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Abstract In this study, we dynamically monitored the glomerular filtration rate and other assessment of renal function and markers of injury in various mice models of acute kidney injury. Male C57BL/6 mice were utilized to establish acute kidney injury models of sepsis, ischemia reperfusion, cisplatin, folic acid, aristolochic acid and antibiotic. In addition to the real time glomerular filtration rate, renal LCN-2 and HAVCR-1 mRNA expression levels, and serum creatinine, urea nitrogen and cystatin c levels were also used to evaluate renal function. In addition, the protein levels of LCN-2 and HAVCR-1 in renal, serum and urine were measured. Our results demonstrated that the changes in biomarkers always lagged the real time glomerular filtration rate during the progression and recovery of renal injury. Cystatin-c can reflect renal injury earlier than other markers, but it remains higher in the recovery stage. Perhaps the glomerular filtration rate does not reflect the greater injury caused by vancomycin plus piperacillin.

Abstract Purpose We aimed to compare the therapeutic effect of radiotherapy (RT) plus systemic therapy (ST) with RT alone in patients with simple brain metastasis (BM) after first-line treatment of limited-stage small cell lung cancer (LS-SCLC). Methods The patients were treated at a single center from January 2011 to January 2022. BM only without metastases to other organs was defined as simple BM. The eligible patients were divided into RT alone (monotherapy arm) and RT plus ST (combined therapy arm). Univariate and multivariate Cox proportional hazards analyses were used to examine factors associated with increased risk of extracranial progression. After 1:1 propensity score matching analysis, two groups were compared for extracranial progression-free survival (ePFS), PFS, overall survival (OS), and intracranial PFS (iPFS). Results 133 patients were identified and 100 were analyzed (monotherapy arm: n = 50, combined therapy arm: n = 50). The ePFS of the combined therapy was significantly longer than that of the monotherapy, with a median ePFS of 13.2 months (95% CI, 6.6–19.8) in combined therapy and 8.2 months (95% CI, 5.7–10.7) in monotherapy (P = 0.04). There were no statistically significant differences in PFS (P = 0.057), OS (P = 0.309), or iPFS (P = 0.448). Multifactorial analysis showed that combined therapy was independently associated with better ePFS compared with monotherapy (HR = 0.617, P = 0.034); more than 5 BMs were associated with worse ePFS compared with 1–5 BMs (HR = 1.808, P = 0.012). Conclusions Compared with RT alone, combined therapy improves ePFS in patients with simple BM after first-line treatment of LS-SCLC. Combined therapy and 1–5 BMs reduce the risk of extracranial recurrence.

Indentations in rolling bearings from particle contamination introduce surface damage because they disturb lubrication and produce stress concentrations. In this article, a methodology is proposed where non-failed bearings that have been running in the field are inspected, indentations are counted and their geometry is characterized. With this information and the use of a mathematical model previously developed, the inferred damage in the bearing can be estimated and with this also the actual contamination parameter, ηc as described in the ISO 281 standard. In this way giving more certainty on the real contamination conditions in the application than other indirect assessment methods.

Background and objectiveDespite its acknowledged benefits, the selection of an optimal regional block for analgesia pediatric hernia surgery remains a subject of debate. This study endeavored to conduct a network meta-analysis and systematic review of randomized clinical trials, aiming to amalgamate insights from both direct and indirect comparisons concerning the analgesic effectiveness and safety of various regional blocks post-inguinal hernia repair in children.MethodA comprehensive literature search was performed across PubMed, EMBASE, Web of Science, and the Cochrane Library up to 12 November 2022 by two independent reviewers, employing a standardized protocol. The inclusion criteria encompassed randomized trials focusing on children undergoing inguinal hernia repair utilizing either local infiltration analgesia or regional analgesia. The primary outcomes assessed were pain scores at 2, 6, and 24 h post-operation.ResultsThe initial search yielded 281 records relating to 1,137 patients. The analysis of ranking probability indicated that Paravertebral Block (PVB) holds the highest likelihood (88% and 48%) of being the most effective in alleviating pain at 2 h and 6 h post-surgery. Trans vs. Abdominis Plane Block (TAPB) emerged as the superior choice for mitigating pain (83%) and decreasing morphine consumption (93%) at 24 h following the operation. Local Anesthetic Infiltration (LAI) was identified as the most effective in shortening the hospital stay, with a 90% probability.ConclusionsRegional anesthesia significantly enhances postoperative pain management in pediatric inguinal hernia repair surgery. For short-term postoperative pain relief, PVB emerges as the most effective technique. Meanwhile, TAPB provides more prolonged analgesia. Although TAPB does not exhibit a pronounced advantage in short-term analgesia, its simplicity and the absence of a need for a special position render it a viable option. However, the interpretation of these results should be approached with caution due to the presence of limited data and heterogeneity.Systematic Review RegistrationPROSPERO (CRD42022376435; www.crd.york.ac.uk/prospero).

Abstract Objective The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. Methods This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut‐off value. The Kaplan–Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). Results The best cut‐off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte‐to‐lymphocyte ratio (MLR), and neutrophil‐to‐lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional‐hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. Conclusion We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.

Abstract Benthic δ18O stacks are the benchmarks by which paleoceanographic data are stratigraphically aligned and compared. However, a recent study found that between 1.8 and 1.9 million years ago (Ma) several Ceara Rise records differed substantially from the widely used LR04 global stack. Here, we use new Bayesian stacking software to construct regional stacks and demonstrate a geographical divergence in benthic δ18O features from 1.8 to 1.9 Ma. The pattern of isotopic stage features observed in the Ceara Rise is widespread throughout the Atlantic and differs notably from Pacific records. We propose that this regional difference in isotopic stages may be the result of relatively strong precession forcing and weaker obliquity forcing between 1.8 and 1.9 Ma. In accordance with the Antiphase Hypothesis, our results highlight a period of apparent sensitivity to regional precession forcing that is masked during most of the 41‐Kyr world due to the amplitude modulation of obliquity forcing.

The highly active and selective oxygen reduction reaction (ORR) is vital to promote the performance of advanced energy conversion systems, such as fuel cells and other electrochemical devices. Porous framework materials have the capability to combine the catalytic performance of catalytic active units with their porous characteristics, making them promising oxygen reduction catalysts. However, due to the difficulty in designing and synthesizing catalytic active units, the pore size modulation of framework materials is primarily achieved by altering the linkers. We herein report the design and synthesis of three cobalt-corrole-based porous organic polymers (Co-POP-1, Co-POP-2 and Co-POP-3) with different pore sizes, which were obtained by extending 5,15-meso substituents of Co corroles. Compared to Co-POP-1 and Co-POP-2, Co-POP-3 has the largest pore size. Benefiting from the enhanced mass transfer and the highly exposed active sites, Co-POP-3 displayed remarkably boosted activity for the selective four-electron/four-proton (4e−/4 H+) ORR with a half-wave potential of E1/2 = 0.89 V versus reversible hydrogen electrode (RHE) in 0.1 M KOH solutions. This work not only presents a cobalt-corrole-based porous organic polymer catalyst with high ORR activity and selectivity but also provides a new strategy to moderate the pore size of porous framework materials.

Abstract Conductive grease has been considered as a potential solution in addressing electric erosion issue inside motor bearings. Understanding the conductive grease performance, especially the electric and tribological behaviour is crucial for its application. This paper combines bulk grease characterization and contact film study considering both electrical and tribological loading conditions. The results show that the electric performance for the selected conductive grease sample is electric field dependent, including both frequency and voltage amplitude. Its film impedance inside the contact area is closely related to the external electric field, running condition, and lubrication regime. The following film impedance calculation tells that not only bulk grease electric parameters, but the contact parameter, lubricant film contour and lubrication condition should be considered when performing the overall bearing electrical modelling.

Abstract Background The ratio of non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) (NHHR) serves as a reliable lipid indicator associated with atherogenic characteristics. Studies have indicated a potential connection between suicidality and lipid metabolism. This research aims to investigate any possible association between the NHHR and the emergence of suicidal ideation within the confines of the study. Methods This study examined the association between NHHR levels and suicidal ideation using data from the National Health and Nutrition Examination Survey (NHANES), conducted in the United States spanning 2005 and 2016. Calculation of the NHHR corresponds to the proportion of HDL-C to Non-HDL-C. The Patient Health Questionnaire-9’s ninth question was implemented for assessing suicidal ideation. Using subgroup analysis, smooth curve fitting, and multivariate logistic regression analysis, the research was conducted. Results Encompassing a cohort of 29,288 participants, the analysis identified that 3.82% of individuals reported suicidal ideation. After using multivariable logistic regression and thorough adjustments, elevated NHHR levels were significantly and positively associated with a heightened likelihood of suicidal ideation, according to the findings (odds ratio [OR] = 1.06; 95% confidence interval [CI]: 1.02–1.11; P = 0.0048). Despite extensive adjustment for various confounding factors, this relationship remained consistent. An inverted U-shaped curve was utilized to illustrate the link between NHHR and suicidal ideation among nonsmokers; the curve’s inflection point was situated at 7.80. Subgroup analysis and interaction tests (all P for interaction > 0.05) demonstrated that there was no significant influence of the following variables on this positive relationship: age, sex, race, body mass index, education level, married status, hypertension, diabetes, and smoking status. Conclusion Significantly higher NHHR levels were associated with an elevated likelihood of suicidal ideation. Based on these results, it is probable that NHHR may serve as a predictive indicator of suicidal ideation, emphasizing its potential utility in risk assessment and preventive strategies.

Abstract Background Numerous studies have demonstrated a positive correlation between diet quality and cognitive performance, indicating that improving diet quality may be beneficial in preventing cognitive decline in older adults. However, few study has investigated the causal relationship between diet quality and cognitive performance. The purpose of this study is to evaluate the causal effects of diet quality on cognitive performance in Chinese adults aged 55 years and older. Particularly, we utilize the Chinese Diet Quality Index (CHEI), a dietary assessment tool tailored for Chinese populations, as a proxy for older adults’ diet quality. Methods Data were obtained from the China Health and Nutrition Survey (CHNS) ( $$N = 2337$$ N = 2337 , $$\ge$$ ≥ 55 years old) conducted in 2004 and 2006. Cognitive function was tested by a subset of items from the Telephone Interview for Cognitive Status-Modified (TICS-m). Data on dietary intake was retrieved from three consecutive 24 hour recalls by participants and its quality was assessed by the 17-items Chinese Healthy Eating Index (CHEI). An Instrumental Variable technique was used to deal with the potential endogeneity of dietary quality. The instrumental variable used in our study is the community mean of CHEI. Results After adjusting for socio-demographic factors (age, gender, education, per capita household income), lifestyle habits (smoking, alcohol consumption, physical activity, BMI), and chronic diseases (hypertension, diabetes), our findings revealed that improving diet quality had a significant positive effect on cognitive performance ( $$P = 0.020$$ P = 0.020 ), particularly in females aged 55-65 years ( $$P = 0.003$$ P = 0.003 ) and females with primary education and below ( $$P < 0.001$$ P < 0.001 ). Conclusion Our study suggests that improving diet quality and adhering to the Dietary Guidelines for Chinese may enhance cognitive performance in Chinese adults aged 55 years and older.

Abstract Background Sedentary behaviour is considered to contribute to sarcopenia when combined with physical inactivity. Whether sedentary behaviour is independently associated with sarcopenia remains controversial. The aim of this study is to explore the association between sedentary behaviour and sarcopenia in older adults in community and long-term care facility settings. Methods Eight electronic databases including MEDLINE, PsycINFO, Wanfang were searched from inception until August 2023. The review included cross-sectional and longitudinal studies concerning the association between sedentary behaviour and sarcopenia among participants over 60 years old. Evidence was pooled by both random-effects meta-analysis and narrative synthesis. Subgroup analyses explored variation according to adjustment of physical activity, settings, and measurements of sedentary behaviour and sarcopenia. Quality assessment for individual studies was performed with the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Results Seventeen articles (16 cross-sectional studies and 1 longitudinal study) of 25,788 participants from community or long-term care facility settings were included. The overall quality of the included studies was rated high. Meta-analysis of 14 cross-sectional studies showed that sedentary behaviour was independently positively associated with sarcopenia: pooled odd ratio 1.36 (95% confidence interval, 1.18–1.58). The independent positive association remained in subgroup analyses by adjustment of physical activity, settings, and measurements of sedentary behaviour and sarcopenia. The narrative analysis corroborated the findings of the meta-analysis and provided additional evidence suggesting that interruptions in sedentary periods were linked to a decreased likelihood of developing sarcopenia. Conclusions The findings support the hypothesis that sedentary behaviour is independently positively associated with sarcopenia in older adults, providing vital indications for the development of strategies to prevent sarcopenia. Systematic review registration The systematic review protocol has been registered with the PROSPERO database (CRD42022311399).

Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive forms of pancreatic cancer with a poor prognosis. YAP1 expression is markedly elevated in PDAC, but how it works is not clear. GL-V9, a derivative of the natural compound wogonin, effectively fights a variety of tumors; however, its effect on PDAC has not yet been studied. Methods: TCGA database analysis, Western blots, immunofluorescence, and real-time PCR were used to evaluate GL-V9’s effect on YAP1 expression and mRNA levels. Immunofluorescence was used to examine the co-location of YAP1 with LAMP2 and p62. Co-immunoprecipitation was used to assess the binding of YAP1 to ubiquitin, p62, and TEAD1. A PDAC graft tumor model was used to test GL-V9’s pharmacological effects. Western blots and immunohistochemistry were used to measure apoptosis- and autophagy-related protein expression. Results: GL-V9 effectively promoted the degradation of YAP1, reduced YAP1 nuclear localization, and induced mitochondrial apoptosis in PDAC cells. YAP1 overexpression led to the upregulation of Bcl-2 and attenuated the caspase cascade induced by GL-V9. Furthermore, we demonstrated that GL-V9 induced autophagosome–lysosome fusion via the AKT/mTOR/TFEB pathway, leading to mitochondrial apoptosis in PDAC cells. In vivo studies also confirmed that GL-V9 exerts anti-tumor effects by suppressing YAP1 expression, while also activating autophagy and inducing mitochondrial apoptosis in BXPC-3-bearing BALB/c nude mice. Conclusions: Our findings underscore the importance of autophagy-mediated YAP1 degradation in PDAC, providing a novel molecular rationale (GL-V9) as a promising treatment for this disease.

Abstract Androgen receptor (AR) antagonists are widely used for the treatment of prostate cancer (PCa), but their therapeutic efficacy is usually compromised by the rapid emergence of drug resistance. However, the lack of the detailed interaction between AR and its antagonists poses a major obstacle to the design of novel AR antagonists. Here, funnel metadynamics is employed to elucidate the inherent regulation mechanisms of three AR antagonists (hydroxyflutamide, enzalutamide, and darolutamide) on AR. For the first time it is observed that the binding of antagonists significantly disturbed the C‐terminus of AR helix‐11, thereby disrupting the specific internal hydrophobic contacts of AR‐LBD and correspondingly the communication between AR ligand binding pocket (AR‐LBP), activation function 2 (AF2), and binding function 3 (BF3). The subsequent bioassays verified the necessity of the hydrophobic contacts for AR function. Furthermore, it is found that darolutamide, a newly approved AR antagonist capable of fighting almost all reported drug resistant AR mutants, can induce antagonistic binding structure. Subsequently, docking‐based virtual screening toward the dominant binding conformation of AR for darolutamide is conducted, and three novel AR antagonists with favorable binding affinity and strong capability to combat drug resistance are identified by in vitro bioassays. This work provides a novel rational strategy for the development of anti‐resistant AR antagonists.

Of all malignancies, pancreatic ductal adenocarcinoma (PDAC), constituting 90% of pancreatic cancers, has the worst prognosis. Glycolysis is overactive in PDAC patients and is associated with poor prognosis. Drugs that inhibit glycolysis as well as induce cell death need to be identified. However, glycolysis inhibitors often fail to induce cell death. We here found that FV-429, a derivative of the natural flavonoid wogonin, can induce mitochondrial apoptosis and inhibit glycolysis in PDAC in vivo and in vitro. In vitro, FV-429 inhibited intracellular ATP content, glucose uptake, and lactate generation, consequently leading to mitochondrial dysfunction and apoptosis in PDAC cells. Furthermore, it decreased the expression of PKM2 (a specific form of pyruvate kinase) through the ERK signaling pathway and enhanced PKM2 nuclear translocation. TEPP-46, the activator of PKM2, reversed FV-429-induced glycolysis inhibition and mitochondrial apoptosis in the PDAC cells. In addition, FV-429 exhibited significant tumor suppressor activity and high safety in BxPC-3 cell xenotransplantation models. These results thus demonstrated that FV-429 decreases PKM2 expression through the ERK signaling pathway and enhances PKM2 nuclear translocation, thereby resulting in glycolysis inhibition and mitochondrial apoptosis in PDAC in vitro and in vivo, which makes FV-429 a promising candidate for pancreatic cancer treatment.

ABSTRACT: The poultry skeletal system serves multiple functions, not only providing structural integrity but also maintaining the balance of essential minerals such as calcium and phosphorus. However, in recent years, the consideration of skeletal traits has been overlooked in the selective breeding of broilers, resulting in an inadequate adaptation of the skeletal system to cope with the rapid increase in body weight. Consequently, this leads to lameness and bone diseases such as tibial dyschondroplasia (TD), which significantly impact the production performance of broilers. Accumulating evidence has shown that microRNAs (miRNA) play a crucial role in the differentiation, formation, and disease of cartilage. However, the miRNA-mediated molecular mechanism underlying chicken TD formation is still poorly understood. The objective of this study was to investigate the biological function and regulatory mechanism of miRNA in chicken TD formation. Based on transcriptome sequencing of tibial cartilage in the healthy group and TD group, miR-206a-3p was found to be highly expressed in TD cartilage. The function of miR-206a-3p was explored through the transfection test of miR-206a-3p mimics and miR-206a-3p inhibitor. In this study, we utilized qRT-PCR, CCK-8, EdU, western blot, and flow cytometry to detect the proliferation, differentiation, and apoptosis of chondrocytes. The results revealed that miR-206a-3p suppressed the proliferation and differentiation of TD chondrocytes while promoting their programmed cell death. Furthermore, through biosynthesis and dual luciferase assays, it was determined that BMP6 was the direct target gene of miR-206a-3p. This finding was further supported by rescue experiments which confirmed the involvement of BMP6 in the regulatory pathway governed by miR-206a-3p. Our results suggest that miR-206a-3p can inhibits the proliferation and differentiation promote apoptosis through the target gene BMP-6 and suppressing the Smad2/3 signaling pathway in chicken TD chondrocytes.

Summary: Prostate cancer (PCa) is a serious health concern for men due to its high incidence and mortality rate. The first therapy typically adopted is androgen deprivation therapy (ADT). However, patient response to ADT varies, and 20–30% of PCa cases develop into castration-resistant prostate cancer (CRPC). This article investigates the anti-PCa effect of a drug candidate named GL-V9 and highlights the significant mechanism involving the AKT-hexokinase II (HKII) pathway. In both androgen receptor (AR)-expressing 22RV1 cells and AR-negative PC3 cells, GL-V9 suppressed phosphorylated AKT and mitochondrial location of HKII. This led to glycolytic inhibition and mitochondrial pathway-mediated apoptosis. Additionally, GL-V9 inhibited AR activity in 22RV1 cells and disrupted the feedback activation of AKT signaling in condition of AR inhibition. This disruption greatly increased the anti-PCa efficacy of the AR antagonist bicalutamide. In conclusion, we present a novel anti-PCa candidate and combination drug strategies to combat CRPC by intervening in the AR-AKT-HKII signaling network.

Abstract Background Chimeric antigen receptor T (CAR-T) cell therapy, a new adoptive cell therapy, has been widely used to treat lymphoma patients. Immune checkpoint blockade may improve the cytotoxicity of CAR-T cells by reducing the failure of CAR-T cells and improving antitumor activity. It has shown promising efficacy. Method We searched PubMed, the Cochrane Library, Embase and Web of Science from January 2012 to August 2022 to find data reporting the results of CAR-T cells therapy combined with PD-1 in tumor patients. An updated search was conducted in October 2023. The partial response rate (PR), complete response rate (CR), objective response rate (ORR), mortality rate, and incidence of adverse reactions were calculated. Results We analyzed 57 lymphoma patients from 5 clinical trials. The pooled partial, complete and overall response rates were 21% (95% CI 0.06–0.39, I2 = 0.37%), 27% (95% CI 0.03–0.60, I2 = 60.43%) and 65% (95% CI 0.23–0.98, I2 = 76.31%), respectively. The pooled incidence of cytokine release syndrome, neutropenia, fever, and fatigue was estimated to be 57% (95% CI 0.08–0.99, I2 = 85.20%), 47% (95% CI 0.14–0.81, I2 = 74.17%), 59% (95% CI 0.27–0.89, I2 = 60.23%), and 50% (95% CI 0.13–0.87, I2 = 73.89%), respectively. Conclusion CAR-T-cell therapy combined with anti-PD-1 immunotherapy in the treatment of lymphoma patients has efficacy, and the most common adverse effect is fever. Registration The protocol was registered in prospero, with the registration number CRD42022342647.

Abstract This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer (odds ratio [OR] 0.95; 95% CI 0.90–0.99, p = 0.02). Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type (OR 0.91; 95% CI 0.86–0.97, p = 0.005). However, there was no causal association between ER-negative breast cancer and survival (OR 1.00; 95% CI 0.94–1.06, p = 0.89). Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association.

Abstract Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia–spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury.

The intensive use of chemical fertilizers in China to maintain high crop yields has led to significant environmental degradation and destabilized crop production. Returning straw to soil presents a potential alternative to reduce chemical fertilizer requirements and enhance soil fertility. This study investigates the effects of different nitrogen (N) input levels and straw additions on crop phosphorus (P) uptake and soil P availability based on a long-term N-fertilizer trial. The treatments included no fertilizer input (CK), conventional (NPK), reduced NPK (0.75NPK), and straw-amended (SNPK) treatments. Results indicate that SNPK significantly enhances shoot P uptake and crop yields by 43.7–61.9% and 29.3–39.6%, respectively. The SNPK treatment improved rhizosphere P availability and increased the phosphorus activation coefficient (PAC) by 1.72-fold compared to NPK alone. The enhanced soil P availability under SNPK was primarily attributed to an abundance of functional microbes, leading to higher P storage in the microbial biomass P pool and its turnover. Additionally, SNPK promoted root exudate and phosphate-mobilizing microbes, enhancing P mobilization and uptake. Nitrogen fertilization primarily influenced root functional traits related to P acquisition. These findings provide valuable insights for developing effective fertilizer management strategies in maize–oilseed rape rotation systems, emphasizing the benefits of integrating straw with chemical fertilizers.

Small molecules are significant risk factors for causing food safety issues, posing serious threats to human health. Sensitive screening for hazards is beneficial for enhancing public security. However, traditional detection methods are unable to meet the requirements for the field screening of small molecules. Therefore, it is necessary to develop applicable methods with high levels of sensitivity and specificity to identify the small molecules. Aptamers are short−chain nucleic acids that can specifically bind to small molecules. By utilizing aptamers to enhance the performance of recognition technology, it is possible to achieve high selectivity and sensitivity levels when detecting small molecules. There have been several varieties of aptamer target recognition techniques developed to improve the ability to detect small molecules in recent years. This review focuses on the principles of detection platforms, classifies the conjugating methods between small molecules and aptamers, summarizes advancements in aptamer−based conjugate recognition techniques for the detection of small molecules in food, and seeks to provide emerging powerful tools in the field of point−of−care diagnostics.

Abstract Background The purpose of this paper was to systematically evaluate the application value of artificial intelligence in predicting mortality among COVID-19 patients. Methods The PubMed, Embase, Web of Science, CNKI, Wanfang, China Biomedical Literature, and VIP databases were systematically searched from inception to October 2022 to identify studies that evaluated the predictive effects of artificial intelligence on mortality among COVID-19 patients. The retrieved literature was screened according to the inclusion and exclusion criteria. The quality of the included studies was assessed using the QUADAS-2 tools. Statistical analysis of the included studies was performed using Review Manager 5.3, Stata 16.0, and Meta-DiSc 1.4 statistical software. This meta-analysis was registered in PROSPERO (CRD42022315158). Findings Of 2193 studies, 23 studies involving a total of 25 AI models met the inclusion criteria. Among them, 18 studies explicitly mentioned training and test sets, and 5 studies did not explicitly mention grouping. In the training set, the pooled sensitivity was 0.93 [0.87, 0.96], the pooled specificity was 0.94 [0.87, 0.97], and the area under the ROC curve was 0.98 [0.96, 0.99]. In the validation set, the pooled sensitivity was 0.84 [0.78, 0.88], the pooled specificity was 0.89 [0.85, 0.92], and the area under the ROC curve was 0.93 [1.00, 0.00]. In the subgroup analysis, the areas under the summary receiver operating characteristic (SROC) curves of the artificial intelligence models KNN, SVM, ANN, RF and XGBoost were 0.98, 0.98, 0.94, 0.92, and 0.91, respectively. The Deeks funnel plot indicated that there was no significant publication bias in this study (P > 0.05). Interpretation Artificial intelligence models have high accuracy in predicting mortality among COVID-19 patients and have high prognostic value. Among them, the KNN, SVM, ANN, RF, XGBoost, and other models have the highest levels of accuracy.

Abstract Background Triple‐negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real‐world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real‐world setting and to explore possible correlates. Methods The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Results Eighty‐one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression‐free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later‐line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. Conclusions ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.

Abstract Background Cuproptosis is a regulated cell death form associated with tumor progression, clinical outcomes, and immune response. However, the role of cuproptosis in pancreatic adenocarcinoma (PAAD) remains unclear. This study aims to investigate the implications of cuproptosis-related genes (CRGs) in PAAD by integrated bioinformatic methods and clinical validation. Methods Gene expression data and clinical information were downloaded from UCSC Xena platform. We analyzed the expression, mutation, methylation, and correlations of CRGs in PAAD. Then, based on the expression profiles of CRGs, patients were divided into 3 groups by consensus clustering algorithm. Dihydrolipoamide acetyltransferase (DLAT) was chosen for further exploration, including prognostic analysis, co-expression analysis, functional enrichment analysis, and immune landscape analysis. The DLAT-based risk model was established by Cox and LASSO regression analysis in the training cohort, and then verified in the validation cohort. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) assays were performed to examine the expression levels of DLAT in vitro and in vivo, respectively. Results Most CRGs were highly expressed in PAAD. Among these genes, increased DLAT could serve as an independent risk factor for survival. Co-expression network and functional enrichment analysis indicated that DLAT was engaged in multiple tumor-related pathways. Moreover, DLAT expression was positively correlated with diverse immunological characteristics, such as immune cell infiltration, cancer-immunity cycle, immunotherapy-predicted pathways, and inhibitory immune checkpoints. Submap analysis demonstrated that DLAT-high patients were more responsive to immunotherapeutic agents. Notably, the DLAT-based risk score model possessed high accuracy in predicting prognosis. Finally, the upregulated expression of DLAT was verified by RT-qPCR and IHC assays. Conclusions We developed a DLAT-based model to predict patients’ clinical outcomes and demonstrated that DLAT was a promising prognostic and immunological biomarker in PAAD, thereby providing a new possibility for tumor therapy.

Abstract Background Immunotherapy has transformed cancer treatment patterns for advanced hepatocellular carcinoma (aHCC) in recent years. Therefore, the identification of predictive biomarkers has important clinical implications. Methods We collected medical records from 117 aHCC patients treated with anti-PD-1 antibody. Kaplan-Meier analysis and Cox proportional hazard regression were used to evaluate the association between peripheral blood biomarkers and overall survival (OS) and progression-free survival (PFS). Finally, the prognostic nomogram was constructed. Results The mPFS and mOS were 7.0 months and 18.7 months, respectively. According to Kaplan-Meier analysis and Cox regression analysis, we regarded the treatment regimen (p = 0.020), hemoglobin (Hb) at 6-week (p = 0.042), neutrophil-to-lymphocyte ratio (NLR) at 6-week (p

IntroductionRecent studies have found that the sound-induced alleviation of visual attentional blink, a well-known phenomenon exemplifying the beneficial influence of multisensory integration on time-based attention, was larger when that sound was semantically congruent relative to incongruent with the second visual target (T2). Although such an audiovisual congruency effect has been attributed mainly to the semantic conflict carried by the incongruent sound restraining that sound from facilitating T2 processing, it is still unclear whether the integrated semantic information carried by the congruent sound benefits T2 processing.MethodsTo dissociate the congruence-induced benefit and incongruence-induced reduction in the alleviation of visual attentional blink at the behavioral and neural levels, the present study combined behavioral measures and event-related potential (ERP) recordings in a visual attentional blink task wherein the T2-accompanying sound, when delivered, could be semantically neutral in addition to congruent or incongruent with respect to T2.ResultsThe behavioral data clearly showed that compared to the neutral sound, the congruent sound improved T2 discrimination during the blink to a higher degree while the incongruent sound improved it to a lesser degree. The T2-locked ERP data revealed that the early occipital cross-modal N195 component (192–228 ms after T2 onset) was uniquely larger in the congruent-sound condition than in the neutral-sound and incongruent-sound conditions, whereas the late parietal cross-modal N440 component (400–500 ms) was prominent only in the incongruent-sound condition.DiscussionThese findings provide strong evidence that the modulating effect of audiovisual semantic congruency on the sound-induced alleviation of visual attentional blink contains not only a late incongruence-induced cost but also an early congruence-induced benefit, thereby demonstrating for the first time an unequivocal congruent-sound-induced benefit in alleviating the limitation of time-based visual attention.

Abstract Background Clinical epidemiological studies have found that some patients with ulcerative colitis (UC) are prone to mental disorders. DSS-induced acute and chronic UC models are often used to evaluate the efficacy of anti-UC drugs. However, whether DSS has an effect on mouse behavior has not been reported. Methods Acute and chronic UC models were induced by 3% DSS and 1.5% DSS, respectively. The bloody stool, the changes in the colon length, and histopathological changes in the colon were used to evaluate the success of the animal model. The behavior of mice was evaluated by open field experiment, tail suspension experiment and Sucrose preference test. Results The weight of mice in 3% DSS group decreased significantly, the DAI score increased significantly, the colon length of mice was significantly shortened, and the structure of colonic crypts was abnormal, which showed inflammatory cell infiltration and shrinkage of crypts. Compared with the control group, the immobility time of 3%DSS group mice in the tail suspension test and forced swimming test had no effect, the number of running and grooming times was significantly reduced, and there was no significant difference in the number of standing times. No abnormality was observed in HE staining of the hippocampus. However, in 1.5% DSS-induced chronic UC model, behavioral and hippocampal abnormalities were observed not only UC symptoms. Conclusions The acute UC model induced by 3% DSS has certain influence on the behavior of mice, but the mental state of mice is normal, which may be the abnormal behavior caused by UC symptoms; However, the chronic UC model induced by 1.5% DSS has a significant effect on the behavior of mice, and the mice have mental disorders, which are caused by mental disorders.

The development of effective vaccines against SARS-CoV-2 remains a critical challenge amidst the ongoing global pandemic. This study introduces a novel approach to enhancing mRNA vaccine efficacy by leveraging the untranslated region (UTR) of TMSB10, a gene identified for its significant mRNA abundance in antigen-presenting cells. Utilizing the GEO database, we identified TMSB10 among nine genes, with the highest mRNA abundance in dendritic cell subtypes. Subsequent experiments revealed that TMSB10’s UTR significantly enhances the expression of a reporter gene in both antigen-presenting and 293T cells, surpassing other candidates and a previously optimized natural UTR. A comparative analysis demonstrated that TMSB10 UTR not only facilitated a higher reporter gene expression in vitro but also showed marked superiority in vivo, leading to enhanced specific humoral and cellular immune responses against the SARS-CoV-2 Delta variant RBD antigen. Specifically, vaccines incorporating TMSB10 UTR induced significantly higher levels of specific IgG antibodies and promoted a robust T-cell immune response, characterized by the increased secretion of IFN-γ and IL-4 and the proliferation of CD4+ and CD8+ T cells. These findings underscore the potential of TMSB10 UTR as a strategic component in mRNA vaccine design, offering a promising avenue to bolster vaccine-induced immunity against SARS-CoV-2 and, potentially, other pathogens.

Carbon geological storage (CGS) is an important global practice implemented to mitigate the effects of CO2 emissions on temperature, climate, sea level, and biodiversity. The monitoring of CGS leakage and the impact of storage on hydrogeological properties is important for management and long-term planning. In this study, we show the value of passive monitoring methods based on measuring and modeling water-level responses to tides. We review how monitoring can be used to identify time-varying horizontal and vertical permeabilities as well as independently detect time-varying fracture distribution in aquifer–caprock systems. Methods based on water-level responses to Earth tides are minimally invasive, convenient, economic (since they use existing groundwater wells), and time-continuous. We show how measurements can be used to detect aquifer leakage (caprock confinement) and the distribution of surrounding faults and fractures, which are the two most important unsolved quantities in assessing geological CO2 storage strategies.

Abstract Grylloprimevala jilina is a true cave insect living in the dark areas of caves. It has the characteristics of sparse skin pigmentation, degeneration of the compound eyes and monocular eyes, and obvious preference for high‐humidity and low‐temperature environments. Given the highly specialized, rare, and limited distribution, G. jilina is considered an endangered species and also a first‐level national protected insect in China. Cave creatures often undergo dramatic morphological changes in their sensory systems to adapt to the cave environment. Most previous studies mainly focused on morphological adaptive changes in cave insects, and only a few studied the changes at the gene level. In this study, we performed transcriptome analysis of G. jilina and constructed phylogenetic trees of genes that are related to environmental adaptation, including chemosensory, visual‐related, reproduction‐related, temperature adaptation‐related, and winged morph differentiation‐related genes. Besides, the expression levels of environmental adaption‐related genes in different tissues, including antennae, heads, thoraxes, abdomens, legs, and tails, were analyzed. The results showed the loss of chemosensory genes and vision‐related genes, the conservation of reproduction‐related genes and temperature adaptation‐related genes, and the conservation of wing‐related genes despite the loss of wings, and the results were consistent with other cave insects. The identification and expression study of genes possibly related to the environmental adaptability in G. jilina provided basic data for the protection of this endangered species and increased knowledge about insect evolution in general.

Potential cancer therapy can be accomplished by utilizing nano-based platforms that supply facilitated drug penetration inside cancer cells. In this paper, an intelligent therapeutic nano-based system derived from metal–organic framework (MOF) core–shell hybrids with the capacity of potential drug loading, tumor microenvironment-triggered drug release as well as promising cell penetration was developed. The core–shell iron oxide-platinium@MOF/epirubicin (Fe3O4-Pt@MOF/EPI) nanospheres were constructed, where these nanoplatforms endow the system with the capability of pH-responsive drug release. The synthesized Fe3O4-Pt@MOF/EPI nanoparticles were characterized using different well-known techniques. The Fe3O4-Pt@MOF/EPI nanospheres were shown to have a dried size of around 50 nm (evidenced by SEM analysis), a spherical/core–shell/porous structure (evidenced by TEM), and an average hydrodynamic size of 92.89 nm (evidenced by DLS). Additionally, TGA analysis revealed that Fe3O4-Pt@MOF/EPI nanospheres had a weight loss at temperatures between 220 and 450 °C associated with the removal of MOF and EPI from the structure of core–shell nanospheres. The N2 adsorption–desorption data also reflected the porosity of core–shell Fe3O4-Pt@MOF nanospheres by indicating type IV behavior with an apparent hysteresis loop in the range of 0.38–0.98. Furthermore, XRD analysis disclosed the changes in the peak intensity at positions of 57.2° and 39.5°, which indicated the effects of loaded MOF on Fe3O4-Pt nanosphere. Moreover, core–shell Fe3O4-Pt@MOF/EPI nanospheres showed high loading capacity and drug release in a pH-responsive manner. Cell viability and cellular uptake assays on mouse fibroblast (NIH3T3) and triple-negative 4 T1 breast (TNFB) tumors showed that the core–shell Fe3O4-Pt@MOF/EPI nanospheres effectively inhibited TNFB cancer cells proliferation through inducing higher cell penetration compared to free EPI while having good biocompatibility against NIH3T3 cells. In conclusion, the present study may provide useful information about the development of efficient anticancer platforms against breast cancer cells, while further in vivo and pre-clinical assays are required to support this study.

Ovarian aging is a significant challenge in gynecology, and there is currently no effective treatment for it. However, the medicinal agent Qingxin Zishen decoction (QZD) has shown potential in the treatment of ovarian dysfunction. The present study aimed to evaluate the mitochondrial apoptotic mechanism of delayed ovarian aging in QZD in aging rats. The healthy female Sprague-Dawley (SD) rats (n = 40, 350 ± 20 g) were randomly assigned to different dosage groups and 4-month-old SD rats (n = 10) were assigned to the control group. QZD groups were treated with QZD for four weeks, and ovarian tissues were extracted for mRNA and protein assays to examine the role of the apoptotic pathway in QZD. The results showed that QZD treatment for four weeks significantly increased the mRNA and protein expressions of the anti-apoptotic gene B-cell lymphoma 2 (Bcl-2) and Bcl-2/Bax ratio, as well as downregulated the pro-apoptotic genes Bax, caspase-3, and caspase-9. Moreover, QZD treatment effectively reduced the expression of cytochrome C (cyto-C) and apoptotic protease-activating factor 1 (Apaf-1), both of which are components of the intrinsic apoptotic pathway. These changes exhibited a dose-response manner. The findings suggest that QZD might have therapeutic potential in delaying ovarian mitochondrial function decline and in preventing and treating ovarian aging-related diseases by downregulating and upregulating the pro-apoptotic (Bax, caspase-3, caspase-9, cyto-C, Apaf-1) and anti-apoptotic (Bcl-2 and Bcl-2/Bax ratio) genes, respectively.

The sparse leaf patch of seashore paspalum (Paspalum vaginatum Sw.) caused by Microdochium paspali seriously impacts the landscape value of turf and poses a challenge to the maintenance and management of golf courses. Little is known about the genome of M. paspali or the potential genes underlying pathogenicity. In this study, we present a high-quality genome assembly of M. paspali with 14 contigs using the Nanopore and Illumina platform. The M. paspali genome is roughly 37.32 Mb in size and contains 10,365 putative protein-coding genes. These encompass a total of 3,830 pathogen-host interactions (PHI) genes, 481 carbohydrate-active enzymes (CAZymes) coding genes, 105 effectors, and 50 secondary metabolite biosynthetic gene clusters (SMGCs) predicted to be associated with pathogenicity. Comparative genomic analysis suggests M. paspali has 672 species-specific genes (SSGs) compared to two previously sequenced non-pathogenic Microdochium species, including 24 species-specific gene clusters (SSGCs). Comparative transcriptomic analyses reveal that 739 PHIs, 198 CAZymes, 40 effectors, 21 SMGCs, 213 SSGs, and 4 SSGCs were significantly up-regulated during the process of infection. In conclusion, the study enriches the genomic resources of Microdochium species and provides a valuable resource to characterize the pathogenic mechanisms of M. paspali.

Probability of arc re-strike increases with the increment of break voltage, especially in an arc chamber of DC bridge-type contacts equipped with permanent magnets. Among all types of arc re-strikes, the most dangerous one is that part of the arc re-enters the contact gap, which is defined as swirl re-strike in this paper. In this paper, the arc images and arc voltage waveforms were analyzed, and the typical features of arc re-strike were identified. In addition, the probability of arc swirl re-strike when the supply voltages range from 270 V to 730 V and the magnetic flux densities ranges from 30 mT to 70 mT were revealed. Mechanism of the swirl re-strike is explained and it is due to the randomness of positions of both the arc igniting and the arc-root transferring on stationary contacts, as well as the non-uniformly distributed magnetic field in the arcing region. Finally, measures to prevent arc re-strike were proposed, and their effectiveness on eliminating re-strike were verified at the voltage range of up to 730V and magnetic flux. Occurrence probability of arc re-strike drops from unity to 13% at 730 V.

Parkinson’s disease (PD) is a neurodegenerative disease of the brain associated with motor symptoms. With the maturation of machine learning (ML), especially deep learning, ML has been used to assist in the diagnosis of PD. In this paper, we explore graph neural networks (GNNs) to implement PD prediction using MRI data. However, most existing GNN models suffer from the efficiency of graph construction on MRI data and the problem of overfitting on small data. This paper proposes a novel multi-layer GNN model that incorporates a fast graph construction method and a sparsity-based pooling layer with an attention mechanism. In addition, graph structure sparsity is plugged into the graph pooling layer as prior knowledge to mitigate overfitting in model training. Experimental results on real-world datasets demonstrate the effectiveness of the proposed model and its superiority over baseline methods.

Pharmaceutical analysis is a discipline based on chemical, physical, biological, and information technologies. At present, biotechnological analysis is a short branch in pharmaceutical analysis; however, bioanalysis is the basis and an important part of medicine. Biotechnological approaches can provide information on biological activity and even clinical efficacy and safety, which are important characteristics of drug quality. Because of their advantages in reflecting the overall biological effects or functions of drugs and providing visual and intuitive results, some biotechnological analysis methods have been gradually applied to pharmaceutical analysis from raw material to manufacturing and final product analysis, including DNA super-barcoding, DNA-based rapid detection, multiplex ligation-dependent probe amplification, hyperspectral imaging combined with artificial intelligence, 3D biologically printed organoids, omics-based artificial intelligence, microfluidic chips, organ-on-a-chip, signal transduction pathway-related reporter gene assays, and the zebrafish thrombosis model. The applications of these emerging biotechniques in pharmaceutical analysis have been discussed in this review.

Gout is a metabolic disease that can result in the formation of gout stones. It is essential to promptly identify and confirm the type of gout stone to alleviate pain and inflammation in patients and prevent complications associated with gout stones. Traditional detection methods, such as X-ray, ultrasound, CT scanning, and blood uric acid measurement, have limitations in early diagnosis. Therefore, this article aims to explore the use of micro Raman spectroscopy, Fourier transform infrared spectroscopy, and Terahertz time-domain spectroscopy systems to detect gout stone samples. Through comparative analysis, Terahertz technology and Raman spectroscopy have been found to provide chemical composition and molecular structure information of different wavebands of samples. By combining these two technologies, faster and more comprehensive analysis and characterization of samples can be achieved. In the future, handheld portable integrated testing instruments will be developed to improve the efficiency and accuracy of testing. Furthermore, this article proposes establishing a spectral database of gout stones and urinary stones by combining Raman spectroscopy and Terahertz spectroscopy. This database would provide accurate and comprehensive technical support for the rapid diagnosis of gout in clinical practice.

BackgroundObsessive-compulsive disorder (OCD) is a common and chronic mental illness with a high rate of disability. Internet-based cognitive behavioral therapy (ICBT) makes online treatment available to patients and has been shown to be effective. However, 3-arm trials on ICBT, face-to-face cognitive behavioral group therapy (CBGT), and only medication are still lacking. ObjectiveThis study is a randomized, controlled, assessor-blinded trial of 3 groups for OCD: ICBT combined with medication, CBGT combined with medication, and conventional medical treatment (ie, treatment as usual [TAU]). The study aims to investigate the efficacy and cost-effectiveness of ICBT related to CBGT and TAU for adults with OCD in China. MethodsIn total, 99 patients with OCD were selected and randomly assigned to the ICBT, CBGT, and TAU groups for treatment for 6 weeks. The primary outcomes were the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the self-rating Florida Obsessive-Compulsive Inventory (FOCI), compared at baseline, during treatment (3 weeks), and after treatment (6 weeks), to analyze efficacy. The secondary outcome was the EuroQol Visual Analogue Scale (EQ-VAS) scores of the EuroQol 5D Questionnaire (EQ-5D). The cost questionnaires were recorded to analyze cost-effectiveness. ResultsRepeated-measures ANOVA was used for data analysis, and the final effective sample size was 93 (ICBT: n=32, 34.4%; CBGT: n=28, 30.1%; TAU: n=33, 35.5%). After 6-week treatment, the YBOCS scores of the 3 groups significantly decreased (P

Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future.

Abstract Neutrophils are important effector cells during inflammation, which play complex roles. Therefore, investigating the regulation of neutrophil accumulation during inflammation might provide targets for treating related diseases. In the present study, we generated a ripk3-deficient zebrafish line to study the roles of Ripk3 in neutrophil-related inflammation. The homeostatic hematopoiesis and cytokine expression of the ripk3-deficient larvae were unaltered. The ripk3-deficient larvae with caudal fin fold injury exhibited similar neutrophil enrichment with wild-type larvae, suggesting that Ripk3 is not essential for non-infectious inflammatory responses. When challenged with lipopolysaccharide (LPS), the ripk3-deficient larvae showed significantly less neutrophil accumulation in the injection site and differential expression of several key cytokines. Ripk3 inhibitors could also attenuate neutrophil accumulation in wild-type larvae, indicating that Ripk3 could serve as a candidate target for inflammation treatment. In summary, our study indicated that Ripk3 has an essential role in LPS-induced inflammatory responses. It was suggested that the ripk3-deficient zebrafish might be applied in developing infectious disease models, while Ripk3 also has potential as an inflammation-treatment target.

GL-V9, a new synthetic flavonoid derived from wogonin, has shown beneficial biological functions. In this study, accurate and sensitive UPLC-MS/MS methods were developed and validated for the quantification of GL-V9 and its glucuronide metabolite (5-O-glucuronide GL-V9) in Beagle dog plasma. The chromatographic separation was performed on a C8 column (ACE Excel 5 C8 50×3.0 mm) using 0.1% formic acid and acetonitrile were used as mobile phase. Mass detection was performed on a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) interface operating in positive ion mode. Quantitative analysis was performed in multiple reaction monitoring (MRM) mode with the transitions of m/z 410.2→126.1 for GL-V9, m/z 586.3→410.0 for 5-O-glucuronide GL-V9 and m/z 180.0→110.3 for phenacetin (internal standard), respectively. The calibration curves for GL-V9 and 5-O-glucuronide GL-V9 showed excellent linearity over the concentration range of 0.5-500 ng/mL with correlation coefficient greater than 0.99. The intra- and inter-day accuracies were within 99.86% to 109.20% for GL-V9 and 92.55% to 106.20% for 5-O-glucuronide GL-V9, respectively. The mean recovery was 88.64% ± 2.70% for GL-V9, and 92.31% ± 6.28% for 5-O-glucuronide GL-V9, respectively. The validated method was successfully applied to the pharmacokinetic study in Beagle dogs after oral and intravenous administration. The oral bioavailability of GL-V9 was approximately 2.47%~4.35% in Beagle dogs and reached steady state on the fifth day after repeated dosing.

Background: The Delta variant of concern (VOC) is rapidly becoming the dominant strain globally. We report the clinical characteristics and severity of hospitalized patients infected with Delta and Beta VOCs during the local outbreak in Harbin, Heilongjiang Province, China, and the effect of vaccines on the Delta variant. Methods: We collected a total of 735 COVID-19 patients from the First Affiliated Hospital of Harbin Medical University, including 96 cases infected with the Delta VOC and 639 cases infected with the Beta VOC. Demographic, clinical characteristic and laboratory findings were collected and compared. Results: Differences in viral shedding, IgG and IgM levels, and the neutrophil-to-lymphocyte ratio were noted between the Delta and Beta VOCs (p < 0.05). Survival analysis of the two groups revealed longer viral shedding of the Delta VOC (p < 0.05). For the Delta VOC, the longer the vaccination period, the lower the IgG and IgM levels. IgM levels were higher in the convalescent plasma group, whereas lymphocyte counts were lower. Conclusions: Delta VOC virus shedding was longer compared with Beta VOC shedding. Vaccination with inactivated vaccines can reduce the severe illness rate of the Delta VOC. IgG and IgM levels are reduced as the time period between the first and second vaccine doses increases.

IntroductionBreast cancer (BRCA) is the most common malignancy among women worldwide. It was widely accepted that autophagy and the tumor immune microenvironment play an important role in the biological process of BRCA. Long non-coding RNAs (lncRNAs), as vital regulatory molecules, are involved in the occurrence and development of BRCA. The aim of this study was to assess the prognosis of BRCA by constructing an autophagy-related lncRNA (ARlncRNA) prognostic model and to provide individualized guidance for the treatment of BRCA.MethodsThe clinical data and transcriptome data of patients with BRCA were acquired from the Cancer Genome Atlas database (TCGA), and autophagy-related genes were obtained from the human autophagy database (HADb). ARlncRNAs were identified by conducting co‑expression analysis. Univariate and multivariate Cox regression analysis were performed to construct an ARlncRNA prognostic model. The prognostic model was evaluated by Kaplan–Meier survival analysis, plotting risk curve, Independent prognostic analysis, clinical correlation analysis and plotting ROC curves. Finally, the tumor immune microenvironment of the prognostic model was studied.Results10 ARlncRNAs(AC090912.1, LINC01871, AL358472.3, AL122010.1, SEMA3B-AS1, BAIAP2-DT, MAPT-AS1, DNAH10OS, AC015819.1, AC090198.1) were included in the model. Kaplan–Meier survival analysis of the prognostic model showed that the overall survival(OS) of the low-risk group was significantly better than that of the high-risk group (p< 0.001). Multivariate Cox regression analyses suggested that the prognostic model was an independent prognostic factor for BRCA (HR = 1.788, CI = 1.534–2.084, p < 0.001). ROCs of 1-, 3- and 5-year survival revealed that the AUC values of the prognostic model were all > 0.7, with values of 0.779, 0.746, and 0.731, respectively. In addition, Gene Set Enrichment Analysis (GSEA) suggested that several tumor-related pathways were enriched in the high-risk group, while several immune‑related pathways were enriched in the low-risk group. Patients in the low-risk group had higher immune scores and their immune cells and immune pathways were more active. Patients in the low-risk group had higher PD-1 and CTLA-4 levels and received more benefits from immune checkpoint inhibitors (ICIs) therapy.DiscussionThe ARlncRNA prognostic model showed good performance in predicting the prognosis of patients with BRCA and is of great significance to guide the individualized treatment of these patients.

Objectives The purpose of this study was systematically and quantitatively to assess the value of the neutrophil-to-lymphocyte ratio (NLR) for the diagnosis of neonatal sepsis by systematic review and meta-analysis.Design Systematic review and meta-analysis.Methods Eight major databases, including The Cochrane, PubMed, Embase, Web of Science, CNKI, Wanfang, China Biomedical Literature Database and VIP Database, were systematically searched for NLR diagnoses of neonatal sepsis from inception to June 2022. Two investigators independently conducted the literature search, screening, data extraction and quality evaluation with the Quality Assessment of Diagnostic Accuracy Studies-2 checklist. Statistical analysis was performed using Review Manager V.5.3, Stata V.16.0, R (V.3.6.0) and Meta-DISC V.1.4.Results A total of 14 studies comprising 1499 newborns were included in this meta-analysis. With a cut-off value ranging from 0.1 to 9.4, the pooled sensitivity of the NLR in the diagnosis of neonatal sepsis was 0.74 (95% CI: 0.61 to 0.83), the pooled specificity was 0.88 (95% CI: 0.73 to 0.95), the positive likelihood ratio (LR+) was 6.35 (95% CI: 2.6 to 15.47), the negative likelihood ratio (LR−) was 0.30 (95% CI: 0.19 to 0.46), the diagnostic OR (DOR) was 12.88 (95% CI: 4.47 to 37.08), area under the curve (AUC) was 0.87 (95% CI: 0.84 to 0.89). In the subgroup analysis of early-onset neonatal sepsis, the pooled sensitivity was 0.75 (95% CI: 0.47 to 0.91), the pooled specificity was 0.99 (95% CI: 0.88 to 1.00), the LR+ was 63.3 (95% CI: 5.7 to 696.8), the LR− was 0.26 (95% CI: 0.10 to 0.63), the DOR was 247 (95% CI: 16 to 3785) and the AUC was 0.97 (95% CI: 0.95 to 0.98).Conclusions Our findings suggest that the NLR is a helpful indicator for the diagnosis of early neonatal sepsis, but it still needs to be combined with other laboratory tests and specific clinical manifestations.

IntroductionWe did a systematic review and meta-analysis to assess the efficacy and safety of immune checkpoint inhibitors combined with or without chemotherapies in patients with esophageal squamous cell carcinoma.MethodsData related to the treatment of esophageal squamous cell carcinoma with immune checkpoint inhibitors therapy were retrieved from the database construction to August 2022. The risk of bias was assessed using the Cochrane Manual standard and RevMan 5.3 software for data synthesis. The outcome measures observed included overall survival, 12-month survival, disease control rate, objective response rate, treatment-related adverse events of grade 3 or higher, and progression-free survival. The adverse reactions included fatigue, diarrhea, hypothyroidism, rash, anemia, and anorexia.ResultsIn this meta-analysis, a total of 17 randomized controlled trials were included. In first-line therapy, immune checkpoint inhibitors combined with or without chemotherapy in the treatment of esophageal squamous cell carcinoma was more effective than chemotherapy alone. Overall survival, 12-month survival rate, and objective response rate were statistically significant. Among second-line treatments, immune checkpoint inhibitors combined with or without chemotherapy in the treatment of esophageal squamous cell carcinoma had statistically significant overall survival, 12-month survival, objective response rate, treatment-related adverse events of grade 3 or higher, and progression-free survival compared with chemotherapy alone.ConclusionBoth first- and second-line immune checkpoint inhibitors are effective for esophageal squamous cell carcinoma, and the adverse reactions are controllable and safe.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021282586.

The presence of undesirable microorganisms in silage always leads to poor fermentation quality and low aerobic stability. Pyroligneous acid (PA), a by-product of biochar production, is known to have strong antimicrobial and antioxidant activities. To investigate the effects of PA on fermentation characteristics, aerobic stability, and microbial communities, Napier grass was ensiled with or without 1 and 2% PA for 30 days and then aerobically stored for 5 days. The results showed that PA application decreased (P < 0.01) the pH value, ammonia nitrogen content, and number of undesirable microorganisms (coliform bacteria, yeasts, and molds) after 30 days of ensiling and 5 days of exposure to air. The temperature of the PA-treated group was stable during the 5-day aerobic test, which did not exceed room temperature more than 2°C. The addition of PA also enhanced the relative abundance of Lactobacillus and reduced that of Klebsiella and Kosakonia. The relative abundance of Candida was higher in PA-treated silage than in untreated silage. The addition of PA decreased the relative abundance of Kodamaea and increased that of Monascus after 5 days of exposure to air. The abundances of Cladosporium and Neurospora were relatively high in 2% PA-treated NG, while these genera were note observed in the control group. These results suggested that the addition of PA could improve fermentation characteristics and aerobic stability, and alter microbial communities of silage.

To investigate the feasibility of developing litchi leaves as silage, we determined the fermentation quality of four varieties of litchi leaves (including “Wanpu”, “Wuyejiu”, “Tongzai” and “Zhuangyuanhong”) ensiled with or without Lactobacillus plantarum on day 3, 7, 14 and 30. The in vitro dry matter digestibility and gas production of litchi leaves silages were also determined after 30 days of ensiling. The results showed that Lactobacillus plantarum significantly reduced pH value (p < 0.01), inhibited coliform bacteria, and reduced the production of ammonia nitrogen (p < 0.01) in all the four kinds of litchi leaves silage. Moreover, Lactobacillus plantarum treated litchi leaves (“Wanpu” and “Zhuangyuanhong”) had lower yeasts than the untreated litchi leaves during ensiling. The number of molds in Lactobacillus plantarum treated groups (“Tongzai” and “Zhuangyuanhong”) was below the detected level after 30 days ensiling, which was lower than that of the untreated groups. The addition of Lactobacillus plantarum also contributed to improving IVDMD and markedly reduced (p < 0.01) gas production of all litchi leaves silages. Conclusions: Lactobacillus plantarum can improve the fermentation quality and in vitro digestion characteristics of litchi leaves silage. Developing litchi leaves as silage material is a feasible way to recycle litchi leaves.

Summary Endophytes may participate in the conversion of metabolites within medicinal plants, influencing the efficacy of host. However, the distribution of endophytes within medicinal plants P. notoginseng and how it contributes to the conversion of saponins are not well understood. Here, we determined the distribution of saponins and endophytes within P. notoginseng compartments and further confirm the saponin conversion by endophytes. We found metabolites showed compartment specificity within P. notoginseng. Potential saponin biomarkers, such as Rb1, Rg1, Re, Rc and Rd, were obtained. Endophytic diversity, composition and co‐occurrence networks also showed compartment specificity, and bacterial alpha diversity values were highest in root compartment, consistently decreased in the stem and leaf compartments, whereas those of fungi showed the opposite trend. Potential bacterial biomarkers, such as Rhizobium, Bacillus, Pseudomonas, Enterobacter, Klebsiella, Pantoea and fungal biomarkers Phoma, Epicoccum, Xylariales, were also obtained. Endophytes related to saponin contents were found by Spearman correlation analysis, and further verification experiments showed that Enterobacter chengduensis could convert ginsenoside Rg1 to F1 at a rate of 13.24%; Trichoderma koningii could convert ginsenoside Rb1 to Rd at a rate of 40.00% and to Rg3 at a rate of 32.31%; Penicillium chermesinum could convert ginsenoside Rb1 to Rd at a rate of 74.24%.