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Abstract This study aimed to investigate the clinical outcomes of local muscle or myocutaneous flap transfer for emergent repair of Gustilo IIIB open tibiofibular fractures. This retrospective case series study included patients with Gustilo IIIB open tibiofibular fractures treated by local muscle or myocutaneous flap transfer in Weifang People’s Hospital between May 2016 and April 2021. Fifteenpatients (11 males aged 19–72 years) were included. The follow-up ranged from 8 to 24 months. The ranges of bone healing time and wound healing time were 6–17 months and 1–3 weeks, respectively. The length of hospital stay was 26 days (11–50 days). All patients reported acceptable functional recovery and satisfactory leg appearance, with Johner-Wruhs scores of excellent, good, and fair in 10, four, and one patients, respectively. The excellent-good rate was 93.3%. The complications included one case of infection and one case of nonunion. In conclusion, local muscle or myocutaneous flap transfer for emergent repair of Gustilo IIIB open tibiofibular fractures may be useful in providing adequate soft tissue coverage and fracture healing with low complication and infection rates.

Abstract Background There is no consensus on the cause and effect of systemic chronic inflammation (SCI) regarding chronic obstructive pulmonary disease (COPD). The impact of second-hand smoke (SHS) on COPD has reached inconsistent conclusions. Methods The China Kadoorie Biobank cohort was followed up from the 2004–08 baseline survey to 31 December 2018. Among the selected 445,523 participants in the final analysis, Cox and linear regressions were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of tobacco exposure with COPD risk and baseline levels of log-transformed inflammatory factors [βs (95% CIs)], respectively. Results Participants were followed up for a median of 12.1 years and 11,825 incident COPD events were documented. Ever-smokers were associated with a higher risk of COPD than non-smokers with non-weekly SHS exposure. A younger age to start smoking, a greater amount of daily tobacco consumption, and deeper inhalation were associated with increased risk of COPD and correlated with elevated levels of plasma high-sensitivity C-reactive protein (hs-CRP, all P trend

Abstract Little is known about the prospective association between autosomal mosaic chromosomal alterations (mCAs), a group of large-scale somatic mutations on autosomes, and bladder cancer. Here we utilized data from 99,877 participants who were free of physician-diagnosed cancer at baseline (2004–2008) of the China Kadoorie Biobank to estimate the associations between autosomal mCAs and bladder cancer (ICD-10: C67). A total of 2874 autosomal mCAs events among 2612 carriers (2.6%) were detected. After a median follow-up of 12.4 years, we discovered that participants with all autosomal mCAs exhibited higher risks of bladder cancer, with a multivariable-adjusted hazard ratio (HR) (95% confidence interval [CI]) of 2.60 (1.44, 4.70). The estimate of such association was even stronger for mosaic loss events (HR [95% CI]: 6.68 [2.92, 15.30]), while it was not significant for CN-LOH events. Both expanded (cell fraction ≥10%) and non-expanded autosomal mCAs, as well as mosaic loss, were associated with increased risks of bladder cancer. Of interest, physical activity (PA) significantly modified the associations of autosomal mCAs and mosaic loss (P interaction = 0.038 and 0.012, respectively) with bladder cancer. The increased risks of bladder cancer were only observed with mCAs and mosaic loss among participants with a lower level of PA (HR [95% CI]: 5.11 [2.36, 11.09] and 16.30 [6.06, 43.81]), but not among participants with a higher level of PA. Our findings suggest that peripheral leukocyte autosomal mCAs may represent a novel risk factor for bladder cancer, and PA may serve as a potential intervention target for mCAs carriers.

Abstract Perineural invasion (PNI) is a new approach of cervical cancer invasion and metastasis, involving the cross-talk between tumor and nerve. However, the initiating signals and cellular interaction mechanisms of PNI remain largely elusive. The nerve-sparing radical hysterectomy (NSRH) proposed to improve postoperative quality of life is only applicable to cervical cancer patients without PNI. Therefore, it is important to elucidate the underlying mechanisms initiating PNI, and suggest the effective biomarkers to predict PNI before NSRH surgery. Here, we found that PNI is the characteristic of advanced cervical cancer, and Schwann cells were the antecedent cells that initiating PNI. Further, neuropeptide neuromedin B (NMB) produced by cervical cancer cells was determined to induce PNI by reprogramming Schwann cells, including driving their morphological and transcriptional changes, promoting their proliferation and migration, and initiating PNI by secreting CCL2 and directing axon regeneration. Mechanistically, cervical cancer cells-produced NMB activated its receptor NMBR in Schwann cells, and opened the T-type calcium channels to stimulate Ca2+ influx through PKA signaling, which could be blocked by the inhibitor. Clinically, combined examination of serum NMB and CCL2 levels was suggested to effectively predict PNI in cervical cancer patients. Our data demonstrate that cervical cancer-produced NMB initiates the reprograming of Schwann cells, which then direct axon regeneration, thus causing PNI onset. The elevated serum NMB and CCL2 levels may be useful for the decision-making to nerve sparing during hysterectomy surgery of cervical cancer patients.

ABSTRACTFollowing the national dynamic zero-COVID strategy adjustment, the utilization of broad-spectrum nasal neutralizing antibodies may offer an alternative approach to controlling the outbreak of Omicron variants between late 2022 and early 2023 in China. This study involved an investigator-initiated trial (IIT) to assess the pharmacokinetic, safety and efficacy of the F61 nasal spray. A total of 2,008 participants were randomly assigned to receive F61 nasal spray (24 mg/0.8 mL/dose) or normal saline (0.8 mL/dose) and 1336 completed the follow-up in the IIT. Minimal absorption of F61 antibody into the bloodstream was detected in individuals receiving F61 nasal spray for seven consecutive days. No treatment-emergent adverse reactions of grade 3 severity or higher were reported. In the one-dose cohort, the 7-day cumulative SARS-CoV-2 infection rate was 79.0% in the F61 group and 82.6% in the placebo group, whereas, in the multiple-dose (once daily for 7 consecutive days) cohort, the rates were 6.55% in the F61 group and 23.83% in the placebo group. The laboratory-confirmed efficacy of F61 was 3.78% (−3.74%–10.75%) in the one-dose cohort and 72.19% (57.33%–81.87%) in the multiple-dose cohort. In the real-world study, 60,225 volunteers in four different regions were administered the F61 nasal spray based on the subject's wishes, over 90% efficacy rate was observed against different Omicron variants. The F61 nasal spray, with its favourable safety profile, could be a promising prophylactic monoclonal antibody against SARS-CoV-2 VOCs.

To explore the thermoformability of Mn–Cr–Ni–Co steel for ball mill liner, isothermal compression tests were performed on Mn–Cr–Ni–Co steel using a Gleeble-3800 thermal compressive testing machine. Flow stress curves at 900 °C–1200 °C and 0.01s−1∼10s−1 were obtained. Results show Mn–Cr–Ni–Co steel has obvious positive strain rate sensitivity, with peak stress decreasing with increasing temperature. A constitutive equation for Mn–Cr–Ni–Co steel was established using the Arrhenius model based on strain compensation, and fitted values were compared to experimental values. A hot working map for Mn–Cr–Ni–Co steel was established and analyzed. Hot working process parameters are: deformation temperature of 980∼1200 °C, strain rate of 0.04–1.78s−1, providing a basis for selecting the hot forging process of the ball mill liner. Forging and forming experiments of the ball mill liner were carried out using the optimal parameters of Mn–Cr–Ni–Co steel from the hot working map. The ball mill liner has good forming quality with a relatively uniform martensitic structure inside. Tensile and impact tests were performed on the ball mill liner. Compared to the mechanical properties of traditional cast Mn13 ball mill liners, results show the tensile strength increased by 159.75%, elongation by 18.8%, and impact capacity by about 16.7%.

Background: Immune checkpoint inhibitors (ICIs), especially anti-PD-1/PD-L1 antibodies, have emerged as promising therapeutic options for cervical cancer. However, the efficacy of anti-PD-1 antibody monotherapy is limited. Cryoablation could elicit an anti-tumor immune response, thereby presenting itself as a potential approach to augment the response of ICIs. The aim of our study was to investigate the systemic immunological effects of cryoablation and the potential synergistic anti-tumor effects of cryoablation and anti-PD-1 antibody in cervical cancer. Methods: We established U14 murine bilateral subcutaneous cervical cancer model, wherein the primary tumors were treated with cryoablation. Flow cytometry, immunohistochemistry and RNA-seq were used to analyze the immune cell infiltration and immune-associated pathways in the secondary tumor. Results: Our study revealed that cryoablation reprogrammed the immune landscape, leading to an enhanced infiltration of CD8+ T cell in distant tumors. Cryoablation created a conducive environment for increasing the efficacy of anti-PD-1 immunotherapy. Cryoablation in combination with anti-PD-1 antibody inhibited distant tumors growth and improved mouse survival. Mechanistically, this combination therapy could augment the infiltration of CD8+ T cells, CD4+ T cells, dendritic cells and M1-like tumor-associated macrophages, enhance multiple aspects of antitumor immune response, and reduce immunosuppressive cells such as M2-like tumor-associated macrophages and myeloid-derived suppressor cells in distant tumors. Conclusions: Combination therapy with cryoablation and anti-PD-1 antibody induces an effective abscopal effect in murine model of cervical cancer and may be a novel therapeutic approach for patients with advanced/recurrent cervical cancer.

Increasing throughput at container terminals leads to higher yard occupancy rates, reduced yard service capacity, and inefficient use of space. These issues result in longer waiting times for trucks, underutilized yard slots, and longer distances between berth positions and the yard, particularly under high occupancy conditions. Traditional methods for allocating yard space fail to adequately consider dynamic container arrival patterns, conflict between container operations, and efficient use of yard resources. This paper introduces an innovative approach to improve yard efficiency by dividing yard container retrieval into time intervals and dynamically reserving yard slots within each interval. This method aims to minimize operational conflicts, reduce distances between blocks and berths, and avoid excessive reservations. We propose a dynamic reservation algorithm based on a reward-penalty mechanism to handle the problem's complexity and real-time demands. Furthermore, a time-series reward-penalty mechanism, which considers past reservation feedback and future reservation potential, ensures the concentration and continuity of container groups in the yard. Our evaluation metrics and multiple experimental scenarios demonstrate that this method significantly enhances yard efficiency and overall port productivity compared to static and other dynamic algorithms.

This study aims to comprehensively analyze and evaluate the quality of college physical dance education using Convolutional Neural Network (CNN) models and deep learning methods. The study introduces a teaching quality evaluation (TQE) model based on one-dimensional CNN, addressing issues such as subjectivity and inconsistent evaluation criteria in traditional assessment methods. By constructing a comprehensive TQE system comprising 24 evaluation indicators, this study innovatively applies deep learning technology to quantitatively assess the quality of physical dance education. This TQE model processes one-dimensional evaluation data by extracting local features through convolutional layers, reducing dimensions via pooling layers, and feeding feature vectors into a classifier through fully connected layers to achieve an overall assessment of teaching quality. Experimental results demonstrate that after 150 iterations of training and validation on the TQE model, convergence is achieved, with mean squared error (MSE) decreasing to 0.0015 and 0.0216 on the training and validation sets, respectively. Comparatively, the TQE model exhibits significantly lower MSE on the training, validation, and test sets compared to the Back-Propagation Neural Network, accompanied by a higher R2 value, indicating superior accuracy and performance in data fitting. Further analysis on robustness, parameter sensitivity, multi-scenario adaptability, and long-term learning capabilities reveals the TQE model's strong resilience and stability in managing noisy data, varying parameter configurations, diverse teaching contexts, and extended time-series data. In practical applications, the TQE model is implemented in physical dance courses at X College to evaluate teaching quality and guide improvement strategies for instructors, resulting in notable enhancements in teaching quality and student satisfaction. In conclusion, this study offers a comprehensive evaluation of university physical dance education quality through a multidimensional assessment system and the application of the 1D-CNN model. It introduces a novel and effective approach to assessing teaching quality, providing a scientific foundation and practical guidance for future educational advancements.

Summary: Background: In non-high-risk individuals, risk-category-based atherosclerotic cardiovascular disease (ASCVD) screening strategies may be more cost-effective than one-size-fits-all approaches. However, current decisions are constrained by a lack of research evidence. We aimed to explore appropriate risk-category-based screening interval strategies for non-high-risk individuals in ASCVD primary prevention in the Chinese population. Methods: We used data from 28,624 participants in the China Kadoorie Biobank (CKB) who had completed at least two field surveys. The risk assessment tools were the 10-year ASCVD risk prediction models developed based on the CKB cohort. We constructed multistate Markov models to model disease progression and estimate transition probabilities between different risk categories. The total person-years spent unidentified in the high-risk state over a 10-year period were calculated for each screening interval protocol. We also estimated the number of ASCVD events prevented, quality-adjusted life years (QALYs) gained, and costs saved when compared to the 3-yearly screening protocol. Findings: When compared to the uniform 3-yearly protocol, most risk-category-based screening interval protocols would identify more high-risk individuals timely, thus preventing more ASCVD events and gaining QALYs. A few of them would reduce total health-care costs. The protocol, which used 6-year, 3-year, and 2-year screening intervals for low-risk, intermediate-low-risk, and intermediate-high risk individuals, was optimal, and would reduce the person-years spent unidentified in the high-risk category by 17.9% (95% CI: 13.1%–21.9%), thus preventing an estimated 113 thousand (95% CI: 83–138) hard ASCVD events for Chinese adults aged 30–79 over a 10-year period. When using a lower cost of statin therapy, more screening protocols would gain QALYs while saving costs. Interpretation: For the primary prevention of ASCVD, risk-category-based screening protocols outperformed the one-size-fits-all approach in the Chinese population. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82388102, 82192900) and grants (2023YFC2509400) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303, 81941018), and Chinese Ministry of Science and Technology (2011BAI09B01).

Abstract Background Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. Methods The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004–2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. Results During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02–1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78–0.95) for > 12 months compared with those who breastfed for 7–12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. Conclusion Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Mutation of the MAPK7 gene was related to human scoliosis. Mapk7 regulated the development of limb bones and skulls in mice. However, the role of MAPK7 in vertebral development is still unclear. In this study, we constructed Col2a1-cre; Mapk7f/f transgenic mouse model to delete Mapk7 in cartilage, which displayed kyphosis and osteopenia. Mechanistically, Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes, which impaired chondrocyte hypertrophy and attenuated vertebral ossification. In vivo, systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency. Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development, which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine.

Phellinus igniarius is a medicinal fungus. Nonetheless, research on its water-soluble intracellular polysaccharides (IPSW-2 to 4) fractionation, structural elucidation, and antioxidant activity is limited. In this study, water-soluble intracellular polysaccharides (IPSW-2 to 4) were extracted and fractionated from P. igniarius mycelia, and their antioxidant and structural properties were assessed using GC-FID, GC-MS, FTIR, and NMR spectroscopy (1H and 13C). In the water-eluted P. igniarius polysaccharide fractions (IPS30W, IPS60W, and IPS80W) of anion-exchange chromatography, the polysaccharide content was 79.05%, 68.25%, and 62.06%, with higher yields of 25.07%, 21.38%, and 20.34%, respectively. In contrast, the salt (NaCl) elution fractions (IPS30S1, IPS60S1, IPS60S2, and IPS80S1) of anion-exchange chromatography had lower polysaccharide content and yield. Hence, water elution fractions (IPS30W, IPS60W, and IPS80W) were selected for further purification. After repeated purification using size-exclusion chromatography, IPSW-2 to 4 were obtained with a yield of 8% to 15.83%. The IPSW-2 to IPSW-4 structures were elucidated, and they showed no triple helical conformation. Based on periodate oxidation, Smith degradation, methylation analysis, and 1H and 13C NMR spectroscopy, the primary structures of IPSW-2, IPSW-3, and IPSW-4 were all glucan, with the main chain consisting of (1→6)-α-D-Glcp, (1→3,4)-α-D-Glcp, and (1→3, 6)-α-D-Glcp, with α-D-Glcp as a side chain. Finally, antioxidant analysis showed that IPS30W, IPS60W, and IPS80W were all more capable of scavenging superoxide anions than the polysaccharides of Phyllostachys (13.8%) and floribunda (15.1%) at the same concentration (0.40 mg/mL). This will serve as a guide for the development of functional foods.

Yellowhorn (Xanthoceras sorbifolium Bunge) is a valuable ornamental, medicinal, and woody oilseed species that is indigenous to China. The breeding improvement of yellowhorn has been hindered by a lack of suitable markers and sufficient information regarding the molecular diversity of this species. In this study, we conducted a comprehensive analysis of the yellowhorn genome to characterize the simple sequence repeat (SSR) loci. A total of 4,007,201 SSRs were successfully identified. Among these markers, mono-nucleotide SSRs were most abundant in the genome, while the tri-nucleotide SSRs accounted for the highest proportion in coding sequences. The GO and KEGG function enrichment analysis revealed that most SSR loci in coding sequences were associated with potential biological functions. Additionally, we used 30 pairs of primers to amplify SSR markers to gain a better understanding of the genetic variation in yellowhorn germplasms. The average values of observed heterozygosity and polymorphism information content were 0.625 and 0.517, respectively. Population structure, phylogeny and principal component analyses identified two distinct subclusters. Furthermore, yellowhorn germplasms with the same geographical distribution tended to group together. Moreover, a total of 26 yellowhorn core collections, which accounted for approximately 14.94% of the total yellowhorn germplasms, effectively represented the genetic diversity of all original germplasms. Our findings not only unveiled the genetic diversity and population structure of yellowhorn germplasms but also investigated the yellowhorn core collection, which will serve as a strong basis for yellowhorn management and genetic improvement.

Summary: Background: Hospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers. Methods: In a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009–2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics. Findings: About 64–68% of stroke and IHD cases in urban areas and 27–29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas. Interpretation: Patient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use. Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.

Objectives: During the COVID-19 pandemic, there was a decline in vaccine coverage, and the implementation of combined vaccines and co-administration strategies emerged as potential solutions to alleviate this predicament. Our objective is to delve into the concurrent administration of the sabin-strain-based inactivated poliovirus vaccine (sIPV), the diphtheria-tetanus-acellular pertussis vaccine (DTaP), and measles-mumps-rubella vaccine (MMR), with the intention of bridging the evidentiary gap pertaining to vaccine co-administration in Chinese infants, and to ensure a safe and effective vaccination strategy, ultimately leading to an augmentation in immunization coverage. Methods: This study was a follow-up trial of the “Immunogenicity and safety of concomitant administration of the sIPV with the DTaP vaccine in children: a multicenter, randomized, non-inferiority, controlled trial.” Blood samples were collected on day 0 and day 30, and serum antibody levels were detected to measure antibody responses to each of the antigens. Local and systemic adverse events were monitored and compared among groups. This study is the first to fill the knowledge gap in China regarding the safe and effective combined vaccination of sIPV, DTaP, and MMR vaccines. Results: The geometric mean titer of the poliovirus types I, II, and III neutralizing antibodies were 1060.22 (95% CI: 865.73-1298.39), 1537.06 (95% CI: 1324.27-1784.05), and 1539.10 (95% CI: 1296.37-1827.29) in group I on day 30; geometric mean titer of antibodies against DTaP and MMR in the simultaneous vaccination group was non-inferior to those in the DTaP alone and MMR alone group. Reporting rates of local and systemic adverse reactions were similar between groups and no serious adverse events were reported throughout the clinical study period. Conclusion: Co-administration of the sIPV, DTaP, and MMR was safe and did not impact immunogenicity, which would help to mitigate administrative costs and enhance vaccine coverage rates.

Introduction Inactivated virus vaccines are the most widely used tool to prevent disease. To meet vaccine production demands, increasing attention has been placed on identifying methods to improve vaccine production efficiency. The use of suspended cells can greatly increase vaccine production. Suspension acclimation is a traditional method to convert adherent cells to suspension strains. Furthermore, as genetic engineering technology has developed, increasing attention has focused on the development of suspension cell lines using targeted genetic engineering techniques. Areas covered This review systematically summarizes and analyzes the development and research progress of various inactivated viral vaccine production suspension cell lines and provides protocols and candidate target genes for the engineered establishment of additional suspension cell lines for vaccine production. Expert opinion The use of suspended cells can significantly improve the production efficiency of inactivated virus vaccines and other biological products. Presently, cell suspension culture is the key component to improve many vaccine production processes.

Objective: To investigate the optimal process for preparing peppermint essential oil/β-cyclodextrin (β-CD) inclusion complex using high-speed shearing combined with freeze-drying. Methods: The effects of freeze-drying and vacuum drying, high-speed shearing, and stirring on the encapsulation process were compared. Based on single-factor experiments, the ratio of β-CD to essential oil, encapsulation temperature, and mass fraction of β-CD were considered as influencing factors. The comprehensive score of oil content and encapsulation efficiency was used as an evaluation index to investigate the Box-Behnken response surface method for optimizing the encapsulation process. The content of pulegone in the inclusion complex was measured by high-performance liquid chromatography (HPLC). Fourier transform infrared spectroscopy (FTIR) was used to characterize the inclusion complex. Results: The yield of inclusion complex prepared by freeze-drying was higher, with an average yield of 97.6%. The oil content and encapsulation efficiency by the high-speed shearing method were relatively high, being about 3% and 19% higher than those by the stirring method, respectively. The optimized conditions were as follows: The weight ratio of β-CD to volatile oil was 9:1 (g/mL), the encapsulation temperature was 55 ℃, and the mass fraction of β-CD was 17%. Under these conditions, the essential oil content was 10.9%, the encapsulation efficiency was 97.6%, the comprehensive score was 99.7, the RSD value was 1.59%, and the optimized process was stable and feasible. The content of pulegone in the inclusion complex was found to be 2.465 mg/g by HPLC. The formation of the peppermint oil/β-CD inclusion complex was confirmed by analysis using FTIR. Conclusion: The combination of high-speed shearing and freeze-drying for the preparation of peppermint essential oil inclusion complex had the advantages of high efficiency, simple process, and it improved theyield, would provide guidance for the production process.

Abstract With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.

Abstract The recent outbreaks of mpox have raised concerns over the need for effective vaccines. However, the current approved vaccines have either been associated with safety concerns or are in limited supply. mRNA vaccines, which have shown high efficacy and safety against SARS-CoV-2 infection, are a promising alternative. In this study, three mRNA vaccines are developed that encode monkeypox virus (MPXV) proteins A35R and M1R, including A35R extracellular domain -M1R fusions (VGPox 1 and VGPox 2) and a mixture of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induce early anti-A35R antibodies in female Balb/c mice, but only VGPox 1 and 2 generate detectable levels of anti-M1R antibodies at day 7 after vaccination. However, all three mRNA vaccine groups completely protect mice from a lethal dose of vaccinia virus (VACV) challenge. A single dose of VGPox 1, 2, and 3 provide protection against the lethal viral challenge within 7 days post-vaccination. Long-term immunity and protection were also observed in all three candidates. Additionally, VGPox 2 provided better passive protection. These results suggest that the VGPox series vaccines enhance immunogenicity and can be a viable alternative to current whole-virus vaccines to defend against mpox.

At cold temperatures, the stress after welding a blast furnace shell is not completely released because of the fast cooling speed, which results in cracks. To solve this problem, an integrated method combining gray relational analysis, back propagation (BP) neural network, and genetic algorithm-BP (GA-BP) was proposed in this study. Its aim was to analyze the dominant mechanism of residual stress in multi-layer and multi-pass welding process under the heating of ceramic sheet and achieve super-objective collaborative optimization of residual stress. GRA indicated that through the correlation analysis of welding parameters, residual stress, maximum temperature of characteristic point, and deformation, welding speed was determined to be an all-important factor affecting welding quality. A BP prediction model of residual stress was established. The predicted value was in good agreement with the experimental value, and the maximum error was 8.75%. The influence of each factor on the quality of welding seam is not a single, but a complex mechanism of mutual influence. GA-BP determined the combination of low level welding speed 28 mm/min, medium level welding current 210A and medium and low level welding voltage 21V as the optimal solution of low residual stress. The maximum prediction error of residual stress was 13.76%. The experimental results show that the maximum prediction error of residual stress is 4.4%, and the optimized weld has better macro and micro structure, which proves the feasibility of the multi-objective optimization method. Most importantly, the proposed method can effectively identify the optimal welding parameters, which can provide a reliable theoretical basis for engineering practice.

Abstract Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.

Abstract Background The present study aimed to explore the time of maximum bacterial load and main colonization knee site in bacterial infection process based on a novel rat model of septic arthritis (SA) after anterior cruciate ligament reconstruction (ACLR). Methods Ninety-five Wistar rats with unilateral ACLR, random enrolled into control surgery (CS) group; joint inject (JI) group; presoaking (PS) group, were injected with 30 μl sterile saline or 30 μl × 107 colony forming units/ml Staphylococcus aureus via the knee joint or graft with presoaked Staphylococcus aureus during ACLR, respectively. At 1, 4, 7, 11, and 14 days postoperatively, samples were harvested to evaluate progress of knee joint infection by postoperative body weight, body temperature, knee temperature, knee width, scales of tissue damage, serum inflammatory markers, microbiological counting, microcomputed tomography (Micro-CT), digital radiography, magnetic resonance imaging (MRI) examination, and scanning electron microscopy (SEM). Results No systemic infection was observed in all rats. Comparing with serum inflammatory markers, tissue scores of inflammatory reactions, bacterial counts in the CS group, these data were significantly elevated in the JI group and PS group. The bone mass around the bone tunnel was lower and the soft tissue of knee showed more obvious swelling on MRI in the infection groups than that in the CS group at 7 and 14 days postoperatively. Staphylococcus aureus clusters on the surface of screw and graft were observed in the infection group. The whole colony forming units of Staphylococcus aureus maintained a continuous upward trend peaking 7 and 11 days followed by a balanced curve in the infection groups. Bone and soft tissue were found to have more bacterial counts than graft and screws. Conclusion This animal model effectively mimics the acute knee infection after ACLR. We found that the bacterial colonization exhibited the peak of acute infection between 7 and 11 days postoperatively, with the major bacteria loads found in the bone, soft tissue.

China consumes 35% of the world’s fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria, Nitrospirae, and Bacteroidetes. Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19–related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor–mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B, the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A, the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic–based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.

Summary: Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI

Introduction Cohort evidence of the association of diabetes mellitus (DM) with chronic kidney disease (CKD) is limited. Previous studies often describe patients with kidney disease and diabetes as diabetic kidney disease (DKD) or CKD, ignoring other subtypes. The present study aimed to assess the prospective association of diabetes status (no diabetes, pre-diabetes, screened diabetes, previously diagnosed controlled/uncontrolled diabetes with/without antidiabetic treatment) and random plasma glucose (RPG) with CKD risk (including CKD subtypes) among Chinese adults.Research design and methods The present study included 472 545 participants from the China Kadoorie Biobank, using baseline information on diabetes and RPG. The incident CKD and its subtypes were collected through linkage with the national health insurance system during follow-up. Cox regression models were used to calculate the HR and 95% CI.Results During 11.8 years of mean follow-up, 5417 adults developed CKD. Screened plus previously diagnosed diabetes was positively associated with CKD (HR=4.52, 95% CI 4.23 to 4.83), DKD (HR=33.85, 95% CI 29.56 to 38.76), and glomerulonephritis (HR=1.66, 95% CI 1.40 to 1.97). In those with previously diagnosed diabetes, participants with uncontrolled diabetes represented higher risks of CKD, DKD, and glomerulonephritis compared with those with controlled RPG. The risk of DKD was found to rise in participants with pre-diabetes and increased with the elevated RPG level, even in those without diabetes.Conclusions Among Chinese adults, diabetes was positively associated with CKD, DKD, and glomerulonephritis. Screen-detected and uncontrolled DM had a high risk of CKD, and pre-diabetes was associated with a greater risk of DKD, highlighting the significance of lifelong glycemic management.

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear.Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy.Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles.Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

Sepsis is a systemic syndrome involving physiological, pathological, and biochemical abnormalities precipitated by infection and is a major global public health problem. Endothelial cells (ECs) dysfunction is a major contributor to sepsis-induced multiple organ failure. This bibliometric analysis aimed to identify and characterize the status, evolution of the field, and new research trends of ECs and sepsis over the past 20 years.For this analysis, the Web of Science Core Collection database was searched to identify relevant publications on ECs in sepsis published between January 1, 2002, and December 31, 2022. Microsoft Excel 2021, VOSviewer software, CiteSpace software, and the online analysis platform of literature metrology (http://bibliometric.com) were used to visualize the trends of publications’ countries/regions, institutions, authors, journals, and keywords.In total, 4200 articles were identified and screened, primarily originating from 86 countries/regions and 3489 institutions. The USA was the leading contributor to this research field, providing 1501 articles (35.74 %). Harvard University's scientists were the most prolific, with 129 articles. Overall, 21,944 authors were identified, among whom Bae Jong Sup was the most prolific, contributing 129 publications. Additionally, Levi Marcel was the most frequently co-cited author, appearing 538 times. The journals that published the most articles were SHOCK, CRITICAL CARE MEDICINE, and PLOS ONE, accounting for 10.79 % of the total. The current emerging hotspots are concentrated on ''endothelial glycocalyx,'' ''NLRP3 inflammasome,'' ''extracellular vesicle,'' ''biomarkers,'' and ''COVID-19,'' among others.In conclusion, this study provides a comprehensive overview of the scientific productivity and emerging research trends in the field of ECs in sepsis. The evidence supporting the significant role of ECs in both physiological and pathological responses to sepsis is continuously growing. More in-depth studies of the molecular mechanisms underlying sepsis-induced endothelial dysfunction and EC-targeted therapies are warranted in the future.

Abstract Medroxyprogesterone (MPA) has therapeutic effect on endometrial carcinoma (EC), while it could promote the carcinogenesis of breast cancer (BC) by activating receptor activator of NF-kB ligand (RANKL). However, the selective mechanism of MPA in endometrium and breast tissue remains obscure. Multiomics analysis of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were performed in cell lines derived from endometrial cancer and mammary tumor to screen the differential co-regulatory factors of progesterone receptor (PR). Dual-luciferase assays and ChIP-PCR assays were used to validate the transcriptional regulation. Co-immunoprecipitation (Co-IP) and immunofluorescence assays were carried out to explore molecular interactions between PR, the cofactor transcriptional repressor GATA binding 1 (TRPS1), and histone deacetylase 2 (HDAC2). Subsequently, human endometrial cancer/breast cancer xenograft models were established to investigate the regulation effect of cofactor TRPS1 in vivo. In the current study, we found that MPA downregulated RANKL expression in a time- and dose-dependent manner in EC, while had the opposite effect on BC. Then PR could recruit cofactor TRPS1 to the promoter of RANKL, leading to histone deacetylation of RANKL to repress its transcription in EC, whereas MPA disassociated the PR/TRPS1/HDAC2 complex to enhance RANKL histone acetylation in BC. Therefore, TRPS1, the coregulator recruited by PR played a critical role in the selective mechanism of progesterone in EC and BC and could become a potential candidate for targeted therapy to improve the anticancer effect of MPA on EC and avoid its carcinogenic effect on BC.

The crude polysaccharide of Phellinus igniarius mycelia was prepared by the method of water extraction and ethanol precipitation. Then it was preliminarily fractionated by ammonium sulfate solution with the final concentration of 30%, 45% and 60%, respectively. The antioxidant and anti-tumor activities of the polysaccharides fractions were tested and compared with each other. The fraction which showed the strongest activity was further purified by ion exchange resin column chromatography. And the homogeneity and average molecular weight (MW) of purified polysaccharides were evaluated and determined by size-exclusion chromatography combined with multi-angel laser light scattering and refractive indexdetector (SEC-MALLS-RI). The results showed that 45% ammonium sulfate solution supernatant fraction (IPS45) had the strongest anti-tumor activity and better scavenging superoxide anion activity in fractions fractionated by different concentrations of ammonium sulfate. Four fractions were obtained from IPS45 by DEAE-52 cellulose ion exchange column purification. SEC-MALLS-RI analysis results showed that the ddH2O elution fraction (IPS45-W) was a homogeneous polysaccharide with a MW of 79.1 kDa. GC analysis indicated that IPS45-W was composed of mannose:glucose:galactose:unknown monosaccharide in a molar ratio of 1.57:8.38:1.09:1.00. The IPS45-W could inhibit the growth of HepG2 cells. Its inhibition rate was 56.74% at the concentration of 50 μg/mL. This inhibition rate of IPS45-W was higher than that of the homopolysaccharide (11%~35%) against HepG2 cells at same concentration, which from the Phellinus igniarius myceli polysaccharide fractionated by ethanol precipitation in previous studies. The results would provide the basis for the separation and application of different components of Phellinus igniariusmycelia polysaccharides.

Abstract Background Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. Methods By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. Results Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. Conclusion Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Abstract The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2–5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection.

In this paper, a novel method was proposed to improve the production efficiency and formability of titanium alloy, which was named triple-layer sheet hot stamping with a cold die cooling (THF). The titanium alloy sheet was clamped by two steel sheets with no adhesive added, then heated, transferred and formed together. In order to verify the ability in enhancing formability of this process, spherical part forming tests were carried out to study the formability under the single-layer sheet hot stamping (SHF) and THF. Finally, a plug socket part was formed to verify the practicability of the novel forming process. The finite element (FE) model was established to analyze the forming process finding that the formability of the parts were significantly improved after using THF process. Comparing with SHF process, the stamping depth increases by 135.7% at 900 °C in the THF process. The forming limit strain increases from 0.18 of the single-layer sheet to 0.51 of the triple-layer sheet. The forming limit strain obtained by the THF process is close to that of isothermal forming. The friction state is one of the main reason for improving formability. Moreover, for plug socket parts, there is almost no thinning of the part in the THF process at 900 °C. In conclusion, it has great advantages in improving the formability of titanium alloy using the THF process.

Abstract Background Rather low vaccination rates for Human papillomavirus (HPV) and pre-existing cervical cancer patients with limited therapeutic strategies ask for more precise prognostic model development. On the other side, the clinical significance of circadian clock signatures in cervical cancer lacks investigation. Methods Subtypes classification based upon eight circadian clock core genes were implemented in TCGA-CESC through k-means clustering methods. Afterwards, KEGG, GO and GSEA analysis were conducted upon differentially expressed genes (DEGs) between high and low-risk groups, and tumor microenvironment (TME) investigation by CIBERSORT and ESTIMATE. Furthermore, a prognostic model was developed by cox and lasso regression methods, and verified in GSE44001 by time-dependent receiver-operating characteristic curve (ROC) analysis. Lastly, FISH and IHC were used for validation of CCL20 expression in patients’ specimens and U14 subcutaneous tumor models were built for TME composition. Results We successfully classified cervical patients into high-risk and low-risk groups based upon circadian-oscillation-signatures. Afterwards, we built a prognostic risk model composed of GJB2, CCL20 and KRT24 with excellent predictive value on patients’ overall survival (OS). We then proposed metabolism unbalance, especially for glycolysis, and immune related pathways to be major enriched signatures between the high-risk and low-risk groups. Then, we proposed an ‘immune-desert’-like suppressive myeloid cells infiltration pattern in high-risk group TME and verified its resistance to immunotherapies. Finally, CCL20 was proved positively correlated with real-world patients’ stages and induced significant less CD8+ T cells and more M2 macrophages infiltration in mouse model. Conclusions We unraveled a prognostic risk model based upon circadian oscillation and verified its solidity. Specifically, we unveiled distinct TME immune signatures in high-risk groups.

Abstract Background Continuous cropping is a significant obstacle to sustainable development in the pea (Pisum sativum L.) industry, but the underlying mechanisms of this remain unclear. In this study, we used 16 S rDNA sequencing, transcriptomics, and metabolomics to analyze the response mechanism of roots and soil bacteria to continuous cropping and the relationship between soil bacteria and root phenotypes of different pea genotypes (Ding wan 10 and Yun wan 8). Results Continuous cropping inhibited pea growth, with a greater effect on Ding wan 10 than Yun wan 8. Metabolomics showed that the number of differentially accumulated metabolites (DAMs) in pea roots increased with the number of continuous cropping, and more metabolic pathways were involved. Transcriptomics revealed that the number of differentially expressed genes (DEGs) increased with the number of continuous cropping. Continuous cropping altered the expression of genes involved in plant-pathogen interaction, MAPK signal transduction, and lignin synthesis pathways in pea roots, with more DEGs in Ding wan 10 than in Yun wan 8. The up-regulated expression of genes in the ethylene signal transduction pathway was evident in Ding wan 10. Soil bacterial diversity did not change, but the relative abundance of bacteria significantly responded to continuous cropping. Integrative analysis showed that the bacteria with significant relative abundance in the soil were strongly associated with the antioxidant synthesis and linoleic acid metabolism pathway of pea roots under continuous cropping once. Under continuous cropping twice, the bacteria with significant relative abundance changes were strongly associated with cysteine and methionine metabolism, fatty acid metabolism, phenylpropanoid biosynthesis, terpenoid backbone biosynthesis, linoleic acid, and amino sugar and nucleotide sugar metabolism. Conclusion Ding wan 10 was more sensitive to continuous cropping than Yun wan 8. Continuous cropping times and pea genotypes determined the differences in root metabolic pathways. There were common metabolic pathways in the two pea genotypes in response to continuous cropping, and the DEGs and DAMs in these metabolic pathways were strongly associated with the bacteria with significant changes in relative abundance in the soil. This study provides new insights into obstacles to continuous cropping in peas.

Abstract Background Pulmonary tuberculosis (TB) can impair pulmonary function (PF), especially in the elderly. The risk factors associated with the severity of PF impairment in the elderly with pulmonary TB remain unclear. Hence, this retrospective study aimed to address this issue to help improve the management of TB in the elderly population. Methods From January 2019 to February 2022, the elderly who were admitted to our hospital for pulmonary TB and underwent PF testing were included in this analysis. The forced expiratory volume in one second percent of predicted (FEV1% predicted) and clinical characteristics were collected and analyzed retrospectively. The extent of impaired PF was then categorized based on the FEV1% predicted and classified as grade 1–5. Logistic regression analysis was used to analyze the risk factors for impaired PF. Results A total of 249 patients who met the enrollment criteria were included in this analysis. According to the results of FEV1% predicted, all patients were classified as grade 1 (n = 37), grade 2 (n = 46), grade 3 (n = 55), grade 4 (n = 56), or grade 5 (n = 55). Statistical analysis showed that albumin (adjusted odds ratio (aOR) = 0.928, P = 0.013), body mass index (BMI)

The yellowfin tuna represents a significant fishery resource in the Pacific Ocean. Its resource endowment status and spatial variation mechanisms are intricately influenced by marine environments, particularly under varying climate events. Consequently, investigating the spatial variation patterns of dominant environmental factors under diverse climate conditions, and understanding the response of yellowfin tuna catch volume based on the spatial heterogeneity among these environmental factors, presents a formidable challenge. This paper utilizes comprehensive 5°×5° yellowfin tuna longline fishing data and environmental data, including seawater temperature and salinity, published by the Western and Central Pacific Fisheries Commission (WCPFC) and the Inter-American Tropical Tuna Commission (IATTC) for the period 2000–2021 in the Pacific Ocean. In conjunction with the Niño index, a multiscale geographically weighted regression model based on geographically weighted principal component analysis (GWPCA-MGWR) and spatial association between zones (SABZ) is employed for this study. The results indicate the following: (1) The spatial distribution of dominant environmental factors affecting the catch of Pacific yellowfin tuna is primarily divided into two types: seawater temperature dominates in the western Pacific Ocean, while salinity dominates in the eastern Pacific Ocean. When El Niño occurs, the area with seawater temperature as the dominant environmental factor in the western Pacific Ocean further extends eastward, and the water layers where the dominant environmental factors are located develop to deeper depths; when La Niña occurs, there is a clear westward expansion in the area with seawater salinity as the dominant factor in the eastern Pacific Ocean. This change in the spatial distribution pattern of dominant factors is closely related to the movement of the position of the warm pool and cold tongue under ENSO events. (2) The areas with a higher catch of Pacific yellowfin tuna are spatially associated with the dominant environmental factor of mid-deep seawater temperature (105–155 m temperature) to a greater extent than other factors, the highest correlation exceeds 70%, and remain relatively stable under different ENSO events. The formation of this spatial association pattern is related to the vertical movement of yellowfin tuna as affected by subsurface seawater temperature. (3) The GWPCA-MGWR model can fully capture the differences in environmental variability among subregions in the Pacific Ocean under different climatic backgrounds, intuitively reflect the changing areas and influencing boundaries from a macro perspective, and has a relatively accurate prediction on the trend of yellowfin tuna catch in the Pacific Ocean.

Conducting polymers like polypyrrole, polyaniline, and polythiophene with nanostructures offers several advantages, such as high conductivity, a conjugated structure, and a large surface area, making them highly desirable for energy storage applications. However, the direct synthesis of conducting polymers with nanostructures poses a challenge. In this study, we employed a hard template method to fabricate polystyrene@polypyrrole (PS@PPy) core–shell nanoparticles. It is important to note that PS itself is a nonconductive material that hinders electron and ion transport, compromising the desired electrochemical properties. To overcome this limitation, the PS cores were removed using organic solvents to create hollow PPy nanospheres. We investigated six different organic solvents (cyclohexane, toluene, tetrahydrofuran, chloroform, acetone, and N,N-dimethylformamide (DMF)) for etching the PS cores. The resulting hollow PPy nanospheres showed various nanostructures, including intact, hollow, buckling, and collapsed structures, depending on the thickness of the PPy shell and the organic solvent used. PPy nanospheres synthesized with DMF demonstrated superior electrochemical properties compared to those prepared with other solvents, attributed to their highly effective PS removal efficiency, increased specific surface area, and improved charge transport efficiency. The specific capacitances of PPy nanospheres treated with DMF were as high as 350 F/g at 1 A/g. And the corresponding symmetric supercapacitor demonstrated a maximum energy density of 40 Wh/kg at a power density of 490 W/kg. These findings provide new insights into the synthesis method and energy storage mechanisms of PPy nanoparticles.

Establishing plant regeneration systems and efficient genetic transformation techniques plays a crucial role in plant functional genomics research and the development of new crop varieties. The inefficient methods of transformation and regeneration of recalcitrant species and the genetic dependence of the transformation process remain major obstacles. With the advancement of plant meristematic tissues and somatic embryogenesis research, several key regulatory genes, collectively known as developmental regulators, have been identified. In the field of plant genetic transformation, the application of developmental regulators has recently garnered significant interest. These regulators play important roles in plant growth and development, and when applied in plant genetic transformation, they can effectively enhance the induction and regeneration capabilities of plant meristematic tissues, thus providing important opportunities for improving genetic transformation efficiency. This review focuses on the introduction of several commonly used developmental regulators. By gaining an in-depth understanding of and applying these developmental regulators, it is possible to further enhance the efficiency and success rate of plant genetic transformation, providing strong support for plant breeding and genetic engineering research.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is capable of large‐scale transmission and has caused the coronavirus disease 2019 (COVID‐19) pandemic. Patients with COVID‐19 may experience persistent long‐term health issues, known as long COVID. Both acute SARS‐CoV‐2 infection and long COVID have resulted in persistent negative impacts on global public health. The effective application and development of blood‐derived products are important strategies to combat the serious damage caused by COVID‐19. Since the emergence of COVID‐19, various blood‐derived products that target or do not target SARS‐CoV‐2 have been investigated for therapeutic applications. SARS‐CoV‐2‐targeting blood‐derived products, including COVID‐19 convalescent plasma, COVID‐19 hyperimmune globulin, and recombinant anti‐SARS‐CoV‐2 neutralizing immunoglobulin G, are virus‐targeting and can provide immediate control of viral infection in the short term. Non‐SARS‐CoV‐2‐targeting blood‐derived products, including intravenous immunoglobulin and human serum albumin exhibit anti‐inflammatory, immunomodulatory, antioxidant, and anticoagulatory properties. Rational use of these products can be beneficial to patients with SARS‐CoV‐2 infection or long COVID. With evidence accumulated since the pandemic began, we here summarize the progress of blood‐derived product therapies for COVID‐19, discuss the effective methods and scenarios regarding these therapies, and provide guidance and suggestions for clinical treatment.

ABSTRACTSince May 2022, human mpox cases have increased unexpectedly in non-endemic countries. The first imported case of human mpox in Hong Kong was reported in September 2022. Here we report the isolation and identification of MPXV from the vesicle swabs of this patient. In this research, the vesicle swabs were inoculated in Vero and Vero E6 cells. In addition to observing cytopathic effects (CPEs) in Vero or Vero E6 cells, the isolated virus was identified as mpox virus (MPXV) using quantitative Real-Time PCR (RT–PCR), transmission electron microscopy, and high-throughput sequencing. The experiment also assessed the cross-protective efficacy of sera from the smallpox vaccinated population and preliminarily assessed the inhibitory effect of anti-smallpox virus drugs against MPXV. CPEs can be observed on Vero E6 cells at 24 h and Vero cells at 48 h. The virus particles could be observed by transmission electron microscope, showing typical orthopoxvirus morphology. In addition, F3L and ATI genes which from MPXV A39R, B2R, HA genes which from orthopoxvirus were confirmed by conventional PCR and Sanger sequencing. The next generation sequencing (NGS) suggests that the MPXV strain belongs to B.1 branch of the West African linage, and has a high identity with the sequence of the 2022 ongoing outbreak. PRNT50 results showed that 26.7% of sera from individuals born before 1981 who had been immunized with smallpox were positive, but no MPXV-neutralizing antibodies were found in sera from individuals born later. All four anti-smallpox virus drugs evaluated demonstrated inhibition of mpox virus.

Abstract Background DNA methylation clocks emerged as a tool to determine biological aging and have been related to mortality and age-related diseases. Little is known about the association of DNA methylation age (DNAm age) with coronary heart disease (CHD), especially in the Asian population. Results Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip for 491 incident CHD cases and 489 controls in the prospective China Kadoorie Biobank. We calculated the methylation age using a prediction model developed among Chinese. The correlation between chronological age and DNAm age was 0.90. DNA methylation age acceleration (Δage) was defined as the residual of regressing DNA methylation age on the chronological age. After adjustment for multiple risk factors of CHD and cell type proportion, compared with participants in the bottom quartile of Δage, the OR (95% CI) for CHD was 1.84 (1.17, 2.89) for participants in the top quartile. One SD increment in Δage was associated with 30% increased risk of CHD (OR = 1.30; 95% CI 1.09, 1.56; Ptrend = 0.003). The average number of cigarette equivalents consumed per day and waist-to-hip ratio were positively associated with Δage; red meat consumption was negatively associated with Δage, characterized by accelerated aging in those who never or rarely consumed red meat (all P

Facial amphiphilicity is an extraordinary chemical structure feature of a variety of antimicrobial peptides and polymers. Vast efforts have been dedicated to small molecular, macromolecular and dendrimer-like systems to mimic this highly preferred structure or conformation, including local facial amphiphilicity and global amphiphilicity. This work conceptualizes Facial Amphiphilicity Index (FAI) as a numerical value to quantitatively characterize the measure of chemical compositions and structural features in dictating antimicrobial efficacy. FAI is a ratio of numbers of charges to rings, representing both compositions of hydrophilicity and hydrophobicity. Cationic derivatives of multicyclic compounds were evaluated as model systems for testing antimicrobial selectivity against Gram-negative and Gram-positive bacteria. Both monocyclic and bicyclic compounds are non-antimicrobial regardless of FAIs. Antimicrobial efficacy was observed with systems having larger cross-sectional areas including tricyclic abietic acid and tetracyclic bile acid. While low and high FAIs respectively lead to higher and lower antimicrobial efficacy, in consideration of cytotoxicity, the sweet spot is typically suited with intermediate FAIs for each specific system. This can be well explained by the synergistic hydrophobic-hydrophobic and electrostatic interactions with bacterial cell membranes and the difference between bacterial and mammalian cell membranes. The adoption of FAI would pave a new avenue toward the design of next-generation antimicrobial macromolecules and peptides.

This article aims to discuss the consensus mechanism of software-defined blockchain in the Internet of Things, analyze the characteristics of the traditional consensus mechanism algorithms, on the basis of comparing the advantages of each model, the traditional consensus mechanism algorithm is improved. Later, a supervisable consensus scheme based on improved DPOS-PBFT (Delegated proof of stake-Practical Byzantine Fault Tolerance) was proposed. In the context of the development of the Internet of Things technology, the decentralized distributed computing paradigm is used to improve the blockchain smart contract technology, and the DPOS blockchain consensus mechanism is optimized based on the DPOS protocol of the credit model. In addition, through the dynamic grouping algorithm of credibility, the research ranks the credit level of the consensus nodes of the blockchain network, thus further realizing the supervision of the Internet of Things system. The results of the case analysis show that the success rate of the mechanism algorithm can still be maintained at about 97% after 3000 user requests, the maximum delay remains below 8s after 3000 user requests, the minimum delay is always around 3s, the average delay is 2.38s, the overall performance of the algorithm is superior. It can ensure the final consistency of data transmission of each node in the Internet of Things, the research on the blockchain consensus mechanism in the Internet of Things has practical reference value.

Due to a large number of mutations in the spike protein and immune escape, the Omicron variant (B.1.1.529) has become a predominant variant of concern (VOC) strain. To prevent the disease, we developed a candidate inactivated vaccine (Omicron COVID-19 Vaccine (Vero Cell), Inactivated). To evaluate the safety of the vaccine, we tested the repeat-dose toxicity in Sprague-Dawley (SD) rats. The doses were administered randomly to three groups: physiological saline solution (control), aluminum adjuvant in PBS solution adjuvant (adjuvant group), and low-dose and high-dose omicron vaccines (vaccine group) for 6 weeks. The SD rats were allowed to recover for 4 weeks after withdrawal. We evaluated the physiological condition of the rats, including their ophthalmological condition, body weight, food intake, body temperature, blood biochemistry, urine, neutralizing antibody, inflammation at the injection site, and organs weight. In summary, no dose-dependent adverse toxicological changes were observed, and a recovery trend was obvious, which proved the preclinical safety of the candidate omicron vaccine and provided evidence for clinical trials in humans.

Hyperuricemia is an independent risk factor for the progression of chronic kidney disease. High levels of uric acid can lead to a series of pathological conditions, such as gout, urinary stones, inflammation, and uric acid nephropathy. There is a close relationship between uric acid and the NLRP3 inflammasome. NLRP3 inflammasome activation can cause cell damage and even death through endoplasmic reticulum stress, lysosome destruction, mitochondrial dysfunction, and the interaction between the Golgi apparatus and extracellular vesicles. In addition, the NLRP3 inflammasome acts as a molecular platform, triggering the activation of caspase-1 and the lysis of IL-1β, IL-18 and Gasdermin D (GSDMD) through different molecular mechanisms. Cleaved NT-GSDMD forms pores in the cell membrane and triggers pyrophosphorylation, thereby inducing cell death and releasing many intracellular proinflammatory molecules. In recent years, studies have found that hyperuricemia or uric acid crystals can activate NLRP3 inflammasomes, and the activation of NLRP3 inflammasomes plays an important role in kidney disease. This article reviews the possible pathophysiological mechanisms by which uric acid activates inflammasomes and induces kidney damage at the cellular and molecular levels.

Abstract Bioreactors are one of the most important, basic pieces of equipment in the biopharmaceutical industry. Understanding the effects of mechanical damage and other factors on the physiological state of cells during cell matrix culture is the basis for continuously achieving greater efficiency and higher product quality. In this study, Vero cells were used as a model and apoptosis, senescence, transcriptomics, proteomics, and metabolomics were carried out for analysis at the cellular and molecular levels. The results showed that compared with cells cultured in the simulated natural state, the cells cultured in the basket bioreactor displayed no obvious senescence. Additionally, the proportion of early apoptotic cells increased, but the proportions of damaged, late apoptotic and dead cells did not change significantly. The transcription levels of aminoacyl-tRNA synthetase and cyclin D1 and the expression levels of DNA replication licensing factor, methenyltetrahydrofolate cyclohydrolase, arachidonic acid and other metabolites of cells cultured in the basket bioreactor were significantly increased. These results suggest that DNA replication, protein translation and the metabolic activities in cells cultured in basket bioreactors are more active, which is more conducive to cell amplification and target product production. In this study, the growth and physiological state of cells in a basket bioreactor were characterized at the molecular level for the first time. Additionally, a tool to evaluate the physiological state of cells in a bioreactor was established, which can be used to guide the development and optimization of cell matrix culture conditions in industrial production and improve the production efficiency of the target products.

Abstract Background Little is known about the effects of maintaining healthy sleep patterns on frailty transitions. Methods Based on 23,847 Chinese adults aged 30–79 in a prospective cohort study, we examined the associations between sleep patterns and frailty transitions. Healthy sleep patterns included sleep duration at 7 or 8 h/d, without insomnia disorder, and no snoring. Participants who persisted with a healthy sleep pattern in both surveys were defined as maintaining a healthy sleep pattern and scored one point. We used 27 phenotypes to construct a frailty index and defined three statuses: robust, prefrail, and frail. Frailty transitions were defined as the change of frailty status between the 2 surveys: improved, worsened, and remained. Log-binomial regression was used to calculate the prevalence ratio (PR) to assess the effect of sleep patterns on frailty transitions. Results During a median follow-up of 8.0 years among 23,847 adults, 45.5% of robust participants, and 10.8% of prefrail participants worsened their frailty status, while 18.6% of prefrail participants improved. Among robust participants at baseline, individuals who maintained sleep duration of 7 or 8 h/ds, without insomnia disorder, and no-snoring were less likely to worsen their frailty status; the corresponding PRs (95% CIs) were 0.92 (0.89–0.96), 0.76 (0.74–0.77), and 0.85 (0.82–0.88), respectively. Similar results were observed among prefrail participants maintaining healthy sleep patterns. Maintaining healthy sleep duration and without snoring, also raised the probability of improving the frailty status; the corresponding PRs were 1.09 (1.00–1.18) and 1.42 (1.31–1.54), respectively. Besides, a dose-response relationship was observed between constantly healthy sleep scores and the risk of frailty transitions (P for trend

Background Madin-Darby canine kidney (MDCK) cells are a cellular matrix in the production of influenza vaccines. The proliferation rate of MDCK cells is one of the critical factors that determine the vaccine production cycle. It is yet to be determined if there is a correlation between cell proliferation and alterations in metabolic levels. This study aimed to explore the metabolic differences between MDCK cells with varying proliferative capabilities through the use of both untargeted and targeted metabolomics. Methods To investigate the metabolic discrepancies between adherent cell groups (MDCK-M60 and MDCK-CL23) and suspension cell groups (MDCK-XF04 and MDCK-XF06), untargeted and targeted metabolomics were used. Utilizing RT-qPCR analysis, the mRNA expressions of key metabolites enzymes were identified. Results An untargeted metabolomics study demonstrated the presence of 81 metabolites between MDCK-M60 and MDCK-CL23 cells, which were mainly affected by six pathways. An analysis of MDCK-XF04 and MDCK-XF06 cells revealed a total of 113 potential metabolites, the majority of which were impacted by ten pathways. Targeted metabolomics revealed a decrease in the levels of choline, tryptophan, and tyrosine in MDCK-CL23 cells, which was in accordance with the results of untargeted metabolomics. Additionally, MDCK-XF06 cells experienced a decrease in 5’-methylthioadenosine and tryptophan, while S-adenosylhomocysteine, kynurenine, 11Z-eicosenoic acid, 3-phosphoglycerate, glucose 6-phosphate, and phosphoenolpyruvic acid concentrations were increased. The mRNA levels of MAT1A, MAT2B, IDO1, and IDO2 in the two cell groups were all increased, suggesting that S-adenosylmethionine and tryptophan may have a significant role in cell metabolism. Conclusions This research examines the effect of metabolite fluctuations on cell proliferation, thus offering a potential way to improve the rate of MDCK cell growth.