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Abstract Stroke is a severe cerebrovascular disease. This study aimed to determine the association between triglyceride‑glucose (TyG) index and stroke among middle-aged and elderly Chinese. Data was extracted from China Health and Retirement Longitudinal Study survey 2015 and survey 2018. Logistic regression, trend test and subgroup analysis were conducted to assess the association. Possible nonlinear relationships were explored with restricted cubic spline (RCS). Propensity score matching (PSM) was conducted to attenuate the effect of confounding factors. ORs of stroke was positively associated with TyG index. The ORs in RCS analysis also increased with the rising TyG, though p for non-linearity was bigger than 0.05. After PSM, the ORs in the full adjusted models were 1.28 (1.01, 1.62). TyG was suggested as an independent risk factor for stroke in the middle aged and elderly Chinese.

Abstract Enlightenment modernity brings about the domination of industrialization, bureaucracy and instrumental rationality over the subject and its school life. At this time, the subject is like living in what Weber called the “iron cage” ruled by instrumental rationality. The worship of rational authority in education has reached such an extent that aesthetics characterized by perceptual enjoyment has been suppressed, denied and outlawed, which is embodied in the loss of transcendence of aesthetic education. Utilitarianism and entertainment are the main manifestations of the loss of transcendence in aesthetic education. Therefore, it is necessary to regain the transcendence of aesthetic education in three aspects: first, to redeem the rigid and bureaucratic school life through aesthetics, to save the “beautiful risk” of education dominated by instrumental rationality in education; second, to resist the one-sided development of human beings through aesthetic education, and to create unique and individualized personality traits by cultivating students’ individualized aesthetic interest; Thirdly, we should resist the “standard answer” through the interpretation of the pluralistic meaning of works of art in aesthetic education.

Abstract Economic and social factors pose an enormous threat to forest ecological security, which in turn affects the development of ecological civilization. This paper applies a geographically weighted regression model to study the impact of urbanization, industrial structure, and foreign direct investment on forest ecological security of 30 provinces in 2013 and 2018 and reveals the spatial differences of various influencing factors in different provinces. First, the overall forest ecological security in China is at an average level, with slight improvement. Second, urbanization has the greatest impact on forest ecological security in all provinces, which shows a rising trend. Third, the positive impact of industrial structure on forest ecological security has improved. Fourth, in 2013, FDI (foreign direct investment) had a negative correlation with forest ecological security. In 2018, FDI had a positive impact on the forest ecological security index of 16 provinces, while it had a negative correlation in other provinces. Therefore, it is necessary to formulate a coordinated security improvement plan for neighboring provinces. The government should promote rural revitalization, plan the layout of cities rationally, increase the proportion of tertiary industry, appropriately raise access barriers to foreign investment and strengthen environmental supervision over existing foreign-invested enterprises.

Abstract Background Chelerythrine is an important alkaloid used in agriculture and medicine. However, its structural complexity and low abundance in nature hampers either bulk chemical synthesis or extraction from plants. Here, we reconstructed and optimized the complete biosynthesis pathway for chelerythrine from (S)-reticuline in Saccharomyces cerevisiae using genetic reprogramming. Results The first-generation strain Z4 capable of producing chelerythrine was obtained via heterologous expression of seven plant-derived enzymes (McoBBE, TfSMT, AmTDC, EcTNMT, PsMSH, EcP6H, and PsCPR) in S. cerevisiae W303-1 A. When this strain was cultured in the synthetic complete (SC) medium supplemented with 100 µM of (S)-reticuline for 10 days, it produced up to 0.34 µg/L chelerythrine. Furthermore, efficient metabolic engineering was performed by integrating multiple-copy rate-limiting genes (TfSMT, AmTDC, EcTNMT, PsMSH, EcP6H, PsCPR, INO2, and AtATR1), tailoring the heme and NADPH engineering, and engineering product trafficking by heterologous expression of MtABCG10 to enhance the metabolic flux of chelerythrine biosynthesis, leading to a nearly 900-fold increase in chelerythrine production. Combined with the cultivation process, chelerythrine was obtained at a titer of 12.61 mg per liter in a 0.5 L bioreactor, which is over 37,000-fold higher than that of the first-generation recombinant strain. Conclusions This is the first heterologous reconstruction of the plant-derived pathway to produce chelerythrine in a yeast cell factory. Applying a combinatorial engineering strategy has significantly improved the chelerythrine yield in yeast and is a promising approach for synthesizing functional products using a microbial cell factory. This achievement underscores the potential of metabolic engineering and synthetic biology in revolutionizing natural product biosynthesis.

Abstract Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry-based surrogate classification for the “Fudan University Shanghai Cancer Center (FUSCC) subtyping” has been developed and is considered more suitable for clinical application. Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing and the specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. AKT1 and BRCA1 mutations were identified as independent prognostic factors in TNBC. TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of TNBC stratified therapy in the future.

Abstract Background Several studies have focused on the impact of frailty on the health outcomes of individuals with diabetes mellitus (DM). This meta-analysis aims to systematically synthesize the existing evidence on frailty and its association with mortality, hospitalizations, cardiovascular diseases, and diabetic complications in DM. Methods A comprehensive search in PubMed, Embase, and SCOPUS was carried out to identify relevant studies assessing the impact of frailty on mortality, hospitalizations, complications, and cardiovascular events in individuals with DM. The quality of the included studies was evaluated using the New Castle Ottawa Scale. Results From the 22 studies included, our meta-analysis revealed significant associations between frailty and adverse outcomes in individuals with DM. The pooled hazard ratios for mortality and frailty showed a substantial effect size of 1.84 (95% CI 1.46–2.31). Similarly, the odds ratio for hospitalization and frailty demonstrated a significant risk with an effect size of 1.63 (95% CI 1.50–1.78). In addition, frailty was associated with an increased risk of developing diabetic nephropathy (HR, 3.17; 95% CI 1.16–8.68) and diabetic retinopathy (HR, 1.94; 95% CI 0.80–4.71). Conclusion Our results show a consistent link between frailty and increased mortality, heightened hospitalization rates, and higher risks of cardiovascular disease, diabetic nephropathy, and diabetic retinopathy for patients with DM. PROSPERO Registration Number: CRD42023485166

Abstract Symbiotic microbial communities are crucial for human health, and dysbiosis is associated with various diseases. Plant-derived nanovesicles (PDNVs) have a lipid bilayer structure and contain lipids, metabolites, proteins, and RNA. They offer unique advantages in regulating microbial community homeostasis and treating diseases related to dysbiosis compared to traditional drugs. On the one hand, lipids on PDNVs serve as the primary substances that mediate specific recognition and uptake by bacteria. On the other hand, due to the multifactorial nature of PDNVs, they have the potential to enhance growth and survival of beneficial bacterial while simultaneously reducing the pathogenicity of harmful bacteria. In addition, PDNVs have the capacity to modulate bacterial metabolism, thus facilitating the establishment of a harmonious microbial equilibrium and promoting stability within the microbiota. These remarkable attributes make PDNVs a promising therapeutic approach for various conditions, including periodontitis, inflammatory bowel disease, and skin infection diseases. However, challenges such as consistency, isolation methods, and storage need to be addressed before clinical application. This review aims to explore the value of PDNVs in regulating microbial community homeostasis and provide recommendations for their use as novel therapeutic agents for health protection. Graphical Abstract

This work discussed the influences of voltage on the microstructure and corrosion resistance of micro-arc oxidation (MAO) coating developed on Mg–2Zn-0.3Ca (ZX20) alloys. The MAO coatings on ZX20 alloy surface consist of MgO and Mg2SiO4 compounds. They feature two layers, namely a porous outer layer and a dense inner layer. Higher voltage forms a thicker MAO coating on ZX20 alloy, meanwhile, larger diameter micropores and more thermal micro-cracks are generated in the coating. The MAO coating on ZX20 alloy obtained at 400V has the largest thickness (5.98 ± 0.23 μm), the largest diameter of the micropores (1.02 ± 0.64 μm), the most thermal cracks and the most amount of Mg2SiO4. The MAO coating on ZX20 alloy obtained at 300V has the largest contact angle value and the highest bonding strength. During the immersion corrosion, the corrosive ions such as Cl− can enter the outer layer of the coating and react with MgO to generate Mg(OH)2, resulting in the dissolution of the coating. With the prolong of the immersion time, local corrosion and cracks form at the weak site of the coating, speeding up the corrosion. While, the dense inner layer containing chemically stable Mg2SiO4 has less defect, providing an effective physical barrier for the substrate and enhancing the corrosion resistance of ZX20 alloy. The ZX20 alloy coated at 300V exhibits the lowest degradation rate (PH = 0.13 mm y−1) due to its dense inner layer, as well as having the largest contact angle value and the highest bonding strength.

The cooling curves of the Al–Zn–In–Mg–Ag alloys in copper mold, iron mold, and 400 °C-preheated iron mold cast were simulated and three solidification rates were calculated to be 7.05 °C/s, 0.76 °C/s, and 0.28 °C/s. The effects of cooling rate on the microstructure, electrochemical characteristics, and corrosion morphologies of Al–Zn–In–Mg–Ag alloys are investigated. The results demonstrate that the alloy with a low cooling rate has the lowest self-corrosion rate (0.09 mm/year), the highest actual capacity (2503.16 Ah/Kg2), as well as the highest anode current efficiency (87.46%). The anode current efficiency of the Al alloys is affected by the self-corrosion and the detachment of the second phases and grains. As the cooling rate decreases, the grain size becomes larger, the amount of the MgZn2 second phase decreases, and the content of In, Zn, and Ag activation elements increases in the matrix. The corrosion of the Al–Zn–In–Mg–Ag alloy initiates from the micro-galvanic corrosion between the MgZn2 second phase and the Al matrix. It then extends along the grain boundaries and towards the intragranular, accompanied by the shedding of the MgZn2 particles and the grains.

[Objective] Carbon Capture, Utilization, and Storage(CCUS) technology is recognized as a crucial technology for strategically reducing CO2 emissions. Supercritical CO2 pipeline transmission represents the most cost-effective method to connect carbon capture with carbon storage. Due to the decompression wave characteristics of supercritical CO2 and the Joule-Thomson effect of CO2, CO2 pipelines are susceptible to long-distance crack propagation following fractures, posing a threat to the safety of pipeline operation. [Methods] Instrumented impact experiments were conducted, using transverse specimens from the base metal of L360M pipes, to investigate the crack propagation mechanism of supercritical CO2 pipelines. Following that, a numerical simulation model was established and the Cohesive Zone Model(CZM) was utilized to describe material damage. By comparing curves from the experiments and simulations, parameters were calibrated for the CZM, leading to the development of a finite element model for crack propagation in supercritical CO2 pipelines. Simulations were performed after inputting the calibrated CZM parameters into the finite element model, to explore the effects of internal pressure, wall thickness, and pipe diameter on the crack propagation velocity. [Results] The CZM effectively simulated the dynamic progression of crack propagation, and the simulation results exhibited an overall trend consistent with the experimental results. The CZM parameters calibrated and verified through comparison with experimental results proved effective in numerically simulating crack propagation within the pipeline model. In supercritical CO2pipelines, the crack propagation velocity increased with higher internal pressure, larger pipe diameter, and lower wall thickness.[Conclusion] Crack arrest pressures corresponding to different pipe diameters and wall thicknesses and the minimum wall thickness suitable for a pipe diameter of 323 mm were identified for supercritical CO2 pipelines through calculations based on the above results.The research outcomes lay a theoretical groundwork for understanding crack arrest in supercritical CO2 pipelines and offer practical engineering applications with a useful reference point.

Abstract This study delves into the potential connections between cardiac oxidative stress, inflammatory cytokine response, cardiac pump function, and prognosis in individuals following myocardial infarction. A total of 276 patients were categorized into two groups: the control group (n = 130) and the observation group (n = 146), based on the drug intervention strategies. The control group received standard drug treatment, while the observation group received early drug intervention targeting antioxidant and anti-inflammatory treatment in addition to standard treatment. Serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-9 (IL-6), were assessed using enzyme-linked immuno sorbent assay (ELISA) kits. The Forkhead Box Protein A2 (FOX2) reagent was used to determine the overall oxidation level. Left Ventricular End-Diastolic Diameter (LVEDD), Left Ventricular Ejection Fraction (LVEF), and End-Systolic Diameter (ESD) were measured using Doppler ultrasound. The observation group exhibited significantly reduced serum levels of TNF-α, IL-1β, and IL-6 compared to the control group (P

Abstract Objective Mice are routinely utilized as animal models of drug-induced liver injury (DILI), however, there are significant differences in the pathogenesis between mice and humans. This study aimed to compare gene expression between humans and mice in acetaminophen (APAP)-induced liver injury (AILI), and investigate the similarities and differences in biological processes between the two species. Methods A pair of public datasets (GSE218879 and GSE120652) obtained from GEO were analyzed using “Limma” package in R language, and differentially expressed genes (DEGs) were identified, including co-expressed DEGs (co-DEGs) and specific-expressed DEGS (specific-DEGs). Analysis of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed analyses for specific-DEGs and co-DEGs. The co-DEGs were also used to construct transcription factor (TF)-gene network, gene-miRNA interactions network and protein-protein interaction (PPI) network for analyzing hub genes. Results Mouse samples contained 1052 up-regulated genes and 1064 down-regulated genes, while human samples contained 1156 up-regulated genes and 1557 down-regulated genes. After taking the intersection between the DEGs, only 154 co-down-regulated and 89 co-up-regulated DEGs were identified, with a proportion of less than 10%. It was suggested that significant differences in gene expression between mice and humans in drug-induced liver injury. Mouse-specific-DEGs predominantly engaged in processes related to apoptosis and endoplasmic reticulum stress, while human-specific-DEGs were concentrated around catabolic process. Analysis of co-regulated genes reveals showed that they were mainly enriched in biosynthetic and metabolism-related processes. Then a PPI network which contains 189 nodes and 380 edges was constructed from the co-DEGs and two modules were obtained by Mcode. We screened out 10 hub genes by three algorithms of Degree, MCC and MNC, including CYP7A1, LSS, SREBF1, FASN, CD44, SPP1, ITGAV, ANXA5, LGALS3 and PDGFRA. Besides, TFs such as FOXC1, HINFP, NFKB1, miRNAs like mir-744-5p, mir-335-5p, mir-149-3p, mir-218-5p, mir-10a-5p may be the key regulatory factors of hub genes. Conclusions The DEGs of AILI mice models and those of patients were compared, and common biological processes were identified. The signaling pathways and hub genes in co-expression were identified between mice and humans through a series of bioinformatics analyses, which may be more valuable to reveal molecular mechanisms of AILI.

Here we report an ultrafast quadruplex RT-qPCR assay with robust diagnostic ability to detect and distinguish pan-SARS-CoVs and influenza A/B viruses within 35 min. This quadruplex RT-qPCR assay comprised of one novel RNA-based internal control targeting human β2-microglobulin (B2M) for process accuracy and three newly-designed primers-probe sets targeting the envelope protein (E) of pan-SARS-CoV, matrix protein (MP) of influenza A virus and non-structural (NS) region of influenza B virus. This quadruplex assay exhibited a sensitivity comparable to its singleplex counterparts and a slightly higher to that of the Centers for Disease Control and Prevention-recommended SARS-CoV-2 and influenza A/B assays. The novel assay showed no false-positive amplifications with other common respiratory viruses, and its 95 % limits of detection for pan-SARS-CoV and influenza A/B virus was 4.26–4.52 copies/reaction. Moreover, the assay was reproducible with less than 1 % coefficient of variation and adaptable testing different clinical and environmental samples. Our ultrafast quadruplex RT-qPCR assay can serve as an attractive tool for effective differentiation of influenza A/B virus and SARS-CoV-2, but more importantly prognose the reemergence/emergence of SARS and novel coronaviruses or influenza viruses from animal spillover.

Temporal lobe epilepsy (TLE) stands as the predominant adult focal epilepsy syndrome, characterized by dysfunctional intrinsic brain dynamics. However, the precise mechanisms underlying seizures in these patients remain elusive. Our study encompassed 116 TLE patients compared with 51 healthy controls. Employing microstate analysis, we assessed brain dynamic disparities between TLE patients and healthy controls, as well as between drug-resistant epilepsy (DRE) and drug-sensitive epilepsy (DSE) patients. We constructed dynamic functional connectivity networks based on microstates and quantified their spatial and temporal variability. Utilizing these brain network features, we developed machine learning models to discriminate between TLE patients and healthy controls, and between DRE and DSE patients. Temporal dynamics in TLE patients exhibited significant acceleration compared to healthy controls, along with heightened synchronization and instability in brain networks. Moreover, DRE patients displayed notably lower spatial variability in certain parts of microstate B, E and F dynamic functional connectivity networks, while temporal variability in certain parts of microstate E and G dynamic functional connectivity networks was markedly higher in DRE patients compared to DSE patients. The machine learning model based on these spatiotemporal metrics effectively differentiated TLE patients from healthy controls and discerned DRE from DSE patients. The accelerated microstate dynamics and disrupted microstate sequences observed in TLE patients mirror highly unstable intrinsic brain dynamics, potentially underlying abnormal discharges. Additionally, the presence of highly synchronized and unstable activities in brain networks of DRE patients signifies the establishment of stable epileptogenic networks, contributing to the poor responsiveness to antiseizure medications. The model based on spatiotemporal metrics demonstrated robust predictive performance, accurately distinguishing both TLE patients from healthy controls and DRE patients from DSE patients.

Background and objectiveAllergic rhinitis (AR) is a common chronic inflammatory disease that significantly impacts the quality of life of patients. However, there is limited research on the relationship between the Dietary Inflammatory Index (DII) and the risk of AR. Our study aimed to assess the association between DII and AR in a sample of adults from North China.MethodsIn a case–control study, we selected 166 cases of AR and 166 age- and gender-matched controls. Dietary intake was assessed using a validated food frequency questionnaire. The energy-adjusted DII (E-DII) scores were calculated based on the quantity of diet components with inflammatory or anti-inflammatory potential. We used conditional logistic regression models to examine the association between E-DII and AR.ResultsOur findings indicate a positive correlation between E-DII and AR risk. After controlling for confounders, individuals in the highest E-DII tertile exhibited a 4.41-fold increased risk of AR compared to those in the lowest tertile (OR 4.41, 95% CI 2.31–8.41). Additionally, stratified analysis showed that E-DII was positively associated with AR subtype (seasonal vs. perennial), duration (≤6 years vs. >6 years), severity (mild vs. moderate–severe), and onset time (intermittent vs. persistent). Furthermore, individuals in the highest E-DII tertile had higher intake of total fat, SFA, PUFAs, and n-6 PUFAs.ConclusionIn conclusion, we realized that there is a positive association between the E-DII score and AR. The consumption of diets abundant in anti-inflammatory nutrients and low in pro-inflammatory nutrient contents is recommended as a preventative strategy against AR.

Abstract Background Liver metastasis of CRC is still the main cause of poor prognosis in patients with CRC. Previous studies have suggested that serpin family C member 1(SERPINC1) is involved in the development of a variety of tumours, but its effect on colorectal cancer progression has been poorly elucidated. Methods Based on the GEO database, this study identifies the core gene SERPINC1 associated with liver metastasis in CRC. We used transcriptomic data and immunohistochemical staining to explore the expression of SERPINC1 in normal, cancer, and liver metastases tissue from CRC patients. Clinical data obtained from our hospital were used to explore the impact of SERPINC1 on the prognosis of colon cancer patients. Mechanistically, the biological functions exerted by SERPINC1 in CRC were predicted by bioinformatics, and the results were validated by the results of the experiments in vitro. Cell lines with knockdown of SERPINC1 were performed a series assay such as trans well, CCK‐8 and colony formation assay to explore the relationship between SERPINC1 and proliferation and metastasis of CRC cells. Finally, the effect of SERPINC1 on the sensitivity of colon cancer patients to immune checkpoint therapy was evaluated. Results In CRC liver metastatic tissues, we found significantly high expression of SERPINC1. Briefly, 212 CRC cohorts showed that SERPINC1 was significantly associated with TNM stage and plasma CA19‐9 and CEA in CRC patients. Univariate and multivariate Cox demonstrated that SERPINC1 was significantly associated with 5‐year survival after radical surgery for colorectal cancer (p

BackgroundEtomidate can induce myoclonus with an incidence of 50 ~ 85% during anesthesia induction. Dexamethasone, as a long-acting synthetic glucocorticoid, has neuroprotective effects. However, the effects of dexamethasone on the etomidate-induced myoclonus remain uncertain.MethodsAdult male Sprague–Dawley rats were randomly assigned to receive etomidate (1.5 mg/kg) plus dexamethasone (4 mg/kg) (etomidate plus dexamethasone group) or etomidate (1.5 mg/kg) plus the same volume of normal saline (NS) (etomidate plus NS group). The mean behavioral scores, local field potentials and muscular tension were recorded to explore the effects of dexamethasone on etomidate-induced myoclonus. Liquid chromatography coupled with tandem mass spectrometric system (LC–MS/MS), quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting were applied to analyze the levels of glutamate and γ-aminobutyric acid (GABA), the mRNA and protein expression of excitatory amino acid transporters (EAATs), and plasma corticosterone levels at different time points after anesthesia.ResultsCompared with the etomidate plus NS treatment, the etomidate plus dexamethasone treatment significantly decreased the mean behavioral score at 1, 3, 4, and 5 min after administration; the peak power spectral density (PSD) (p = 0.0197) in the analysis of ripple waves; and the glutamate level (p = 0.0139) in the neocortex. However, compared with etomidate plus NS, etomidate plus dexamethasone increased the expression of the neocortical proteins of EAAT1 (p = 0.0207) and EAAT2 (p = 0.0022) and aggravated the inhibition of corticosterone at 4 h (p = 0.0019), 5 h (p = 0.0041), and 6 h (p = 0.0009) after administration.ConclusionDexamethasone can attenuate the myoclonus, inhibit the glutamate accumulation, and reverse the suppression of EAATs in the neocortex induced by etomidate following myoclonus, while conversely aggravating etomidate-induced adrenal suppression.

BackgroundThis study focuses on determining the prognostic and predictive value of the comprehensive prognostic nutrition index (FIDA) in individuals undergoing treatment for Non-Small-Cell Lung Carcinoma (NSCLC).MethodsThis retrospective analysis encompassed 474 of NSCLC patients treated from January 2010 through December 2019. Employing the Lasso-COX regression approach, eight blood parameters were identified as significant prognostic indicators. These parameters contributed to the formulation of the comprehensive prognostic nutrition index FIDA. Utilizing X-tile software, the patient cohort was categorized into either a high or low FIDA group based on an established optimal threshold. The cohort was then randomly segmented into a training set and a validation set using SPSS software. Subsequent steps involved conducting univariate and multivariate regression analyze to develop a prognostic nomogram. The effectiveness of this nomogram was evaluated by calculating the AUC.ResultsAnalysis of survival curves for both the training and validation sets revealed a poorer prognosis in the high FIDA group compared to the low FIDA group. This trend persisted across various subgroups, including gender, age, and smoking history, with a statistical significance (p

The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and neurological diseases with high morbidity. Two distinct strains, NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), contribute to outbreaks in different geographical areas. Currently, there are no commercially licensed vaccines or drugs available for prevention or treatment. In response to this urgent need for protection against NiV and related henipaviruses infections, we developed a novel homotypic virus-like nanoparticle (VLP) vaccine co-displaying NiV attachment glycoproteins (G) from both strains, utilizing the self-assembling properties of ferritin protein. In comparison to the NiV G subunit vaccine, our nanoparticle vaccine elicited significantly higher levels of neutralizing antibodies and provided complete protection against a lethal challenge with NiV infection in Syrian hamsters. Remarkably, the nanoparticle vaccine stimulated the production of antibodies that exhibited superior cross-reactivity to homologous or heterologous henipavirus. These findings underscore the potential utility of ferritin-based nanoparticle vaccines in providing both broad-spectrum and long-term protection against NiV and emerging zoonotic henipaviruses challenges.

Climate change significantly impacts ecological resistance and ecological corridors. However, the difficulty in evaluating this impact lies in two crucial issues: (i) the uncertainty arising from spatial heterogeneity, and (ii) the diversity of impacts arising from this uncertainty. A set pair analysis (SPA) model is designed to assess the impact of climate change on ecological resistance and ecological corridors for addressing the aforementioned problems. First, the ecological resistance and corridors under different climate change scenarios are simulated. Then, the five-element connection number is used to reflect changes in ecological resistance and corridors influenced by climate change and uncertainty. Finally, the influence indices are constructed to quantify the three distinct impacts of climate change on them. The evaluation results for Jiangxi Province are as follows. (i) The province’s UR index values are 0.085, 0.127, 0.351, 0.501, and 0.468 under five climate change scenarios, respectively. The impact of climate change on ecological resistance is rapidly deteriorating, and the central region is the high-value center for future ecological resistance. (ii) The values of UC in the central and southern regions range from − 0.568 to − 0.320 and from − 0.816 to − 0.446, respectively. In the two regions, the assessments of the impact of climate change on ecological corridors are negative, which results in a reduction in connectivity. (iii) The crucial meteorological risks with the greatest impact on ecological resistance and corridors are floods and high-temperature disasters. (iv) The proposals for Jiangxi Province to address climate change are as follows: enhancing flood prevention, improving high-temperature monitoring, and establishing an ecological management system. (v) The SPA model can effectively assess the different impacts of climate change with spatial uncertainty on ecological resistance and corridors.

Abstract Background Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. Methods Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). Results Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. Conclusions This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

Due to the deformable surface and unknown biomechanical properties of human skin tissue, it brings a large impact on the contact position and force control of robotic massage. In this paper, an adaptive hybrid impedance control method is proposed. To adapt the massage robot to the environmental changes of muscle tissues in the human massage area, a human muscle tissue model was established, and a recursive least squares algorithm was optimized to identify the model parameters online. To determine the parameters of the impedance controller, a fuzzy system between the parameters of the skin tissue model and the robot contact dynamics model was developed. To keep the robot with proper end-effector orientation and stable contact force during the massage process, an adaptive force-position hybrid control strategy is proposed. On the one hand, a position controller for adaptive attitude adjustment is used to control the move position and the normal direction of the robot. On the other hand, a force controller based on impedance control is used to ensure a stable contact force during dynamic interaction with human. Furthermore, since massage is a human contact task, the adaptive impedance control strategy also improves the interaction safety performance and contact detection. The effectiveness and feasibility of the massage system using adaptive fuzzy impedance control adapted to the variation of human muscle tissue is verified through experiments on the robot massage movement.

Underwater photography is challenged by optical distortions caused by water absorption and scattering phenomena. These distortions manifest as color aberrations, image blurring, and reduced contrast in underwater scenes. To address these issues, this paper proposes a novel underwater image enhancement model, called DIRBW-Net, leveraging an improved inverted residual network. In order to minimize the interference of the Batch Normalization (BN) layer on color information, newly designed Double-layer Inverted Residual Blocks (DIRBs) are introduced, which omit the BN layer and extract deep feature information from the input images. Subsequently, each input image is fused with the intermediate feature map using skip connections to ensure consistency between local and global image information, thus effectively enhancing the image quality. In the concluding phase, effects of diverse activation functions are studied, opting for the h-swish activation function to further boost the overall model performance. DIRBW-Net is evaluated on a public dataset, with comparisons drawn against existing representative models. The experiments showcase a notable success in enhancing the underwater image quality when using the proposed model.

Abstract Gangliosides play vital biological regulatory roles and are associated with neurological system diseases, malignancies, and immune deficiencies. They have received extensive attention in developing targeted drugs and diagnostic markers. However, it is difficult to obtain enough structurally defined gangliosides and analogs especially at an industrial-relevant scale, which prevent exploring structure-activity relationships and identifying drug ingredients. Here, we report a highly modular chemoenzymatic cascade assembly (MOCECA) strategy for customized and large-scale synthesis of ganglioside analogs with various glycan and ceramide epitopes. We typically accessed five gangliosides with therapeutic promising and systematically prepared ten GM1 analogs with diverse ceramides. Through further process amplification, we achieved industrial production of ganglioside GM1 in the form of modular assembly at hectogram scale. Using MOCECA-synthesized GM1 analogs, we found unique ceramide modifications on GM1 could enhance the ability to promote neurite outgrowth. By comparing the structures with synthetic analogs, we further resolved the problem of contradicting descriptions for GM1 components in different pharmaceutical documents by reinterpreting the exact two-component structures of commercialized GM1 drugs. Because of its applicability and stability, the MOCECA strategy can be extended to prepare other glycosphingolipid structures, which may pave the way for developing new glycolipid drugs.

Abstract Background Fermitin family member 1 (FERMT1) is highly expressed in many tumors and acts as an oncogene. Nonetheless, the precise function of FERMT1 in non-small cell lung cancer (NSCLC) has not been clearly elucidated. Methods Bioinformatics software predicted the FERMT1 expression in NSCLC. Transwell assays facilitated the detection of NSCLC cell migration and invasion. Western blotting techniques were employed to detect the protein levels regulated by FERMT1. Results FERMT1 exhibited high expression levels in NSCLC and was linked to the patients’ poor prognosis, as determined by a variety of bioinformatics predictions combined with experimental verification. FERMT1 promoted the migration and invasion of NSCLC and regulated epithelial to mesenchymal transition (EMT) -related markers. Further studies showed that FERMT1 could up-regulate the expression level of plakophilin 3(PKP3). Further research has indicated that FERMT1 can promote cell migration and invasion via up-regulating PKP3 expression. By exploring downstream signaling pathways, we found that FERMT1 has the capability to activate the p38 mitogen-activated protein kinases (p38 MAPK) signaling pathway, and knocking down PKP3 can counteract the activation induced by FERMT1 overexpression. Conclusions FERMT1 was highly expressed in NSCLC and can activate the p38 MAPK signaling pathway through up-regulation of PKP3, thus promoting the invasion and migration of NSCLC.

With the continuous promotion of energy revolution and energy transition, the product oil consumption in China will peak, and the trend of low delivery volume of product oil pipelines becomes evident increasingly, which puts enormous pressure on product oil pipeline companies. At the same time, as the “ammonia-hydrogen” green energy and “liquid sunshine” carbon neutralization technical routes are hotly promoted, and the related industries are developed vigorously, the production of liquid ammonia and methanol is bound to grow massively in the future. Therefore, a technical route for the large-scale batch transportation of liquid ammonia, methanol and other liquid new energy through the existing product oil pipeline systems was proposed, aiming to help the product oil pipeline companies create new growth poles.The batch transportation technology of liquid ammonia/methanol in product oil pipelines was systematically overviewed. Besides, five major technical challenges, including the hydraulic and thermal characteristics in batch transportation, prediction of mixed oil development,batch establishment and mixed oil cutting and treatment, applicability of pipeline materials and equipment, and leakage diffusion and safety protection, were elaborated. This could provide reasonable suggestions and reference directions for the field application of the batch transportation technology of liquid ammonia/methanol/product oil.

Abstract Background While representing a model bacterium and one of the most used chassis in biomanufacturing, performance of Escherichia coli is often limited by severe stresses. A super-robust E. coli chassis that could efficiently tolerant multiple severe stresses is thus highly desirable. Sterols represent a featured composition that distinguishes eukaryotes from bacteria and all archaea, and play a critical role in maintaining the membrane integrity of eukaryotes. All sterols found in nature are directly synthesized from (S)-2,3-oxidosqualene. However, in E. coli, (S)-2,3-oxidosqualene is not present. Results In this study, we sought to introduce (S)-2,3-oxidosqualene into E. coli. By mining and recruiting heterologous enzymes and activation of endogenous pathway, the ability of E. coli to synthesize (S)-2,3-oxidosqualene was demonstrated. Further analysis revealed that this non-native chemical confers E. coli with a robust and stable cell membrane, consistent with a figurative analogy of wearing an “Iron Man’s armor”-like suit. The obtained Iron Man E. coli (IME) exhibited improved tolerance to multiple severe stresses, including high temperature, low pH, high salt, high sugar and reactive oxygen species (ROS). In particular, the IME strain shifted its optimal growth temperature from 37 °C to 42–45 °C, which represents the most heat-resistant E. coli to the best of our knowledge. Intriguingly, this non-native chemical also improved E. coli tolerance to a variety of toxic feedstocks, inhibitory products, as well as elevated synthetic capacities of inhibitory chemicals (e.g., 3-hydroxypropionate and fatty acids) due to improved products tolerance. More importantly, the IME strain was effectively inhibited by the most commonly used antibiotics and showed no undesirable drug resistance. Conclusions Introduction of the non-native (S)-2,3-oxidosqualene membrane lipid enabled E. coli to improve tolerance to various stresses. This study demonstrated the effectiveness of introducing eukaryotes-featured compound into bacteria for enhancing overall tolerance and chemical production.

Abstract The lack of desirable diffusion barrier layers currently prohibits the long-term stable service of bismuth telluride thermoelectric devices in low-grade waste heat recovery. Here we propose a new design principle of barrier layers beyond the thermal expansion matching criterion. A titanium barrier layer with loose structure is optimized, in which the low Young’s modulus and particle sliding synergistically alleviates interfacial stress, while the TiTe2 reactant enables metallurgical bonding and ohmic contact between the barrier layer and the thermoelectric material, leading to a desirable interface characterized by high-thermostability, high-strength, and low-resistivity. Highly competitive conversion efficiency of 6.2% and power density of 0.51 W cm−2 are achieved for a module with leg length of 2 mm at the hot-side temperature of 523 K, and no degradation is observed following operation for 360 h, a record for stable service at this temperature, paving the way for its application in low-grade waste heat recovery.

Rhamnoolipids are the most widely studied and used biosurfactants, which can be used in microbial flooding to enhance oil recovery. Pseudomonas aeruginosa is the main species of rhamnoolipids synthesized at present. In this study, wild strain WJ was modified by directional genetic engineering, and the strong promoter PoprL was used to replace the original promoter of rhlAB gene, and the genetically engineered strain with increased copy number of Popr-Rhlab gene was constructed, which was named as the genetically engineered strain WJPAB. The optimal carbon source of WJPAB was rapeseed oil. Under the optimal fermentation conditions, the product yield of WJPAB was 57.83g/L, which was 91.17% higher than that of wild strain WJ.The metabolites of strain WJPAB are purified and analyzed by high performance liquid chromatography mass spectrometry (HPLC-MS). The products are confirmed to be rhamnose homologues, including 3 single rhamnose homologues and 5 double rhamnose homologues. The physical and chemical properties of the metabolites of strain WJPAB were studied, and it was found that the metabolites of strain WJPaB had good surface/interfacial activity, which could reduce the surface tension of water to 27.34 mN/m, and change the surface of oil-wet core from oil-wet surface to water-wet surface. The emulsification index of simulated oil, cetane and liquid paraffin is above 60%. In addition, bacterial metabolites have good stability and can maintain good surface activity even at pH 3–11, salinity 0–20g/L and temperature 120 °C, and can adapt to a wide range of reservoir environmental conditions. In the oil displacement experiment, a compound oil displacement system is established by combining fermentation broth and xanthan gum. The compound system can increase the recovery rate by 15.45%, save the separation and purification process of biosurfactant, and reduce the application cost. The results show that Pseudomonas aeruginosa WJPAB has a good application prospect in the microbial oil recovery field.

The traditional Grey Water Footprint (GWF) model, rooted in the assumption that the hazard of each pollutant is independent, faces a limitation when dealing with heavy metals, whose hazards to aquatic organisms accumulate. The objective of this study is to develop a GWF model that reflects the cumulative threat posed by heavy metals to aquatic organisms, using the Hazard Quotient (HQ) as a foundation. The model comprises three parts: (i) defining the minimum virtual water volume required to control the HQ within the allowable limits, which includes long-term GWF (L-GWF) and short-term GWF (S-GWF); (ii) calculating the hazard level of heavy metal pollution (HHL); and (iii) determining the contribution rates of each heavy metal to L-GWF and S-GWF. The evaluation results of the heavy metal pollution discharged from the Guixi Smelter show that (i) The GWF of heavy metals from the Guixi Smelter decreases dramatically in 2014, with L-GWF and S-GWF of 2.39 and 0.22 billion m3, respectively, which are only 49.9 % and 47.1 % of L-GWF and S-GWF in 2013. (ii) The HHL values in 2012 and 2013 are 1.52 and 1.43, respectively, with a grade of “moderate.” In contrast, the HHL values in 2014 and 2015 significantly decrease to 0.82 and 0.74, respectively, both with a grade of “low”. (iii) The L-GWF contributors of heavy metals in the Guixi Smelter are Cu > Cd > Pb, and the S-GWF contributors are Cu > Pb > Cd > As. (iv) The GWF model based on HQ overcomes the limitations of conventional GWF and provides an effective assessment of the cumulative heavy metal hazards to aquatic organisms.

Extinction selectivity determines the direction of macroevolution, especially during mass extinction; however, its driving mechanisms remain poorly understood. By investigating the physiological selectivity of marine animals during the Permian-Triassic mass extinction, we found that marine clades with lower O2-carrying capacity hemerythrin proteins and those relying on O2 diffusion experienced significantly greater extinction intensity and body-size reduction than those with higher O2-carrying capacity hemoglobin or hemocyanin proteins. Our findings suggest that animals with high O2-carrying capacity obtained the necessary O2 even under hypoxia and compensated for the increased energy requirements caused by ocean acidification, which enabled their survival during the Permian-Triassic mass extinction. Thus, high O2-carrying capacity may have been crucial for the transition from the Paleozoic to the Modern Evolutionary Fauna.

BackgroundPreeclampsia (PE) is one of the most common hypertensive diseases, affecting 2%-8% of all pregnancies. The high maternal and fetal mortality rates of PE are due to a lack of early identification of affected pregnant women that would have led to closer monitoring and care. Recent data suggest that misfolded proteins might be a promising biomarker for PE prediction, which can be detected in urine samples of pregnant women according to their congophilia (aggregated) characteristic. ObjectiveThe main purpose of this trial is to evaluate the value of the urine congophilia-based detection of misfolded proteins for the imminent prediction of PE in women presenting with suspected PE. The secondary objectives are to demonstrate that the presence of urine misfolded proteins correlates with PE-related maternal or neonatal adverse outcomes, and to establish an accurate PE prediction model by combining misfolded proteins with multiple indicators. MethodsAt least 300 pregnant women with clinical suspicion of PE will be enrolled in this prospective cohort study. Participants should meet the following inclusion criteria in addition to a suspicion of PE: ≥18 years old, gestational week between 20+0 and 33+6, and single pregnancy. Consecutive urine samples will be collected, blinded, and tested for misfolded proteins and other PE-related biomarkers at enrollment and at 4 follow-up visits. Clinical assessments of PE status and related complications for all participants will be performed at regular intervals using strict diagnostic criteria. Investigators and participants will remain blinded to the results. Follow-up will be performed until 42 days postpartum. Data from medical records, including maternal and fetal outcomes, will be collected. The performance of urine misfolded proteins alone and combined with other biomarkers or clinical variables for the prediction of PE will be statistically analyzed. ResultsEnrollment started in July 2023 and was still open upon manuscript submission. As of March 2024, a total of 251 eligible women have been enrolled in the study and enrollment is expected to continue until August 2024. Results analysis is scheduled to start after all participants reach the follow-up endpoint and complete clinical data are collected. ConclusionsUpon completion of the study, we expect to derive an accurate PE prediction model, which will allow for proactive management of pregnant women with clinical suspicion of PE and possibly reduce the associated adverse pregnancy outcomes. The additional prognostic value of misfolded proteins is also expected to be confirmed. Trial RegistrationChinese Clinical Trials Registry ChiCTR2300074878; https://www.chictr.org.cn/showproj.html?proj=202096 International Registered Report Identifier (IRRID)PRR1-10.2196/54026

Although the input of desert dust as a key source of trace metals in the Southern Ocean (SO) has been previously studied, the dissolution process of metals in surface waters, particularly iron (Fe), remain poorly understood. Given the crucial role of Fe in primary production and the biological carbon pump in the SO, we focused on experimental estimations of Fe dissolution from Patagonian dust, the primary natural dust source in the SO. Our study considered both current and projected future conditions, encompassing sea-surface warming, acidification, increased photosynthetically active radiation, and doubled dust inputs. Through controlled laboratory experiments using filtered SO seawater, conducted over 7 days, we assessed changes in particulate Fe (pFe) concentrations, Fe redox speciation (Fe(II)/Fe(III)), and in the mineralogy of Fe-bearing dust in abiotic condition. The predominant minerals in the dust included quartz and aluminosilicates, with silicon (Si), aluminum (Al), and Fe as the major elements. No significant alterations in the mineralogy and the elemental composition of the dust were recorded during the dissolution experiments, neither under present nor under projected future conditions. The particulate Fe(II)/Fe(III) ratio remained consistently at 0.25 during the experiments, unaffected by changed conditions. Consequently, changes in environmental conditions in the SO would therefore not significantly alter the mineralogy and redox speciation of pFe in the Patagonian dust. On the contrary, pFe exhibited a dissolution rate of 3.8% and 1.6% per day under present and future conditions, respectively. The environmental changes anticipated for 2100 in the SO will likely to result in a decrease in the dissolution rate of pFe. Thus, even though a doubling of dust input by 2100 is anticipated, it will unlikely provide significantly more dissolved Fe (dFe) in seawater in the SO. Consequently, the future intensification of Patagonian dust inputs may not alleviate the Fe limitation in the SO.

Summary: The question of whether serofast status of syphilis patients indicates an ongoing low-grade Treponema pallidum (T. pallidum) infection remains unanswered. To address this, we developed a machine learning model to identify T. pallidum in cell-free DNA (cfDNA) using next-generation sequencing (NGS). Our findings showed that a TP_rate cut-off of 0.033 demonstrated superior diagnostic performance for syphilis, with a specificity of 92.3% and a sensitivity of 71.4% (AUROC = 0.92). This diagnosis model predicted that 20 out of 92 serofast patients had a persistent low-level infection. Based on these predictions, re-treatment was administered to these patients and its efficacy was evaluated. The results showed a statistically significant decrease in RPR titers in the prediction-positive group compared to the prediction-negative group after re-treatment (p

Potato early blight (PEB), a foliar disease of potato during the growing period, caused by Alternaria sp., is common in major potato-producing areas worldwide. Effective agents to control this disease or completely resistant potato varieties are absent. Large-scale use of fungicides is limited due to possibility of increase in pathogen resistance and the requirements of ecological agriculture. In this study, we focused on the composition and infection characteristics of early blight pathogens in Yunnan Province and screened candidate pathogenesis-related pathways and genes. We isolated 85 strains of Alternaria sp. fungi from typical early blight spots in three potato-growing regions in Yunnan Province from 2018 to 2022, and identified 35 strains of Alternaria solani and 50 strains of Alternaria alternata by morphological characterization and ITS sequence comparison, which were identified as the main and conditional pathogens causing early blight in potato, respectively. Scanning electron microscope analysis confirmed only A. solani producing appressorium at 4 h after inoculation successfully infected the leaf cells. Via genome assembly and annotation, combine transcriptome and proteomic analysis, the following pathogenicity-related unit, transcription factors and metabolic pathway were identified: (1) cell wall-degrading enzymes, such as pectinase, keratinase, and cellulase; (2) genes and pathways related to conidia germination and pathogenicity, such as ubiquitination and peroxisomes; and (3) transcription factors, such as Zn-clus, C2H2, bZIP, and bHLH. These elements were responsible for PEB epidemic in Yunnan.

ObjectiveTo investigate the effects of different rehabilitation modalities on cardiopulmonary function in patients with acute coronary syndrome after revascularization.MethodsTwo randomized controlled trials were conducted. All patients were stable for more than 48 h and less than 1 week after revascularization for acute coronary syndrome and were randomly assigned to Group A (home-based rehabilitation group) or Group B (center guided home-based rehabilitation group). The cardiopulmonary exercise test was mainly performed before and 3 months after cardiac rehabilitation (at the end of intervention). The primary endpoints of the study were peak oxygen uptake (VO2peak), and the secondary endpoints were maximum metabolic equivalents (METs), anaerobic threshold exercise load (Load AT), maximal workload (Load max), and anaerobic threshold oxygen uptake (VO2 AT).ResultsA total of 106 patients were included in the study, with 47 patients in Group A (with 6 losses) and 50 patients in Group B (with 3 losses). There were no significant difference between the two groups in terms of age, gender, body mass index (BMI), left ventricular ejection fraction(LVEF), low-density lipoprotein cholesterol(LDL-C),cardiovascular risk factors. In Group A, no significant differences in CPET indices were observed before and after the intervention. In Group B, values of maximum metabolic equivalents (METs), peak heart rate (PHR), anaerobic threshold exercise load (Load AT), maximal workload (Load max), maximum ventilation per minute (VE max), peak oxygen uptake (VO2peak), anaerobic threshold oxygen uptake (VO2 AT) and maximum oxygen pulse (VO2/HRmax) were higher than those before the intervention (P

Abstract Background There is a gender difference in the acceptance of osteoporosis diagnosis and treatment in patients after fragility fractures, but this difference is rarely assessed during hospitalization, and it is unclear whether these differences are age-dependent. This study aimed to evaluate the differences between male and female fragility fracture patients of different age groups who received the diagnosis and treatment of osteoporosis during hospitalization. Methods 31,265 fragility fracture patients aged ≥ 50 years from the Fragility Fracture Management Database in a high-volume orthopedic hospital from December 2019 to February 2023 were included in this study. We compared the differences in the rates of men and women with fragility fracture who received the measurement of bone mineral density (BMD) and bone metabolism biochemical markers (BMBMs) and treatment with anti-osteoporosis medications (AOMs), and follow-up to the internal medicine clinic within 3 months after discharge, across all age groups and across different age stages (50–59, 60–69, 70–79, and ≥ 80 years). Results The detection rates of female patients receiving BMD and BMBMs during hospitalization were 31.88% and 5.30%, respectively, compared with 22.23% and 2.69% for men. The rate of receiving any AOMs treatment was 44.63% for women and 31.60% for men. The follow-up rate of returning to the internal medicine clinic within 3 months after discharge was 9.79% for women compared to 3.00% for men. There was a significant difference between males compared to females (P

The thermal stability of Al–Cu–Li alloy is critical to the quality and reliability of aerospace structural components. In this work, the microstructure and properties of rapidly solidified Al–Cu–Li alloy (T84) thermally exposed at 150 °C, 175 °C, 200 °C and 225 °C for 500 h were systematically studied. The results show that the T84 alloy exhibits excellent thermal stability with increased strength after thermally exposed at 150 °C, which is attributed to the increased number density of the T1 phase -Al2CuLi. With the further increase of thermal exposure temperature, the size of the T1 phase increases, the number density decreases significantly, and coarse precipitates such as T2 phase-Al6CuLi3 are formed. Meanwhile, the grain boundary precipitates coarsen and the precipitation free zones widen. The strengthening mechanism of the T1 phase transforms from shear mechanism to by-passing mechanism, and its contribution to yield strength decreases dramatically. In addition, the calculated activation energy indicates that coarsening of the T1 phase is controlled by the diffusion of Cu atoms.

Abstract TP53 mutation (TP53 mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53 mut remains a significant challenge in DLBCL treatment. Here we assessed TP53 mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53 mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53 mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53 mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53 mut patient-derived xenograft models and TP53 mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53 mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53 mut-driven cancers.

Abstract Background Severe acute pancreatitis complicated by acute respiratory distress is a common cause of intensive care unit (ICU) admission. These patients are at risk of a decline in physical activity due to bed rest. Neuromuscular electrical stimulation (NMES) has been recommended for ICU patients to strengthen muscles, but its effects on muscle atrophy, respiratory function, multiple organ dysfunction, and functional status of these patients remain to be proven. Methods Patients (n = 80) will be prospectively randomized into an NMES group and a control group. The NMES group will receive NMES for 1 h per day for 7 days, and both the control and NMES groups will receive usual care. The efficacy will be assessed by an experienced physiotherapist and sonographer who will be blinded to the patient’s group assignment. Muscle power assessment (MRC scale), lower extremity circumference, grip strength, activities of daily living (Barthel index), and Marshall scores will be measured at baseline and posttreatment. The functions of the diaphragm assessments will be measured daily. Barthel index measurements will be followed up in the 1st month, 3rd month, and 6th month after discharge. Discussion The trial will explore the effectiveness of NMES in functional status and diaphragm function in patients with SAP complicated with ARDS. The results of this trial will provide strong evidence of the efficacy of NMES in treating SAP patients with ARDS. Trial registration This trial has been registered at the Chinese Clinical Trial Registry, and the registry name is “Effectiveness of neuromuscular electrical stimulation in severe acute pancreatitis complicated patients with acute respiratory distress syndrome: study protocol for a randomized controlled trial,” URL: https://www.chictr.org.cn , numbered ChiCTR2300068995. Date of Registration: 2023-03-03.

Objective To investigate the predictive value of preoperative hematological inflammatory markers in gastric cancer (GC) with lymphovascular invasion(LVI). Methods A retrospective study was conducted on 341 GC patients who undergoing surgical resection and confirmed by pathological examination in Jiangsu Cancer Hospital from October 2020 to July 2022. The patients were divided into a positive group (n=163) and a negative group (n=178) based on the presence or absence of vascular cancer thrombi in postoperative pathology. Before operation, the following clinical data were collected, including neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio(LMR), fibrinogen-lymphocyte ratio (FLR) and common tumor markers. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of NLR, PLR and FLR for LVI to find the optimal cut-off values. Univariate logistic regression was used to analyze the influencing factors of LVI in GC patients, and a logistic regression model for predicting LVI in GC patients was constructed. Results Compared with those in the patients with LVI negative, the levels of NLR, PLR, FLR and carbohydrate antigen (CA)19-9, the tumor infiltration depth and the rate of lymph node metastasis rate significantly increased in LVI positive patients(P＜0.05). ROC curve analysis showed that the best cutoff values of NLR, PLR and FLR were 1.68, 115.29 and 1.96 respectively. The logistic regression model of LVI in GC patients showed that Logit(P)=-2.117+0.890×X1+0.286×X2+0.917×X3(X1=PLR, X2=cT, X3=lymph node metastasis) had a good model fit(χ=58.405, P＜0.01), with the prediction accuracy of 67.26% and an AUC of 0.733 (95%CI: 0.680-0.786, P＜0.01), and this model analysis suggested that PLR(＞115.29, OR=2.436, 95%CI: 1.386-4.282, P=0.002), cT stage (OR=1.331, 95%CI: 1.031-1.749, P=0.030) and lymph node metastasis(OR=2.503, 95%CI: 1.507-4.156, P＜0.001) were the independent risk factors for LVI in patients with GC. Conclusion Preoperative monitoring of PLR level has a certain predictive value in evaluating the occurrence of LVI in GC patients, and can be used as a supplementary indicator to judge the formation of LVI.

The rapid concentration of tailings is a crucial initial step in the cemented paste backfill (CPB) process, as it ensures the stability of the backfilling slurry concentration and the continuity of the backfilling process. The structure of flocs plays a pivotal role in tailings concentration, directly contributing to such critical technical parameters as settling speed and bottom flow concentration. However, most of the current studies focus on flocculant addition rather than the tailings slurry itself. Also, there is a lack of uniform characterization of the flocculant structure in the flocculation and settling system. This study establishes a semi-quantitative assessment system for evaluating the fine structure of tailings flocs based on indicators such as the exposure state of coarse particles, floc size, and floc compactness (porosity). The findings reveal that, during the settling process, the higher true density of tailings (3.156 g/cm3) and intermediate particles (40 wt% of 38 μm–74 μm particles) attenuates the clamping effect of turbulence on settling, leading to a faster settling rate to 0.65 cm/s and 0.29 cm/s respectively. Moreover, in the thickening process, tailings located at the bottom of the mud layer expedite the precipitation of interstitial water within the floc structure through the combined influence of gravity and rake frame shear. Consequently, a denser floc structure forms, as evidenced by a higher concentration of bottom flow at a macroscopic level. This conclusion provides a theoretical basis for faster preparation of highly concentrated tailings slurry in CPB.

PURPOSETo assess the quantification accuracy of pulmonary nodules using virtual monoenergetic images (VMIs) derived from spectral-detector computed tomography (CT) under an ultra-low-dose scan protocol.METHODSA chest phantom consisting of 12 pulmonary nodules was scanned using spectral-detector CT at 100 kVp/10 mAs, 100 kVp/20 mAs, 120 kVp/10 mAs, and 120 kVp/30 mAs. Each scanning protocol was repeated three times. Each CT scan was reconstructed utilizing filtered back projection, hybrid iterative reconstruction, iterative model reconstruction (IMR), and VMIs of 40–100 keV. The signal-to-noise ratio and air noise of images, absolute differences, and absolute percentage measurement errors (APEs) of the diameter, density, and volume of the four scan protocols and ten reconstruction images were compared.RESULTSWith each fixed reconstruction image, the four scanning protocols exhibited no significant differences in APEs for diameter and density (all P > 0.05). Of the four scan protocols and ten reconstruction images, APEs for nodule volume had no significant differences (all P > 0.05). At 100 kVp/10 mAs, APEs for density using IMR were the lowest (APE-mean: 6.69), but no significant difference was detected between VMIs at 50 keV (APE-mean: 11.69) and IMR (P = 0.666). In the subgroup analysis, at 100 kVp/10 mAs, there were no significant differences between VMIs at 50 keV and IMR in diameter and density (all P > 0.05). The radiation dose at 100 kVp/10 mAs was reduced by 77.8% compared with that at 120 kVp/30 mAs.CONCLUSIONCompared with IMR, reconstruction at 100 kVp/10 mAs and 50 keV provides a more accurate quantification of pulmonary nodules, and the radiation dose is reduced by 77.8% compared with that at 120 kVp/30 mAs, demonstrating great potential for ultra-low-dose spectral-detector CT.

The evolution of grain structure, precipitates and mechanical properties of the ZL205A alloy prepared by wire arc additive manufacturing were investigated. The results show that the as-deposited alloy consists of equiaxed and columnar grains in the bottom region. As the deposition height increases, the alloy mainly consists of equiaxed grains. The evolution of columnar to equiaxed grains is explained by the solidification theory. The needle-like θ′-Al2Cu precipitates in Cu-rich regions surrounding the α-Al+θ-Al2Cu eutectics. As the part deposited first is subjected to multiple cycles of heating by the subsequently deposited layers, the volume fraction and average size of θ′ precipitates gradually decrease with the increase of deposition heights. The microhardness of the as-deposited alloy fluctuates in the range of 74.6–84.5 HV. The mechanical properties of the horizontal specimens at different heights are affected by the combination of grain structure, precipitates and pores, and that of the specimens in the middle region are optimal. The mechanical properties of the horizontal and vertical specimens show isotropic. Attributed to the grain boundary strengthening and precipitation strengthening, the yield strength (132.9 MPa) and elongation (15.9%) of the as-deposited alloy are approximately 31.3% and 211.8% higher than that of the as-cast alloy, respectively.

The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment.

[This corrects the article DOI: 10.1371/journal.pone.0302631.].

With the rapid progress of urbanization in China, the real estate industry, characterized by a long industrial chain, has become a pillar industry for economic development. Therefore, we inspect the nexus between land finance, housing prices, and economic growth. For this purpose, we use the panel data of 277 cities at the prefecture level or above in China from 2011 to 2019, and empirically examine it by using the Panel Vector Auto Regression (PVAR) model. The results show that there is a causal relationship between housing prices and economic growth. Housing prices promote economic growth in the short term and inhibit it in the long term. Both economic growth and housing prices have a significant impact on land finance. The economic growth show a significantly positive impact, while housing prices promote land finance in the short term with a long-term trend from positive to negative. This is the first study that tries to probe the relationship between urban housing prices, land finance, and economic growth by considering 277 prefecture-level and above cities in China. To promote the stable development of the regional economy, local governments need to overcome their dependence on the housing market and land finance and promote the healthy development of the housing market.

Two-dimensional organic-inorganic hybrid perovskite materials are considered to have great potential for radiation detection due to their outstanding operational stability and excellent optoelectronic properties. However, most currently used single crystal (SC) growth methods impose strict requirements on growth conditions, and their potential effectiveness also faces significant challenges, especially for those perovskite systems with significant differences in solubility between raw materials and target products. In this study, a dynamic seed rotation method was developed to relieve the above dilemma. With the help of this method, centimeter-sized high-quality [(TMOD)2PbBr4]5·H2O (TMOD is thiomorpholine-1,1-dioxide) SCs were harvested. X-ray detectors based on the as-prepared SC exhibit a high sensitivity of 5.35 × 103 μC Gyair−1 cm−2 and a low detection limit of 3.1 nGyair s−1. We believe this strategy can also be applied to the preparation of other perovskite materials, paving the way for the application of high-quality optoelectronic devices.

ABSTRACT Helicobacter pylori (H. pylori) causes a cascade from gastritis to gastric neoplasia. During the chronic stages, the oncogenic transcription factor forkhead box protein M1 (FOXM1) becomes increasingly expressed. Given certain strains of the gastric commensal Cutibacterium acnes (C. acnes) produce thiopeptides that directly inhibit FOXM1, we hypothesized that coinfection with thiopeptide-positive C. acnes would decrease Foxm1 expression and alter H. pylori-induced pathogenesis. C. acnes was isolated from 31% of gastric biopsies from Nicaraguan patients, and thiopeptide-positive strains were identified by whole genome sequencing. Germ-free INS-GAS mice were inoculated with thiopeptide-positive C. acnes, H. pylori SS1, H. pylori 1 week before C. acnes, C. acnes 2 weeks before H. pylori, or no bacteria. At 17 weeks post-infection, males dosed with C. acnes followed by H. pylori exhibited increased inflammation scores by histopathology; however, males dosed with H. pylori followed by C. acnes exhibited reduced gastric Foxm1, pro-inflammatory cytokine (Il-1β, Ifn-γ, Tnf-α, Il-17a, and iNOS), regulatory cytokine (Foxp3) gene expression, pro-inflammatory IgG2a antibodies, and gastric lymph node RORγT expression compared to H. pylori-monoinfected mice. Male mice coinfected with C. acnes followed by H. pylori exhibited reduced gastric inflammatory markers (IL-17, IL-10, GM-CSF, M-CSF, MCP-1, MIP-1α, MIP-2, RANTES, and VEGF) by cytokine array analysis and reduced H. pylori gastric colonization. These data show that thiopeptide-positive C. acnes exhibited anti-inflammatory and anti-FOXM1 properties in the context of H. pylori gastritis. IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.