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AbstractBackground Butorphanol has been used to reduce the incidence and severity of neuraxial morphine-induced pruritus. Palonosetron is a commonly used antiemetic for the prevention of postoperative nausea and vomiting. The aim of our study was to compare the effective dose in 50% of subjects (ED50) of intravenous butorphanol infusion with or without a single intravenous bolus of palonosetron for preventing pruritus induced by epidural administration of morphine.Methods A total of 120 parturients were randomly assigned to receive an intravenous bolus injection of palonosetron plus continuous infusion of butorphanol (Group P + B) or an intravenous bolus of saline plus continuous infusion of butorphanol (Group B) after epidural administration of morphine. The antipruritic effect was graded as satisfactory (numerical rating scale (NRS) of pruritus ≤3) or unsatisfactory (NRS >3) within 48 h after morphine treatment. The first patient in each group received butorphanol infusion at a rate of 4 µg/kg/h. The infusion dose for each subsequent patient in the corresponding group was increased by 0.2 µg/kg/h after an unsatisfactory response or decreased by 0.2 µg/kg/h after a satisfactory response. The ED50 was calculated for each group and compared using up-down sequential analysis.Results The ED50 (mean [95% confidence interval (CI)]) of the dose of intravenous butorphanol infusion for preventing moderate to severe pruritus was lower in Group P + B (3.29 µg/kg/min [3.25–3.34 µg/kg/min]) than in Group B (3.57 µg/kg/min [3.47–3.67 µg/kg/min]) (p

Abstract Malignant tumors pose a serious risk to human health. Ascorbic acid (AA) has potential for tumor therapy; however, the mechanism underlying the ability of AA to selectively kill tumor cells remains unclear. AA can cause redox disequilibrium in tumor cells, resulting in the release of abundant reactive oxygen species, represented by hydrogen peroxide (H2O2). Therefore, the detection of H2O2 changes can provide insight into the selective killing mechanism of AA against tumor cells. In this work, inspired by the ion‐exchange mechanism in coral formation, a flexible H2O2 sensor (PtNFs/CoPi@CC) is constructed to monitor the dynamics of H2O2 in the cell microenvironment, which exhibits excellent sensitivity and spatiotemporal resolution. Moreover, the findings suggest that dehydroascorbic acid (DHA), the oxidation product of AA, is highly possible the substance that actually acts on tumor cells in AA therapy. Additionally, the intracellular redox disequilibrium and H2O2 release caused by DHA are positively correlated with the abundance and activity of glucose transporter 1 (GLUT1). In conclusion, this work has revealed the potential mechanism underlying the ability of AA to selectively kill tumor cells through the construction and use of PtNFs/CoPi@CC. The findings provide new insights into the clinical application of AA.

The fruit fly Drosophila melanogaster has emerged as a valuable model for investigating human biology, including the role of the microbiome in health and disease. Historically, studies involving the infection of D. melanogaster with single microbial species have yielded critical insights into bacterial colonization and host innate immunity. However, recent evidence has underscored that multiple microbial species can interact in complex ways through physical connections, metabolic cross-feeding, or signaling exchanges, with significant implications for healthy homeostasis and the initiation, progression, and outcomes of disease. As a result, researchers have shifted their focus toward developing more robust and representative in vivo models of co-infection to probe the intricacies of polymicrobial synergy and dysbiosis. This review provides a comprehensive overview of the pioneering work and recent advances in the field, highlighting the utility of Drosophila as an alternative model for studying the multifaceted microbial interactions that occur within the oral cavity and other body sites. We will discuss the factors and mechanisms that drive microbial community dynamics, as well as their impacts on host physiology and immune responses. Furthermore, this review will delve into the emerging evidence that connects oral microbes to systemic conditions in both health and disease. As our understanding of the microbiome continues to evolve, Drosophila offers a powerful and tractable model for unraveling the complex interplay between host and microbes including oral microbes, which has far-reaching implications for human health and the development of targeted therapeutic interventions.

ABSTRACTThrombocytopenia is one of the most common hematological adverse reactions in chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKI) therapy, causing life-threatening bleeding cases. However, there are fewer therapeutic drugs for TKI-induced thrombocytopenia. Eltrombopag is a non-peptide thrombopoietin receptor agonist used for the treatment of immune thrombocytopenia， aplastic anemia, and hepatitis C-associated thrombocytopenia. Nevertheless, studies of eltrombopag for TKI-induced thrombocytopenia are still lacking. This study retrospectively analyzed the clinical and test data of 21 CML patients with TKI-related thrombocytopenia. The results demonstrated that the median baseline value of thrombocytopenia in the 21 CML patients was 15.57 × 109/L [2–28 × 109/L]. Following treatment with eltrombopag, 16 patients had a significant increase in their platelet levels. The peak median for platelet increase in effective responders was 145.12 × 109/L (51–460 × 109/L). However, 5 patients failed to respond to eltrombopag. Moreover, 4 of the 21 patients enrolled had adverse reactions, including reversible liver function impairment, palpitation, headache, insomnia, and loss of appetite. Nonetheless, no cases of disease progression, thrombotic events, or myelofibrosis were observed. Hence, eltrombopag may be a useful adjunctive therapy for relieving TKI-related thrombocytopenia in patients with CML.

ABSTRACTObservational studies have been conducted to investigate the correlation between adiponectin and diabetic retinopathy (DR), but no consistent relationship has been established. In this study, we employed an integrative analysis that combined Mendelian randomization (MR) and bioinformatics analyses to comprehensively explore the association between DR and adiponectin, aiming to provide a unified answer of their relationship. Using the inverse-variance weighted (IVW) method, the odd ratio (OR) of developing DR per 1 mg/dL increment in genetically predicted log-transformed adiponectin concentration was estimated to be 0.949 (P = 0.557). Other robust MR methods produced consistent results, confirming the absence of a causal effect of adiponectin on DR. Additionally, the expression levels of the six adiponectin-related genes showed no significant differences among normal controls, individuals with diabetes but without DR, and those with DR Furthermore, the biological pathways enriched by these genes were not strongly relevant to DR. At both the individual gene and pathway levels, there were no overlaps between the adiponectin-related genes and the differentially expressed genes, indicating a lack of association between adiponectin and DR based on gene expression profiles. In summary, the integrative analysis, which combined MR and bioinformatics data mining, yielded compelling evidence supporting the notion that adiponectin is not a risk factor for DR.

ABSTRACTHeterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) plays an important role in regulating the replication of many viruses. However, it remains elusive whether and how hnRNPA1 regulates fish virus replication. In this study, the effects of twelve hnRNPs on the replication of snakehead vesiculovirus (SHVV) were screened. Three hnRNPs, one of which was hnRNPA1, were identified as anti-SHVV factors. Further verification showed that knockdown of hnRNPA1 promoted, while overexpression of hnRNPA1 inhibited, SHVV replication. SHVV infection reduced the expression level of hnRNPA1 and induced the nucleocytoplasmic shuttling of hnRNPA1. Besides, we found that hnRNPA1 interacted with the viral phosphoprotein (P) via its glycine-rich domain, but not with the viral nucleoprotein (N) or large protein (L). The hnRNPA1-P interaction competitively disrupted the viral P-N interaction. Moreover, we found that overexpression of hnRNPA1 enhanced the polyubiquitination of the P protein and degraded it through proteasomal and lysosomal pathways. This study will help understanding the function of hnRNPA1 in the replication of single-stranded negative-sense RNA viruses and providing a novel antiviral target against fish rhabdoviruses.

Hexavalent chromium [Cr(VI)] is an occupational carcinogen that accumulates in the lungs and causes lung injury and even lung cancer. 36 SD male rats received inhalable intratracheal instillation of Cr(VI) (0.05, 0.25 mg Cr/kg) or the same volume (3 ml/kg) of normal saline weekly for 28 days (total 5 times). After 28 days of exposure, half of the rats in each group were sacrificed for investigation, and the rest stopped exposure and began to be self-repaired for two weeks. Histopathology analyses revealed that Cr(VI) induced slight dilatation and hemorrhage of perialveolar capillaries, pulmonary bronchodilation, and congestion with peripheral flaky-like necrosis accompanied by inflammatory cell infiltration, especially the 0.25 mg Cr/kg group. Cr(VI) exposure caused the increase of blood Cr, urinary Cr, MDA, urinary 8-hydroxy-2′ -deoxyguanosine (8-OHdG), and the decrease of GSH and MDA, while two-week repair only reduced urinary Cr. Exposure to Cr(VI) significantly upregulated FOXO1 and downregulated p-AKT and p-FOXO1 for two weeks. PI3K in the 0.25 mg Cr/kg group was inhibited after two weeks of repair. Cr(VI) exposure mainly promoted GADD45a and CHK2 in the exposure group, promoted Bim, Bax/Bcl-2, and suppressed Bcl-2 and Bcl-xL in the repair group. These results demonstrate that Cr(VI) may induce DNA damage repair and apoptosis in the lung by activating the PI3K/AKT/FOXO1 pathway. Two-week repair may alleviate oxidative stress and DNA damage induced by Cr(VI) exposure but couldn’t eliminate its effects. This study provides a new perspective for exploring the Cr(VI) induced lung cancer mechanism.

Reasonable adjustment of crop acreage can improve the sustainability of agriculture in arid zones by promoting economic development, alleviating water scarcity, and improving resource utilization efficiency but meets the challenges of various decision-maker preferences and uncertainties. With the objectives of maximizing economic benefits, minimizing evapotranspiration, and maximizing water productivity and water production efficiency, this study developed a grey entropy based multi-objective fuzzy constraint interval programming model (GEMOFCIP) through incorporation of information entropy technology, fuzzy constraints and interval programming approaches within a general optimization framework. The model is capable of (1) generating the crop acreage management schemes through trading off the different development goals; (2) dealing with the structure and parameter uncertainties of the optimization model; (3) measuring the relative importance of multiple objectives by the introduction of information entropy with the insufficient decision-maker’s preference information. Taking the crop acreage planning problem in Liangzhou, northwest China as a case study, the model was solved under different water-saving and satisfaction degree scenarios. It turned out that, after optimization, the economic benefit, water productivity and water production efficiency have been significantly improved, while the total ET and the total irrigation water have been significantly compressed in the study area. The GEMOFCIP model is superior to the previous models in that it takes into account the randomness of the relative importance of system objective, the vagueness of system constraints and the fluctuations of system coefficients, which would make the model more reasonable, stable and objective. Optimal results can help manage crop pattern with the economy-resource-efficiency consideration and accelerate the healthy development of agriculture in arid zones.

BackgroundJob burnout is common among working populations. The current situation and influencing factors of job burnout have been studied in workers of many industries at home and abroad, except the express industry in China.ObjectiveTo understand the current situation of job burnout in express industry in a city of China, and to provide a scientific basis for developing measures to reduce the occurrence of job burnout. MethodsIn 2022, 432 express delivery workers in a city were selected by cluster random sampling, and their job burnout, anxiety symptoms, and depressive symptoms were evaluated by using the General Burnout Scale, Generalized Anxiety Disorder-7, and Patient Health Questionnaire-9. Chi-square test was used to compare inter-group positive rates of job burnout. Spearman correlation analysis was used to analyze the correlation between selected variables. Positive job burnout, high level of exhaustion, and high level of cynicism were selected as dependent variables. Single-factor analysis was firstly carried out to identify statistically significant variables for subsequent logistic regression analysis. ResultsA total of 460 questionnaires were distributed and 432 valid questionnaires were recovered, with an effective recovery rate of 93.9%. There were 286 (66.2%) express delivery workers reporting job burnout. The positive rate of anxiety symptoms was 41.0%, and the positive rate of depressive symptoms was 34.0%. The job burnout score of the express industry workers [M (P25, P75)] was 1.8 (1.0, 2.5); the scores [M (P25, P75)] of exhaustion, cynicism, and professional efficacy were 1.0 (0.0, 2.6), 1.0 (0.0, 2.2), and 3.5 (1.2, 5.8), respectively; the score [M (P25, P75)] of anxiety symptoms was 1.5 (0.0, 7.0); the score [M (P25, P75)] of depressive symptoms was 1.0 (0.0, 8.0). There were statistical differences in the positive rates of job burnout among the express industry workers grouped by gender, education, monthly income, work shift system, overtime, anxiety symptoms, and depressive symptoms (P

BackgroundThe risks of unhealthy working mood and physical and mental health problems are high in the workers of petrochemical enterprises. Resilience is a positive psychological factor, which can provide positive ability to manage stress and job burnout, relieve tension, depression, anxiety, and other psychological discomfort. ObjectiveTo explore the moderating or mediating effect of resilience on the association between job burnout and sleep disorders in workers of petrochemical enterprises. MethodsA survey with questionnaire of general information, resilience, job burnout (including exhaustion, cynicism, and professional efficacy), and sleep disorders was conducted among 1087 workers who were selected by cluster sampling from a petrochemical enterprise in Henan Province in April 2022. Mann-Whitney U test and Kruskal-Wallis H test were used to test the differences of scores among different demographic groups. Resilience, job burnout (including exhaustion, cynicism, and professional efficacy), and sleep disorder scores were analyzed by partial correlation analysis. The moderating effect of resilience was examined by linear regression analysis, and the mediating effect of resilience by Bootstrap method. Results A total of 861 questionnaires were collected, of which 857 were effective, and the effective rate was 99.5%. The M (P25, P75) of job burnout score was 1.24 (0.65, 2.22) and the incidence of job burnout was 36.4% (312/857); the scores [M (P25, P75)] of exhaustion, cynicism, and professional efficacy were 1.40 (0.80, 3.00), 1.00 (0.20, 1.60), and 5.50 (4.00, 6.00), respectively. The M (P25, P75) of resilience score was 36.00 (30.00, 41.00). The M (P25, P75) of sleep disorder score was 11.00 (7.00, 15.00). The partial correlation analysis results showed that job burnout, exhaustion, and cynicism were negatively correlated with resilience (r=−0.387, −0.248, −0.247, P

BackgroundJob burnout is prevalent among the occupational population, which may lead to individual physical and mental discomfort and affect the quality of life and productivity of suffered workers. Most current chemical fiber factory workers are engaged in hazardous tasks with high frequency and high repetition, which are highly associated with anxiety and depressive symptoms, and subsequently lead to job burnout. ObjectiveTo understand the current situation and influencing factors of job burnout in workers of a chemical fiber factory in Xinxiang City of Henan Province, and to provide empirical evidence for preventing and reducing the occurrence of job burnout in target workers. MethodsIn 2022, the workers of a chemical fiber factory in Xinxiang City were selected by cluster random sampling. The Chinese versions of the Burnout Scale, Generalized Anxiety Disorder-7, and Patient Health Questionnaire-9 were used to conduct a survey. SPSS 25.0 software was used for rank sum test, correlation analysis, and logistic regression analysis. ResultsA total of 1463 valid questionnaires were collected, with an effective recovery rate of 90.0%. The positive rate of mild and moderate job burnout in the chemical fiber factory employees was 39.4%, and the positive rate of serious job burnout was 14.3%. There were statistical differences in the positive rates of job burnout among the workers by gender, age, education level, position, work shift system, anxiety symptom severity, and depressive symptom severity (P

Abstract We developed an inductively coupled plasma mass spectrometry method for testing 23 elements, namely, Mg, Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Ba, W, Tl, Pb, and U, in human serum. The serum samples were analyzed after diluting 1/25 with 0.5% nitric acid, 0.02% Triton-X-100, and 2% methanol. Sc, In, Y, Tb, and Bi were assigned internal standards to correct the baseline drift and matrix interference. The kinetic energy discrimination mode of the instrument with helium gas as the collision gas eliminated polyatomic interference. All 23 elements exhibited excellent linearity in their testing range, with a coefficient of determination ≥ 0.9996. The limits of detection of the 23 elements were within the range of 0.0004–0.2232 µg/L. The intra- and inter-day precision (relative standard deviation) were

Abstract Purpose The study aimed to predict acute radiation esophagitis (ARE) with grade ≥ 2 for patients with locally advanced lung cancer (LALC) treated with intensity-modulated radiation therapy (IMRT) using multi-omics features, including radiomics and dosiomics. Methods 161 patients with stage IIIA−IIIB LALC who received chemoradiotherapy (CRT) or radiotherapy by IMRT with a prescribed dose from 45 to 70 Gy from 2015 to 2019 were enrolled retrospectively. All the toxicity gradings were given following the Common Terminology Criteria for Adverse Events V4.0. Multi-omics features, including radiomics, dosiomics (including dose−volume histogram dosimetric parameters), were extracted based on the planning CT image and three-dimensional dose distribution. All data were randomly divided into training cohorts (N = 107) and testing cohorts (N = 54). In the training cohorts, features with reliably high outcome relevance and low redundancy were selected under random patient subsampling. Four classification models (using clinical factors (CF) only, using radiomics features (RFs) only, dosiomics features (DFs) only, and the hybrid features (HFs) containing clinical factors, radiomics and dosiomics) were constructed employing the Ridge classifier using two-thirds of randomly selected patients as the training cohort. The remaining patient was treated as the testing cohort. A series of models were built with 30 times training–testing splits. Their performances were assessed using the area under the ROC curve (AUC) and accuracy. Results Among all patients, 51 developed ARE grade ≥ 2, with an incidence of 31.7%. Next, 8990 radiomics and 213 dosiomics features were extracted, and 3, 6, 12, and 13 features remained after feature selection in the CF, DF, RF and DF models, respectively. The RF and HF models achieved similar classification performance, with the training and testing AUCs of 0.796 ± 0.023 (95% confidence interval (CI [0.79, 0.80])/0.744 ± 0.044 (95% CI [0.73, 0.76]) and 0.801 ± 0.022 (95% CI [0.79, 0.81]) (p = 0.74), respectively. The model performances using CF and DF features were poorer, with training and testing AUCs of 0.573 ± 0.026 (95% CI [0.56, 0.58])/ 0.509 ± 0.072 (95% CI [0.48, 0.53]) and 0.679 ± 0.027 (95% CI [0.67, 0.69])/0.604 ± 0.041 (95% CI [0.53, 0.63]) compared with the above two models (p

In order to explore the optimum extraction process of polysaccharide and antioxidant activity in vitro in Peristrophe roxburghiana. In this study, Peristrophe roxburghiana was used as raw material to explore the effects of solid-liquid ratio, extraction temperature, time and frequency on the yield of polysaccharide. The extraction process of polysaccharide in Peristrophe roxburghiana was optimized by response surface methodology and the antioxidant activity of the polysaccharide was investigated by measuring its scavenging ability on DPPH·, ·OH, ABTS+· and other free radicals. The results showed that we could get the most quantity of polysaccharide extracted from Peristrophe roxburghiana, which reaches up to 11.05%, in these conditions: The solid-liquid ratio was 1:31 g/mL, the extraction temperature was 85 ℃, the extraction time was 118 min and the extraction frequency was 3 times. The scavenging ability of the polysaccharide against free radical was quantitatively related to the concentration of polysaccharide within a certain range. The IC50 values of DPPH·, ·OH and ABTS+· radicals scavenged by the polysaccharide solution were 0.18, 0.73 and 0.64 mg/mL, respectively, indicating that the polysaccharide extracted from Peristrophe roxburghiana was with certain antioxidant activity. By exploring the optimal process and antioxidant activity of the polysaccharide extracted from Peristrophe roxburghiana, we provide a theoretical basis and reference for the further development and application of the polysaccharide in the future.

Viral co-infections, in which a host is infected with multiple viruses simultaneously, are common in the human population. Human viral co-infections can lead to complex interactions between the viruses and the host immune system, affecting the clinical outcome and posing challenges for treatment. Understanding the types, mechanisms, impacts, and identification methods of human viral co-infections is crucial for the prevention and control of viral diseases. In this review, we first introduce the significance of studying human viral co-infections and summarize the current research progress and gaps in this field. We then classify human viral co-infections into four types based on the pathogenic properties and species of the viruses involved. Next, we discuss the molecular mechanisms of viral co-infections, focusing on virus–virus interactions, host immune responses, and clinical manifestations. We also summarize the experimental and computational methods for the identification of viral co-infections, emphasizing the latest advances in high-throughput sequencing and bioinformatics approaches. Finally, we highlight the challenges and future directions in human viral co-infection research, aiming to provide new insights and strategies for the prevention, control, diagnosis, and treatment of viral diseases. This review provides a comprehensive overview of the current knowledge and future perspectives on human viral co-infections and underscores the need for interdisciplinary collaboration to address this complex and important topic.

An Rtec ball-on-disk tribometer was used to investigate the tribological performance of the synthesised water-based nanolubricants containing hBN/TiO2 nanocomposite at room temperature. The water-based nanolubricants with different concentrations were prepared by adding glycerol and sodium dodecyl benzene sulfonate (SDBS) under ultrasonication. These as-prepared nanolubricants demonstrated exceptional dispersion stability for 7 days without distinct sedimentation. The results indicate that the water-based nanolubricants with an overall concentration of 1.0 wt% at different ratios (hBN: TiO2 = (1:0), (0.7:0.3), (0.5:0.5), (0.3:0.7), (0:1)) can effectively reduce the coefficient of friction (COF) and the wear of the ball and disk. In particular, the water-based nanolubricant containing 0.5 wt% hBN and 0.5 wt% TiO2 exhibited the best tribological performance, leading to a significant reduction in COF up to 70%, and decreased the wear area of the ball and disk by up to 79.57% and 60.40%, respectively, compared to those obtained using distilled water. The lubrication mechanisms were mainly attributed to the formation of a protective film, and the mending, polishing, rolling, and synergistic effects of the hBN nanosheets and TiO2 nanoparticles.

In recent years, the interaction of intracellular organelles such as mitochondria and lysosomal functions has attracted increasing attention. Recent evidence suggests that mitochondrion-lysosomal contact plays a key role in regulating lysosomal biogenesis and maintaining cellular homeostasis. Myocardial ischemia and reperfusion will lead to corresponding changes in the autophagy flux in cardiomyocytes, and lysosomes are a key link in the process of autophagy, and the fusion of lysosomes and autophagosomes is an essential link in the occurrence of autophagy. Therefore, the function and homeostasis of lysosomes also undergo different changes during myocardial ischemia and reperfusion. Lysosomal-related biological factors and membrane proteins also play different roles. This article will review the mechanism of lysosomes in myocardial ischemia-reperfusion injury and the research progress of lysosomal-related proteins.

Bragg peak FLASH radiotherapy (RT) uses a distal tracking method to eliminate exit doses and can achieve superior OAR sparing. This study explores the application of this novel method in stereotactic body radiotherapy prostate FLASH-RT. An in-house platform was developed to enable intensity-modulated proton therapy (IMPT) planning using a single-energy Bragg peak distal tracking method. The patients involved in the study were previously treated with proton stereotactic body radiotherapy (SBRT) using the pencil beam scanning (PBS) technique to 40 Gy in five fractions. FLASH plans were optimized using a four-beam arrangement to generate a dose distribution similar to the conventional opposing beams. All of the beams had a small angle of two degrees from the lateral direction to increase the dosimetry quality. Dose metrics were compared between the conventional PBS and the Bragg peak FLASH plans. The dose rate histogram (DRVH) and FLASH metrics of 40 Gy/s coverage (V40Gy/s) were investigated for the Bragg peak plans. There was no significant difference between the clinical and Bragg peak plans in rectum, bladder, femur heads, large bowel, and penile bulb dose metrics, except for Dmax. For the CTV, the FLASH plans resulted in a higher Dmax than the clinical plans (116.9% vs. 103.3%). For the rectum, the V40Gy/s reached 94% and 93% for 1 Gy dose thresholds in composite and single-field evaluations, respectively. Additionally, the FLASH ratio reached close to 100% after the application of the 5 Gy threshold in composite dose rate assessment. In conclusion, the Bragg peak distal tracking method can yield comparable plan quality in most OARs while preserving sufficient FLASH dose rate coverage, demonstrating that the ultra-high dose technique can be applied in prostate FLASH SBRT.

With the advent of cancer immunotherapy, there is a growing interest in vaccine development as a means to activate the cellular immune system against cancer. Despite the promise of DNA vaccines in this regard, their effectiveness is hindered by poor immunogenicity, leading to modest therapeutic outcomes across various cancers. The role of Type 1 conventional dendritic cells (cDC1), capable of cross-presenting vaccine antigens to activate CD8+T cells, emerges as crucial for the antitumor function of DNA vaccines. To address the limitations of DNA vaccines, a promising approach involves targeting antigens to cDC1 through the fusion of XCL1, a ligand specific to the receptor XCR1 on the surface of cDC1. Here, female C57BL/6 mice were selected for tumor inoculation and immunotherapy. Additionally, recognizing the complexity of cancer, this study explored the use of combination therapies, particularly the combination of cDC1-targeted DNA vaccine with the chemotherapy drug Gemcitabine (Gem) and the anti-PD1 antibody in a mouse lung cancer model. The study’s findings indicate that fusion antigens with XCL1 effectively enhance both the immunogenicity and antitumor effects of DNA vaccines. Moreover, the combination of the cDC1-targeted DNA vaccine with Gemcitabine and anti-PD1 antibody in the mouse lung cancer model demonstrates an improved antitumor effect, leading to the prolonged survival of mice. In conclusion, this research provides important support for the clinical investigation of cDC1-targeting DNA vaccines in combination with other therapies.

Gastrointestinal tumors remain a significant healthcare burden worldwide, necessitating the development of innovative therapeutic strategies. mRNA vaccines have emerged as a promising approach in cancer immunotherapy, harnessing the immune system's potential to recognize and eliminate tumor cells. mRNA vaccines offer several advantages, including their ability to elicit both innate and adaptive immune responses, ease of production, and adaptability to different tumor types. In the context of gastrointestinal tumors, mRNA vaccines hold great potential as a therapeutic strategy. In this review, we will delve into the immunomodulatory mechanisms and immunotherapy strategies of mRNA vaccines in gastrointestinal tumors. Additionally, we will discuss the challenges and ongoing research efforts in optimizing mRNA vaccine development, delivery, and stability. By understanding the potential of mRNA vaccines in addressing the unmet medical need of gastrointestinal tumors, we aim to pave the way for improved treatment strategies and better patient outcomes.

To address crises like habitat loss and environmental pollution caused by human modifications, protected areas have been established as a fundamental strategy, providing on-site protection for species and their habitats. Systematic evaluation of PAs is crucial for guiding decision-making, planning, and public perception. Besides assessing their effectiveness in safeguarding habitats and ecosystem services, considering the impacts of human activities is essential. A comprehensive assessment, encompassing ecological and social factors, enhances our understanding of the complex interactions between conservation efforts and human needs. Using the Propensity Score Matching (PSM) method, we evaluated the conservation effectiveness of PAs in the Six Provinces in China’s Pan-Pearl River Delta Region, focusing on reducing human modification, sustaining ecosystem services, and improving habitat quality. The results indicated that PAs at higher elevations generally exhibit a lower degree of human modification than those at lower elevations. While the human modification score outside PAs in the SP-PPRD increased by 82.67%, the scores within PAs increased by only 64.51%. Among the 188 PAs, 32 showed a decrease in ecosystem services, with 71.87% located in Hainan Province. The average Habitat quality of PAs in the SP-PPRD declined during the study period, although the number categorized as “Very High” increased from 135 to 140. After PSM matching and relative effectiveness evaluation, 27 PAs (14.36%) were categorized as “High Effective”, 50.00% as “Medium Effective”, and 8.86% as “Ineffective”. Furthermore, the study suggests that PAs were often located in areas unlikely to face land conversion pressure even without the protection. However, many PAs in regions with high levels of human modification have seen an improvement in ecosystem services and habitat quality. Based on our research findings, we advocate the adoption of more resilient conservation strategies that carefully balance the preservation of nature with the promotion of sustainable social development.

Necrotizing enterocolitis (NEC) is an inflammatory intestinal disease that profoundly affects preterm infants. Currently, the pathogenesis of NEC remains controversial, resulting in limited treatment strategies. The preterm infants are thought to be susceptible to gut inflammatory disorders because of their immature immune system. In early life, intestinal macrophages (IMφs), crucial components of innate immunity, demonstrate functional plasticity and diversity in intestinal development, resistance to pathogens, maintenance of the intestinal barrier, and regulation of gut microbiota. When the stimulations of environmental, dietary, and bacterial factors interrupt the homeostatic processes of IMφs, they will lead to intestinal disease, such as NEC. This review focuses on the IMφs related pathogenesis in NEC, discusses the multi-functional roles and relevant molecular mechanisms of IMφs in preterm infants, and explores promising therapeutic application for NEC.

Abstract The increasing demand for clean energy conversion and storage has increased interest in hydrogen production via electrolytic water splitting. However, the simultaneous production of hydrogen and oxygen in this process poses a challenge in extracting pure hydrogen without using ionic conducting membranes. Researchers have developed various innovative designs to overcome this issue, but continuous water splitting in separated tanks remains a desirable approach. This study presents a novel, continuous roll‐to‐roll process that enables fully decoupled hydrogen evaluation reaction (HER) and oxygen evolution reaction (OER) in two separate electrolyte tanks. The system utilizes specially designed “cable‐car” electrodes (CCE) that cycle between the HER and OER tanks, resulting in continuous hydrogen production with a purity of over 99.9% and Coulombic efficiency of 98% for prolonged periods. This membrane‐free water splitting system offers promising prospects for scaled‐up industrial‐scale green hydrogen production, as it reduces the cost and complexity of the system, and allows for the use of renewable energy sources to power the electrolysis process, thus reducing the carbon footprint of hydrogen production.

Introduction: Improving energy efficiency is significant for achieving carbon emission reduction and promoting the transformation of green economic development. In the sustainable development framework set out in the 2030 Agenda for Sustainable Development, Goal 7.3 explicitly aims to double the global rate of energy efficiency improvement by 2030. The rapid development of digital technology, along with its universality and penetrative characteristics, has provide a feasible solution for improving energy efficiency and environmental conditions. However, the theoretical understanding of the impact and underlying logic of digital technology on energy efficiency remains unclear.Methods: Based on the panel data of 30 provinces in China from 2006 to 2021, this paper adopts econometric methods, including two-way fixed effect, instrumental variable method, and Driscoll-Kraay standard error. It investigates the influence of digital technology on energy efficiency and its internal mechanism from single factor and all factor levels.Result: The results show that Digital technology, represented by industrial robots, significantly improves energy efficiency, whether measured by the energy consumption intensity of GDP or the total-factor energy efficiency estimated using the SBM-GML model. The results still hold even after conducting endogeneity tests and robustness tests. Digital technology can improve energy efficiency by increasing virtual industrial agglomeration and promoting outward foreign direct investment.Discussion: In addition to promoting the theoretical understanding of the impact of digital technology on energy efficiency and exploring its mechanism, this paper also provides empirical evidence for policy makers and enterprises to formulate effective measures and strategies to improve energy efficiency under the background of digital economy.

Summary: The nocturnal and cryptic nature of bats makes it difficult to determine their foraging behavior and predatory sensory cues. Here, we present a protocol for determining the behavioral strategies and sensory cues of bat predation on airborne prey. We describe steps for indoor foraging behavior simulation, dual-choice acoustic playback, and visual presentation experiments. This protocol was used to study the avivorous bat, Ia io, but it can be adapted for studying other aerial-hawking bats and even other taxa.For complete details on the use and execution of this protocol, please refer to Gong et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disease. In this study, we generated an induced pluripotent stem cell (iPSC) line from the dermal fibroblasts of a 69-year-old female patient carrying APOEε3/ε4 allele and diagnosed with sporadic AD. The iPSC line will be a useful tool for investigating the pathogenesis mechanisms and for drug tests in AD.

BackgroundNoise exposure could lead to hearing loss and disorders of various organs. Recent studies have reported the close relations of environmental noise exposure to the metabolomics dysregulations and gut microbiota disturbance in the exposers. However, the associations between gut microbial homeostasis and the body metabolism during noise-induced hearing loss (NIHL) were unclear. To get a full understanding of their synergy in noise-associated diseases, it is essential to uncover their impacts and associations under exposure conditions.MethodsWith ten male rats with background noise exposure (≤ 40 dB) as controls (Ctr group), 20 age- and weight-matched male rats were exposed to 95 dB Sound pressure level (SPL) (LN group, n = 10) or 105 dB SPL noise (HN group, n = 10) for 30 days with 4 h/d. The auditory brainstem response (ABR) of the rats and their serum biochemical parameters were detected to investigate their hearing status and the potential effects of noise exposure on other organs. Metabolomics (UPLC/Q-TOF-MS) and microbiome (16S rDNA gene sequencing) analyses were performed on samples from the rats. Multivariate analyses and functional enrichments were applied to identify the dysregulated metabolites and gut microbes as well as their associated pathways. Pearson correlation analysis was performed to investigate the associations of the dysregulations of microbiota and the metabolites.ResultsNIHL rat models were constructed. Many biochemical parameters were altered by noise exposure. The gut microbiota constitution and serum metabolic profiles of the noise-exposed rats were also dysregulated. Through metabolomics analysis, 34 and 36 differential metabolites as well as their associated pathways were identified in LN and HN groups, respectively. Comparing with the control rats, six and 14 florae were shown to be significantly dysregulated in the LN group and HN group, respectively. Further association analysis showed significant correlations between differential metabolites and differential microbiota.ConclusionThere were cochlea injuries and abnormalities of biochemical parameters in the rats with NIHL. Noise exposure could also disrupt the metabolic profiles and the homeostatic balance of gut microbes of the host as well as their correlations. The dysregulated metabolites and microbiota might provide new clues for prevention of noise-related disorders.

Objective: To investigate the value of dual-source CT dual-energy virtual plain scan in the preoperative diagnosis of extramural vascular invasion (EMVI) in rectal cancer. Methods: A total of 150 patients with rectal cancer (64 females (42.7%) and 86 males (57.3%), with an average age of (62.3±11.8) years) who were scheduled for surgical treatment in our hospital from November 2019 to December 2021 were selected for the preoperative dual-source CT dual-energy virtual plain scan;. Two senior radiologists independently analyzed preoperative imaging data (including ctEMVI status, local lymph node infiltration, and distant metastasis) to determine the existence of preoperative EMVI. With pathological results as the gold standard, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of VNC in the diagnosis of EMVI were evaluated, and the area under the receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficiency. Results: Among 150 patients with rectal cancer, 56 (37.3%) were positive for EMVI and 94 (62.7%) were negative for EMVI. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of EMVI evaluation by physician 1 were 86%, 80.36%, 89.36%, 81.82%, and 88.42%, respectively, and the AUC was 0.831 (95%CI, 0.756~0.905). The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of physician 2 were 88.67%, 80.36%, 93.62%, 88.24%, and 88.89%, respectively, and the AUC was 0.870 (95%CI, 0.802~0.938). The consistency of the evaluation results between physician 1 and physician 2 was high (k=0.943). Conclusion: Dual-source CT dual-energy virtual plain scan has a certain diagnostic value in the preoperative evaluation of EMVI of rectal cancer.

The composition of endophytic bacteria in different tissues of Artemisia argyi var. argyi ‘Qiai’, and the antibacterial activities of their secondary metabolites were the main focus of this study. The tissue culture method was used to isolate the endophytic bacteria from roots, stems and leaves of Artemisia argyi var. argyi ‘Qiai’ and then, the antibacterial activity of the volatiles from endophytic bacterial fermentation broth against six common pathogenic bacteria was assayed by the disk diffusion test. Meanwhile, the minimum inhibitory concentrations(MICs) and the minimum bactericidal concentrations(MBCs) were also determined. Finally, the isolated strains were identified based on phenotypical and biochemical properties as well as 16S rRNA gene sequencing. The results showed that, (1)among the thirteen strains isolated, strains lzy-21, lzy-20 and lzy-1 have strong capacity of producing cellulase, protease and lipase respectively. (2)The MICs of the volatiles of lzy-20 and wnn4-3 to Escherichia coli, Enterobacter aerogenes and Bacillus subtilis were all 16 μg·mL-1. The MBCs of the them were 32, 32, 16 μg·mL-1 and 16, 32, 32 μg·mL-1, respectively. (3)The MICs of lzy-12 against Staphylococcus aureus and Yersinia enterocolitica were 16 μg·mL-1, and the MBCs of them were 32 μg·mL-1 and 16 μg·mL-1, respectively. (4)The MICs of both lzy-17 and lzy-21 against Y. enterocolitica were 16 μg·mL-1, and the MBCs were 16 μg·mL-1 and 32 μg·mL-1 respectively. Strain lzy-1 was identified as Acinetobacter pittii, which was isolated from plants for the first time. lzy-20, lzy-21, wnn4-3, lzy-12, and lzy-17 were identified as Bacillus altitudinis, B. koreensis, B. siamensis, Luteibacter pinisoli, and Paenarthrobacter nicotinovorans, respectively. The above results lay a foundation for making full use of endophytic bacteria resources to produce industrial enzymes, and further exploring the mechanisms of how endophytic bacteria interact with Artemisia argyi var. argyi ‘Qiai’.

Abstract Background Infants with rule-out infections are responsible for the majority of empirical antibiotics treatment (EAT) in neonatal intensive care units (NICUs), particularly very preterm infants (VPIs). Antibiotic overuse has been linked to adverse outcomes. There is a paucity of data on the association between EAT and clinical outcomes (containing the nutritional outcomes) of VPIs without infection-related morbidities. Methods Clinical data of VPIs admitted in 28 hospitals in 20 provinces of China from September 2019 to December 2020 were collected. EAT of VPIs was calculated as the number of days with initial usage in the first week after birth, and then categorized into 3 groups (antibiotic exposure: none, 1-4 days, and > 4 days). Clinical characteristics, nutritional status , and the short-term clinical outcomes among 3 groups were compared and analyzed. Results In total, 1834 VPIs without infection-related morbidities in the first postnatal week were enrolled, including 152 cases (8.3%) without antibiotics, 374 cases (20.4%) with EAT ≤4 days and 1308 cases (71.3%) with EAT > 4 days. After adjusting for the confounding variables, longer duration of EAT was associated with decreased weight growth velocity and increased duration of reach of full enteral feeding in EAT > 4 days group (aβ: -4.83, 95% CI: − 6.12 ~ − 3.53; aβ: 2.77, 95% CI: 0.25 ~ 5.87, respectively) than those receiving no antibiotics. In addition, the risk of feeding intolerance (FI) in EAT > 4 days group was 4 times higher than that in non-antibiotic group (aOR: 4.14, 95%CI: 1.49 ~ 13.56) and 1.8 times higher than that in EAT ≤4 days group (aOR: 1.82, 95%CI: 1.08 ~ 3.17). EAT > 4 days was also a risk factor for greater than or equal to stage 2 necrotizing enterocolitis (NEC) than those who did not receive antibiotics (aOR: 7.68, 95%CI: 1.14 ~ 54.75) and those who received EAT ≤4 days antibiotics (aOR: 5.42, 95%CI: 1.94 ~ 14.80). Conclusions The EAT rate among uninfected VPIs was high in Chinese NICUs. Prolonged antibiotic exposure was associated with decreased weight growth velocity, longer duration of reach of full enteral feeding, increased risk of feeding intolerance and NEC ≥ stage 2. Future stewardship interventions to reduce EAT use should be designed and implemented.

Abstract Background Patients with gynecological cancer are prone to anxiety, and many of them are accompanied by hypertension, which seriously affects the quality of life (QOL). The study was to explore the interaction of anxiety and hypertension on QOL, and the moderating effect of perceived social support (PSS) in the impact of anxiety and hypertension on QOL of patients with gynecological cancer. Methods A cross-sectional study was conducted in 2020, and 566 patients have been collected from the Affiliated Hospital of China Medical University. The Self-Rating Anxiety Scale (SAS), the Functional Assessment of Cancer Therapy Genera tool (FACT-G), and the Multidimensional Scale of Perceived Social Support Scale (MSPSS) were used. The interaction was analyzed by additive model, and the moderating effect was conducted by regression analysis and the simple slope analysis. Results We found that 68.8% of patients had poor QOL due to the interaction between anxiety and hypertension. The relative excess risk ratio (RERI) was 22.238 (95%CI:44.119–88.596); the attribution ratio (AP) was 0.688 (95%CI:0.234–1.142); The interaction index (S) was 3.466 (95%CI: 0.823–14.435). The interaction items of PSS and anxiety were negatively correlated with QOL (β = -0.219, P

RNA research and applications are underpinned by in vitro transcription (IVT), but RNA impurities resulting from the enzymatic reagents severely impede downstream applications. To improve the stability and purity of synthesized RNA, we have characterized a novel single-subunit RNA polymerase (RNAP) encoded by the psychrophilic phage VSW-3 from a plateau lake. The VSW-3 RNAP is capable of carrying out in vitro RNA synthesis at low temperatures (4–25°C). Compared to routinely used T7 RNAP, VSW-3 RNAP provides a similar yield of transcripts but is insensitive to class II transcription terminators and synthesizes RNA without redundant 3’-cis extensions. More importantly, through dot-blot detection with the J2 monoclonal antibody, we found that the RNA products synthesized by VSW-3 RNAP contained a much lower amount of double-stranded RNA byproducts (dsRNA), which are produced by transcription from both directions and are significant in T7 RNAP IVT products. Taken together, the VSW-3 RNAP almost eliminates both terminal loop-back dsRNA and full-length dsRNA in IVT and thus is especially advantageous for producing RNA for in vivo use.

Abstract Congenital hypothyroidism (CH) will cause cognitive impairment in the condition of delayed treatment. The hippocampus is one of the most affected tissues by CH, in which the functional structures of hippocampal neurons manifest deficiency due to aberrant expression of effector molecules. The Ca2+/Calmodulin-dependent protein kinase, CaMKIV, is downregulated in the hippocampal neurons, influencing the growth of dendritic spines in response to CH. However, the underlying mechanism is not fully elucidated. In the present study, the early growth response factor 3 (EGR3) was regulated by CaMKIV in the hippocampal neurons of CH rat pups, as was analyzed by transcriptome sequencing and in vitro cell experiments. EGR3 localized within hippocampal neurons in CA1, CA3, and dentate gyrus regions. Deficient EGR3 in the primary hippocampal neurons significantly reduced the density of dendritic spines by downregulating the expression of BDNF, and such effects could be rescued by supplementing recombinant BDNF protein. Taken together, CH mediates cognitive impairment of pups through the inactivation of CaMKIV in the hippocampal neurons, which decreases the expression of EGR3 and further reduces the production of BDNF, thereby impairing the growth of dendritic spines. Identifying CaMKIV/EGR3/BDNF pathway in the hippocampal neurons in the context of CH will benefit the drug development of intellectual disability caused by CH.

In the process of sewage treatment, the sewage usually needs to be aerated, so the oxygenation efficiency is an important indicator for the aerator. The general oxygenation technique is to inject large amount of natural air into the aeration tank over long time, which has lower efficiency and leads to dramatic waste of energy. Based on the gas-liquid fusion mass transfer model and combined the oxygen enrichment mechanism by magnetization of the gas into the aerator, a novel method to improve the efficiency of wastewater oxygenation is proposed. This method is based on the fact that oxygen and nitrogen exhibit completely different magnetic characteristics in gradient magnetic fields, and then the special shaped permanent magnets can be used to build a target gradient magnetic field to increase the oxygen content as the gas is injected into the sewage by the aerator, which reaches the oxygenation enhancement effect. Through theoretical analysis and experiments, it is concluded that the efficiency of sewage oxygenation treatment is dramatically improved with the permanent magnet oxygen enrichment technique. HIGHLIGHTS A new method is introduced to improve the aerator's oxygenation effect, and the method is proven to be effective through theory and experiment.; The method uses a magnetized oxygen enrichment device installed on the aerator, which consists of permanent magnets with a triangular cross section. The permanent magnets in the device build up a high gradient non-uniform magnetic field.;

Background: The incidence of extrauterine growth retardation (EUGR) varies considerably in different countries due to the distinct definitions and inclusion criteria of individual studies. Most studies included small for gestational age (SGA) very preterm infants (VPIs), resulting in a higher incidence of EUGR. Experts have suggested the accurate definition of “EUGR” in SGA infants is not “true EUGR”. The postnatal growth curve of multiple premature births also differs from that of singletons. As far as we know, there is no study about relationship between singleton-non-SGA preterm infants and EUGR. Objectives: To analyze the factors influencing EUGR among VPIs who were singleton-non-SGA in China. Methods: A prospective-multicenter study was conducted in 28 hospitals distributed through China from September 2019 to December 2020. The clinical data on singleton-non-SGA among VPIs were divided into EUGR group (n = 692) and non-EUGR group (n = 912). Results: Compared to non-EUGR group, the mean gestational age (GA), mean birth weight (BW) and percentage of BW in Fenton curve in EUGR group were lower (P < 0.001 for all). The incidence of EUGR among distinct GA groups (classifications of GA < 28weeks, 28–28+6 weeks, 29–29+6 weeks, 30–30+6 weeks and 31–31+6 weeks) and distinct BW groups (classifications of BW

Signal transducer and activator of transcription 3 (STAT3) plays a key role in promoting tumor malignant progression. Suppression of hyperactivated STAT3 signaling has emerged as a potential therapeutic strategy for many cancer types. In this study, the effect of 6-ethoxydihydrosanguinarine (6-EDS), a secondary transformation product formed from dihydrosanguinarine, isolated from Macleaya (Papaveraceae), was evaluated in gastric cancer (GC). We demonstrated that 6-EDS inhibited the survival, migration, and invasiveness of GC cells in vitro. Moreover, 6-EDS inhibited STAT3 phosphorylation and transcriptional activity, thus suppressing the mRNA expression of downstream target genes associated with the malignant survival, migration, and invasiveness of GC cells. Molecular docking indicated that 6-EDS directly bound the SH2 domain of STAT3. Molecular dynamics simulations suggested that 6-EDS inhibited the binding of phosphorylated and non-phosphorylated STAT3 to target DNA. Cellular thermal-shift assays and microscale thermophoresis further confirmed the direct binding of 6-EDS to STAT3. Site-directed mutagenesis indicated that the S611 residue in the SH2 domain of STAT3 is critical for 6-EDS binding. In vivo, 6-EDS decreased tumor growth in xenografted nude mice by blocking STAT3 signaling. These findings indicated that 6-EDS, a direct STAT3 inhibitor, may be a potent anticancer candidate for GC therapy.

Abstract Background Both schizophrenia (SZ) and overweight/obesity (OWB) have shown some structural alterations in similar brain regions. As higher body mass index (BMI) often contributes to worse psychiatric outcomes in SZ, this study was designed to examine the effects of OWB on gray matter volume (GMV) in patients with SZ. Methods Two hundred fifty subjects were included and stratified into four groups (n = 69, SZ patients with OWB, SZ-OWB; n = 74, SZ patients with normal weight, SZ-NW; n = 54, healthy controls with OWB, HC-OWB; and n = 53, HC with NW, HC-NW). All participants were scanned using high-resolution T1-weighted sequence. The whole-brain voxel-based morphometry was applied to examine the GMV alterations, and a 2 × 2 full factorial analysis of variance was performed to identify the main effects of diagnosis (SZ vs HC), BMI (NW vs OWB) factors, and their interactions. Further, the post hoc analysis was conducted to compare the pairwise differences in GMV alterations. Results The main effects of diagnosis were located in right hippocampus, bilateral insula, rectus, median cingulate/paracingulate gyri and thalamus (SZ

In this study, we investigate the synergistic effect of gemcitabine (Gem) and a novel DNA vaccine in the treatment of pancreatic cancer in mice and explore the anti-tumor mechanism of this combination therapy. Fibroblast activation protein α-expressing cancer-associated fibroblasts (FAPα+ CAFs), a dominant component of the tumor microenvironment (TME), have been shown to modulate the extracellular matrix (ECM) to promote the growth, invasion, and metastasis of pancreatic cancer (PC). Therefore, FAPα+ CAFs may be an ideal target for the treatment of PC. However, treatments that solely target FAPα+ CAFs do not directly affect tumor cells. We recently constructed a novel chimeric DNA vaccine (OsFS) against human FAPα and survivin, which simultaneously targets FAPα+ CAFs and tumor cells. In Panc02 tumor-bearing mice, OsFS vaccination not only reduced the proportion of immunosuppressive cells but also promoted the recruitment of tumor-infiltrating lymphocytes, which remodeled the TME to support anti-tumor immune responses. Furthermore, after depletion of regulatory T cells (Tregs) by metronomic low-dose Gem therapy, the anti-tumor effects of OsFS were enhanced. Taken together, our results indicate that the combination of the FAPα/survivin co-targeting DNA vaccine and low-dose Gem may be an effective therapy for PC.

Grain refinement occurs during manufacturing process, and grain size has a significant impact on mechanical properties. It is essential to establish the relationship between grain evolution and plastic behavior. The quasi-static and dynamic compression experiments for three kinds of oxygen-free high-conductivity (OFHC) copper with different grain sizes have been carried out. The true stress–strain curves were corrected to the isothermal curves, in which the temperature dependence of the specific heat capacity was used. It was found that the grain size has a significant influence on the yield stress, strain rate sensitivity, and thermal softening. A new phenomenon-based constitutive model considering the grain size and the coupling between strain hardening and strain rate was developed, and the results of the quasi-static and dynamic compression experiments were used to fit the parameters. The experimental data and the predicted results of the newly developed constitutive model agree well, which proves the constitutive model has a high prediction accuracy. The fitted constitutive model depicted that the strain rate sensitivity increases and thermal softening degree declines as the rise of the grain size of OFHC copper. The developed constitutive model could be used to the numerical simulation for the manufacturing process of OFHC copper considering the grain refinement.

Platelet-rich plasma (PRP) is rich in growth factors, cytokines and other biological active substances, which can promote cell proliferation, differentiation, matrix synthesis, tissue regeneration and repair, etc. Although its production process is not complicated, there is still no unified production standard in the world. Androgenetic alopecia (AGA) is a common type of hair loss in clinic. PRP has been proved to be an effective and safe treatment for AGA by several experiments and clinical studies in recent years. In addition to simple subscalp injection of PRP, PRP combined with microneedles, drugs, adipose transplantation, low energy laser therapy, non-ablative Er: YAG and other treatments have been derived. This paper summarized and analyzed relevant literatures and experiments in recent years, aiming to review the research progress of PRP in the treatment of AGA in terms of mechanism of action, preparation method and treatment method, and provide more theoretical and practical basis for clinicians.

Abstract Background Progressive neuronal death is the key pathological feature of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the neuronal death in AD patients have not been fully elucidated. Necroptosis reportedly activates and induces neuronal death in patients with Alzheimer’s disease (AD); however, the main mediators and mechanisms underlying necroptosis induction in AD remain elusive. Methods The function of hyperphosphorylated tau (pTau) in inducing necroptosis in neuronal cell was examined using Western blotting, RT-PCR and flow cytometry. Tau-induced inflammation was identified via RNA sequencing and transwell assay. Pharmacological methods and CRISPR–Cas9 technology were used to verify the role of necrosome proteins in pTau-stimulated neuronal death and inflammation. TauP301S model mice were treated with Nec-1 s to evaluate the role of necroptosis in tau pathology. Results Hyperphosphorylated tau could induce necroptosis in neuronal cells by promoting the formation of the RIPK1/RIPK3/MLKL necrosome. In addition, pTau significantly stimulated cell-autonomous overexpression of cytokines and chemokines via the intracellular nuclear factor kappa B (NF-κB) signaling pathway. Importantly, the RIPK1/RIPK3/MLKL axis was essential for the pTau-mediated NF-κB activation and cytokine storm. Furthermore, necroptosis stimulation, NF-κB activation, and cytokine induction have been detected in TauP301S mice and blocking necroptosis markedly ameliorated behavioral defects and excessive neuroinflammation in AD mice. Conclusions Our study, for the first time, revealed that pTau contributes to neuronal death by inducing necroptosis and inflammation, mediated by activating the RIPK1/RIPK3/MLKL and NF-κB pathways, thereby delineating the hierarchical molecular network of neuronal necroptosis induction in AD.

Abstract Background Mammals rely on the circadian clock network to regulate daily systemic metabolism and physiological activities. The liver is an important peripheral organ in mammals, and it has a unique circadian rhythm regulation process. As the only mammals that can fly, bats have attracted much research attention due to their nocturnal habits and life histories. However, few research reports exist concerning the circadian rhythms of bat liver gene expression and the relevant biological clock regulation mechanisms in the liver. Results In this study, the expression levels of liver genes of Asian particolored bats were comparatively analyzed using RNA-seq at four different time points across 24 h. A total of 996 genes were found to be rhythmic, accounting for 65% of the total number of expressed genes. The critical circadian rhythm genes Bmal1, Rev-erbα, Cry, and Ror in the liver exhibited different expression patterns throughout the day, and participated in physiological processes with rhythmic changes, including Th17 cell differentiation (ko04659), antigen processing and presentation (ko04612), the estrogen signaling pathway (ko04915), and insulin resistance (ko04931). In addition, previous studies have found that the peroxisome proliferator-activated receptor (PPAR) metabolic signaling pathway (ko03320) may play a vital role in the rhythmic regulation of the metabolic network. Conclusions This study is the first to demonstrate diurnal changes in bat liver gene expression and related physiological processes. The results have thus further enriched our understanding of bats’ biological clocks.

Abstract The literature has shown that mobile phone addiction is an important risk factor for depression. However, the internal mechanisms of mobile phone addiction leading to depression are still not clear. This study examined the mediating role of sleep quality and moderating role of peer relationships in the association between mobile phone addiction and depression. A sample of 450 Chinese medical students were recruited to complete measures of mobile phone addiction, depression, sleep quality and peer relationships. In this study, SPSS 25.0 and macro PROCESS were used to conduct statistical analysis on the collected data. The results showed that sleep quality partially mediated the association between mobile phone addiction and depression. Moreover, the effect of sleep quality on depression was moderated by peer relationships. The present study can advance our understanding of how and when mobile phone addiction leads to depression. Limitations and implications of this study are discussed.

Background and objectiveUterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to analyze the causal association between various factors and uterine leiomyoma using Mendelian randomization (MR).MethodsGenetic variables associated with risk factors were obtained from genome-wide association studies. Summary-level statistical data for uterine leiomyoma were obtained from FinnGen and the UK Biobank (UKB) consortium. We used inverse variance weighted, MR-Egger, and weighted median methods in univariate analysis. Multivariable MR analysis was used to identify independent risk factors. A fixed-effect model meta-analysis was used to combine the results of the FinnGen and UKB data.ResultsIn the FinnGen data, higher genetically predicted age at natural menopause, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting insulin were associated with an increased risk of uterine leiomyoma, while higher age at menarche was associated with a reduced risk of uterine leiomyoma. Multivariable MR analysis of SBP and DBP showed that higher DBP might be an independent risk factor of uterine leiomyoma. In the UKB data, the results for age at natural menopause, SBP, DBP, and age at menarche were replicated. The result of the meta-analysis suggested that uterine leiomyoma could also be affected by polycystic ovary syndrome (PCOS), endometriosis, and 2-hour glucose level.ConclusionOur MR study confirmed that earlier menstrual age, hypertension, obesity, and elevated 2-hour glucose post-challenge were risk factors for uterine leiomyoma, and the causal relationship between smoking and uterine leiomyoma was ruled out. In addition, later age of menopause and endometriosis were found to increase the risk of uterine leiomyoma, while PCOS was found to decrease the risk.

Introduction: The effect of the conventional treatment methods of glioblastoma (GBM) is poor and the prognosis of patients is poor. The expression of MCL-1 in GBM is significantly increased, which shows a high application value in targeted therapy. In this study, we predicted the prognosis of glioblastoma patients, and therefore constructed MCL-1 related prognostic signature (MPS) and the development of MCL-1 small molecule inhibitors.Methods: In this study, RNA-seq and clinical data of 168 GBM samples were obtained from the TCGA website, and immunological analysis, differential gene expression analysis and functional enrichment analysis were performed. Subsequently, MCL-1-associated prognostic signature (MPS) was constructed and validated by LASSO Cox analysis, and a nomogram was constructed to predict the prognosis of patients. Finally, the 17931 small molecules downloaded from the ZINC15 database were screened by LibDock, ADME, TOPKAT and CDOCKER modules and molecular dynamics simulation in Discovery Studio2019 software, and two safer and more effective small molecule inhibitors were finally selected.Results: Immunological analysis showed immunosuppression in the MCL1_H group, and treatment with immune checkpoint inhibitors had a positive effect. Differential expression gene analysis identified 449 differentially expressed genes. Build and validate MPS using LASSO Cox analysis. Use the TSHR HIST3H2A, ARGE OSMR, ARHGEF25 build risk score, proved that low risk group of patients prognosis is better. Univariate and multivariate analysis proved that risk could be used as an independent predictor of patient prognosis. Construct a nomogram to predict the survival probability of patients at 1,2,3 years. Using a series of computer-aided techniques, two more reasonable lead compounds ZINC000013374322 and ZINC000001090002 were virtually selected. These compounds have potential inhibitory effects on MCL-1 and provide a basis for the design and further development of MCL-1 specific small molecule inhibitors.Discussion: This study analyzed the effect of MCL-1 on the prognosis of glioblastoma patients from the perspective of immunology, constructed a new prognostic model to evaluate the survival rate of patients, and further screened 2 MCL-1 small molecule inhibitors, which provides new ideas for the treatment and prognosis of glioblastoma.

Background: Hypertension, a major cardiovascular risk factor, severely impacts patients’ quality of life. Qiangli Dingxuan tablet (QDT) is a formally approved Chinese patent medicine, which has been widely used as an adjunctive treatment for hypertension. This study aimed to investigate the antihypertensive efficacy and safety of QDT combined with amlodipine besylate in patients with essential hypertension.Methods: In this randomized, double-blind, placebo-controlled, parallel-group, multicenter trial conducted in China, patients diagnosed with grade 1 to 2 essential hypertension were randomly assigned in a 1:1 to the treatment of QDT or placebo for 12 weeks, alongside their ongoing treatment with amlodipine besylate. The primary outcome was the change in office blood pressure (BP) from baseline to 12 weeks. In addition, safety analysis included the assessment of vital signs and laboratory values.Results: At baseline, 269 patients were randomly assigned to the QDT group (n = 133) or the placebo group (n = 136), and there were no significant differences in baseline characteristics between the two groups. The primary outcome based on the full analysis set from baseline to 12 weeks showed that the mean difference in the change of office systolic BP reduction between the two groups was 6.86 mmHg (95%CI, 4.84 to 8.88, p < 0.0001), for office diastolic BP, the mean difference in the change of office diastolic BP reduction between the two groups was 4.64 mmHg (95%CI, 3.10 to 6.18, p < 0.0001). In addition, traditional Chinese medicine symptom scores were significantly decreased in the QDT group compared with the placebo group. No severe adverse events attributable to QDT were reported.Conclusion: The combination of QDT and amlodipine besylate demonstrates superior efficacy compared to amlodipine besylate monotherapy in the management of essential hypertension. QDT shows potential as an adjunctive treatment for essential hypertension. However, further rigorous clinical trials are warranted to validate these findings.Clinical Trial Registration: [https://clinicaltrials.gov/study/NCT05521282?cond=NCT05521282&rank=1]; Identifier: [NCT05521282]

ABSTRACT Antibiotic tolerance within a biofilm community presents a serious public health challenge. Here, we report the identification of a 2-aminoimidazole derivative that inhibits biofilm formation by two pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. In S. mutans, the compound binds to VicR, a key response regulator, at the N-terminal receiver domain, and concurrently inhibits expression of vicR and VicR-regulated genes, including the genes that encode the key biofilm matrix producing enzymes, Gtfs. The compound inhibits S. aureus biofilm formation via binding to a Staphylococcal VicR homolog. In addition, the inhibitor effectively attenuates S. mutans virulence in a rat model of dental caries. As the compound targets bacterial biofilms and virulence through a conserved transcriptional factor, it represents a promising new class of anti-infective agents that can be explored to prevent or treat a host of bacterial infections. IMPORTANCE Antibiotic resistance is a major public health issue due to the growing lack of effective anti-infective therapeutics. New alternatives to treat and prevent biofilm-driven microbial infections, which exhibit high tolerance to clinically available antibiotics, are urgently needed. We report the identification of a small molecule that inhibits biofilm formation by two important pathogenic Gram-positive bacteria, Streptococcus mutans and Staphylococcus aureus. The small molecule selectively targets a transcriptional regulator leading to attenuation of a biofilm regulatory cascade and concurrent reduction of bacterial virulence in vivo. As the regulator is highly conserved, the finding has broad implication for the development of antivirulence therapeutics that selectively target biofilms.

ABSTRACT Hypermucoviscosity is a hallmark of hypervirulent Klebsiella pneumoniae (hvKP). However, the molecular basis of its regulation is largely unknown. We hypothesize that hypermucoviscosity is modulated via two-component signal transduction systems (TCSs). In-frame deletion mutants of all 33 response regulators of hvKP ATCC43816 were generated using CRISPR/CAS and evaluated for their impacts on hypermucoviscosity. The response regulator OmpR is required for hypermucoviscosity in vitro and virulence in vivo in a mouse pneumonia model. The ΔompR mutant lost its mucoidy but retained its capsule level and comparable rmpADC expression, so transcriptomic analysis by RNA-Seq was performed to identify differentially expressed genes (DEGs) in ΔompR mutant. The top 20 Gene Ontology terms of 273 DEGs belong to purine ribonucleotide triphosphate biosynthetic and metabolic process, transmembrane transport, and amino acid metabolism. Among the overexpressed genes in the ΔompR mutant, the atp operon encoding F-type ATP synthase and the gcvTHP encoding glycine cleavage system were characterized further as overexpression of either operon reduced the mucoviscosity and increased the production of ATP. Furthermore, OmpR directly bound the promoter region of the atp operon, not the gcvTHP, suggesting that OmpR regulates the expression of the atp operon directly and gcvTHP indirectly. Hence, the loss of OmpR led to the overexpression of F-type ATP synthase and glycine cleavage system, which altered the energetic status of ΔompR cells and contributed to the subsequent reduction in the mucoviscosity. Our study has uncovered a previously unknown regulation of bacterial metabolism by OmpR and its influence on hypermucoviscosity. IMPORTANCE Hypermucoviscosity is a critical virulent factor for Klebsiella pneumoniae infections, and its regulation remains poorly understood at the molecular level. This study aims to address this knowledge gap by investigating the role of response regulators in mediating hypermucoviscosity in K. pneumoniae. We screened 33 response regulators and found that OmpR is essential for hypermucoviscosity and virulence of K. pneumoniae in a mouse pneumonia model. Transcriptomic analysis uncovered that genes involved in energy production and metabolism are highly upregulated in the ΔompR mutant, suggesting a potential link between bacterial energy status and hypermucoviscosity. Overexpression of those genes increased production of ATP and reduced mucoviscosity, recapitulating the ΔompR mutant phenotype. Our findings provide new insights into the regulation of K. pneumoniae hypermucoviscosity by a two-component signal transduction system, highlighting the previously unknown role of OmpR in regulating bacterial energy status and its influence on hypermucoviscosity.