0.757/0.714/0.765, and the AUC of the training/internal/external cohort of M3 was 0.838/0.764/0.835. M3 showed better performance than M1 and M2. Through the survival analysis, patients with higher hybrid model scores had a shorter time to reach DFS. Conclusion The proposed hybrid model could be used as a personalised non-invasive tool, which is helpful for predicting LNM in operable cervical cancer. The score of the hybrid model could also reflect the DFS of operable cervical cancer. Critical relevance statement Lymph node metastasis is an important factor affecting the prognosis of cervical cancer. Preoperative prediction of lymph node status is helpful to make treatment decisions, improve prognosis, and prolong survival time. Key points • The MRI-based deep-learning model can predict the LNM in operable cervical cancer. • The hybrid model has the highest diagnostic efficiency for the LNM prediction. • The score of the hybrid model can reflect the DFS of operable cervical cancer. Graphical Abstract

BackgroundCholangiocarcinoma (CCA) is a typical inflammation-induced malignancy, and elevated serum interleukin-6 (IL-6) levels have been reported to be linked to the onset and progression of CCA. We aim to investigate the potential prognostic value of the IL-6 pathway for CCA.MethodsWe detected the expressions of IL-6, IL-6R, glycoprotein (gp130), C-reactive protein (CRP), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) in CCA tissue microarray using multiplex immunofluorescence. Furthermore, the clinical associations and prognostic values were assessed. Finally, single-cell transcriptome analysis was performed to evaluate the expression level of IL-6 pathway genes in CCA.ResultsThe results revealed that the expression of IL-6 was lower, while the expression of STAT3 was higher in tumor tissues compared to normal tissues. Especially in tumor microenvironment, the expression of IL-6 pathway genes was generally downregulated. Importantly, gp130 was strongly correlated with JAK2 in tumor tissues, while it was moderately correlated with JAK2 in normal tissue. Although none of the gene expressions were directly associated with overall survival and disease-free survival, our study found that IL-6, IL-6R, CRP, gp130, and JAK2 were inversely correlated with vascular invasion, which is a risk factor for poor prognosis in patients with CCA.ConclusionThe findings from this study suggest that the IL-6 signaling pathway may have a potential prognostic value for CCA. Further investigation is needed to understand the underlying molecular mechanisms of the IL-6 pathway in CCA.

BackgroundThe current investigation examines the association between artificial sweetener (AS) consumption and the likelihood of developing chronic kidney disease (CKD), along with its impact on kidney function.MethodsWe utilized data from the National Health and Nutrition Examination Survey from 2003–2006 to conduct covariance analysis and weighted adjusted logistic regression, aiming to assess the association between artificial sweetener intake and CKD risk, as well as kidney function indicators. Subsequently, we employed Mendelian randomization methods to validate the causal relationship between the intake of artificial sweeteners, CKD risk, and kidney function indicators. Instrumental variable analysis using inverse-variance weighting and Robust adjusted profile score were the primary analytical methods employed.ResultsA total of 20,470 participants were included in the study, with 1,257 participants ultimately included in the analysis. In all adjusted logistic regression models, no significant association was found between the intake of artificial sweeteners and CKD risk. Similarly, the summary odds ratios (OR) for each unit change in genetically predicted CKD risk were 2.14 (95% CI: 0.83, 5.21, p = 0.092), 1.41 (95% CI: 0.54, 3.63, p = 0.482), and 1.50 (95% CI: 0.50, 4.52, p = 0.468) for the impact of artificial sweeteners added to cereals, tea, and coffee, respectively. It was only observed that adding artificial sweeteners to coffee was associated with a modest reduction in urinary albumin-to-creatinine ratio (OR = 0.94, 95% CI: −0.108, −0.022, p = 0.003), the effect appeared to be relatively small and may not directly impact the individual level.ConclusionOur study does not support a causal relationship between artificial sweetener intake and the risk of CKD. However, due to the limitations and potential confounding factors, these findings need to be further validated through larger sample sizes in observational studies and Mendelian randomization analyses.

This study observed the effect of salidroside on improving oxidative aging induced by D-galactose in mice by enhancing aerobic swimming. In this study, the oxidative aging model of mice was established by D-galactose, and the changes of organ index, histopathological changes, and mRNA expression in serum and tissue of oxidative aging mice after aerobic swimming and aerobic swimming+salidroside were detected. The results showed that aerobic swimming and aerobic swimming+salidroside inhibited the decline of heart index, liver index, spleen index and kidney index caused by oxidative aging in mice. Aerobic swimming and aerobic swimming+salidroside increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH) in serum, liver and spleen of oxidative aging mice, and decreased the level of malondialdehyde (MDA). The study also found that aerobic swimming and aerobic swimming+salidroside can reduce the damage of oxidative aging to liver and spleen tissues. Quantitative polymerase chain reaction (qPCR) showed that aerobic swimming and aerobic swimming+salidroside could up-regulate the mRNA expression of CAT, GSH, Cu/Zn-SOD, Mn-SOD and GSH-PX in mouse liver tissue. The results showed that aerobic swimming could effectively inhibit the oxidative aging of mice induced by D-galactose, and the effect of aerobic swimming+salidroside was better than that of aerobic swimming alone. It can be seen that salidroside can enhance the improvement of aerobic swimming on oxidative aging and can be used as a sports supplement.

BackgroundAluminum activates signal transducer and activator of transcription 3 (STAT3), causing microglial nucleotide-binding and oligomerization domain-like receptors protein 3 (NLRP3) inflammasome activation and inflammatory responses and producing neurotoxicity.ObjectiveTo explore the role of STAT3 regulated NLRP3 inflammasomes in the inflammatory response of mouse microglia cell line (BV2) cells induced by maltol aluminum [Al(mal)3].MethodsBV2 cells were assigned to five groups: one control group, three Al(mal)3 exposure groups (low, medium, and high doses at 40, 80, and 160 μmol·L−1 Al(mal)3 respectively), and one C188-9 (STAT3 antagonist) intervention group [10 μmol·L−1 C188-9 +160 μmol·L−1 Al(mal)3]. Cell viability was detected by CCK8. The expression of M1/M2 type markers, i.e. CD68/CD206, STAT3, p-STAT3, NLRP3, cleaved-casepase-1, and apoptosis-associated speck-like protein (ASC) in BV2 cells were detected by Western blotting, and proinflammatory cytokines interleukin (IL)-1β and IL-18, and anti-inflammatory cytokine IL-10 were determined by ELISA.ResultsThe results of cell viability assay showed that cell viability gradually decreased with the increase of Al(mal)3 dose. Compared with the control group, the cell viability of the Al(mal)3 high-dose group was decreased by 18% (P0.05). Compared with the control group, the expression level of NLRP3 protein increased by 75% in the Al(mal)3 high-dose group (P0.05).ConclusionAluminum can induce inflammatory responses in BV2 microglia and is predominantly pro-inflammatory, and the mechanism may involve STAT3 regulation of NLRP3 inflammasome secretion of inflammatory factors.

Abstract Background Intracardiac leiomyoma is a rare benign right heart tumor that usually extends from the intravenous system. The patient often has a history of uterine leiomyoma. Case presentation We report a 46-year-old female patient who presented to us with exertional dyspnea, chest tightness, and shortness of breath for two weeks and had a history of uterine leiomyoma resection. Echocardiography showed a pedunculated solid mass in the right heart with the pedicle attached to the inferior vena cava. The surgery was performed under cardiopulmonary bypass established through the femoral artery and vein with a probable diagnosis of leiomyoma. The tumor was removed by ingenious surgical technique: a snare made of silk suture in which the tumor’s pedicle was trapped, and the tumor with its pedicle was carefully removed with the help of a scalpel along the silk suture. The histopathology report confirmed the diagnosis of intravenous leiomyoma. The postoperative course was uneventful and the patient was discharged a week later. Conclusion Intracardiac leiomyoma is a rare benign smooth muscle tumor. Surgery is the mainstay of treatment with different surgical approaches available. It is possible to completely remove cardiac leiomyomas through sternotomy without the need for an abdominal incision if the leiomyoma is originated in the inferior vena cava not far from the right atrium.

Abstract Kawasaki disease (KD), described as “mucocutaneous lymph node syndrome”, affects infants and toddlers. Patients with KD suffer from an inflammatory cascade leading to vasculitis with a predilection for coronary arteries. While the symptoms and pathogenesis of KD have received more and more attention, the precise mechanisms are still debated. Researches show that endothelial dysfunction process in KD leads to arterial damage and affect clinical outcome. In this study, we constructed a Candida albicans water soluble fraction (CAWS)-induced KD murine model and penetrated investigating the mechanisms behind endothelial dysfunction. CAWS-induced mice presented remarkably elevated vascular endothelial cell growth factor (VEGF) levels. Abundant expression of VEGF was documented in all vessels that showed edema from acute KD. It has been reported that Platelet-derived growth factor (PDGF) co-expression normalizes VEGF-induced aberrant angiogenesis. Hyperexpression of PDGFRβ was induced in the thickened medial layer and vascular endothelium of KD mice. Masitinib (Mas) is an oral tyrosine kinase inhibitor of numerous targets, which can selectively target PDGFR signaling. We set out to explore whether Mas could regulate coronary pathology in KD. Mas administration significantly reduced the VEGF-induced endothelial cells migration. NOX4 was activated in vascular endothelial cells to produce more ROS. Mitochondrial dysregulated fission and mitophagy caused by DRP-1 overexpression precipitated the arterial endothelial cells injury. Here, mitophagy seemed to work as the driving force of DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. In summary, how mitophagy is regulated by DRP-1 under pathologic status is critical and complex, which may contribute to the development of specific therapeutic interventions in cardiovascular diseases patients, for example Masatinib, the inhibitor of PDGFRβ. Facts and questions Kawasaki disease causing systemic vasculitis, affects infants and toddlers. Coronary artery injury remains the major causes of morbidity and mortality. DRP-1 overexpression induces DRP-1/Bak/BNIP3-dependent endothelial cells apoptosis. PDGFRβ was high-expressed in the thickened medial layer of CAWS-induced KD mice. Inhibition of PDGFRβ signaling alleviates arterial endothelial cells injury.

Abstract Background Oncomelania hupensis is the sole intermediate host of Schistosoma japonicum. Its emergence and recurrence pose a constant challenge to the elimination of schistosomiasis in China. It is important to accurately predict the snail distribution for schistosomiasis prevention and control. Methods Data describing the distribution of O. hupensis in 2016 was obtained from the Yunnan Institute of Endemic Disease Control and Prevention. Eight machine learning algorithms, including eXtreme Gradient Boosting (XGB), support vector machine (SVM), random forest (RF), generalized boosting model (GBM), neural network (NN), classification and regression trees (CART), k-nearest neighbors (KNN), and generalized additive model (GAM), were employed to explore the impacts of climatic, geographical, and socioeconomic variables on the distribution of suitable areas for O. hupensis. Predictions of the distribution of suitable areas for O. hupensis were made for various periods (2030s, 2050s, and 2070s) under different climate scenarios (SSP126, SSP245, SSP370, and SSP585). Results The RF model exhibited the best performance (AUC: 0.991, sensitivity: 0.982, specificity: 0.995, kappa: 0.942) and the CART model performed the worst (AUC: 0.884, sensitivity: 0.922, specificity: 0.943, kappa: 0.829). Based on the RF model, the top six important variables were as follows: Bio15 (precipitation seasonality) (33.6%), average annual precipitation (25.2%), Bio2 (mean diurnal temperature range) (21.7%), Bio19 (precipitation of the coldest quarter) (14.5%), population density (13.5%), and night light index (11.1%). The results demonstrated that the overall suitable habitats for O. hupensis were predominantly distributed in the schistosomiasis-endemic areas located in northwestern Yunnan Province under the current climate situation and were predicted to expand north- and westward due to climate change. Conclusions This study showed that the prediction of the current distribution of O. hupensis corresponded well with the actual records. Furthermore, our study provided compelling evidence that the geographical distribution of snails was projected to expand toward the north and west of Yunnan Province in the coming decades, indicating that the distribution of snails is driven by climate factors. Our findings will be of great significance for formulating effective strategies for snail control. Graphical Abstract

High-speed traveling wave acquisition devices often use a mutation start algorithm with a low threshold value, which can collect a large number of interference clutters. If the devices automatically screen out a flashover fault traveling wave from a massive traveling wave, the traveling wave fault location performance could be improved. In this paper, a fault and interference classification method based on the random forest algorithm, which uses a convolutional neural network as a supervised feature extractor of traveling wave data, is proposed. First, one-dimensional traveling wave data are mapped to a two-dimensional matrix by dividing the information section, and a gray image is used to characterize it. Next, a two-dimensional convolution neural model of traveling wave data is constructed to realize the self-learning of traveling wave data characteristics, and the waveform feature sequence of traveling wave data is obtained. Then, on this basis, a random forest algorithm is used to realize automatic identification and screening of flashover fault traveling waves. Finally, a large number of tests on the simulation and measured data show that the proposed combined algorithm based on the feature extraction and classification of stochastic forest algorithm has better recognition effect of fault and interference than the traditional support vector machine, single stochastic forest algorithm, and convolutional neural network.

Being one of the pivotal adipocytokines, adiponectin binds to various receptors and exerts diverse biological functions, encompassing anti-fibrosis, anti-atherosclerosis, anti-ischemia-reperfusion, regulation of inflammation, and modulation of glucose and lipid metabolism. Alterations in adiponectin levels are observed in patients afflicted with diverse cardiovascular diseases. This paper comprehensively reviews the impact of adiponectin on the pathogenesis and progression of cardiovascular diseases, elucidating the underlying cellular and molecular mechanisms along with the associated cell signaling pathways. Furthermore, it deliberates on the diagnostic and predictive efficacy of adiponectin as a protein marker for cardiovascular diseases. Additionally, it outlines methods for manipulating adiponectin levels in vivo. A thorough understanding of these interconnections can potentially inform clinical strategies for the prevention and management of cardiovascular diseases.

Abstract In order to realize the intelligent energy management of the complex ship energy system, achieve the carbon peaking and carbon neutrality goal and reduce the ship carbon emissions and ship operating costs, this paper proposes a distributed energy management method for ships entering and leaving ports based on polymorphic network considering computing power resources. Firstly, a polymorphic network-based energy management system for ships entering and leaving ports is proposed to enhance the information exchange between ship computing power, power and port power, simultaneously improve the communication quality and communication security among different modes. Secondly, in order to reduce the ship operating costs and port carbon emissions, the energy management model of ships entering and leaving ports is constructed considering computing power resources. Then, according to the ship’s berthing and departing operation modes, this paper uses the distributed algorithm to solve the energy management problem, and explores the impact on the ship microgrid when the ship’s data load changes. Finally, simulation results verify the effectiveness of the proposed algorithm.

BackgroundAluminum and fluoride are neurotoxic, and aluminum exposure alone is closely related to the overall cognitive function of operational workers. It is unclear about the effect of aluminum and fluoride interactions on cognitive function.ObjectiveTo evaluate a potential interaction effect of blood aluminum and urinary fluoride on the overall cognitive function of workers working in an aluminum plant.MethodsUsing cluster sampling, 230 workers in the electrolysis workshop of an aluminum group company in Shanxi Province were selected, and plasma aluminum concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS) and urinary fluoride by ion-selective electrode. The study participants were divided into a low blood aluminum group and a high blood aluminum group according to the median (M) of blood aluminum concentration, and a low urinary fluoride group and a high urinary fluoride group by a predetermined cutoff point (2.160 mg·L−1). The Montreal Cognitive Assessment-Beijing (MoCA-BJ) was used to assess overall cognitive function of the workers. Logistic regression model was used to analyze the relationship between blood aluminum, urinary fluoride, and mild cognitive impairment (MCI), including multiplicative interaction analysis and correlation analysis; R language was used to fit an additive interaction model of blood aluminum and urinary fluoride on MCI and to calculate synergy index (S), relative excess risk due to interaction (RERI), and attributable proportion due to interaction (API).ResultsAmong the 230 operational workers, the median blood aluminum concentration (P25, P75) was 40.11 (25.16, 58.89) µg·L−1, and there were 104 cases of abnormal urinary fluoride, with an abnormality rate of 45.2%. There was a multiplicative interaction (OR=7.783, 95%CI: 1.377, 43.991) and no additive interaction (RERI=0.030, 95%CI: −0.498, 0.559; API=0.018, 95%CI: −0.279, 0.316; S=1.049, 95%CI: 0.519, 2.118) for the effect between blood aluminum and urinary fluoride on overall cognitive function of the workers. The logistic regression analysis showed that the risk of MCI was 12.105 (95%CI: 2.802, 52.287) times higher in workers with both high blood aluminum and high urinary fluoride than in those with low blood aluminum and low urinary fluoride, after adjusting for selected influencing factors.ConclusionOccupational exposure related high blood aluminum and high urinary fluoride are risk factors for cognitive dysfunction, and the coexistence of both indicators increases the risk of MCI in workers with occupational aluminum exposure, with a multiplicative interaction.

Background. Serine proteinase inhibitors, clade B, member 3 (SerpinB3) and B4 are highly similar in amino acid sequences and associated with inflammation regulation. We investigated SerpinB3 and B4 expression and their roles in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods. The expression of SerpinB3 and B4 in nasal mucosa tissues, brush cells, and secretions from CRSwNP patients was measured, and their regulation by inflammatory cytokines were investigated. Their functions were also analyzed using air–liquid interface (ALI)-cultured primary human nasal epithelial cells (HNECs) and transcriptomic analysis. Results. Both SerpinB3 and B4 expression was higher in nasal mucosa, brush cells, and secretions from eosinophilic (E) CRSwNP and nonECRSwNP patients than in healthy controls. Immunofluorescence staining indicated that SerpinB3 and B4 were primarily expressed in epithelial cells and their expression was higher in CRSwNP patients. SerpinB3 and B4 expression was upregulated by interleukin-4 (IL-4), IL-5, IL-6, and IL-17a. Transcriptomic analysis identified differentially expressed genes (DEGs) in response to recombinant SerpinB3 and B4 stimulation. Both the DEGs of SerpinB3 and B4 were associated with disease genes of nasal polyps and inflammation in DisGeNET database. Pathway enrichment indicated that downregulated DEGs of SerpinB3 and B4 were both enriched in cytokine–cytokine receptor interactions, with CXCL8 as the hub gene in the protein–protein interaction networks. Furthermore, CXCL8/IL-8 expression was downregulated by recombinant SerpinB3 and B4 protein in ALI-cultured HNECs, and upregulated when knockdown of SerpinB3/B4. Conclusion. SerpinB3/B4 expression is upregulated in nasal mucosa of CRSwNP patients. SerpinB3/B4 may play an anti-inflammatory role in CRSwNP by inhibiting the expression of epithelial cell-derived CXCL8/IL-8.

BackgroundThe microbiome plays a pivotal role in mediating immune deviation during the development of early-life viral infections. Recurrent infections in children are considered a risk factor for disease development. This study delves into the metagenomics of the microbiome in children suffering from severe infections, seeking to identify potential sources of these infections.AimsThe aim of this study was to identify the specific microorganisms and factors that significantly influence the treatment duration in patients suffering from severe infections. We sought to understand how these microbial communities and other variables may affect the treatment duration and the use of antibiotics of these patients with severe infections.MethodWhole-genome shotgun sequencing was conducted on samples collected from children aged 0–14 years with severe infections, admitted to the Pediatrics Department of Xiamen First Hospital. The Kraken2 algorithm was used for taxonomic identification from sequence reads, and linear mixed models were employed to identify significant microorganisms influencing treatment duration. Colwellia, Cryptococcus, and Citrobacter were found to significantly correlate with the duration of clinical treatment. Further analysis using propensity score matching (PSM) and rank-sum test identified clinical indicators significantly associated with the presence of these microorganisms.ResultsUsing a linear mixed model after removed the outliers, we identified that the abundance of Colwellia, Cryptococcus, and Citrobacter significantly influences the treatment duration. The presence of these microorganisms is associated with a longer treatment duration for patients. Furthermore, these microorganisms were found to impact various clinical measures. Notably, an increase in hospitalization durations and medication costs was observed in patients with these microorganisms. In patients with Colwellia, Cryptococcus, and Citrobacter, we discover significant differences in platelets levels. We also find that in patients with Cryptococcus, white blood cells, hemoglobin, and neutrophils levels are lower.ConclusionThese findings suggest that Colwellia, Cryptococcus, and Citrobacter, particularly Cryptococcus, could potentially contribute to the severity of infections observed in this cohort, possibly as co-infections. These microorganisms warrant further investigation into their pathogenic roles and mechanisms of action, as their presence in combination with disease-causing organisms may have a synergistic effect on disease severity. Understanding the interplay between these microorganisms and pathogenic agents could provide valuable insights into the complex nature of severe pediatric infections and guide the development of targeted therapeutic strategies.

High-intensity vortex beams with tunable topological charges and low coherence are highly demanded in applications such as inertial confinement fusion (ICF) and optical communication. However, traditional optical vortices featuring nonuniform intensity distributions are dramatically restricted in application scenarios that require a high-intensity vortex beam owing to their ineffective amplification resulting from the intensity-dependent nonlinear effect. Here, a low-coherence perfect vortex beam (PVB) with a topological charge as high as 140 is realized based on the super-pixel wavefront-shaping technique. More importantly, a globally adaptive feedback algorithm (GAFA) is proposed to efficiently suppress the original intensity fluctuation and achieve a flat-top PVB with dramatically reduced beam speckle contrast. The GAFA-based flat-top PVB generation method can pave the way for high-intensity vortex beam generation, which is crucial for potential applications in ICF, laser processing, optical communication and optical trapping.

The present study examines the influence of perceived procedural justice (PPJ) on four fundamental dimensions of customer citizenship behaviours (helping other customers, advocacy, customer tolerance, and feedback) and the mediating role of customer perceived support (CPS). Our research setting is the smartphone after-sales service sector in China. Structural equation modeling (SEM) using AMOS is employed to empirically test our hypotheses on the basis of survey data from 368 smartphone customers. We find that PPJ significantly contributes to the customer citizenship behaviours of helping other customers, advocacy, and feedback. Surprisingly, we do not find a significant relationship between PPJ and customer tolerance. Our evidence indicates that CPS partially mediates the relationships between PPJ and helping other customers, advocacy, and feedback, but fully mediates the effect of PPJ on customer tolerance. This research contributes to managers’ understanding of how voluntary behaviours can be effectively managed by enhancing PPJ and CPS. Further, it enriches our theoretical understanding of key antecedents of customer citizenship behaviours.

BackgroundHypertriglyceridemia is a risk factor for cardiovascular diseases. Internet usage in China is increasing, giving rise to large-scale data sources, especially to access, disseminate, and discuss medical information. Social media listening (SML) is a new approach to analyze and monitor online discussions related to various health-related topics in diverse diseases, which can generate insights into users’ experiences and expectations. However, to date, no studies have evaluated the utility of SML to understand patients’ cognizance and expectations pertaining to the management of hypertriglyceridemia. ObjectiveThe aim of this study was to utilize SML to explore the disease cognition level of patients with hypertriglyceridemia, choice of intervention measures, and the status quo of online consultations and question-and-answer (Q&A) search platforms. MethodsAn infosurveillance study was conducted wherein a disease-specific comprehensive search was performed between 2004 and 2020 in Q&A search and online consultation platforms. Predefined single and combined keywords related to hypertriglyceridemia were used in the search, including disease, symptoms, diagnosis, and treatment indicators; lifestyle interventions; and therapeutic agents. The search output was aggregated using an aggregator tool and evaluated. ResultsDisease-specific consultation data (n=69,845) and corresponding response data (n=111,763) were analyzed from 20 data sources (6 Q&A search platforms and 14 online consultation platforms). Doctors from inland areas had relatively high voice volumes and appear to exert a substantial influence on these platforms. Patients with hypertriglyceridemia engaging on the internet have an average level of cognition about the disease and its intervention measures. However, a strong demand for the concept of the disease and “how to treat it” was observed. More emphasis on the persistence of the disease and the safety of medications was observed. Young patients have a lower willingness for drug interventions, whereas patients with severe hypertriglyceridemia have a clearer intention to use drug intervention and few patients have a strong willingness for the use of traditional Chinese medicine. ConclusionsFindings from this disease-specific SML study revealed that patients with hypertriglyceridemia in China actively seek information from both online Q&A search and consultation platforms. However, the integrity of internet doctors’ suggestions on lifestyle interventions and the accuracy of drug intervention recommendations still need to be improved. Further, a combined prospective qualitative study with SML is required for added rigor and confirmation of the relevance of the findings.

ABSTRACTPharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4–5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of “fast-to-FIH” approaches in combination with BeiGene’s de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

Introduction Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by autoantibody production, joint inflammation and bone destruction. Nearly 1/3 of RA patients with the active disease also exhibit a normal range of ESR and CRP. Here we assessed the performance and clinical significance of soluble CD24 (sCD24) as a biomarker of disease activity in RA.Methods A total of 269 RA patients, 59 primary Sjogren’s syndrome (SS) patients, 81 systematic lupus erythematosus (SLE) patients, 76 osteoarthritis (OA) patients and 97 healthy individuals (HC) were included in this study. Soluble CD24 in sera were detected by ELISA. Therefore, the concentration of sCD24 was analyzed in RA patients with different disease activity statuses.Results The sCD24 was significantly increased in RA (2970 pg/mL), compared to other rheumatic diseases (380-520 pg/mL) and healthy individuals (320 pg/mL). Moreover, sCD24 was elevated in 66.67% of early RA and 61.11% of seronegative RA patients. In addition, sCD24 was significantly correlated with the disease activity duration and inflammatory indicators. There was an increased sCD24 in 64.23% of RA patients with normal ESR and CRP.Conclusion The sCD24 could be an inflammatory biomarker in RA patients, especially in early and seronegative patients.

ABSTRACTAspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp–Gly (DG), Asp–Ser (DS), and Asp–Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization, and they are considered “hot spots” in antibodies. In contrast, the Asp-His (DH) motif is usually considered a silent spot with low isomerization propensity. However, in monoclonal antibody mAb-a, the isomerization rate of an Asp residue, Asp55, in the aspartic acid-histidine-lysine (DHK) motif present in CDRH2 was found to be unexpectedly high. By determining the conformation of DHK motif in the crystal structure of mAb-a, we found that the Cgamma of the Asp side chain carbonyl group and the back bone amide nitrogen of successor His were in proximal contact, which facilitates the formation of succinimide intermediate, and the +2 Lys played an important role in stabilizing such conformation. The contributing roles of the His and Lys residues in DHK motif were also verified using a series of synthetic peptides. This study identified a novel Asp isomerization hot spot, DHK, and the structural-based molecular mechanism was revealed. When 20% Asp55 isomerization in this DHK motif occurred in mAb-a, antigen binding activity reduced to 54%, but the pharmacokinetics in rat was not affected significantly. Although Asp isomerization of DHK motif in CDR does not appear to have a negative impact on PK, DHK motifs in the CDRs of antibody therapeutics should be removed, considering the high propensity of isomerization and impact on antibody activity and stability.

BackgroundPrevious studies show that aluminum exposure could increase the expression of miRNA-134-3p, which is involved in the mechanism of aluminum induced learning and memory impairment. However, it has not been investigated whether the expression level of miRNA-134-3p in the peripheral blood of occupational aluminum exposed workers is related to the blood aluminum concentration yet.ObjectiveTo evaluate a potential correlation between aluminum concentration in peripheral blood and miR-134-3p expression in occupational aluminum exposed workers.MethodsA total of 184 male aluminum workers in the electrolytic aluminum workshop, aluminum oxide workshop, and thermal power workshop of an aluminum plant in Shanxi were selected by cluster sampling. They were divided into four groups (Q1-Q4) according to the quartiles of blood aluminum concentration, with 46 workers in each group. The basic information of workers was collected by questionnaire survey, and the cognitive function of workers was evaluated by Montreal Cognitive Assessment (MoCA). The plasma of workers was collected, and the relative expression level of miR-134-3p in plasma was detected by real-time quantitative polymerase chain reaction (RT-PCR). The plasma aluminum concentration was detected by inductively coupled plasma mass spectrometry (ICP-MS). The associations among workers' peripheral blood aluminum concentration, plasma miR-134-3p expression level, and total MoCA score were evaluated by generalized linear models.ResultsThe workers' medians (P25, P75) of blood aluminum concentration, plasma relative expression level of miR-134-3p, and MoCA score were 39.31 (25.30, 57.41) μg·L-1, 2.93 (2.29, 3.74), and 22.0 (20.0, 26.0), respectively. The results of the generalized linear model showed that after adjusting for age, body mass index, smoking, and alcohol consumption, compared with the Q1 group, blood aluminum in the Q2, Q3, or Q4 group had an impact on related plasma miR-134-3p expression level and total MoCA score (P0, Ptrend0.05).ConclusionOccupational aluminum exposure can lead to an increase in the expression level of miR-134-3p in plasma of workers, which may be related to a decrease in cognitive function of workers.

Abstract Background Alcohol consumption is known to be associated with an increased risk of type 2 diabetes (T2DM). However, the effect of alcohol intake on the incidence of T2DM remains controversial due to inconsistent results across studies. This study aimed to bridge the gap among available literature in order to better define the association between alcohol consumption and incidence of T2DM. Methods We performed a secondary analysis using open-access data from a retrospective Japanese cohort of 15,464 participants who underwent regular medical examinations at Murakami Memorial Hospital. All participants underwent an initial exam including a questionnaire survey, physical examination, and blood biochemical testing to establish a at baseline. The primary outcome was new-onset T2DM during the follow-up exam. Statistical analysis was conducted using Cox regression and Kaplan–Meier methods to assess the risk of alcohol consumption on T2DM. Results During a median follow-up time of 5.39 years, 373 new-onset T2DM events were observed. The cumulative risk of T2DM incidence was higher in the heavy alcohol consumption group vs. the other three groups: none/minimal, light, and moderate consumption (log-rank test, P = 0.0002). Multivariate Cox regression analysis indicated incidental T2DM was independently associated with alcohol consumption. The adjusted hazard ratio relative to the none/minimal consumption group was as follows: 1.02 (95% confidence interval: 0.71, 1.48) for light consumption, 1.06 (0.71, 1.57) for moderate consumption, and 2.06 (1.30, 3.24) for heavy consumption (P value = 0.024). Subsequent subgroup analysis confirmed the association between alcohol consumption and T2DM incidence in men, but not in women. Conclusion Heavy alcohol consumption was independently associated with an increased risk of new-onset T2DM in Japanese men.

Laboratory experiments and point monitoring of reservoir sediments have proven that stable sulfate reduction (SSR) can lower the concentrations of toxic metals and sulfate in acidic groundwater for a long time. Here, we hypothesize that SSR occurred during in situ leaching after uranium mining, which can impact the fate of acid groundwater in an entire region. To test this, we applied a sulfur isotope fractionation method to analyze the mechanism for natural attenuation of contaminated groundwater produced by acid in situ leaching of uranium (Xinjiang, China). The results showed that δ34S increased over time after the cessation of uranium mining, and natural attenuation caused considerable, area-scale immobilization of sulfur corresponding to retention levels of 5.3%–48.3% while simultaneously decreasing the concentration of uranium. Isotopic evidence for SSR in the area, together with evidence for changes of pollutant concentrations, suggest that area-scale SSR is most likely also important at other acid mining sites for uranium, where retention of acid groundwater may be strengthened through natural attenuation. To recapitulate, the sulfur isotope fractionation method constitutes a relatively accurate tool for quantification of spatiotemporal trends for groundwater during migration and transformation resulting from acid in situ leaching of uranium in northern China.

BackgroundOccupational aluminum exposure may associate with cognitive impairment in workers. At present, brain functional imaging data are not available for evaluating cognitive dysfunction in workers with occupational exposure to aluminum. The role of brain functional connectivity in cognitive decline associated with occupational aluminum exposure is not clear yet. ObjectiveTo explore potential mediating effect of brain functional connectivity value on cognitive decline induced by occupational aluminum exposure, to assess the relationship between cognitive impairment and brain functional connectivity, and to identify appropriate imaging evidence of early cognitive changes induced by occupational aluminum exposure. MethodsThis study used a subset data from a previous cross-sectional survey. Based on the data of aluminum-exposed workers, over 40 years old, aluminum-exposed working years >1 year, Montreal International Cognitive Assessment (MoCA) (Beijing version) score

In order to cleanly and efficiently extract zirconium from zircon sand (the main component is ZrSiO4), sodium hydroxide sub-molten salt was used to decompose ZrSiO4 in this study. When ZrSiO4 reacts with sodium hydroxide sub-molten salt, the formation of Na2ZrSiO5 (a water-insoluble product) considerably affects the separation efficiency of Zr and Si and increases production cost. Thus, it is necessary to control the formation of Na2ZrSiO5. The influence of NaOH content, reaction temperature, reaction time, and NaOH/ore mass ratio on the formation of Na2ZrSiO5 were systematically investigated. The optimum reaction parameters for the inhibition of Na2ZrSiO5 formation were as follows: 80% NaOH content, 245 °C reaction temperature, 4:1 NaOH/ore mass ratio, 10 h reaction time, and 400 r/min agitation speed. These results indicate that ZrSiO4 is decomposed to Na2ZrO3 and Na2SiO3 by reacting with NaOH, realizing the separation of Zr and Si, and then the reactions between Na2ZrO3 and Na2SiO3 result in the formation of Na2ZrSiO5, during the decomposition of ZrSiO4 using NaOH sub-molten salt. The sub-molten salt decomposition process can realize the clean extraction of zirconium, which is conducive to the sustainable development of zirconium resources.

Abstract Background Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. Results A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations. Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patients and 15 patients from 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES was performed in 122 CCDDs patients. Ten pathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM) and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. Conclusions This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.

Background Inflammation and oxidative stress (OS) are important contributors to psoriasis pathogenesis. Proanthocyanidins (PCs) have anti-inflammatory and anti-oxidative activities. Previously, we discovered that PCs alleviated psoriasis-like mice symptoms, likely via mitigating inflammation and OS damage.Objective To elucidate the protective mechanism underlying PCs against the damage of TNF-ɑ-induced psoriasis-like cell models.Methods Psoriasis-like cell models were established with 7.5 ng/mL TNF-ɑ and then subjected to different-concentrations PCs treatment. Finally, inflammatory and oxidative parameters were determined. Besides, LY294002 (PI3K inhibitor) and ZnPP (HO-1 inhibitor) were employed to investigate the roles of PI3K/AKT and HO-1 in PCs against psoriasis-like cell models.Results After TNF-α treatment, cells organized tightly and proliferated greatly (P

Objective To study the characteristics of voluntary apheresis platelet donors in Zhoushan Islands and its influence on the collection and supply of apheresis platelets. Methods From January 1, 2017 to December 31, 2021, 1038 eligible donors were selected out of 1151 apheresis candidates for demographic analysis, donation time analysis, blood routine test. We also investigated whether the current supply of apheresis platelet met the needs of clinical. The lapsed donors(with only one donation) were telephone interviewed to investigate the lapsing reasons. Results From 2017 to 2021, the median (M) ratio of platelet donors to the population in Zhoushan City was 0.454 ‰. And 90.18% (1038/1151) of the candidates completed donation, involving 2659 donations and 3205 U products. The per capita donation amount was (1.29±0.77) U per person, which basically met the blood demand in clinical of Zhoushan Islands. The 1038 platelet donors were 18 to 59 yeas old[M(QR) 34(16)], and 47.50% (493/1038) of them aged 31 to 45; the ratio of male to female blood donors was 2.0∶1; 70.61% (733/1038) had college education or above; ABO blood group profile was A>O>B>AB. There were several peak periods of donation during 2017~2021: the second and third quarters of 2017~2019 and the third quarter of 2020; none in 2021, as yeae 2021 was volatile. The donation proportion of the first quarter was the lowest throughout 2017~2021. In 2017 and 2018, the proportion of donors with one donation accounted for 79.79% (75/94) and 51.63% (95/184), respectively. From 2019 to 2021, the proportion of donors with twice or more donation accounted for 60.35% (137/227), 57.36% (187/326) and 53.13% (170/320) , respectively. During 5 years, 10.88% (113/1051) of the candidates failed to donate platelets, of whom 72.57% (82/113) were due to unqualified pre-donation testing. Conclusion The donation behaviors in Zhoushan have been affected by each above-mentioned demographic factors. The awareness of donation and donation services in Zhoushan have been improved as combing the special geographic condition and demographic characteristics together, and the donation units is elevating yearly which has met the clinical needs of the whole island.

Background: Cancer-related fatigue (CRF) is a common and burdensome symptom in cancer patients that is influenced by multiple factors. Identifying factors associated with CRF may help in developing tailored interventions for fatigue management. This study aimed to examine the correlates of CRF among colorectal cancer patients undergoing postoperative adjuvant therapy based on the theory of unpleasant symptoms. Methods: A cross-sectional study was implemented, and finally, a sample of 363 participants from one tertiary general hospital and one tertiary cancer hospital was purposively recruited. Data were collected using the general information questionnaire, cancer fatigue scale, the distress disclosure index, Herth hope index, and perceived social support scale. Univariate analysis and multiple linear regression analysis were performed to determine the correlates of CRF. Results: The mean score of CRF among colorectal cancer patients was 21.61 (SD = 6.16, 95% CI 20.98–22.25), and the fatigue degree rating was “moderate”. The multiple linear regression model revealed that 49.1% of the variance in CRF was explained by hope, sleep disorder, internal family support, self-disclosure, pain, and time since operation. Conclusions: Our study identified several significant, modifiable factors (self-disclosure, hope, internal family support, pain, and sleep disorder) associated with CRF. Understanding these correlates and developing targeted psychosocial interventions may be associated with the improvement of CRF in patients with colorectal cancer.

Accurate abdomen tissues segmentation is one of the crucial tasks in radiation therapy planning of related diseases. However, abdomen tissues segmentation (liver, kidney) is difficult because the low contrast between abdomen tissues and their surrounding organs. In this paper, an attention-based deep learning method for automated abdomen tissues segmentation is proposed. In our method, image cropping is first applied to the original images. U-net model with attention mechanism is then constructed to obtain the initial abdomen tissues. Finally, level set evolution which consists of three energy terms is used for optimize the initial abdomen segmentation. The proposed model is evaluated across 470 subsets. For liver segmentation, the mean dice are 96.2 and 95.1% for the FLARE21 datasets and the LiTS datasets, respectively. For kidney segmentation, the mean dice are 96.6 and 95.7% for the FLARE21 datasets and the LiTS datasets, respectively. Experimental evaluation exhibits that the proposed method can obtain better segmentation results than other methods.

Abstract Carbon loading in airway cells has shown to worsen function of antimicrobial peptides, permitting increased survival of pathogens in the respiratory tract; however, data on the impacts of carbon particles on childhood acute respiratory infection (ARI) is limited. We assembled daily health data on outpatient visits for ARI (bronchitis, pneumonia, and total upper respiratory infection [TURI]) in children aged 0–14 years between 2015 and 2019 in Beijing, China. Anthropogenic carbons, including black carbon (BC) and its emission sources, and wood smoke particles (delta carbon, ultra‐violet absorbing particulate matter, and brown carbon) were continuously monitored. Using a time‐stratified case‐crossover approach, conditional logistic regression was performed to derive risk estimates for each outcome. A total of 856,899 children were included, and a wide range of daily carbon particle concentrations was observed, with large variations for BC (0.36–20.44) and delta carbon (0.48–57.66 μg/m3). Exposure to these particles were independently associated with ARI, with nearly linear exposure‐response relationships. Interquartile range increases in concentrations of BC and delta carbon over prior 0–8 days, we observed elevation of the odd ratio of bronchitis by 1.201 (95% confidence interval, 1.180, 1.221) and 1.048 (95% CI, 1.039, 1.057), respectively. Stronger association was observed for BC from traffic sources, which increased the odd ratio of bronchitis by 1.298 (95% CI, 1.273, 1.324). Carbon particles were also associated with elevated risks of pneumonia and TURI, and subgroup analyses indicated greater risks among children older than 6 years. Our findings suggested that anthropogenic carbons in metropolitan areas may pose a significant threat to clinical manifestations of respiratory infections in vulnerable populations.