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Abstract Background Environmental heat stress (HS) can have detrimental effects on milk production by compromising the mammary function. Mammary plasma flow (MPF) plays a crucial role in nutrient supply and uptake in the mammary gland. In this experiment, we investigated the physiological and metabolic changes in high-yielding cows exposed to different degrees of HS: no HS with thermal-humidity index (THI) below 68 (No-HS), mild HS (Mild-HS, 68 ≤ THI ≤ 79), and moderate HS (Mod-HS, 79

Summary: Background: This was a multicenter, single-arm dose-ranging phase 2 study aimed to assess the efficacy and safety of LY01610, a liposomal irinotecan, at various doses for patients with relapsed small cell lung cancer (SCLC). Methods: This study (NCT04381910) enrolled patients with relapsed SCLC at 10 hospitals across China, who have failed with previous platinum-based treatments. LY01610 was administered at doses of 60 mg/m2, 80 mg/m2, and 100 mg/m2. Primary endpoints were investigator-assessed objective response rate (ORR) and investigator-assessed duration of response (DoR). Secondary endpoints included investigator-assessed disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Findings: From September 3, 2020 to March 3, 2022, a total of 66 patients were enrolled, with 6, 30, and 30 allocated to the 60 mg/m2, 80 mg/m2, and 100 mg/m2 dose groups, respectively, with 68% (45/66) having a chemotherapy-free interval

ABSTRACTFollowing viral infection, the innate immune system senses viral products, such as viral nucleic acids, to activate innate defence pathways, leading to inflammation and apoptosis, control of cell proliferation, and consequently, threat to the whole body. The ocular surface is exposed to the external environment and extremely vulnerable to viral infection. Several studies have revealed that viral infection can induce inflammation of the ocular surface and reduce tear secretion of the lacrimal gland (LG), consequently triggering ocular morphological and functional changes and resulting in dry eye disease (DED). Understanding the mechanisms of DED caused by viral infection and its potential therapeutic strategies are crucial for clinical interventional advances in DED. This review summarizes the roles of viral infection in the pathogenesis of DED, applicable diagnostic and therapeutic strategies, and potential regions of future studies.

IntroductionTranscranial photobiomodulation (tPBM) is a non-invasive neuromodulation technology which has become a promising therapy for treating many brain diseases. Although it has been confirmed in studies targeting neurological diseases including Alzheimer’s and Parkinson’s that tPBM can improve cognitive function, the effectiveness of interventions targeting TBI patients remains to be determined. This systematic review examines the cognitive outcomes of clinical trials concerning tPBM in the treatment of traumatic brain injury (TBI).MethodsWe conducted a systematic literature review, following the PRISMA guidelines. The PubMed, Web of Science, Scopus, EMBASE, and Cochrane Library databases were searched before October 31, 2023.ResultsThe initial search retrieved 131 articles, and a total of 6 studies were finally included for full text-analysis after applying inclusion and exclusion criteria.ConclusionResults showed improvements in cognition for patients with chronic TBI after tPBM intervention. The mechanism may be that tPBM increases the volume of total cortical gray matter (GM), subcortical GM, and thalamic, improves cerebral blood flow (CBF), functional connectivity (FC), and cerebral oxygenation, improving brain function. However, due to the significant heterogeneity in application, we cannot summarize the optimal parameters for tPBM treatment of TBI. In addition, there is currently a lack of RCT studies in this field. Therefore, given this encouraging but uncertain finding, it is necessary to conduct randomized controlled clinical trials to further determine the role of tPBM in cognitive rehabilitation of TBI patients.

Abstract Background Most patients with ovarian cancer (OC) treated with platinum-based chemotherapy have a dismal prognosis owing to drug resistance. However, the regulatory mechanisms of circular RNA (circRNA) and p53 ubiquitination are unknown in platinum-resistant OC. We aimed to identify circRNAs associated with platinum-resistant OC to develop a novel treatment strategy. Methods Platinum-resistant circRNAs were screened through circRNA sequencing and validated using quantitative reverse-transcription PCR in OC cells and tissues. The characteristics of circNUP50 were analysed using Sanger sequencing, oligo (dT) primers, ribonuclease R and fluorescence in situ hybridisation assays. Functional experimental studies were performed in vitro and in vivo. The mechanism underlying circNUP50-mediated P53 ubiquitination was investigated through circRNA pull-down analysis and mass spectrometry, luciferase reporters, RNA binding protein immunoprecipitation, immunofluorescence assays, cycloheximide chase assays, and ubiquitination experiments. Finally, a platinum and si-circNUP50 co-delivery nanosystem (Psc@DPP) was constructed to treat platinum-resistant OC in an orthotopic animal model. Results We found that circNUP50 contributes to platinum-resistant conditions in OC by promoting cell proliferation, affecting the cell cycle, and reducing apoptosis. The si-circNUP50 mRNA sequencing and circRNA pull-down analysis showed that circNUP50 mediates platinum resistance in OC by binding p53 and UBE2T, accelerating p53 ubiquitination. By contrast, miRNA sequencing and circRNA pull-down experiments indicated that circNUP50 could serve as a sponge for miR-197-3p, thereby upregulating G3BP1 to mediate p53 ubiquitination, promoting OC platinum resistance. Psc@DPP effectively overcame platinum resistance in an OC tumour model and provided a novel idea for treating platinum-resistant OC using si-circNUP50. Conclusions This study reveals a novel molecular mechanism by which circNUP50 mediates platinum resistance in OC by modulating p53 ubiquitination and provides new insights for developing effective therapeutic strategies for platinum resistance in OC. Graphical Abstract

Abstract Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease and a risk factor for lung cancer. Small cell lung cancer is a neuroendocrine tumor with a high degree of malignancy and an overall five-year survival rate of less than 7%. Cases presentation Herein, we report the case of an 68-year-old male presented to the respiratory department with cough, sputum, and dyspnea. He was diagnosed as community acquired pneumonia and treated with intravenous anti-infection. Previous pulmonary function was definitively diagnosed as COPD. About 7 months after discharge, the patient returned to the hospital for cough and dyspnea. After diagnosis of the tumor, cisplatin, etoposide and durvalumab were administered. Finally the patient died of respiratory failure approximately 9 months after his diagnosis. Conclusions For COPD patients with immunocompromised manifestations, it is necessary to be alert to complications and shorten the follow-up interval of chest CT. COPD may accelerate the formation and progression of SCLC.

Currently, osteoporosis-related fractures become the most cutting-edge problem of diabetes-related complications. Rational diet is not only the basis of glycemic management in type 2 diabetes patients, but also the direction of diabetic bone health.This review highlights the importance of micronutrient supplementation (including calcium, magnesium, zinc, vitamin D, vitamin K, and vitamin C) for patients with T2DM, as well as describing the constructive intermediary role of gut flora between T2DM and bone through nutrients predominantly high in dietary fiber. In addition, it is recommended to combine the Mediterranean dietary pattern with other diversified management approaches to prevent OP. Therefore, this provides a theoretical basis for the potential role of islet β-cells in promoting bone health.

Objective To investigate the variation of hematological parameters in male plateletpheresis donors. Methods A total of 194 male plateletpheresis donors from Fujian Blood Center were divided into two groups according to the frequency of blood donation: Group 1 (n=107), with the number of plateletpheresis donation less than or equal to 12 per year; Group 2 (n=87), with the number of plateletpheresis donation more than 12 per year. Serum ferritin (SF) and related iron metabolism indexes, red blood cell count (RBC), hemoglobin (Hb), hematocrit(Hct), platelet count (Plt) and other blood routine indexes, as well as percentage of reticulocyte counts (RET%), immature reticulocyte fraction(IRF) and other reticulocyte indexes were measured before blood donation and analyzed by statistical methods. Results Compared with Group 2, the RBC, Hb, Hct, SF in Group 1 were significantly higher, while Plt, RET%and IRF were significantly lower(P

Abstract Neural architecture search (NAS) is an extremely complex optimization task. Recently, population-based optimization algorithms, such as evolutionary algorithm, have been adopted as search strategies for designing neural networks automatically. Various population-based NAS methods are promising in searching for high-performance neural architectures. The explosion gravitation field algorithm (EGFA) inspired by the formation process of planets is a novel population-based optimization algorithm with excellent global optimization capability and remarkable efficiency, compared with the classical population-based algorithms, such as GA and PSO. Thus, this paper attempts to develop a more efficient NAS method, called EGFA-NAS, by utilizing the work mechanisms of EGFA, which relaxes the search discrete space to a continuous one and then utilizes EGFA and gradient descent to optimize the weights of the candidate architectures in conjunction. To reduce the computational cost, a training strategy by utilizing the population mechanism of EGFA-NAS is proposed. In addition, a weight inheritance strategy for the new generated dust individuals is proposed during the explosion operation to improve performance and efficiency. The performance of EGFA-NAS is investigated in two typical micro search spaces: NAS-Bench-201 and DARTS, and compared with various kinds of state-of-the-art NAS competitors. The experimental results demonstrate that EGFA-NAS is able to match or outperform the state-of-the-art NAS methods on image classification tasks with remarkable efficiency improvement.

Abstract Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

Abstract Background Rises in global warming and extreme weather occurrence make the risk of heat stress (HS) induced by high ambient temperatures more likely in high-yielding dairy cows, resulting in low milk quality and yield. In animals, oxygen is involved in many physiological and metabolic processes, but the effects of HS on oxygen metabolism remain unclear. Thus, the current study aimed to investigate how oxygen metabolism plays a role in health status of dairy cows by measuring the milk yield, milk composition, and blood biochemical variables of cows under different levels of HS: none (No-HS), mild (Mild-HS), and moderate HS (Mod-HS). Results The HS significantly increased rectal temperature (P treat

The silkworm cocoon (SC), both as a traditional Chinese medicine and as the raw material for biocompatible carriers, has been extensively used in the medical and biomedical fields. This review elaborates on the multiple functions of SC, with an in-depth analysis of its chemical composition, biological activities, as well as its applications in modern medicine. The primary chemical components of SC include silk fibroin (SF), silk sericin (SS), and other flavonoid-like bioactive compounds demonstrating various biological effects. These include hypoglycemic, cardioprotective, hypolipidemic, anti-inflammatory, antioxidant, and antimicrobial actions, which highlight its potential therapeutic benefits. Furthermore, the review explores the applications of silk-derived materials in drug delivery systems, tissue engineering, regenerative medicine, and in vitro diagnostics. It also highlights the progression of SC from laboratory research to clinical trials, emphasizing the safety and efficacy of SC-based materials across multiple medical domains. Moreover, we discuss the market products developed from silk proteins, illustrating the transition from traditional uses to contemporary medical applications. This review provides support in understanding the current research status of SC and the further development and application of its derived products.

Abstract Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either “Unknown” or “Potentially” actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional assays. Variants categorized by PODS as Potentially actionable (N = 204) were more likely to be oncogenic than those categorized as Unknown (N = 230) (37% vs 13%, p = 4.08e-09). Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.

Abstract Background Vesicle trafficking is a highly important process in numerous human diseases, especially in the central nervous system dysfunctions. However, as a key component of vesicle trafficking‐related genes (VRGs), Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has not been systematically elucidated in glioma so far. Methods Differentially expressed VRGs were selected using molecular signatures database (MSigDB), The Cancer Genome Atlas (TCGA), and Genotype‐Tissue Expression (GTEx) mRNA expression profiles. Further exploration of CNIH4 was determined using LASSO‐Cox regression algorithms. Then Kaplan–Meier (K‐M) plotter, receiver operating characteristic (ROC) curves, and multivariate Cox regression analyses were utilized to assess the independent significance of CNIH4 in the CGGA validation cohort. Functional exploration was performed with Gene Set Enrichment Analysis (GSEA) and then verified using a series of functional experiments in glioma cells. Finally, the consensus clustering algorithm was applied to identify clusters in glioma samples. After that, differences in prognosis, the tumor immune microenvironment (TIME), and therapy response were evaluated between clusters. Results CNIH4 was shown to be overexpressed in malignant glioma variants and was frequently observed in GCSs and TMZ‐resistant cell lines. Higher CNIH4 levels were significantly related to poor outcomes and positively correlated with adverse clinicopathological characteristics. Survival analyses revealed CNIH4 as an independent risk factor that outperformed traditional measures. Enrichment analysis indicated that overactive CNIH4 significantly gathered in stem cell processes. Furthermore, functional assays of silencing CNIH4 expression suppressed stem cell‐like properties in vitro and inhibited tumorigenicity in vivo. Finally, the CNIH4‐enriched subgroup negatively modulated immunotherapeutic response and reflected lower chemotherapy sensitivity for glioma patients. Conclusion Our study identified CNIH4 as a potential VRG that regulates tumor stemness, microenvironment immunity, and chemotherapy sensitivity. It may serve as a novel prognostic factor and a promising target against glioma therapy.

ObjectiveTo establish the diagnostic accuracy of RASSF1A (Ras association domain family 1 isoform) methylation using bronchial aspirates as an auxiliary method for diagnosing lung cancer through a systematic review and meta-analysis.MethodsStudies published prior to October 30, 2022, were retrieved from the Embase, PubMed, Web of Science, and Wan Fang databases using the keywords "lung cancer", "RASSF1A", "methylation", and "bronchial aspirates". A fixed or random effect model was used to calculate the combined sensitivity, specificity, positive likelihood ratios (LR), negative LR, diagnostic odds ratio (DOR), along with the respective 95% confidence intervals (CIs) and the area under the curve (AUC) with Q index. The threshold effect was defined by using the Spearman correlation coefficient, and the Deeks funnel plot was generated to evaluate publication bias.ResultsAmong the 12 trials that met the inclusion criteria, a total of 2388 participants were involved. The pooled results for the diagnosis of lung cancer were as follows, when compared to the pathological diagnosis: sensitivity of 0.47 (95% CI: 0.45-0.50), specificity of 0.96 (95% CI: 0.95-0.97), positive LR of 12.18 (95% CI: 8.96-16.55), negative LR of 0.56 (95% CI: 0.52-0.61), DOR of 24.05 (95% CI: 17.29-33.47), and AUC of 0.78 (Q index = 0.72), respectively. The sensitivity of the RASSF1A methylation assay was relatively low in a detailed subgroup analysis, fluctuating between 0.39 and 0.90, indicating a limitation in its diagnostic value for lung cancer. The RASSF1A methylation assay, on the other hand, demonstrated excellent specificity, suggesting a high exclusion value. Of note, the diagnostic sensitivity, specificity, DOR, and AUC for small cell lung cancer were 0.90 (0.84-0.94), 0.95 (0.94-0.97), 249.5 (103.94-598.8), and 0.98, respectively, showing that RASSF1A methylation was a promising biomarker for diagnosing small cell lung cancer with both high diagnostic and exclusion value. Furthermore, RASSF1A methylation using bronchial washings and bronchial aspirates showed a high AUC of 0.998 and 0.93, respectively, indicating excellent diagnostic performance.ConclusionsThe methylation of RASSF1A in bronchial aspirates demonstrated a high level of diagnostic accuracy and has the potential to be a valuable supplementary diagnostic method, especially for identifying small cell lung cancer.

Consumption of fried foods is highly prevalent in the Western dietary pattern. Western diet has been unfavorably linked with high risk of developing cardiovascular diseases. Heart failure (HF) as a cardiovascular disease subtype is a growing global pandemic with high morbidity and mortality. However, the causal relationship between long-term fried food consumption and incident HF remains unclear. Our population-based study revealed that frequent fried food consumption is strongly associated with 15% higher risk of HF. The causal relationship may be ascribed to the dietary acrylamide exposure in fried foods. Further cross-sectional study evidenced that acrylamide exposure is associated with an increased risk of HF. Furthermore, we discover and demonstrate that chronic acrylamide exposure may induce HF in zebrafish and mice. Mechanistically, we reveal that acrylamide induces energy metabolism disturbance in heart due to the mitochondria dysfunction and metabolic remodeling. Moreover, acrylamide exposure induces myocardial apoptosis via inhibiting NOTCH1-phosphatidylinositol 3-kinase/AKT signaling. In addition, acrylamide exposure could affect heart development during early life stage, and the adverse effect of acrylamide exposure is a threat for next generation via epigenetic change evoked by DNA methyltransferase 1 (DNMT1). In this study, we reveal the adverse effects and underlying mechanism of fried foods and acrylamide as a typical food processing contaminant on HF from population-based observations to experimental validation. Collectively, these results both epidemiologically and mechanistically provide strong evidence to unravel the mechanism of acrylamide-triggered HF and highlight the significance of reducing fried food consumption for lower the risk of HF.

Background and Aims. The aim of this study was to investigate the association between serum phosphate levels and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods and Results. The study sample consisted of 1657 T2DM patients hospitalized between 2017 and 2019. Patients were categorized into quartiles based on their serum phosphate levels (Q1–Q4). An increasing trend in the prevalence of DR was observed across these quartiles. Subsequently, logistic regression analysis was employed to adjust for potential confounders, such as gender, age, BMI, and duration of diabetes, and to evaluate the odds ratios (ORs) associated with these quartiles. The prevalence of DR showed an increasing trend with elevated serum phosphate levels. Logistic regression further confirmed that serum phosphate levels remain an independent risk factor for DR. Conclusion. Elevated serum phosphate levels are closely associated with the prevalence of DR in hospitalized T2DM patients. Further studies are needed to establish causality. This trial is registered with chiCTR2000032374.

Scramjet based on solid propellant has become a potential choice for the development of future hypersonic vehicles. In this paper, a boron-containing solid rocket scramjet based on the central strut injection was proposed, and the ground direct-connect experiment with the equivalence ratios of 0.43 to 2.4 under the flight condition of Mach 6, 25 km was carried out. The pressure and flow rate over time were measured in the experiment. The results show that the engine can realize stable supersonic mode or subsonic mode combustion by changing the gas flow rate. The engine can effectively increase the combustor pressure, reduce the unstable combustion time, and advance the strong combustion position by increasing the gas flow rate. The engine achieved high combustion efficiency when the equivalence ratio was about 1, with a maximum of 88.28%. A numerical simulation analysis was also carried out in this paper. Compared to the experimental results, the pressure error obtained by numerical simulation was less than 4%, and the typical position error was less than 3%, suggesting that the simulation model can be used to predict the behavior of scramjet.

Connected Automobile Vehicles (CAVs) enable cooperative driving and traffic management by sharing traffic information between them and other vehicles and infrastructures. However, malicious vehicles create Sybil vehicles by forging multiple identities and sharing false location information with CAVs, misleading their decisions and behaviors. The existing work on defending against Sybil attacks has almost exclusively focused on detecting Sybil vehicles, ignoring the traceability of malicious vehicles. As a result, they cannot fundamentally alleviate Sybil attacks. In this work, we focus on tracking the attack source of malicious vehicles by using a novel detection mechanism that relies on vehicle broadcast beacon packets. Firstly, the roadside units (RSUs) randomly instruct vehicles to perform customized key broadcasting and listening within communication range. This allows the vehicle to prove its physical presence by broadcasting. Then, RSU analyzes the beacon packets listened to by the vehicle and constructs a neighbor graph between the vehicles based on the customized particular fields in the beacon packets. Finally, the vehicle’s credibility is determined by calculating the edge success probability of vehicles in the neighbor graph, ultimately achieving the detection of Sybil vehicles and tracing malicious vehicles. The experimental results demonstrate that our scheme achieves the real-time detection and tracking of Sybil vehicles, with precision and recall rates of 98.53% and 95.93%, respectively, solving the challenge of existing detection schemes failing to combat Sybil attacks from the root.

ObjectiveTo investigate the effectiveness and safety of combining transarterial chemoembolization (TACE) with lenvatinib and camrelizumab in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC).MethodsWe retrospectively analyzed 141 patients with BCLC stage C HCC: 57 were treated with TACE combined with lenvatinib plus camrelizumab (T + L + C), 41 were treated with TACE combined with camrelizumab (T + C), and 43 were treated with TACE (TACE). The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were the objective response rate (ORR) and adverse events (AEs). Factors that affected survival were identified via Cox regression analysis.ResultsComparison of the three groups revealed a significant difference in the median overall survival (mOS), 19.8 months (95% CI 15.7–23.9) in the T + L + C combined group vs 15.7 (95% CI 13.1–18.3) months in the T + C combined group vs 9.4 (95% CI 6.2–12.5) months in the TACE group (P < 0.001). The median progression-free survival (mPFS) was significantly better in the T + L + C combination group than in the T + C combination group and the TACE group [11.4 (95% CI 7.6–15.3) months vs 8.4 (95% CI 6.2–10.5) months vs 4.8 (95% CI 3.2–6.3) months, respectively, P < 0.001)]. The objective response rate (ORR) (57.9%) and the disease control rate (DCR) (75.4%) patients in the combined T + L + C group were higher than those in the other two groups. More patients in the combined T + L + C group experienced AEs, with 16 (28.1%) patients experiencing AEs of grade 3 or higher.ConclusionsIn patients with BCLC stage C HCC, those receiving the T + L + C combination demonstrated a superior survival benefit and acceptable safety profile compared patients receiving either TACE or the T + C combination.

Highlights 1. The relationship between postoperative HPV infection and cervical cancer recurrences was explored for the first time. 2. The genotypes and viral loads of 15 types of HR-HPV were determined. 3. Continuous HR-HPV positivity after surgery and deep 1/3 interstitial infiltration were risk factors for the recurrence of cervical cancer.

Using the high arsenic copper dust from the copper fire refining furnace as the raw material, the low-temperature vacuum carbothermic reduction method is used to remove As from the dust. Differential thermal analysis of the raw materials was carried out by TGA-DSC, and the phase, chemical composition and morphology of the dust and evaporation residue were analyzed by XRD, ICP, SEM and other analytical methods. On the basis of thermodynamic analysis, the effect of evaporation temperature, residual pressure, reducing dose, evaporation time, etc. on the removal rate of As and other valuable metals. The results show that when the evaporation temperature is 350℃, the residual pressure is 100 Pa, the reducing amount is 25%, and the evaporation time is 50 min, the removal rate of As can reach 81.63% while ensuring that other metals do not evaporate basically, realizing As Selective separation of other valuable metals. The evaporate is As2O3 with higher purity, which can be used as primary As2O3 product. Valuable metals are enriched in the evaporation residue, which is convenient for the subsequent recovery of the waste acid leaching process.

ObjectiveThe study aimed to investigate the effects of a 12-week Tai Chi exercise intervention on working memory in older adults using ERP-fNIRS.MethodFifty older adults were randomly assigned to either an experimental group receiving a 12-week Tai Chi exercise intervention or a control group receiving regular daily activities. Working memory was assessed using the n-back task before and after the intervention, and spatial and temporal components of neural function underlying the n-back task were measured using ERP-fNIRS.ResultsThe experimental group demonstrated significant improvements in reaction time and accuracy on the 2-back task and showed higher activation levels in the R-DLPFC. Additionally, the Tai Chi group displayed significant increases in P3 amplitude in the overall n-back task.ConclusionThese findings suggest that Tai Chi interventions can enhance working memory in older adults, as evidenced by increasing neural activity and improving HbO in the R-DLPFC during the 2-back task.

ABSTRACT Many bacteria use small molecules, such as quorum sensing (QS) signals, to perform intraspecies signaling and interspecies or interkingdom communication. Previous studies demonstrated that some bacteria regulate their physiology and pathogenicity by employing 4-hydroxybenzoic acid (4-HBA). Here, we report that 4-HBA controls biological functions, virulence, and anthranilic acid production in Shigella sonnei. The biosynthesis of 4-HBA is performed by UbiC (SSON_4219), which is a chorismate pyruvate-lyase that catalyzes the conversion of chorismate to 4-HBA. Deletion of ubiC caused S. sonnei to exhibit impaired phenotypes, including impaired biofilm formation, extracellular polysaccharide (EPS) production, and virulence. In addition, we found that 4-HBA controls the physiology and virulence of S. sonnei through the response regulator AaeR (SSON_3385), which contains a helix-turn-helix (HTH) domain and a LysR substrate-binding (LysR_substrate) domain. The same biological functions are controlled by AaeR and the 4-HBA signal, and 4-HBA-deficient mutant phenotypes were rescued by in trans expression of AaeR. We found that 4-HBA binds to AaeR and then enhances the binding of AaeR to the promoter DNA regions in target genes. Moreover, we revealed that 4-HBA from S. sonnei reduces the competitive fitness of Candida albicans by interfering with morphological transition. Together, our results suggested that the 4-HBA signaling system plays crucial roles in bacterial physiology and interkingdom communication. IMPORTANCE Shigella sonnei is an important pathogen in human intestines. Following previous findings that some bacteria employ 4-HBA as a QS signal to regulate biological functions, we demonstrate that 4-HBA controls the physiology and virulence of S. sonnei. This study is significant because it identifies both the signal synthase UbiC and receptor AaeR and unveils the signaling pathway of 4-HBA in S. sonnei. In addition, this study also supports the important role of 4-HBA in microbial cross talk, as 4-HBA strongly inhibits hyphal formation by Candida albicans. Together, our findings describe the dual roles of 4-HBA in both intraspecies signaling and interkingdom communication.

In this study, we obtained a diamond nanocone structure using the thermal annealing method, which was proposed in our previous work. Using finite–difference time–domain (FDTD) simulations, we demonstrate that the extraction efficiencies of nitrogen–vacancy (NV) center emitters in nanostructures are dependent on the geometries of the nanocone/nanopillar, emitter polarizations and axis depths. Our results show that nanocones and nanopillars have advantages in extraction from emitter dipoles with s− and p−polarizations, respectively. In our simulations, the best results of collection efficiency were achieved from the emitter in a nanocone with s−polarization (57.96%) and the emitter in a nanopillar with p−polarization (38.40%). Compared with the nanopillar, the photon extraction efficiency of the emitters in the nanocone is more sensitive to the depth and polarization angle. The coupling differences between emitters and the nanocone/nanopillar are explained by the evolution of photon propagation modes and the internal reflection effects in diamond nanostructures. Our results could have positive impacts on the design and fabrication of NV center−based micro− and nano−optics in the future.

Abstract Background Metastasis is the main cause of mortality in cervical cancer (CC). Circular RNAs (circRNAs) have been demonstrated to play a crucial role in carcinoma biology. However, the expression and function of circRNAs in cervical cancer metastasis are still unclear. Methods In the present study, we identified a circRNA with an N6-methyladenosine (m6A) modification, circCCDC134, whose expression was increased in CC tissues by circRNA-Seq and qPCR. CircCCDC134 upregulation in CC was fine-tuned by ALKBH5-mediated m6A modification, which enhanced its stability in a YTHDF2-dependent manner. The functional experiments illustrated that circCCDC134 enhanced tumour proliferation and metastasis in vitro and in vivo. For the comprehensive identification of RNA-binding proteins, circRNA pull-down and mass spectrometry (ChIRP-MS), chromatin immunoprecipitation-seq (Chip-seq), RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were used to perform mechanistic investigations. Results The results revealed that circCCDC134 recruited p65 in the nucleus and acted as a miR-503-5p sponge to regulate the expression of MYB in the cytoplasm, ultimately stimulating HIF1A transcription and facilitating CC growth and metastasis. Conclusion: These findings indicate that circCCDC134 is an important therapeutic target and provide new regulatory model insights for exploring the carcinogenic mechanism of circCCDC134 in CC.

Mesenchymal stem cells (MSC) are particularly effective in promoting cartilage regeneration due to their immunomodulatory, anti-inflammatory and regenerative repair functions of tissues and organs. Meanwhile, the intra-articular delivery and synergy with other therapeutic drugs have been the key issues driving their further application. We report a mussel-inspired multifunctional hydrogel system, which could achieve co-delivery and synergism effect of MSC-derived exosomes (Exos) with icariin (ICA). The ICA and Exos co-delivered articular cavity injection system are expected to retain in the joint cavity and promote cartilage regeneration, due to the thermosensitive, self-healing and adhesion properties of the mussel-inspired multifunctional hydrogel. The experimental results proved that Exos enhanced the cellular uptake of ICA by more than 2-fold evenly, and the synergism of Exos and ICA efficiently improve the cell proliferation and migration. After synergic treatment, the content of matrix metalloproteinase 13 in the supernatant and intracellular decreased by 47% and 59%, respectively. In vivo study, ICA-loaded Exos exhibited prolonged retention behavior by multifunctional hydrogel delivery, thus displayed an increased cartilage protection. In the model of osteoarthritis, co-delivery hydrogel system relieved the cartilage recession, ensuring appropriate cartilage thickness.

Abstract Background Ovarian cancer (OC) is an invasive gynaecologic cancer with a high cancer-related death rate. The purpose of this study was to establish an invasion-related multigene signature to predict the prognostic risk of OC. Methods We extracted 97 invasion-related genes from The Cancer Genome Atlas (TCGA) database. Then, the ConsensusClusterPlus and limma packages were used to calculate differentially expressed genes (DEGs). To calculate the immune scores of the molecular subtypes, we used ESTIMATE to evaluate the stromal score, immune score and ESTIMATE score. MCP-counter and the GSVA package ssgsea were used to evaluate the types of infiltrating immune cells. Survival and nomogram analyses were performed to explore the prognostic value of the signature. Finally, qPCR, immunohistochemistry staining and functional assays were used to evaluate the expression and biological abilities of the signature genes in OC. Results Based on the consistent clustering of invasion-related genes, cases in the OC datasets were divided into two subtypes. A significant difference was observed in prognosis between the two subtypes. Most genes were highly expressed in the C1 group. Based on the C1 group genes, we constructed an invasion-related 6-gene prognostic risk model. Furthermore, to verify the signature, we used the TCGA-test and GSE32062 and GSE17260 chip datasets for testing and finally obtained a good risk prediction effect in those datasets. Moreover, the results of the qPCR and immunohistochemistry staining assays revealed that KIF26B, VSIG4 and COL6A6 were upregulated and that FOXJ1, MXRA5 and CXCL9 were downregulated in OC tissues. The functional study showed that the expression of KIF26B, VSIG4, COL6A6, FOXJ1, MXRA5 and CXCL9 can regulate the migration and invasion abilities of OC cells. Conclusion We developed a 6-gene prognostic stratification system (FOXJ1, MXRA5, KIF26B, VSIG4, CXCL9 and COL6A6) that is independent of clinical features. These results suggest that the signature could potentially be used to evaluate the prognostic risk of OC patients.

Abstract Background Metastatic cervical squamous cell carcinoma (CSCC) has poor prognosis and is recalcitrant to the current treatment strategies, which warrants the necessity to identify novel prognostic markers and therapeutic targets. Given that CSCC is a virus-induced malignancy, we hypothesized that the pattern recognition receptors (PRRs) involved in the innate immune response likely play a critical role in tumor development. Methods A bioinformatics analysis, qPCR, IHC, immunofluorescence, and WB were performed to determine the expression of NOD1/NOD2. The biological characteristics of overexpression NOD1 or NOD2 CSCC cells were compared to parental cells: proliferation, migration/invasion and cytokines secretion were examined in vitro through CCK8/colony formation/cell cycle profiling/cell counting, wound healing/transwell, and ELISA assays, respectively. The proliferative and metastatic capacity of overexpression NOD1 or NOD2 CSCC cells were also evaluated in vivo. FCM, mRNA and protein arrays, ELISA, and WB were used to identify the mechanisms involved, while novel pharmacological treatment were evaluated in vitro and in vivo. Quantitative variables between two groups were compared by Student’s t test (normal distribution) or Mann-Whitney U test (non-normal distribution), and one-way or two-way ANOVA was used for comparing multiple groups. Pearson χ 2 test or Fisher’s exact test was used to compare qualitative variables. Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. P values of < 0.05 were considered statistically significant. Results NOD1 was highly expressed in CSCC with lymph-vascular space invasion (LVSI, P

BackgroundHeart rate variability (HRV), a cardiac vagal tone indicator, has been proven to predict performance on some cognitive tasks that rely on the prefrontal cortex. However, the relationship between vagal tone and working memory remains understudied. This study explores the link between vagal tone and working memory function, combined with behavioral tasks and functional near-infrared spectroscopy (fNIRS).MethodsA total of 42 undergraduate students were tested for 5-min resting-state HRV to obtain the root mean square of successive differences (rMSSD) data, and then divided into high and low vagal tone groups according to the median of rMSSD data. The two groups underwent the n-back test, and fNIRS was used to measure the neural activity in the test state. ANOVA and the independent sample t-test were performed to compare group mean differences, and the Pearson correlation coefficient was used for correlation analysis.ResultsThe high vagal tone group had a shorter reaction time, higher accuracy, lower inverse efficiency score, and lower oxy-Hb concentration in the bilateral prefrontal cortex in the working memory tasks state. Furthermore, there were associations between behavioral performance, oxy-Hb concentration, and resting-state rMSSD.ConclusionOur findings suggest that high vagally mediated resting-state HRV is associated with working memory performance. High vagal tone means a higher efficiency of neural resources, beneficial to presenting a better working memory function.

Abstract Background Siraitia grosvenorii (binomial name Siraitia grosvenorii (Swingle) C. Jeffrey ex Lu et Z. Y. Zhang), also called Arhat Fruit or Monk’s Fruit, is a dried ripe fruit belonging to the Cucurbitaceae Family. S. grosvenorii has a long history of being used for constipation treatment in folk medicine. However, there are few studies where the laxative effect, related mechanisms, and active constituents of S. grosvenorii were investigated. This research explores the relationship between the common components and the laxative effect of aqueous extracts of S. grosvenorii from different habitats in China. Methods The fingerprints of S. grosvenorii aqueous extracts from different habitats were established by HPLC. The constipation mice model was used to investigate the laxative effect of S. grosvenorii aqueous extracts. The motilin (MTL) level in mice serum, and the water content of the large and small intestines in mice were determined. The profile-effect relationship of S. grosvenorii aqueous extracts was preliminarily clarified using gray correlation analysis. Results Nine common peaks were identified from the fingerprint of aqueous extracts of S. grosvenorii. The aqueous extracts obviously shortened the incubation period of defecation, and significantly increased the number of defecations, and the wet and dry weight of defecation in constipated mice. The profile-effect relationship indicated that seven common peaks were highly correlated with the effect of the incubation period of defecation, the number of defecations, and the wet and dry weight of defecation in mice. Conclusion This work provides a promising method for the fingerprint establishment, pharmacodynamic evaluation, and quality control of S. grosvenorii on the basis of its profile-effect relationship.

PurposeTo explore the relationship between retinoic acid receptor gamma (RARG) and ovarian cancer (OC) cell proliferation and the prognosis of patients.MethodsThe transcriptome and clinical information of 379 OC and 88 normal ovarian samples were downloaded from the Cancer Genome Atlas (TCGA) database and the Genotype Tissue Expression (GTEx) database. We compared the mRNA level of RARG between ovrian normal and tumor tissues with the Wilcoxon rank sum test.The R package “limma” was used to analyze the differences in RARG expression between different clinical subgroups. Kaplan−Meier analysis was applied to evaluate the correlation between RARG and prognosis of patients. A nomogram was established to predict the effect of RARG on prognosis of OC patients. Immunohistochemistry and qRT−PCR experiments were conducted to determine the differential expression of RARG between ovarian normal and tumor tissues. Finally, we altered RARG expression using specific siRNA and lentiviral expression vectors to explore the function of RARG by CCK-8, cell cycle, colony formation, and xenograft assays in nude mice.ResultsRARG was highly expressed in ovarian tumors and was an independent predictor of poor overall survival outcomes. Subgroup analysis showed the high expression of RARG was related to FIGO stage III-IV (P=0.027), overall survival time

The carbon emission of shipping industry accounts for about 3% of the global total. With the continuous growth of international trade, the decarbonization and carbon neutralization of shipping industry has become an important direction for future development. New technologies, fuels and operational measures can help reduce the industry’s greenhouse gas emissions, but without appropriate laws and policies, it will be difficult to achieve the targets set by the industry. Therefore, this paper reviews the decarbonization laws and policies introduced by International Maritime Organization, the European Union and the national levels. Then, this paper reviews the literature from two aspects: applicability and evaluation of laws and policies, improvement of laws and policies. On this basis, we summarize the challenges of shipping in formulating laws and policies and suggestions for improving them. Among them, the most important problem is the coordination between unilateral regulation and uniform regulation. Finally, this paper proposes the development principles based on shipping decarbonization laws and policies, that is, to comply with the principle of “common but differentiated responsibilities”, to coordinate the relationship between international trade and international environmental protection, and to guarantee technical assistance to developing countries.

Background: The mechanism by which infiltrating CD8+ T lymphocytes in the tumour microenvironment influence the survival of patients with ovarian cancer (OC) remains unclear. Methods: To identify biomarkers to optimise OC treatment, 13 immune-cell-line-associated datasets, RNA sequencing data, and clinical data from the GEO, TCGA, and the ICGC were collected. Gene expression in OC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining. Results: We identified 520 genes and three immunological clusters (IC1, IC2, and IC3) associated with CD8+ T cells. Higher IFN scores, immune T cell lytic activity, and immune cell infiltration and upregulated expression of immune-checkpoint-related genes indicated that IC3 is more responsive to immunotherapy, whereas IC1 and IC2 have a poorer prognosis. A 10-gene signature, including SEMA4F, CX3CR1, STX7, PASK, AKIRIN2, HEMGN, GBP5, NSG1, and CXorf65, was constructed, and a multivariate Cox regression analysis revealed a significant association between the 10-gene signature-based risk model and overall survival (p < 0.001). A nomogram was constructed with age and the 10-gene signature. Consistent with the bioinformatics analysis, IHC and qRT-PCR confirmed the accuracy of the signatures in OC tissue samples. The predictive ability of the risk model was demonstrated using the Imvigor210 immunotherapy dataset. Conclusions: The development of a novel gene signature associated with CD8+ T cells could facilitate more accurate prognostics and prediction of the immunotherapeutic response of patients with OC.

In this article, we investigate the validity of diversification effect under extreme-value copulas, when the marginal risks of the portfolio are identically distributed, which can be any one having a finite endpoint or belonging to one of the three maximum domains of attraction. We show that Value-at-Risk (V@R) under extreme-value copulas is asymptotically subadditive for marginal risks with finite mean, while it is asymptotically superadditive for risks with infinite mean. Our major findings enrich and supplement the context of the second fundamental theorem of quantitative risk management in existing literature, which states that V@R of a portfolio is typically non-subadditive for non-elliptically distributed risk vectors. In particular, we now pin down when the V@R is super or subadditive depending on the heaviness of the marginal tail risk. According to our results, one can take advantages from the diversification effect for marginal risks with finite mean. This justifies the standard formula for calculating the capital requirement under Solvency II in which imperfect correlations are used for various risk exposures.

Introduction: Some studies have found that probiotics can improve cognitive impairment in Alzheimer’s disease, although the specific molecular mechanism by which this occurs has not been reported. Our previous research found that probiotics inhibited bacteria-related Toll-like receptor 4- and retinoic-acid-inducible gene-I-mediated nuclear factor-κB signaling pathways to improve cognitive impairment. However, it is unclear whether probiotics have similar effects on other pattern recognition receptors that respond to bacteria. Methods: Nine-month-old senescence-accelerated mouse prone 8 (SAMP8) mice received ProBiotic-4 (a mixture of Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus casei, and Bifidobacterium lactis) orally for 12 weeks. The effects on other bacteria-related pattern recognition receptors were then investigated. Results: ProBiotic-4-treated SAMP8 mice showed improvement in memory deficits, synaptic and cerebral neuronal injuries, and microglial activation. ProBiotic-4 also markedly increased the expression of intestinal tight junction proteins (i.e., claudin-1, occludin, and zonula occluden-1), decreased the expression of interleukin-1β at both the mRNA and protein levels, and reduced the expression of caspase-11, cleaved caspase-1, and α-kinase 1 (ALPK1) in the intestine and brain. Conclusions: These findings suggest that probiotics may have therapeutic potential for the treatment of inflammation in the gut-brain axis and for cognitive impairment. The mechanism of action of probiotics appears to be related to inhibition of the caspase-11/caspase-1 pathway and reduction of ALPK1 expression.

Abstract Background Ovarian cancer (OC) is the most lethal gynaecological tumor. Changes in glycolysis have been proven to play an important role in OC progression. We aimed to identify a novel glycolysis-related gene signature to better predict the prognosis of patients with OC. Methods mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype Tissue Expression (GTEx) database. The “limma” R package was used to identify glycolysis-related differentially expressed genes (DEGs). Then, a multivariate Cox proportional regression model and survival analysis were used to develop a glycolysis-related gene signature. Furthermore, the TCGA training set was divided into two internal test sets for validation, while the ICGC dataset was used as an external test set. A nomogram was constructed in the training set, and the relative proportions of 22 types of tumor-infiltrating immune cells were evaluated using the “CIBERSORT” R package. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined by single-sample gene set enrichment analysis (ssGSEA) with the “GSVA” R package. Finally, the expression and function of the unreported signature genes ISG20 and SEH1L were explored using immunohistochemistry, western blotting, qRT-PCR, proliferation, migration, invasion and xenograft tumor assays. Results A five-gene signature comprising ANGPTL4, PYGB, ISG20, SEH1L and IRS2 was constructed. This signature could predict prognosis independent of clinical factors. A nomogram incorporating the signature and three clinical features was constructed, and the calibration plot suggested that the nomogram could accurately predict the survival rate. According to ssGSEA, the signature was associated with KEGG pathways related to axon guidance, mTOR signalling, tight junctions, etc. The proportions of tumor-infiltrating immune cells differed significantly between the high-risk group and the low-risk group. The expression levels of ISG20 and SEH1L were lower in tumor tissues than in normal tissues. Overexpression of ISG20 or SEH1L suppressed the proliferation, migration and invasion of Caov3 cells in vitro and the growth of xenograft tumors in vivo. Conclusion Five glycolysis-related genes were identified and incorporated into a novel risk signature that can effectively assess the prognosis and guide the treatment of OC patients.

Abstract Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels. In some tumor types, especially in gastrointestinal cancers, expression of ACE2 and TMPRSS2 is highly correlated. Furthermore, we found infiltration with T-cell and natural killer (NK) cell infiltration to be particularly pronounced in ACE2-high tumors. These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibly promote the frequently detrimental hyper-immune response in patients infected with this virus.

Abstract Background COVID-19 has caused a global pandemic and the death toll is increasing. However, there is no definitive information regarding the type of clinical specimens that is the best for SARS-CoV-2 detection, the antibody levels in patients with different duration of disease, and the relationship between antibody level and viral load. Methods Nasopharyngeal swabs, anal swabs, saliva, blood, and urine specimens were collected from patients with a course of disease ranging from 7 to 69 days. Viral load in different specimen types was measured using droplet digital PCR (ddPCR). Meanwhile, anti-nucleocapsid protein (anti-N) IgM and IgG antibodies and anti-spike protein receptor-binding domain (anti-S-RBD) IgG antibody in all serum samples were tested using ELISA. Results The positive detection rate in nasopharyngeal swab was the highest (54.05%), followed by anal swab (24.32%), and the positive detection rate in saliva, blood, and urine was 16.22%, 10.81%, and 5.41%, respectively. However, some patients with negative nasopharyngeal swabs had other specimens tested positive. There was no significant correlation between antibody level and days after symptoms onset or viral load. Conclusions Other specimens could be positive in patients with negative nasopharyngeal swabs, suggesting that for patients in the recovery period, specimens other than nasopharyngeal swabs should also be tested to avoid false negative results, and anal swabs are recommended. The antibody level had no correlation with days after symptoms onset or the viral load of nasopharyngeal swabs, suggesting that the antibody level may also be affected by other factors.

Novel coronavirus (COVID-19) outbreak, has raised a calamitous situation all over the world and has become one of the most acute and severe ailments in the past hundred years. The prevalence rate of COVID-19 is rapidly rising every day throughout the globe. Although no vaccines for this pandemic have been discovered yet, deep learning techniques proved themselves to be a powerful tool in the arsenal used by clinicians for the automatic diagnosis of COVID-19. This paper aims to overview the recently developed systems based on deep learning techniques using different medical imaging modalities like Computer Tomography (CT) and X-ray. This review specifically discusses the systems developed for COVID-19 diagnosis using deep learning techniques and provides insights on well-known data sets used to train these networks. It also highlights the data partitioning techniques and various performance measures developed by researchers in this field. A taxonomy is drawn to categorize the recent works for proper insight. Finally, we conclude by addressing the challenges associated with the use of deep learning methods for COVID-19 detection and probable future trends in this research area. The aim of this paper is to facilitate experts (medical or otherwise) and technicians in understanding the ways deep learning techniques are used in this regard and how they can be potentially further utilized to combat the outbreak of COVID-19.

AbstractBackground There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir–ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19.Method In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion.Results A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups.Conclusions and relevance rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.

Abstract Background The interactions between Growth-regulating factors (GRFs) and GRF-Interacting Factors (GIFs) have been well demonstrated but it remains unclear whether different combinations of GRF and GIF play distinctive roles in the pathway downstream of the complex. Results Here we showed that OsGRF1 and OsGIF1 synergistically regulate leaf growth in rice. The expression of OsGIF1 emerged in all tissues with much higher level while that of OsGRF1 appeared preferentially only in the stem tips containing shoot apical meristem (SAM) and younger leaves containing leaf primordium. Overexpression of an OsmiR396-resistant version of mOsGRF1 resulted in expanded leaves due to increased cell proliferation while knockdown of OsGRF1 displayed an opposite phenotype. Overexpression of OsGIF1 did not exhibit new phenotype while knockdown lines displayed pleiotropic growth defects including shrunken leaves. The crossed lines of mOsGRF1 overexpression and OsGIF1 knockdown still exhibited shrunk leaves, indicating that OsGIF1 is indispensable in leaf growth regulated by OsGRF1. The expression of OsGRF1 could be upregulated by gibberellins (GAs) and downregulated by various stresses while that of OsGIF1 could not. Conclusion Our results suggest that OsGIF1 is in an excessive expression in various tissues and play roles in various aspects of growth while OsGRF1 may specifically involve in leaf growth through titrating OsGIF1. Both internal and external conditions impacting leaf growth are likely via way of regulating the expression of OsGRF1.

Rice Growth-Regulating Factors (GRFs) were originally identified to be gibberellin (GA)-induced, but the nature of GA induction has remained unknown because most reports thereafter focused on revealing their roles in growth-promoting activities. GRFs have the WRC (Trp, Arg, Cys) domain to target DNA and contain the QLQ (Gln, Leu, Gln) domain to interact with GRF-Interacting Factor (GIF), which recruits ATP-dependent DNA translocase Switch/Sucrose Non-fermenting (SWI/SNF) for chromatin remodeling. Both GRFs and GIFs exhibit transcriptional activities but GIFs lack a DNA-binding domain. So, GRFs act like a navigator in the GRF-GIF-SWI/SNF complex, determining when and where the complex should work on. The levels of most rice GRFs can be sensitively regulated by miR396, which responds to many developmental and environmental factors. Recent clues from several studies highlight the original question of how GRFs participate in GA signaling. DELLA (contain DELLA motif) protein plays dual roles in controlling the level of GRFs by regulating the level of miR396 and interacting with GRFs. Here we address the question of why this complex plays an essential role in controlling plant growth focusing on the action of GA signaling pivot, DELLA.

Agrimonolide (AM), which is a derivative of isocoumarins, is found mainly in the herb Agrimonia pilosa Ledeb. This compound is highly lipophilic and readily crosses the blood–brain barrier. In recent years, interest has grown in the use of AM as a multitarget natural treatment for various diseases, such as cancer, inflammation, hepatic injury, myocardial damage, and diabetes mellitus. The potential mechanisms of these pharmacological effects have been clarified at cellular and molecular levels. AM shows no cytotoxicity over a range of concentrations in different types of cells, providing evidence for its good safety profile in vitro. These findings indicate that AM is a promising medicinal agent. However, most studies on AM’s pharmacological activities, mechanisms of action, and safety lack substantial animal or human data. Additionally, the pharmacokinetics, metabolism, and disposition of this compound have received little attention. This review highlights the status of current information regarding the sources, properties, pharmacological effects, and safety of AM. Furthermore, potential strategies to resolve problematic issues identified in previous studies are fully discussed. This summary and analysis of the research progress of AM may inspire deeper investigations and more extensive applications of AM in the future.

BackgroundConsiderable evidence suggests that the heterogeneity of ovarian cancer (OC) is a major cause of treatment failure. Single-cell RNA sequencing (scRNA-seq) is a powerful tool to analyse the heterogeneity of the tumour at the single-cell level, leading to a better understanding of cell function at the genetic and cellular levels.MethodsOC scRNA-seq data were extracted from the Gene Expression Omnibus (GEO) database and the FindCluster () package used for cell cluster analysis. The GSVA package was used for single-sample gene set enrichment analysis (ssGSEA) analysis to obtain a Hallmark gene set score and bulk RNA-seq data were used to analyse the key genes of OC-associated immune cell subsets. CIBERSORT was used to identify immune scores of cells and the “WGCNA” package for the weighted correlation network analysis (WGCNA). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses of subtype groups were performed by GSEA. Then, univariate Cox and lasso regression were performed to further establish a signature. Finally, qPCR and immunohistochemistry staining were used to evaluate the expression of signature genes in OC.ResultsTwo scRNA-seq (GSE154600 and GES158937) datasets were integrated to obtain 20 cell clusters. T cells or NK cells (cluster 5, 6, 7, 11), B cells (cluster 16, 19, 20) and myeloid cells (cluster 4, 9, 10) were clustered according to immune cell markers. The ssGSEA revealed that M1- and M2-like myeloid cell-related genes were significantly upregulated in P3 and P4 patients in the GSE154600 data. Immune cell analysis in TCGA-OC showed that a high abundance of M1-like tumour-associated macrophages (TAMS) predicts better survival. WGCNA, univariate Cox and lasso Cox regression established a two-gene signature (RiskScore=-0.059*CXCL13-0.034*IL26). Next, the TCGA-test and TCGA-OC were used to test the risk prediction ability of the signature, showing a good effect in the datasets. Moreover, the qPCR and immunohistochemistry staining revealed that the expression of CXCL13 and IL26 was reduced in OC tissues.ConclusionA two-gene signature prognostic stratification system (CXCL13 and IL26) was developed based on the heterogeneity of OC immune cells to accurately evaluate the prognostic risk.

Background: 5-Methylcytidine (m5C) is the most common RNA modification and plays an important role in multiple tumors including cervical cancer (CC). We aimed to develop a novel gene signature by identifying m5C modification subtypes of CC to better predict the prognosis of patients.Methods: We obtained the expression of 13 m5C regulatory factors from The Cancer Genome Atlas (TCGA all set, 257 patients) to determine m5C modification subtypes by the “nonnegative matrix factorization” (NMF). Then the “limma” package was used to identify differentially expressed genes (DEGs) between different subtypes. According to these DEGs, we performed Cox regression and Kaplan-Meier (KM) survival analysis to establish a novel gene signature in TCGA training set (128 patients). We also verified the risk prediction effect of gene signature in TCGA test set (129 patients), TCGA all set (257 patients) and GSE44001 (300 patients). Furthermore, a nomogram including this gene signature and clinicopathological parameters was established to predict the individual survival rate. Finally, the expression and function of these signature genes were explored by qRT-PCR, immunohistochemistry (IHC) and proliferation, colony formation, migration and invasion assays.Results: Based on consistent clustering of 13 m5C-modified genes, CC was divided into two subtypes (C1 and C2) and the C1 subtype had a worse prognosis. The 4-gene signature comprising FNDC3A, VEGFA, OPN3 and CPE was constructed. In TCGA training set and three validation sets, we found the prognosis of patients in the low-risk group was much better than that in the high-risk group. A nomogram incorporating the gene signature and T stage was constructed, and the calibration plot suggested that it could accurately predict the survival rate. The expression levels of FNDC3A, VEGFA, OPN3 and CPE were all high in cervical cancer tissues. Downregulation of FNDC3A, VEGFA or CPE expression suppressed the proliferation, migration and invasion of SiHa cells.Conclusions: Two m5C modification subtypes of CC were identified and then a 4-gene signature was established, which provide new feasible methods for clinical risk assessment and targeted therapies for CC.