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Abstract Background With the fast pace of modern life, people have less time for meals, but few studies have examined the association between the habit of fast eating and metabolic diseases. Objective Combining the results of the current study and the prior ones, we aimed to investigate the possible relationship between fast eating and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods This is a sub-analysis of a multicenter cross-sectional study of 1965 participants investigated the association between fast eating and MASLD in Chinese. Fast eating was defined as meal time less than five minutes and participants were divided into three categories based on their self-reported frequency of fast eating: ≤1 time/month, ≤1 time/week and ≥2 times/week. We further conducted a literature search for available studies published before November, 2023 as well as a meta-analysis to investigate the association between fast eating and MASLD. Results The proportion of MASLD was 59.3%, 50.5%, and 46.2% in participants with fast eating ≥2 times/week, ≤1 time/week and ≤1 time/month, respectively (P for trend

Abstract Objective To develop a machine learning-based risk prediction model for postoperative parastomal hernia (PSH) in colorectal cancer patients undergoing permanent colostomy, assisting nurses in identifying high-risk groups and devising preventive care strategies. Methods A case-control study was conducted on 495 colorectal cancer patients who underwent permanent colostomy at the Second Affiliated Hospital of Anhui Medical University from June 2017 to June 2023, with a 1-year follow-up period. Patients were categorized into PSH and non-PSH groups based on PSH occurrence within 1-year post-operation. Data were split into training (70%) and testing (30%) sets. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, and binary classification prediction models were established using Logistic Regression (LR), Support Vector Classification (SVC), K Nearest Neighbor (KNN), Random Forest (RF), Light Gradient Boosting Machine (LGBM), and Extreme Gradient Boosting (XgBoost). The binary classification label denoted 1 for PSH occurrence and 0 for no PSH occurrence. Parameters were optimized via 5-fold cross-validation. Model performance was evaluated using Area Under Curve (AUC), specificity, sensitivity, accuracy, positive predictive value, negative predictive value, and F1-score. Clinical utility was evaluated using decision curve analysis (DCA), model explanation was enhanced using shapley additive explanation (SHAP), and model visualization was achieved using a nomogram. Results The incidence of PSH within 1 year was 29.1% (144 patients). Among the models tested, the RF model demonstrated the highest discrimination capability with an AUC of 0.888 (95% CI: 0.881–0.935), along with superior specificity, accuracy, sensitivity, and F1 score. It also showed the highest clinical net benefit on the DCA curve. SHAP analysis identified the top 10 influential variables associated with PSH risk: body mass index (BMI), operation duration, history and status of chronic obstructive pulmonary disease (COPD), prealbumin, tumor node metastasis (TNM) staging, stoma site, thickness of rectus abdominis muscle (TRAM), C-reactive protein CRP, american society of anesthesiologists physical status classification (ASA), and stoma diameter. These insights from SHAP plots illustrated how these factors influence individual PSH outcomes. The nomogram was used for model visualization. Conclusion The Random Forest model demonstrated robust predictive performance and clinical relevance in forecasting colonic PSH. This model aids in early identification of high-risk patients and guides preventive care.

Abstract Due to high computation complexity, traditional design methods for LLC converter usually consider limited kinds of performance, and the process for searching the optimal parameter scheme is discrete, which might cause the missing of real optimal solution. In order to solve these problems, a multi‐objectives optimization design method for the LLC converter is proposed in this paper. According to the numerical calculation method, a closed parameter space for resonant parameters is established under the constraints of operation mode, switching frequency, zero voltage switching (ZVS), and voltage stress of resonant capacitor. Besides, the root‐mean‐square (RMS) value of resonant current and secondary current, as well as the core loss of the transformer, are selected as the optimization objectives. Non‐dominated sorting genetic algorithm (NSGA‐II) is utilized to deal with these multi‐objective formulations. In order to reduce the computation complexity, a data‐driven method, called adaptive polynomial approximation (APA), is selected to obtain the explicit expressions of the parameter space and the optimization objectives. Then, by substituting this simplified surrogate model into the NSGA‐II algorithm, the optimal parameter scheme is obtained. The comprehensive comparison analysis is performed, and a 400 W/48 V experimental prototype was built to verify the theoretical analysis, which shows that the proposed method features the highest efficiency of 95%.

Abstract Background Myopia is one of the most common eye diseases in children and adolescents worldwide, and scleral remodeling plays a role in myopia progression. However, the identity of the initiating factors and signaling pathways that induce myopia-associated scleral remodeling is still unclear. This study aimed to identify biomarkers of scleral remodeling to elucidate the pathogenesis of myopia. Methods The gene expression omnibus (GEO) and comparative toxicogenomics database (CTD) mining were used to identify the miRNA-mRNA regulatory network related to scleral remodeling in myopia. Real-time quantitative PCR (RT-qPCR), Western blot, immunofluorescence, H&E staining, Masson staining, and flow cytometry were used to detect the changes in the FOXO signaling pathway, fibrosis, apoptosis, cell cycle, and other related factors in scleral remodeling. Results miR-15b-5p/miR-379-3p can regulate the FOXO signaling pathway. Confirmatory studies confirmed that the axial length of the eye was significantly increased, the scleral thickness was thinner, the levels of miR-15b-5p, miR-379-3p, PTEN, p-PTEN, FOXO3a, cyclin-dependent kinase (CDK) inhibitor 1B (CDKN1B) were increased, and the levels of IGF1R were decreased in Len-induced myopia (LIM) group. CDK2, cyclin D1 (CCND1), and cell cycle block assessed by flow cytometry indicated G1/S cell cycle arrest in myopic sclera. The increase in BAX level and the decrease in BCL-2 level indicated enhanced apoptosis of the myopic sclera. In addition, we found that the levels of transforming growth factor-β1 (TGF-β1), collagen type 1 (COL-1), and α-smooth muscle actin (α-SMA) were decreased, suggesting scleral remodeling occurred in myopia. Conclusions miR-15b-5p/miR-379-3p can regulate the scleral cell cycle and apoptosis through the IGF1R/PTEN/FOXO signaling pathway, thereby promoting scleral remodeling in myopia progression. Graphical Abstract

Abstract Background Sheep manure and mushroom residue are common agricultural waste which threaten environment but rich in mineral elements and organic matter. Even though fermentation and adding it to soil for crop growth is a commonly used approach, there are concerns about how efficient the fermentation process is and whether the microbial community remains safe for both the crops and those working in agriculture. We have discovered a composite microbial agent, previously known as CMA, that demonstrates significant efficacy in the fermentation of mushroom residue and sheep manure. Despite its high activity, the impact of this microbial agent on soil nutrient release, soil microbial composition, and plant growth remains still uncertain. Results After fermenting sheep manure and mushroom residue with Bacillus CMA, this study investigated the fermentation products mixed with vermiculite and perlite for the cultivation of tomato. The results demonstrate that the composite substrate align closely within the ideal range for seedling substrates. Notably, compounded with CMA compost products and vermiculite in a 2:1 ratio, yields the most favorable growth for tomato, which may be attributed to the increased nutrient release and most favorable microbial conditions. Moreover, it significantly decreased the abundance of pathogenic bacteria harmful to human and animal health, thereby reducing the risk to individuals engaged in field labor, and mitigating the threat of plant pathogenic bacteria. Conclusions Sheep manure and mushroom residue fermentation with CMA added significantly promoted tomatoes growth and reduced the risk of diseases in crops, animals, and people. These findings hold significant implications also for the reuse of agricultural biowaste and residues, besides the crop growth and safety of humans and animals in agricultural environments. Graphical Abstract

Abstract How to raise the bridge barrier with a concrete base height of only 51 cm to SS level of protection is not yet studied. In order to effectively retrofit an existing concrete barrier design to meet new crash testing criteria, the structural dimensions and concrete strength of the existing bridge barrier were investigated, and finite element simulation analysis was carried out, and simulation suggested the existing barrier was insufficient. Based on the structural dimension design principles of bridge barriers, the existing structure of bridge barrier was designed after adding lightweight and high-strength B750HL material crossbeams and posts on top of the concrete base, and the bearing capacity of the bridge barrier was calculated based on the yield line theory. Then, a finite element simulation analysis model was established to study and analyze the blocking, guiding, and cushioning functions of the improved design of bridge barrier. Finally, full-scale-vehicle crash tests were conducted with the SS-level small car, bus, and tractor-van trailer for this bridge barrier design scheme. This paper is the world’s first to use B750HL steel as the material for the crossbeam and post of a bridge barrier with a concrete base height of only 51 cm. According to the research results, the B750HL bridge barrier, which was designed based on the calculation of structural dimension design and yield line theory, effectively reduces the increased constant load on the bridge deck caused by the extra crossbeams and posts. At the same time, it can reduce material costs and save engineering costs. After being verified by finite element simulation crash tests and full-scale-vehicle crash tests, the protective capacity of the B750HL bridge barrier was proven to meet the SS-level evaluation requirements of the Standard for Safety Performance Evaluation of Highway Barriers (JTG B05-01-2013). The research findings of this paper is that the finite element simulation crash tests can effectively simulate full-scale-vehicle crash test, and the finite element simulation crash tests is reliable. If the safety performance of the barrier in the finite element simulation crash tests meets the requirements, the probability of passing the full-scale-vehicle crash test is higher. Therefore, a design scheme is proposed for the B750HL bridge barrier to improve hybrid bridge barriers at a height of 51 cm or more based on various design methods.

Abstract Background Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study. Methods MDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis. Results This study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion. Conclusion Our findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.

Abstract Background The American Heart Association recently introduced a new model for cardiovascular health (CVH) known as Life’s Essential 8 (LE8). The impact of LE8 on hypertensive individuals is currently unclear. In our study, we investigated the correlation between comprehensive and individual CVH indicators as defined by LE8, and the mortality rates in hypertension patients. Methods We analyzed a total of 8,448 hypertensive individuals aged ≥ 20 years who participated in the National Health and Nutrition Examination Survey from 2007 to 2016. These participants were nonpregnant and noninstitutionalized. We identified their mortality by linking their data to the National Death Index until December 31, 2019. The overall cardiovascular health (CVH) was assessed using the LE8 score, which ranged from 0 to 100. Additionally, we evaluated the scores for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure. The CVH were categorized into low (0–49), moderate (50–79), and high (80–100) CVH. Results Over an average follow-up period of 7.41 years, 1,482 (17.54%) of the participants died, among which 472 deaths were attributed to CVD. When compared to adults with lower total CVH scores, those with elevated total CVH scores displayed a 37% reduced risk of mortality from all causes (adjusted hazard ratio [aHR] = 0.63, 95% confidence interval [CI] = 0.45–0.88). In relation to CVD-specific mortality, the corresponding aHRs for moderate and high total CVH scores were 0.76 (0.60–0.97) and 0.54 (0.31–0.94), respectively. Furthermore, after adjusting for potential confounders, it was observed that higher scores on the LE8 index were associated with a reduced risk of both all-cause mortality (aHR for every 10-score increase, 0.91; 95% CI = 0.86–0.96) and CVD-specific mortality (aHR for every 10-score increase, 0.82; 95% CI = 0.75–0.90). Notably, a linear dose–response relationship was observed in this association. Similar patterns were identified in the relationship between health behavior and both all-cause and CVD-specific mortality. Conclusions Achieving a higher CVH score, as per the new LE8 guidelines, has been found to be associated with a reduced risk of mortality from all causes and specifically from CVD in patients with hypertension. Therefore, public health and healthcare initiatives that focus on promoting higher CVH scores could potentially yield significant benefits in terms of reducing mortality rates among individuals with hypertension.

Multifractal features of the pore structures of coal reservoirs control the transport and sustainable production of coalbed methane (CBM), which directly determines the efficiency of CBM extraction and is of great importance for CBM extraction. In order to investigate the multifractal characteristics of the pore structures of medium-high rank coals and their evolutionary trends during coalification, the medium-high rank coal samples from production mines in the Qinshui coal field were collected to investigate the evolution of the multiple fractal characteristics of medium-high rank coals macropores (> 50 nm), mesopores (2−50 nm) and micropores (< 2 nm) during coalification and their influencing factors by using multifractal theories and integrating the mercury intrusion porosimetry, low temperature nitrogen gas adsorption and low temperature carbon dioxide adsorption experiments, respectively. The results show that the generalized dimensional spectrum (Dq−q) and the multifractal singular spectrum (f(α)−α) of macro-, meso- and micropores of medium-high rank coals both satisfy the multifractal characteristics, which implies that the macro-, meso- and micropores of medium-high rank coals all exhibit multifractal behavior. Compared with macropores and mesopores, micropores have stronger non-homogeneity and lower pore connectivity exhibiting larger α0 and ∆D values and smaller H values. Coalification promotes the aggregation of macromolecules in coal, which changes the coal reservoir type from macropores dominant reservoir and macropores-micropores coexisting reservoir to micropores dominant reservoir, and the pore size distribution of different scales in coal tends to be homogenized, leading to the improvement of pore structure homogeneity and pore connectivity in medium-high rank coal reservoirs. Macropore and micropore volume fractions have positive and negative effects on pore structure heterogeneity in their respective pore size ranges, while mesopore volume fraction is not an effective constraint on mesopore pore size distribution heterogeneity. The vitrinite and inertinite groups show opposite effects on the heterogeneity of pore size distribution, with a positive correlation between V/I and H values and a negative correlation with α0. Vitrinite-rich coals develop more micropores and thus showing stronger pore structure homogeneity and better pore connectivity.

Abstract Background The Chinese pig breed Bamei faces numerous challenges, such as antibiotic abuse, feed shortages, weaning stress, low immunity and disease resistance after weaning. Probiotic-fermented feed is an ideal profile that can improve the intestinal microbiota, promote the digestion and absorption of nutrients, and improve immunity. However, the combined effect of long-term intake of probiotic-fermented feeds on the intestinal microbiota, intestinal metabolic profiles, and immunity in pigs is not well understood. Here, we investigated the effects of feeding basal feed, Lactiplantibacillus-fermented feed, Bacillus subtilis-fermented feed, mixed-fermented feed, and antibiotic-added feed for 100 days on the gut microbiota, immunity, and metabolism of Bamei pigs after feeding five different fermented feeds by using 16S rDNA high-throughput sequencing, enzyme-linked immunoassay, and untargeted metabolomics, respectively. Results 16S rDNA sequencing revealed that after the piglets were fed five different feeds for 50 days, the structure of the intestinal microbiota of the Bamei pigs was significantly altered, and feeding the mixed Lactiplantibacillus (L.) plantarum and Bacillus (B.) subtilis-fermented feed not only increased the α-diversity of the intestinal microbiota and the relative abundance of Lactobacillus, but also suppressed the growth of the conditional pathogens, Clostridium and Streptococcus. The Sobs and Shannon indices were significantly lower (p

Abstract As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Abstract Background Epigenetic modifications of histones play important roles in the response of eukaryotic organisms to environmental stress. However, many histone acetyltransferases (HATs), which are responsible for histone acetylation, and their roles in mediating the tick response to cold stress have yet to be identified. In the present study, HATs were molecularly characterized and their associations with the cold response of the tick Haemaphysalis longicornis explored. Methods HATs were characterized by using polymerase chain reaction (PCR) based on published genome sequences, followed by multiple bioinformatic analyses. The differential expression of genes in H. longicornis under different cold treatment conditions was evaluated using reverse transcription quantitative PCR (RT-qPCR). RNA interference was used to explore the association of HATs with the cold response of H. longicornis. Results Two HAT genes were identified in H. longicornis (Hl), a GCN5-related N-acetyltransferase (henceforth HlGNAT) and a type B histone acetyltransferase (henceforth HlHAT-B), which are respectively 960 base pairs (bp) and 1239 bp in length. Bioinformatics analysis revealed that HlGNAT and HlHAT-B are unstable hydrophilic proteins characterized by the presence of the acetyltransferase 16 domain and Hat1_N domain, respectively. RT-qPCR revealed that the expression of HlGNAT and HlHAT-B decreased after 3 days of cold treatment, but gradually increased with a longer period of cold treatment. The mortality rate following knockdown of HlGNAT or HlHAT-B by RNA interference, which was confirmed by RT-qPCR, significantly increased (P

Abstract The purpose of this study was to explore the diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease. In this study, we first collected 161 samples from the GEO database (including 87 in the AD group and 74 in the normal group). Subsequently, through differential expression analysis and the iUUCD 2.0 database, we obtained 3450 Differentially Expressed Genes (DEGs) and 806 Ubiquitin-related genes (UbRGs). After taking the intersection, we obtained 128 UbR-DEGs. Secondly, by conducting GO and KEGG enrichment analysis on these 128 UbR-DEGs, we identified the main molecular functions and biological pathways related to AD. Furthermore, through the utilization of GSEA analysis, we have gained insight into the enrichment of functions and pathways within both the AD and normal groups. Further, using lasso regression analysis and cross-validation techniques, we identified 22 characteristic genes associated with AD. Subsequently, we constructed a logistic regression model and optimized it, resulting in the identification of 6 RUbR-DEGs: KLHL21, WDR82, DTX3L, UBTD2, CISH, and ATXN3L. In addition, the ROC result showed that the diagnostic model we built has excellent accuracy and reliability in identifying AD patients. Finally, we constructed a lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) regulatory network for AD based on six RUbR-DEGs, further elucidating the interaction between UbRGs and lncRNA, miRNA. In conclusion, our findings will contribute to further understanding of the molecular pathogenesis of AD and provide a new perspective for AD risk prediction, early diagnosis and targeted therapy in the population.

Abstract Background The objective was to investigate the efficacy of different doses of levothyroxine therapy among pregnant women exhibiting high-normal thyroid stimulating hormone levels and positive thyroid peroxidase antibodies throughout the first half of pregnancy. Methods Pregnant women exhibiting high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positivity throughout the initial half of pregnancy were selected from January 2021 to September 2023. Based on the different doses of levothyroxine, the pregnant women were categorized into the nonintervention group (G0, 122 women), 25 µg levothyroxine intervention group (G25, 69 women), and 50 µg levothyroxine intervention group (G50, 58 women). Serum parameters, gastrointestinal symptoms, small intestinal bacterial overgrowth (SIBO), maternal and neonatal outcomes were compared after the intervention among the three groups. Results After the intervention, in the G25 and G50 groups, the thyroid stimulating hormone, triglyceride and low-density lipoprotein levels were notably less in contrast to those in the G0 group (P

Abstract The aim of this study was to investigate the association between hypothyroidism in early pregnancy and small intestinal bacterial overgrowth (SIBO) and the effect of probiotics. Patients with hypothyroidism in early pregnancy and normal pregnant women during the same period were included in the methane–hydrogen breath test to compare the incidence of SIBO, smoothed curve fit, and differences in clinical symptoms. For those who combined with SIBO, the rate of clinical symptom conversion, thyroid hormones, and changes in associated inflammatory indexes were compared after 21 days of treatment with probiotics on top of conventional levothyroxine sodium tablets. The results are as follows: (1) The incidence of combined SIBO in patients with hypothyroidism in pregnancy was 56.0%, significantly higher than the 28.0% of normal pregnant women during the same period. (2) The highest value of hydrogen plus methane gas in 90 min in pregnancy hypothyroid patients showed a significant negative correlation with FT4 (p

To ensure the operation safety and efficiency of an autonomous rice transplanter, a path planning method of obstacle avoidance based on the improved artificial potential field is proposed. Firstly, the obstacles are divided into circular or elliptic obstacles according to the difference between the length and width of an obstacle as well as the angle between the vehicle’s forward direction and the length direction of the obstacle. Secondly, improved repulsive fields for circular and elliptic models are developed. To escape the local minimum and goal inaccessibility of the traditional artificial potential field as well as meet the requirements of agronomy and vehicle kinematics constraints, the adaptive setting and adjusting strategy for virtual goal points is proposed according to relative azimuth between obstacle and vehicle. The path smoothing method based on the B-spline interpolation method is presented. Finally, the intelligent obstacle avoidance algorithm is designed, and the path evaluation rule is given to obtain the low-cost, non-collision, smooth and shortest obstacle avoidance path. To verify the effectiveness of the proposed obstacle avoidance algorithm, simulation and field experiments are conducted. Simulation and experimental results demonstrate that the proposed improved collision avoidance algorithm is highly effective and realizable.

Aiming at the problems of traditional image super-resolution reconstruction algorithms in the image reconstruction process, such as small receptive field, insufficient multi-scale feature extraction, and easy loss of image feature information, a super-resolution reconstruction algorithm of multi-scale dilated convolution network based on dilated convolution is proposed in this paper. First, the algorithm extracts features from the same input image through the dilated convolution kernels of different receptive fields to obtain feature maps with different scales; then, through the residual attention dense block, further obtain the features of the original low resolution images, local residual connections are added to fuse multi-scale feature information between multiple channels, and residual nested networks and jump connections are used at the same time to speed up deep network convergence and avoid network degradation problems. Finally, deep network extraction features, and it is fused with input features to increase the nonlinear expression ability of the network to enhance the super-resolution reconstruction effect. Experimental results show that compared with Bicubic, SRCNN, ESPCN, VDSR, DRCN, LapSRN, MemNet, and DSRNet algorithms on the Set5, Set14, BSDS100, and Urban100 test sets, the proposed algorithm has improved peak signal-to-noise ratio and structural similarity, and reconstructed images. The visual effect is better.

ObjectiveThis study aimed to explore the correlation between microbiota dysbiosis and hypothyroidism in early pregnancy by 16S rRNA amplicon sequencing combined with metagenomic sequencing.MethodsSixty pregnant women (30 with hypothyroidism and 30 normal controls) were recruited for 16S rRNA amplicon sequencing, and 6 patients from each group were randomly selected for metagenomic sequencing to assess the gut microbiome profile.ResultsThe 16S rRNA results showed that beta-diversity in the hypothyroidism group was decreased. The relative abundances of the Prevotella and Paraprevotella genera increased in the hypothyroidism group, and Blautia predominated in the controls. The metagenomics results revealed that Prevotella_stercorea_CAG_629, Prevotella_hominis, Prevotella_sp_AM34_19LB, etc. were enriched in the hypothyroidism group at the species level. Functional analysis revealed that the pyridoxal 5’-phosphate synthase pdxT subunit module was decreased, and the short-chain fatty acid (SCFA) transporter and phospholipase/carboxylesterase modules were strongly enriched in the hypothyroidism group. Hypothyroidism patients had increased C-reactive protein (CRP), interleukin-2 (IL-2), IL-4, IL-10, and tumor necrosis factor (TNF)-α levels. The pyridoxal 5’-phosphate synthase pdxT subunit, the SCFA transporter, and the phospholipase/carboxylesterase module were associated with different Prevotella species.ConclusionIn early pregnancy, women with hypothyroidism exhibit microbiota dysbiosis, and Prevotella may affect the metabolism of glutamate, SCFA, and phospholipases, which could be involved in the development of hypothyroidism during pregnancy.

Abstract Commencing with the breakdown of the diabetic osteoimmune microenvironment, multiple pathogenic factors, including hyperglycemia, inflammation, hypoxia, and deleterious cytokines, are conjointly involved in the progression of diabetic periodontal bone regeneration. Based on the challenge of periodontal bone regeneration treatment and the absence of real‐time feedback of blood oxygen fluctuation in diabetes mellitus, a novel self‐adaptive hyperthermia supramolecular cascade nano‐reactor ACFDG is constructed via one‐step supramolecular self‐assembly strategy to address multiple factors in diabetic periodontal bone regeneration. Hyperthermia supramolecular ACFDG possesses high photothermal conversion efficiency (32.1%), and it can effectively inhibit the vicious cycle of ROS‐inflammatory cascade through catalytic cascade reactions, up‐regulate the expression of heat shock proteins (HSPs) under near‐infrared (NIR) irradiation, which promotes periodontal bone regeneration. Remarkably, ACFDG can provide real‐time non‐invasive diagnosis of blood oxygen changes during periodontal bone regeneration through photoacoustic (PA) imaging, thus can timely monitor periodontal hypoxia status. In conclusion, this multifunctional supramolecular nano‐reactor combined with PA imaging for real‐time efficacy monitoring provides important insights into the biological mechanisms of diabetic periodontal bone regeneration and potential clinical theranostics.

Abstract A graphene field‐effect transistor (GFET) based on chemical vapour deposited (CVD) Ge‐based graphene was reported and the low‐temperature electrical characteristics primarily investigated. The self‐alignment technique was used to fabricate a GFET to reduce parasitic effects and improve transconductance and cut‐off frequency. To further explore the electrical properties, the direct current and radio frequency characteristics of the GFET were studied over a temperature range from 4.2 to 300 K, considering the temperature‐dependent resistivity of intrinsic Ge. The direct current characteristic of the GFET for 110‐nm gate length, particularly the transconductance performance, exhibits a tiny variation of only ∼5% across this temperature range. However, the cut‐off frequency experiences a considerable increase, improving several tens of times when the temperature decreases to 4.2 K, with a maximum value of 3.49 GHz. This work illustrates a meaningful advancement in applying GFETs in the low‐temperature, high‐frequency domain.

BackgroundThe sudden emergence of the COVID-19 pandemic in early 2020 posed an enormous threat to public health. Vaccination is currently recognized as the most cost-effective preventive and control measure against the COVID-19 pandemic worldwide and is the key to constructing a line of defense against the virus, while the epidemic prevention policies adopted by governments have an important impact on the protective behavior of the public. The purpose of this study is to analyze the mechanism by which the stringency of epidemic prevention policies affects public vaccination willingness and to explore the mediating effect of public risk perception.MethodsA cross-sectional survey was conducted among 387 adults from December 2022 to June 2023 in China. A multiple linear regression model was used to explore the impact of epidemic prevention policy stringency on public vaccination willingness, and a hierarchical regression model was used to test the mediating effect of public risk perception.ResultsOur results showed that public vaccination willingness increased by approximately 45.5% for every one-unit increase in the stringency of the epidemic prevention policies, which shows that the stringency of epidemic prevention policies has a significant positive influence on public vaccination willingness. In addition, public risk perception increased by approximately 38.9% during the period of stringent government policies on epidemic prevention. For every one-unit increase in risk perception, public vaccination willingness increased by approximately 40.9%, and the relationship between the stringency of epidemic prevention policies and public vaccination willingness was partially mediated by risk perception.ConclusionThe stricter the epidemic prevention policies, the stronger the public vaccination willingness; risk perception plays a mediating effect between the stringency of epidemic prevention policies and public vaccination willingness. This finding is particularly important for exploring and analyzing the factors influencing public vaccination willingness and for improving public health.

Recycled demolition waste (RDW) and ground granulated blast furnace slag-fly ash-based geopolymer (GFG) are promising materials for treating high-plasticity clay (CH) in highway subgrades. However, the underlying synergistic stabilization mechanisms remain unclear. To elucidate the fundamental mechanisms governing post-treatment soil stabilization, a multi-scale laboratory investigation was undertaken. This investigation encompassed the evaluation of mechanical properties (compaction, California bearing ratio (CBR), and unconfined compressive strength (UCS)) to quantify the enhanced performance of the treated soil. Additionally, microstructural and mineralogical characterization was performed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), and atomic force microscopy (AFM) to elucidate the microscopic mechanisms responsible for this improvement. The results indicated that the addition of RDW led to a reduction in the optimum moisture content (OMC) while increasing the maximum dry density (MDD) of CH. Moreover, upon incorporating RDW-GFG, the mechanical properties of the cured soil exhibited significant improvement. Specifically, the addition of 25% RDW to CH resulted in a 184% increase in CBR and effective improvement in water stability (immersion swelling percentage is reduced). Furthermore, when 25% RDW and 15% GFG were added to CH, the UCS has increased significantly by 8 times. The addition of RDW effectively enhanced the particle size distribution, compacted the soil, thus increased the shear strength. The results from XRD and SEM analyses revealed that the inclusion of GFG could generate geopolymer cementitious bonding network in the soil matrix. These materials facilitated bonding between CH particles and RDW, filling the pores and densifying the overall structure, thus increasing its strength. The synergy of RDW-GFG substantially improved the highly plastic soil through physicochemical actions, markedly elevating both its strength and water stability. Consequently, the outcomes of this experimental study offer valuable insights for road engineering applications.

Light is a key factor affecting the growth and quality formation of Dendrobium officinale Kimura et Migo. In this study, we used D. officinale under different light conditions as experimental materials to explore the key genes that regulate its polysaccharide content. In addition, we cloned the UGPase gene and validated the gene by bioinformatics analysis and real-time quantitative PCR. Compared with the natural light control group, 494, 1630 and 599 differentially expressed genes were screened under different light quality conditions of red, blue and yellow, respectively. GO and KEGG enrichment analyses of these differentially expressed genes showed that the differentially expressed genes were enriched in the light signal transduction process under different light quality conditions. Bioinformatics analyses showed that the sequences of the genes were highly conserved with the sequences of the UGPase genes of other species, and had the highest sequence similarity with Phalaenopsis, which is also a member of the orchid family. Real-time quantitative PCR results showed that red light had the most significant promoting effect on the UGPase gene of D. officinale. In this study, we applied high-throughput sequencing technology to establish a transcriptome database of D. officinale under different light conditions and obtained a large amount of transcriptional information about D. officinale. The related genes affecting the quality of D. officinale were analysed at the transcriptional level, and the D. officinale UGPase gene was cloned, and its expression was analysed in different tissues and under different light conditions.

Abstract Background Fusobacterium necrophorum (F. necrophorum)-induced necrotizing pneumonia is a rare but severe pulmonary infection. Insufficient microbiological detection methods can lead to diagnostic difficulties. Methods We report a case of F. necrophorum lung abscess diagnosed by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF). Results BALF-NGS detected F. necrophorum, guiding subsequent targeted antibiotic therapy. With active drainage and metronidazole treatment, the patient’s condition was effectively treated. Conclusion BALF-NGS is a valuable tool for the rapid diagnosis of infections caused by difficult-to-culture bacteria. It played a decisive role in the early identification of F. necrophorum, enabling timely and targeted antibiotic intervention. Early diagnosis and appropriate treatment are crucial for the management of F. necrophorum pneumonia.

Abstract Background Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. Methods From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. Results Age, creatinine, neutrophil-to-lymphocyte ratio, and Child–Turcotte–Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P

Abstract Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Abstract Background Claudin-18.2 (CLDN18.2) has emerged as an alluring therapeutic target against gastrointestinal tumors in recent years. However, a thorough understanding of its regulatory mechanism in gastric cancer remains elusive. Methods We presented a comprehensive study comprising 185 gastric cancer patients, which included 112 cases with high CLDN18.2 expression and 73 cases with low CLDN18.2 expression as determined by immunohistochemistry. After overdressed CLDN18.2 in AGS and NUGC4 cell lines, we elucidated the functions of CLDN18.2 in connecting gastric cancer cells and cancer-associated fibroblasts (CAFs) through an in vitro adhesion models and in vivo lung colonization models. The molecular mechanism underlying CLDN18.2-mediated interaction between gastric cancer cells and CAFs was identified through RNA sequencing and protein-proximity labeling techniques in vivo. Results In our own cohort, a correlation was observed between high levels of CLDN18.2 expression and advanced cancer stage, poor prognosis, and heightened infiltration of CAFs. We elucidated a pivotal role of CLDN18.2 in mediating adhesion between gastric cancer cells and CAFs, which leads to the adhesion of cancer cells to stroma tissue and facilitates the clustering of cancer cells and CAFs into embolus, enhancing gastric cancer’s metastatic progression and the risk of embolic death. Mechanistically, it was discovered that CAFs can activate adhesion and metastasis-related signaling pathways in CLDN18.2-positive gastric cancer cells. Furthermore, using an in vivo protein-proximity labeling approach, we identified S100 calcium binding protein A4 (S100A4) as a distinctive marker of CAFs that interacts with CLDN18.2 to enhance gastric cancer progression. Conclusions Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract

ABSTRACTIn the era of Earth Observation (EO) big data, interactive spatiotemporal aggregation analysis is a critical tool for exploring geographic patterns. However, existing methods are inefficient and complex. Their interactive performance greatly depends on large-scale computing resources, especially data cube infrastructure. In this study, from a green computing perspective, we propose a lightweight data cube model based on the preaggregation concept, in which the frequency histogram of EO data is employed as a specific measure. The cube space was divided into lattice pyramids by the Google S2 grid system, and histogram statistics of the EO data were injected into in-memory cuboids. Therefore, exploratory aggregation analysis of EO datasets could be rapidly converted into multidimensional-view query processes. We implemented the prototype system on a local PC and conducted a case study of global vegetation index aggregation. The experiments showed that the proposed model is smaller, faster and consumes less energy than ArcGIS Pro and XCube, and facilitates green computing strategies involving a cube infrastructure. Due to the standalone mode, larger dataset will result in longer cube building time with indexing latency. The efficiency of the approach comes at the expense of accuracy, and the inherent uncertainties were examined in this paper.

Per- and polyfluoroalkyl substances (PFASs) have been found in toilet paper in Europe, the United States, and Africa; however, their presence in Chinese household paper has not been investigated. In this study, 21 legacy and 30 emerging PFASs were analyzed in tissue and toilet paper from China, including 48 samples of different origins and materials. Median concentrations of chlorinated polyfluorinated ether sulfonates (Cl-PFESAs), hexafluoropropylene oxide homologs (HFPOs), and p-perfluorous nonenoxybenzenesulfonate (OBS) were 0.32, 0.19, and 0.10 ng/g dry weight (dw), respectively. The detection frequencies (DFs) of Cl-PFESAs and OBS both were greater than 96%, followed by hexafluoropropylene oxide trimer acid (HFPO-TrA, DF: 85%). Notably, the level of HFPO-TrA in one sample was as high as 540 ng/g dw, indicating a potential environmental risk to humans. In addition, the concentrations of Cl-PFESAs in toilet paper were significantly higher than that in tissue (p < 0.05). However, no significant differences were observed in the concentrations of PFASs in tissue and toilet paper from different materials and origins. This suggests that PFASs, particularly emerging PFASs, are widely detected in tissue and toilet paper products across China, and their presence is a potential source of landfill contamination and human exposure.

Urban parks are a major component of urban green spaces and are reserved for recreation, aesthetics and cultural heritage. With increasing attention to carbon neutrality in China, urban parks play an important role in carbon sequestration. This new expectation requires us to examine the impacts of current design and management in urban parks on carbon density. This study took Beijing as an example and investigated a total of 9 parks within 4 functional categories, i.e., landscape parks with small, medium, and large sizes and natural forests. As parks worked for various functions, their plants species and tree sizes were distinct. Big trees were scattered in small parks; while big parks had natural-like landscape with ample medium- and small-sized trees. We analysed their aboveground and belowground carbon density, as well as associated variables, such as biodiversity, soil bulk density, nitrogen (N) content, etc. Soil types were the same for different parks, but managements leaded to different soil properties. Medium- and large-sized landscape parks had the highest aboveground carbon density (60.86 t·hm−2 and 79.18 t·hm−2, respectively), which was higher than that of natural forests (43.20 t·hm−2), while small-sized landscape parks had the highest belowground carbon density (185.22 t·hm−2), which was slightly less than that of natural forests (207.17 t·hm−2). The high aboveground carbon density in landscape parks with medium and large sizes was attributed to the well-planted trees and high biodiversity, especially for the high ratio of brush (62.12 %). High belowground carbon density in small landscape parks resulted from careful management, such as timely fertilization and frequent soil loosening, which led to high organic matter and low bulk density (1.1206 kg·cm−3), promoting soil carbon sequestration. We therefore provide specific advice in managing different parks in regard to their carbon density, expecting to increase carbon density in urban parks by an average of 224 %.

BackgroundPatients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) usually present with multisystemic dysfunction with a wide range of clinical manifestations. When the tests for common mitochondrial DNA (mtDNA) point mutations are negative and the mtDNA defects hypothesis remains, urine epithelial cells can be used to screen the mitochondrial genome for unknown mutations to confirm the diagnosis.Case presentationA 66-year-old Chinese woman presented with symptoms of MELAS and was initially misdiagnosed with acute encephalitis at another institution. Although genetic analysis of blood lymphocyte DNA was negative, brain imaging, including magnetic resonance imaging, magnetic resonance spectroscopy, and clinical and laboratory findings, were all suggestive of MELAS. Finally, the patient was eventually diagnosed with MELAS with the mtDNA 5783G>A mutation in the MT-TC gene with a urinary sediment genetic test.ConclusionThis case report expands the genetic repertoire associated with MELAS syndrome and highlights the importance that full mtDNA sequencing should be warranted beside the analysis of classical variants when a mitochondrial disorder is highly suspected. Furthermore, urine sediment genetic testing has played a crucial role in the diagnosis of MELAS.

Purpose: Nascent geographic atrophy (nGA) refers to specific features seen on OCT B-scans, which are strongly associated with the future development of geographic atrophy (GA). This study sought to develop a deep learning model to screen OCT B-scans for nGA that warrant further manual review (an artificial intelligence [AI]-assisted approach), and to determine the extent of reduction in OCT B-scan load requiring manual review while maintaining near-perfect nGA detection performance. Design: Development and evaluation of a deep learning model. Participants: One thousand eight hundred and eighty four OCT volume scans (49 B-scans per volume) without neovascular age-related macular degeneration from 280 eyes of 140 participants with bilateral large drusen at baseline, seen at 6-monthly intervals up to a 36-month period (from which 40 eyes developed nGA). Methods: OCT volume and B-scans were labeled for the presence of nGA. Their presence at the volume scan level provided the ground truth for training a deep learning model to identify OCT B-scans that potentially showed nGA requiring manual review. Using a threshold that provided a sensitivity of 0.99, the B-scans identified were assigned the ground truth label with the AI-assisted approach. The performance of this approach for detecting nGA across all visits, or at the visit of nGA onset, was evaluated using fivefold cross-validation. Main Outcome Measures: Sensitivity for detecting nGA, and proportion of OCT B-scans requiring manual review. Results: The AI-assisted approach (utilizing outputs from the deep learning model to guide manual review) had a sensitivity of 0.97 (95% confidence interval [CI] = 0.93–1.00) and 0.95 (95% CI = 0.87–1.00) for detecting nGA across all visits and at the visit of nGA onset, respectively, when requiring manual review of only 2.7% and 1.9% of selected OCT B-scans, respectively. Conclusions: A deep learning model could be used to enable near-perfect detection of nGA onset while reducing the number of OCT B-scans requiring manual review by over 50-fold. This AI-assisted approach shows promise for substantially reducing the current burden of manual review of OCT B-scans to detect this crucial feature that portends future development of GA. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The biotoxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs) to aquatic organisms has been widely concerned. However, studies on toxic effects of PFASs are usually evaluated directly by using laboratory exposure rather than laboratory validation based on data obtained in the field. In this study, wild catfish (Silurus meridinalis) was explored on the relationship between PFASs bioaccumulation and lipid disorders. Nine and thirteen lipid metabolites were significantly associated with perfluorooctane sulfonate (PFOS) and 6:2/8:2Cl-PFESA (trade name F-53B) exposures, respectively; and the correlated lipid metabolites were the fatty acid (FA) and conjugates, FA esters, steroids, and glycerophosphate subclasses. The effects of PFASs on lipid metabolism of fish and its mechanism were further analyzed through exposure experiments. Zebrafish (Danio rerio) of different sexes underwent PFOS and F-53B exposures for 21 days at 100 ng/L and 100 μg/L. By determining gene expression levels, hepatic lipid contents, and histopathological change, the adverse effects order on lipid metabolism in male or female was 100 μg/L F-53B > 100 μg/L PFOS > 100 ng/L F-53B > 100 ng/L PFOS; the stress response in male was more intensive than that in female. PFOS and F-53B activated the peroxisome proliferator-activated receptor pathway, promoting the processes of FA and total cholesterol (T-CHO) transport, FA β-oxidation, FA synthesis, and finally induced FA and T-CHO transportation from blood into liver, then accelerated FA to FA ester transformation, and CHO into steroids. Laboratory experiments confirmed the field analysis. This study innovatively explored the adverse effects of PFOS and F-53B on lipid metabolism and their mechanisms at field and laboratory levels, highlighting concerns regarding PFASs health risks.

Summary: Background: Benefits of Intermittent fasting (IF) on health-related outcomes have been found in a range of randomised controlled trials (RCTs). Our umbrella review aimed to systematically analyze and synthesize the available causal evidence on IF and its impact on specific health-related outcomes while evaluating its evidence quality. Methods: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane databases (from inception up to 8 January 2024) to identify related systematic reviews and meta-analyses of RCTs investigating the association between IF and human health outcomes. We recalculated the effect sizes for each meta-analysis as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs). Subgroup analyses were performed for populations based on three specific status: diabetes, overweight or obesity, and metabolic syndrome. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. This study is registered with PROSPERO (CRD42023382004). Findings: A total of 351 associations from 23 meta-analyses with 34 health outcomes were included in the study. A wide range of outcomes were investigated, including anthropometric measures (n = 155), lipid profiles (n = 83), glycemic profiles (n = 57), circulatory system index (n = 41), appetite (n = 9), and others (n = 6). Twenty-one (91%) meta-analyses with 346 associations were rated as high confidence according to the AMSTAR criteria. The summary effects estimates were significant at p

Abstract Aim The aim of the study was to investigate the correlation between fear of COVID‐19 and mental health of nurses and the effects of psychological capital and burnout in this relation. Design A cross‐sectional study. Methods The online surveys were conducted among mainland Chinese nurses. Participants (n = 445; average age 32.89 ± 6.76 years) completed an online‐questionnaire based on the Fear of COVID‐19 Scale, the Psychological Capital Scale, Maslach Burnout Inventory Human Services Survey for Medical Professionals Scale and the 12‐Item Short Form Health Survey. Data analysis was conducted by Pearson's correlation analysis, Harman single‐factor test and the bootstrap method for mediating effect testing. Results (1) The study demonstrated a significant direct effect of fear of COVID‐19 on nurses' mental health, as well as on mediating factors such as burnout and psychological capital. (2) Regression analyses confirmed that while psychological capital bolstered mental health, burnout undermined it, with fear of COVID‐19 further imposing a negative influence. (3) Fear of COVID‐19 exerted an effect on the mental health of nurses by the independent and chain intermediary functions of psychological capital and burnout, resulting in a total mediating effect of −0.233.

Abstract Background Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non‐response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF‐α (tumour necrosis factor‐α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond. Methods We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage‐expressed membrane TNF‐α (hmTNF‐α) and IL‐23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb‐Fc. Our study encompassed in vitro and in vivo characterization of BsNb and BsNb‐Fc. Results BsNb‐Fc exhibited an improved serum half‐life, targeting capability and effector function than BsNb. It's demonstrated that BsNb‐Fc exhibited superior anti‐inflammatory effects compared to the anti‐TNF‐α mAb (infliximab, IFX) combined with anti‐IL‐12/IL‐23p40 mAb (ustekinumab, UST) by Transwell co‐culture assays. Notably, in murine models of acute colitis brought on by 2,4,6‐trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb‐Fc effectively alleviated colitis severity. Additionally, BsNb‐Fc outperformed the IFX&UST combination in TNBS‐induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS. Conclusion These findings highlight an enhanced efficacy and improved biostability of BsNb‐Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF‐α inhibition. Key points A bispecific nanobody (BsNb) was created to target TNF‐α and IL‐23p19, exhibiting high affinity and remarkable stability. BsNb‐Fc inhibited the release of cytokines in CD4+T cells during co‐culture experiments. BsNb‐Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.

BackgroundDiabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients.MethodsThis cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level

Acute generalized pustular psoriasis (GPP) is a serious illness. Despite various treatment methods, there is still lack of effective treatment plans for refractory cases with multiple comorbidities. This case report presents a 67-year-old woman with acute GPP, stage 4 chronic kidney disease (CKD), type 2 diabetes, and cardiovascular disease, in whom skin symptom disappearance and kidney function improvement were observed after the use of oral tacrolimus as the sole therapy. This is the first report on the application of tacrolimus in the treatment of acute GPP, especially refractory acute GPP. The successful treatment indicates that there are shared immune pathways between acute GPP and CKD, and the pathways can be interdicted by tacrolimus. Further studies are needed to optimize the therapy to maximize efficacy and minimize toxicity.

BackgroundPorcine deltacoronavirus (PDCoV), a novel swine enteropathogenic coronavirus, challenges the global swine industry. Currently, there are no approaches preventing swine from PDCoV infection.MethodsA new PDCoV strain named JS2211 was isolated. Next, the dimer receptor binding domain of PDCoV spike protein (RBD-dimer) was expressed using the prokaryotic expression system, and a novel nanoparticle containing RBD-dimer and ferritin (SC-Fe) was constructed using the SpyTag/SpyCatcher system. Finally, the immunoprotection of RBD-Fe nanoparticles was evaluated in mice.ResultsThe novel PDCoV strain was located in the clade of the late Chinese isolate strains and close to the United States strains. The RBD-Fe nanoparticles were successfully established. Immune responses of the homologous prime-boost regime showed that RBD-Fe nanoparticles efficiently elicited specific humoral and cellular immune responses in mice. Notably, high level PDCoV RBD-specific IgG and neutralizing antibody (NA) could be detected, and the histopathological results showed that PDCoV infection was dramatically reduced in mice immunized with RBD-Fe nanoparticles.ConclusionThis study effectively developed a candidate nanoparticle with receptor binding domain of PDCoV spike protein that offers protection against PDCoV infection in mice.

Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in lemon, sweet orange, bitter orange, clementine. Hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory, antioxidant, antitumor and antibacterial potential. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as bone diseases, cardiovascular diseases, neurological diseases, respiratory diseases, digestive diseases, urinary tract diseases. This review provides a comprehensive overview of the biological activities of hesperidin and hesperetin, their therapeutic potential in various diseases and their associated molecular mechanisms. This article also discusses future considerations for the clinical applications of hesperidin and hesperetin.

Skin cutaneous melanoma (SKCM) is one of the most malignant forms of skin cancer, characterized by its high metastatic potential and low cure rate in advanced stages. Despite advancements in clinical therapies, the overall cure rate for SKCM remains low due to its resistance to conventional treatments. Inflammation is associated with the activation and regulation of inflammatory responses and plays a crucial role in the immune system. It has been implicated in various physiological and pathological processes, including cancer. However, the mechanisms of inflammasome activation in SKCM remain largely unexplored. In this study, we quantified the expression level of six inflammasome-related gene sets using transcriptomic data from SKCM patients. As a result, we found that inflammasome features were closely associated with various clinical characteristics and served as a favorable prognostic factor for patients. A functional enrichment analysis revealed the oncogenic role of inflammasome features in SKCM. Unsupervised clustering was applied to identify immune clusters and inflammatory subtypes, revealing a significant overlap between immune cluster 4 and SKCM subtype 2. The CASP1, GSDMD, NLRP3, IL1B, and IL18 features could predict immune checkpoint blockade therapy response in various SKCM cohorts. In conclusion, our study highlighted the significant association between the inflammasome and cancer treatment. Understanding the role of inflammasome signaling in SKCM pathology can help identify potential therapeutic targets and improve patient prognosis.

The water oxidation reaction in photosystem II (PS II) produces most of the molecular oxygen in the atmosphere, which sustains life on Earth, and in this process releases four electrons and four protons that drive the downstream process of CO2 fixation in the photosynthetic apparatus. The catalytic center of PS II is an oxygen-bridged Mn4Ca complex (Mn4CaO5) which is progressively oxidized upon the absorption of light by the chlorophyll of the PS II reaction center, and the accumulation of four oxidative equivalents in the catalytic center results in the oxidation of two waters to dioxygen in the last step. The recent emergence of X-ray free-electron lasers (XFELs) with intense femtosecond X-ray pulses has opened up opportunities to visualize this reaction in PS II as it proceeds through the catalytic cycle. In this review, we summarize our recent studies of the catalytic reaction in PS II by following the structural changes along the reaction pathway via room-temperature X-ray crystallography using XFELs. The evolution of the electron density changes at the Mn complex reveals notable structural changes, including the insertion of OX from a new water molecule, which disappears on completion of the reaction, implicating it in the O—O bond formation reaction. We were also able to follow the structural dynamics of the protein coordinating with the catalytic complex and of channels within the protein that are important for substrate and product transport, revealing well orchestrated conformational changes in response to the electronic changes at the Mn4Ca cluster.

Abstract Circular RNAs (circRNAs) play key roles in colorectal cancer (CRC) progression, but little is known about the biological functions of hsa_circRNA_001676 in CRC. Therefore, we explored the potential role of hsa_circRNA_001676 in CRC development. RT-qPCR was performed to determine hsa_circRNA_001676, miR-556-3p and Ras-GTPase-activating SH3 domain-binding-proteins 2 (G3BP2) levels in CRC tissues. Meanwhile, to evaluate the roles of hsa_circRNA_001676, miR-556-3p and G3BP2 on CRC, functional analysis of cell proliferation, migration and stemness were then performed. Our results showed that compared to normal tissues, hsa_circRNA_001676 and G3BP2 level was elevated, but miR-556-3p level was reduced in CRC tissues. Additionally, luciferase reporter results showed that hsa_circRNA_001676 was shown to target miR-556-3p, and G3BP2 was targeted by miR-556-3p. Hsa_circRNA_001676 or G3BP2 overexpression promoted CRC cell proliferation and migration. Conversely, miR-556-3p overexpression suppressed CRC cell proliferation and migration. Moreover, deficiency of hsa_circRNA_001676 or G3BP2 repressed the CRC cell proliferation, migration and stemness. Meanwhile, hsa_circRNA_001676 deficiency obviously reduced tumor growth and stemness in a CRC mouse xenograft model. Furthermore, hsa_circRNA_001676 deficiency notably reduced G3BP2 level, but elevated miR-556-3p level in tumor tissues from tumor-bearing mice. Mechanistically, hsa_circRNA_001676 targeted miR-556-3p to increase G3BP2 level, contributing to the progression of CRC. Collectively, hsa_circRNA_001676 was able to accelerate proliferation, migration and stemness in CRC through regulating miR-556-3p/G3BP2 axis, suggesting that hsa_circRNA_001676 may become a potential therapeutic target in treating CRC.

Ordovician karst water in the North China coalfield is a green energy source that integrates water and heat. Therefore, it is of great significance for the exploration and development of geothermal resources to clarify the formation and evolution characteristics of the recharge source, geothermal reservoir environment, flow and circulation affected by coal mining. The Huaibei coalfield, one of the typical North China type coalfield, was selected as the study area on the basis of full understanding of its geological, hydrogeological and geothermal geological conditions. The hydrochemistry and isotope data and the previous study results were jointly employed to reveal the hydrochemical characteristics of geothermal water and the mechanism of water-rock interactions. Also, they were used to identify the recharge source of geothermal water, evaluate the temperature of geothermal reservoir and the depth of geothermal water circulation, and propose the formation and evolution model of geothermal water in the study area. The results show that the geothermal water of the Zhahe mining district is mainly recharged by precipitation infiltration, and the hydrochemical type and water-rock interaction are dominated by HCO3−Ca and leaching dissolution respectively, indicating that the geothermal water in this area has a rapid renewal rate and a short circulation path. In the Suxian and Linhuan mining districts, the geothermal water is only recharged by precipitation with evaporation infiltration in some areas and is obviously mixed with ancient groundwater. There are various hydrochemical types including SO4−Ca, SO4−Ca·Mg, HCO3·SO4−Ca·Mg, SO4−Ca·Na, Cl·SO4−Na, Cl−Na, etc. Meanwhile, the water-rock interactions are dominated by leaching and dissolution and cation alternating adsorption (positive and negative), accompanied by dedolomitization, indicating that the geothermal water in this area has a long residence time, a long circulation path, and a more closed reservoir environment. The thermal reservoir temperature range from 34.8 to 69.1℃ according to the calculation of quartz and improved SiO2 geothermometer, and the circulation depth range from 881 to 2281 m. The formation and evolution of karst geothermal water in the Huaibei coalfield is obviously controlled by structure, and there are significant spatial differences in geothermal water circulation and renewal capacity, reservoir temperature, circulation depth and hydrochemical environment. Therefore, the development and utilization of karst geothermal resources should comprehensively consider the regional characteristics.

Abstract Background Histone acetylation is involved in the regulation of stress responses in multiple organisms. Dermacentor silvarum is an important vector tick species widely distributed in China, and low temperature is a crucial factor restricting the development of its population. However, knowledge of the histone acetyltransferases and epigenetic mechanisms underlying cold-stress responses in this tick species is limited. Methods Histone acetyltransferase genes were characterized in D. silvarum, and their relative expressions were determined using qPCR during cold stress. The association and modulation of histone acetyltransferase genes were further explored using RNA interference, and both the H3K9 acetylation level and relative expression of KAT5 protein were evaluated using western blotting. Results Three histone acetyltransferase genes were identified and named as DsCREBBP, DsKAT6B, and DsKAT5. Bioinformatics analysis showed that they were unstable hydrophilic proteins, characterized by the conserved structures of CBP (ZnF_TAZ), PHA03247 super family, Creb_binding, and MYST(PLN00104) super family. Fluorescence quantitative PCR showed that the expression of DsCREBBP, DsKAT6B, and DsKAT5 increased after 3 days of cold treatment, with subsequent gradual decreases, and was lowest on day 9. Western blotting showed that both the H3K9 acetylation level and relative expression of KAT5 in D. silvarum increased after treatment at − 4, 4, and 8 °C for 3 and 6 days, whereas they decreased significantly after a 9-day treatment. RNA interference induced significant gene silencing, and the mortality rate of D. silvarum significantly increased at the respective semi-lethal temperatures. Conclusion These results imply that histone acetyltransferases play an important role in tick adaptation to low temperatures and lay a foundation for further understanding of the epigenetic regulation of histone acetylation in cold-stressed ticks. Further research is needed to elucidate the mechanisms underlying histone acetylation during cold stress in ticks. Graphical Abstract

Abstract Background Primary biliary cholangitis (PBC) is an autoimmune liver disease, whose etiology is yet to be fully elucidated. Currently, ursodeoxycholic acid (UDCA) is the only first-line drug. However, 40% of PBC patients respond poorly to it and carry a potential risk of disease progression. So, in this study, we aimed to explore new biomarkers for risk stratification in PBC patients to enhance treatment. Methods We first downloaded the clinical characteristics and microarray datasets of PBC patients from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Hub genes were further validated in multiple public datasets and PBC mouse model. Furthermore, we also verified the expression of the hub genes and developed a predictive model in our clinical specimens. Results A total of 166 DEGs were identified in the GSE79850 dataset, including 95 upregulated and 71 downregulated genes. Enrichment analysis indicated that DEGs were significantly enriched in inflammatory or immune-related process. Among these DEGs, 15 risk-related genes were recognized and further validated in the GSE119600 cohort. Then, TXNIP, CD44, ENTPD1, and PDGFRB were identified as candidate hub genes. Finally, we proceeded to the next screening with these four genes in our serum samples and developed a three-gene panel. The gene panel could effectively identify those patients at risk of disease progression, yielding an AUC of 0.777 (95% CI, 0.657–0.870). Conclusions In summary, combining bioinformatics analysis and experiment validation, we identified TXNIP, CD44, and ENTPD1 as promising biomarkers for risk stratification in PBC patients.

Abstract Anoikis is a unique form of apoptosis associated with vascularization and distant metastasis in cancer. Eliminating anoikis resistance in tumor cells could be a promising target for improving the prognosis of terminal cancer patients. However, current studies have not elaborated on the prognosis effect of anoikis-related long non-coding RNAs (lncRNAs) in cutaneous melanoma. Pre-processed data, including RNA sequences and clinical information, were retrieved from TCGA and GTEx databases. After a series of statistical analyses, anoikis-related lncRNAs with prognostic significance were identified, and a unique risk signature was constructed. Risk scores were further analyzed in relation to the tumor microenvironment, tumor immune dysfunction and exclusion, immune checkpoint genes, and RNA methylation genes. The indicators were also used to predict the potentially sensitive anti-cancer drugs. An anoikis-related lncRNAs risk signature consisting of LINC01711, POLH-AS1, MIR205HG, and LINC02416 was successfully established in cutaneous melanoma. Overall survival and progression-free survival of patients were strongly linked with the risk score, independently of other clinical factors. The low-risk group exhibited a more beneficial immunological profile, was less affected by RNA methylation, and was more sensitive to the majority of anti-cancer drugs, all of which indicated a better prognostic outcome. The 4 hub lncRNAs may be fundamental to studying the mechanism of anoikis in cutaneous melanoma and provide personalized therapy for salvaging drug resistance.

The improvement in the utilization rate and nutritional value of soybean meal (SBM) represents a significant challenge in the feed industry. This study conducted a 50 kg SBM fermentation based on the 300 g small-scale fermentation of SBM in early laboratory research, to explore the combined effects of lactic acid bacteria (LAB) and acid protease on fermentation quality, chemical composition, microbial population, and macromolecular protein degradation during fermentation and aerobic exposure of SBM in simulated actual production. The results demonstrated that the increase in crude protein content and reduction in crude fiber content were considerably more pronounced after fermentation for 30 days (d) and subsequent aerobic exposure, compared to 3 d. It is also noteworthy that the treated group exhibited a greater degree of macromolecular protein degradation relative to the control and 30 d of fermentation relative to 3 d. Furthermore, after 30 d of fermentation, adding LAB and protease significantly inhibited the growth of undesired microbes including coliform bacteria and aerobic bacteria. In the mixed group, the microbial diversity decreased significantly, and Firmicutes replaced Cyanobacteria for bacteria in both groups’ fermentation.

Habitat quality is a comprehensive index reflecting ecological conditions, land use impact, and human survival. Susceptibility to geological disasters is influenced by factors such as ecology, the geological environment, and human activities. Analyzing the effects of habitat quality on geological disaster susceptibility and its spatial dynamics is crucial for ecological protection and assessing geological disaster risks. This research focused on Pingshan County, using the InVEST 3.7.0 model and ArcGIS to evaluate habitat quality and geological disaster susceptibility for 2020. The spatial relationships were examined with GeoDa to investigate the impact of habitat quality on geological disaster susceptibility. The findings are as follows: (1) Pingshan County generally exhibits high habitat quality, showing significant spatial clustering with geological disaster susceptibility—predominantly high–high in the west and low–low in the east. (2) The geological environment significantly influences the relationship between habitat quality and geological disaster susceptibility, with an overall positive correlation but negative correlations in certain areas. Geological disaster susceptibility is primarily governed by geological factors rather than habitat quality. (3) In mountainous regions with comparable ecological and geological conditions, variations in geological disaster susceptibility are chiefly driven by human activities. Including human activities as a metric significantly enhances the evaluation accuracy. This study provides a scientific foundation for ecological protection, the assessment of geological disaster susceptibility, and the development of mitigation policies.