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Abstract As a typical intangible cultural heritage, Toponymic Cultural Heritage (TCH) is rich in geographic information and semantic and physical connotations. In the context of the heritage conservation era, it is highly important to study the spatiotemporal distribution characteristics of toponymic cultural heritage and explore its historical and geographic influencing factors on the sustainable conservation and development of toponymic cultural heritage. However, most existing studies focus on the toponym cultural landscape, and less attention has been given to TCH. Therefore, on the basis of the data of 357 provincial TCH items in Jiangsu Province, this study investigated the spatiotemporal distribution characteristics and historical–geographical influencing factors of the TCH by using geospatial analysis methods, such as the average nearest neighbor, tyson polygon, kernel density estimation, standard deviational ellipse, and superposition coupling analysis, and proposed several strategies for adaptive reuse of TCH. The results show that (1) the TCHs of Jiangsu Province have a spatial distribution characteristic of "sparse in the north, scattered in the middle and dense in the south" and form a high-density agglomeration around the southern part of Jiangsu Province. In the distribution of cultural districts, the Jinling cultural district, the Wu cultural district, and the Huaiyang cultural district have the largest number of TCHs. (2) From the Pre-Qin period to the Ming and Qing Dynasties, TCHs, such as Nanjing, Yangzhou, Zhenjiang, Changzhou, and Suzhou, tended to merge in the southern part of Jiangsu. (3) In terms of type, the roads, streets and alleys of TCHs are the richest, and all types of TCHs are spatially clustered in the southern part of Jiangsu Province, which has a high level of urbanization, industrialization, and a superior geographic environment. (4) TCHs have spatial tendencies toward low altitudes and hydrophilicity, and relatively favorable natural geographical conditions provide a high-quality environment for TCHs in southern Jiangsu Province. Influenced by historical, humanistic, and geographical factors, TCH is unevenly developed spatially. As a historical population concentration area, an important political, economic, and cultural core area, and a center of gravity for cultural development, more TCH resources have survived in the southern part of Jiangsu Province. This study provides a new perspective for interpreting and recognizing TCH as a special intangible cultural heritage and can provide a reference for the sustainable conservation and development of TCH.

Abstract Background Patients with non‐small cell lung cancer (NSCLC) with liver metastasis have a poor prognosis, and there are no reliable biomarkers for predicting disease progression. Currently, no recognized and reliable prediction model exists to anticipate liver metastasis in NSCLC, nor have the risk factors influencing its onset time been thoroughly explored. Methods This study conducted a retrospective analysis of 434 NSCLC patients from two hospitals to assess the association between the risk and timing of liver metastasis, as well as several variables. Results The patients were divided into two groups: those without liver metastasis and those with liver metastasis. We constructed a nomogram model for predicting liver metastasis in NSCLC, incorporating elements such as T stage, N stage, M stage, lack of past radical lung cancer surgery, and programmed death ligand 1 (PD‐L1) levels. Furthermore, NSCLC patients with wild‐type EGFR, no prior therapy with tyrosine kinase inhibitors (TKIs), and no prior radical lung cancer surgery showed an elevated risk of early liver metastasis. Conclusion In conclusion, the nomogram model developed in this study has the potential to become a simple, intuitive, and customizable clinical tool for assessing the risk of liver metastasis in NSCLC patients following validation. Furthermore, it provides a framework for investigating the timing of metachronous liver metastasis.

Abstract The EphA family belongs to a large group of membrane receptor tyrosine kinases. Emerging evidence indicates that the EphA family participates in tumour occurrence and progression. Nonetheless, the expression patterns and prognostic values of the nine EphAs in non-small cell lung cancer (NSCLC) have rarely been studied before. In the current study, we comprehensively analysed the expression and prognostic role of EphA family members by different means. The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis databases were used to investigate the expression of EphAs in NSCLC. The cBioPortal database was applied to analyse the prognostic values and genetic mutations of EphAs.We discovered that the expression of EphA10 was significantly higher in NSCLC tissues than in adjacent noncancerous tissues, and survival analyses showed that a higher level of EphA10 predicted poor prognosis. Further exploration into the role of EphA10 by ESTIMATE, CIBERSORT, and ssGSEA analysis found that it was also related to immune infiltration and higher expression of targets of ICI targets. In conclusion, this study revealed that among the EphA family members, EphA10 played an oncogenic role and was a promising biomarker for poor prognosis and better immunotherapy response in NSCLC.

Abstract Background Non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer and is the leading cause of cancer-related deaths globally. Although various treatment strategies have been introduced, the 5-year survival rate of patients with NSCLC is only 20–30%. Thus, it remains necessary to study the pathogenesis of NSCLC and develop new therapeutic drugs. Notably, PYK2 has been implicated in the progression of many tumors, including NSCLC, but its detailed mechanism remains unclear. In this study, we aimed to elucidate the mechanisms through which PYK2 promotes NSCLC progression. Methods The mRNA and protein levels of various molecules were measured using qRT-PCR, western blot (WB), and immunohistochemistry (IHC), respectively. We established stable PYK2 knockdown and overexpression cell lines, and CCK-8, EdU, and clonogenic assays; wound healing, transwell migration, and Matrigel invasion assays; and flow cytometry were employed to assess the phenotypes of tumor cells. Protein interactions were evaluated with co-immunoprecipitation (co-IP), immunofluorescence (IF)-based colocalization, and nucleocytoplasmic separation assays. RNA sequencing was performed to explore the transcriptional regulation mediated by PYK2. Secreted VGF levels were examined using ELISA. Dual-luciferase reporter system was used to detect transcriptional regulation site. PF4618433 (PYK2 inhibitor) and Stattic (STAT3 inhibitor) were used for rescue experiments. A public database was mined to analyze the effect of these molecules on NSCLC prognosis. To investigate the role of PYK2 in vivo, mouse xenograft models of lung carcinoma were established and examined. Results The protein level of PYK2 was higher in human NSCLC tumors than in the adjacent normal tissue, and higher PYK2 expression was associated with poorer prognosis. PYK2 knockdown inhibited the proliferation and motility of tumor cells and caused G1-S arrest and cyclinD1 downregulation in A549 and H460 cells. Meanwhile, PYK2 overexpression had the opposite effect in H1299 cells. The siRNA-induced inhibition of integrins alpha V and beta 1 led to the downregulation of p-PYK2(Tyr402). Activated PYK2 could bind to STAT3 and enhance its phosphorylation at Tyr705, regulating the nuclear accumulation of p-STAT3(Tyr705). This further promoted the expression of VGF, as confirmed by RNA sequencing in a PYK2-overexpressing H1299 cell line and validated by rescue experiments. Two sites in promoter region of VGF gene were confirmed as binding sites of STAT3 by Dual-luciferase assay. Data from the TGCA database showed that VGF was related to the poor prognosis of NSCLC. IHC revealed higher p-PYK2(Tyr402) and VGF expression in lung tumors than in adjacent normal tissues. Moreover, both proteins showed higher levels in advanced TNM stages than earlier ones. A positive linear correlation existed between the IHC score of p-PYK2(Tyr402) and VGF. Knockdown of VGF inhibited tumor progression and reversed the tumor promoting effect of PYK2 overexpression in NSCLC cells. Finally, the mouse model exhibited enhanced tumor growth when PYK2 was overexpressed, while the inhibitors PF4618433 and Stattic could attenuate this effect. Conclusions The Integrin αVβ1-PYK2-STAT3-VGF axis promotes NSCLC development, and the PYK2 inhibitor PF4618433 and STAT3 inhibitor Stattic can reverse the pro-tumorigenic effect of high PYK2 expression in mouse models. Our findings provide insights into NSCLC progression and could guide potential therapeutic strategies against NSCLC with high PYK2 expression levels.

Abstract Background Acinetobacter lwoffii (A.lwoffii) is a serious zoonotic pathogen that has been identified as a cause of infections such as meningitis, bacteremia and pneumonia. In recent years, the infection rate and detection rate of A.lwoffii is increasing, especially in the breeding industry. Due to the presence of biofilms, it is difficult to eradicate and has become a potential super drug-resistant bacteria. Therefore, eradication of preformed biofilm is an alternative therapeutic action to control A.lwoffii infection. The present study aimed to clarify that baicalin could eradicate A.lwoffii biofilm in dairy cows, and to explore the mechanism of baicalin eradicating A.lwoffii. Results The results showed that compared to the control group, the 4 MIC of baicalin significantly eradicated the preformed biofilm, and the effect was stable at this concentration, the number of viable bacteria in the biofilm was decreased by 0.67 Log10CFU/mL. The total fluorescence intensity of biofilm bacteria decreased significantly, with a reduction rate of 67.0%. There were 833 differentially expressed genes (367 up-regulated and 466 down-regulated), whose functions mainly focused on oxidative phosphorylation, biofilm regulation system and trehalose synthesis. Molecular docking analysis predicted 11 groups of target proteins that were well combined with baicalin, and the content of trehalose decreased significantly after the biofilm of A.lwoffii was treated with baicalin. Conclusions The present study evaluated the antibiofilm potential of baicalin against A.lwoffii. Baicalin revealed strong antibiofilm potential against A.lwoffii. Baicalin induced biofilm eradication may be related to oxidative phosphorylation and TCSs. Moreover, the decrease of trehalose content may be related to biofilm eradication.

Biofilms often engender persistent infections, heightened antibiotic resistance, and the recurrence of infections. Therefor, infections related to bacterial biofilms are often chronic and pose challenges in terms of treatment. The main transcription regulatory factor, CsgD, activates csgABC-encoded curli to participate in the composition of extracellular matrix, which is an important skeleton for biofilm development in enterobacteriaceae. In our previous study, a wide range of natural bioactive compounds that exhibit strong affinity to CsgD were screened and identified via molecular docking. Tannic acid (TA) was subsequently chosen, based on its potent biofilm inhibition effect as observed in crystal violet staining. Therefore, the aim of this study was to investigate the specific effects of TA on the biofilm formation of clinically isolated Escherichia coli (E. coli). Results demonstrated a significant inhibition of E. coli Ec032 biofilm formation by TA, while not substantially affecting the biofilm of the ΔcsgD strain. Moreover, deletion of the csgD gene led to a reduction in Ec032 biofilm formation, alongside diminished bacterial motility and curli synthesis inhibition. Transcriptomic analysis and RT-qPCR revealed that TA repressed genes associated with the csg operon and other biofilm-related genes. In conclusion, our results suggest that CsgD is one of the key targets for TA to inhibit E. coli biofilm formation. This work preliminarily elucidates the molecular mechanisms of TA inhibiting E. coli biofilm formation, which could provide a lead structure for the development of future antibiofilm drugs.

Leaf Trait Networks (LTNs) visually display the intricate trait connections in offering insights into how plants adapt to diverse environments. The pervasive environmental heterogeneity can influence plant diversity and functional traits. Various habitats sustain distinct species diversity and leaf trait differentiation, precisely as the degraded karst-heterogenous ecosystem caused by inhomogeneous microhabitats. However, how the LTNs respond to understory habitat heterogeneity and species diversity in degraded karst forests remains unclear. This study selected fifty-three forest plots for plant community survey and habitat investigation in a typical karst topography to visualize LTNs using twenty-one woody leaf traits. LTN architecture variations were analyzed in relation to habitat heterogeneity and species diversity through network-architectural parameters, including edge density, diameter, average path length, and average clustering coefficient, utilizing regression, principal component analysis, and structural equation model. The results showed a 35% variation in modularity across all plots, indicating distinct network architectural modularization differentiation. Network diameter and average path length displayed significant initial decreases followed by increases with ascending PC1 heterogeneity scores, indicating moderate heterogeneity sustained greater network connectivity. In addition, the network diameter, average path length, and average clustering coefficient significantly decreased with increasing species diversity, indicating that high species diversity enables greater connectivity and complexity. Moreover, the habitat heterogeneity significantly affected species diversity directly and affected the average clustering coefficient, diameter, average path length, and edge density indirectly through species diversity effects via SEM pathway analysis. Overall, habitat heterogeneity and woody plant diversity of karst forests significantly influence LTN architectures in degraded karst forests. In conclusion, moderate heterogeneity sustains greater network connectivity while species diversity jointly enhances connectivity and complexity by combining modular regulation of plant functional traits.

IntroductionAcinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses.MethodsX-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains.ResultsThe receiver domain of PmrA follows the canonical α5β5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.

BackgroundExisting studies on the relationship between tea intake and lung diseases have yielded inconsistent results, leading to an ongoing dispute on this issue. The impact of tea consumption on the respiratory system remained elucidating.Materials and methodsWe conducted a two-sample Mendelian randomization (MR) study to evaluate the associations between five distinct tea intake phenotypes and 15 different respiratory outcomes using open Genome-wide association study (GWAS) data. The inverse variance weighted (IVW) was used for preliminary screening and a variety of complementary methods were used as sensitivity analysis to validate the robustness of MR estimates. Pathway enrichment analysis was used to explore possible mechanisms.ResultsIVW found evidence for a causal effect of standard tea intake on an increased risk of lung squamous cell cancer (LSCC) (OR = 1.004; 95% CI = 1.001–1.007; P = 0.00299). No heterogeneity or pleiotropy was detected. After adjustment for potential mediators, including smoking, educational attainment, and time spent watching television, the association was still robust in multivariable MR. KEGG and GO enrichment predicted proliferation and activation of B lymphocytes may play a role in this causal relation. No causalities were observed when evaluating the effect of other kinds of tea intake on various pulmonary diseases.ConclusionOur MR estimates provide causal evidence of the independent effect of standard tea intake (black tea intake) on LSCC, which may be mediated by B lymphocytes. The results implied that the population preferring black tea intake should be wary of a higher risk of LSCC.

Leaf trait networks (LTNs) visualize the intricate linkages reflecting plant trait-functional coordination. Typical karst vegetation, developed from lithological dolomite and limestone, generally exhibits differential communities, possibly due to habitat rock exposure, soil depth, and soil physicochemical properties variations, leading to a shift from plant trait variation to functional linkages. However, how soil and habitat quality affect the differentiation of leaf trait networks remains unclear. LTNs were constructed for typical dolomite and limestone habitats by analyzing twenty-one woody plant leaf traits across fifty-six forest subplots in karst mountains. The differences between dolomite and limestone LTNs were compared using network parameters. The network association of soil and habitat quality was analyzed using redundancy analysis (RDA), Mantle's test, and a random forest model. The limestone LTN exhibited significantly higher edge density with lower diameter and average path length when compared to the dolomite LTN. It indicates LTN differentiation, with the limestone network displaying a more compact architecture and higher connectivity than the dolomite network. The specific leaf phosphorus and leaf nitrogen contents of dolomite LTN, as well as the leaf mass and leaf carbon contents of limestone LTN, significantly contributed to network degree and closeness, serving as crucial node traits regulating LTN connectedness. Additionally, both habitat LTNs significantly correlated with soil nitrogen and phosphorus, stoichiometric ratios, pH, and organic carbon, as well as soil depth and rock exposure rates, with soil depth and rock exposure showing greater relative importance. Soil depth and rock exposure dominate trait network differentiation, with the limestone habitat exhibiting a more compact network architecture than the dolomite habitat.

ObjectiveTo analyze current situation of assessment on health emergency response capacity of centers for disease control and prevention (CDCs) in China and to provide evidence for developing standards for the capability evaluation. MethodsWe retrieved relevant studies published in Chinese or English from January 1, 2003 to October 31, 2021 via searching Chinese National Knowledge Infrastructure (CNKI) and Web of Science database. Content analysis, co-word clustering and significance assessing were used in sorting and categorizing the information on evaluation indicators adopted and critical issues of the response capability mentioned in the studies. ResultsOf the 93 articles finally included in the analysis, 75 were studied using questionnaires and 70 were investigated by a regional CDC. Various index systems were used but no unified framework or standard was adopted in the studies. Based on co-word clustering analysis, four dimensions of the response capability of the CDCs were evaluated in the studies: emergency preparedness assessed by 8 indicators, monitoring/warning and risk assessment by 2 indicators, emergency response by 3 indicators, and organization by 2 indicators, respectively. As considered in the studies, the most important issue to be promoted in the CDCs′ response capability was the establishment of emergency workforce and rapid response team, followed by other main issues including standardized management on public health emergency, financial support, material reserve, staff training and simulation practice, related research, and development/improvement of preparedness plan and technical guidance. ConclusionThe uniformed framework, standardized assessment criteria and index system are not yet established for the evaluation on CDCs public health emergency response capability nowadays in China and the situation needs to be concerned by national administrative departments.

ObjectiveTo examine current situation of internet sentiment on public health emergencies and strategies for coping with the situation in China to provide evidence for administrative agencies′ effective response to the public sentiment. MethodsPublished studies relevant to internet sentiment on public health emergency published in Chinese or English up to October 30th, 2021 were retrieved through comprehensively searching Chinese National Knowledge Infrastructure (CNKI), Wanfang Database and PubMed. Content analysis, co-word clustering and significance assessing were used to sort out and categorize the characteristics of internet sentiment on public health emergencies and strategies and problems in administrative agencies′ response to the sentiment. Ordinal ranking was adopted to evaluate the importance and severity of the strategies and problems in the agencies′ responses. Results Based on content analysis on 116 literatures included into the study, 29 features were identified in terms of public health emergency-related internet sentiment′s ontology, subject, content, development, communication, society, space and time. Also according to the analysis, 25 problems and 26 strategies in the responses to the internet sentiments were revealed at four stages of prevention, preparation, response and recovery in dealing with a public health emergency. The ordinal ranking for the importance/severity of the 25 problems and 26 response strategies were basically consistent in the 4 stages of public health emergency management; the top serious problems in each stage were delayed management and prevalence of rumors due to the lack of initiative in response stage, without theoretical guidance owing to imperfect laws and regulations in preparation stage, lacking post-event evaluation and accountability as a result of imperfect systemic infrastructure in recovery stage, and too much information noise due to the absence of serial theme propaganda in prevention stage, with the severity/importance index score of 0.1263, 0.0982, 0.0355, and 0.0305; the top important strategies in each stage included dispelling rumors actively in mass media in response state, establishing a mechanism to deal with the internet sentiment in preparation stage, establishing regulations for rapid evaluation and accountability about the internet sentiment in recovery stage, and constructing a media-wide communication system for carrying out positive publicity actively in preparation stage, with the severity/importance index score of 0.1062, 0.1016, 0.0360, and 0.0257, respectively. Conclusion The response to public health emergency-related internet sentiment should be integrated into the whole process responding to public health emergencies and should be addressed in each of the four stages: prevention, preparation, response and recovery. Such considerations should be aligned with risk communication strategies for public health emergency response, for better resolving of social contradictions and satisfying of public needs.

Summary: Type VI secretion system is widely used in Gram-negative bacteria for injecting toxic effectors into neighboring prokaryotic or eukaryotic cells. Various effectors can be loaded onto the T6SS delivery tube via its core components: Hcp, VgrG, or PAAR. Here, we report 2.8-Å resolution cryo-EM structure of intact T6SS Hcp5-VgrG-PAAR cargo delivery system and crystal structure of unbound Hcp5 from B. fragilis NCTC 9343. Loading of Hcp5 hexameric ring onto VgrG causes expansion of its inner cavity and external surface, explaining how structural changes could be propagated to regulate co-polymerization and surrounding contractile sheath. High-affinity binding between Hcp and VgrG causes entropically unfavorable structuring of long loops. Furthermore, interactions between VgrG trimer and Hcp hexamer are asymmetric, with three of the six Hcp monomers exhibiting a major loop flip. Our study provides insights into the assembly, loading, and firing of T6SS nanomachine that contributes to bacterial inter-species competition and host interactions.

BackgroundAtrial fibrill ation (AF) is a predominant public health concern in older adults. Therefore, this study aimed to explore the global, regional, and national burden of AF in older adults aged 60–89 between 1990 and 2019.MethodsThe morbidity, mortality, disability-adjusted life years (DALYs), and age-standardized rates of AF were refined from the Global Burden of Diseases study 2019. The epidemiological characteristics were assessed based on numerical values, age-standardized rates per 100,000 person-years, and estimated annual percentage changes (EAPC).ResultsGlobally, a total of 33.31 million AF cases, 219.4 thousand deaths, and 65.80 million DALYs were documented in 2019. There were no appreciable changes in EAPC from 1990 to 2019. The disease burden of AF differed significantly across different territories and countries. At the national level, China exhibited the highest number of incident cases [818,493 (562,871–1,128,695)], deaths [39,970 (33,722–46,387)], and DALYs [1,383,674 (1,047,540–1,802,516)]. At the global level, high body mass index (BMI) and high systolic blood pressure (SBP) were two predominant risk factors contributing to the proportion of AF-related deaths.ConclusionAF in older adults remains a major public health concern worldwide. The burden of AF varies widely at both national and regional levels. From 1990 to 2019, the cases of incidences, deaths, and DALYs have shown a global increase. The ASIR, ASMR, and ASDR have declined in the high-moderate and high SDI regions; however, the burden of AF increased promptly in the lower SDI regions. Special attention should be paid to the main risk factors for high-risk individuals with AF, which can help control systolic blood pressure and body mass index within normal limits. Over all, it is necessary to illustrate the features of the global AF burden and develop more effective and targeted prevention and treatment strategies.

Enterotoxigenic Bacteroides fragilis (ETBF) can rapidly secrete an enterotoxin termed B. fragilis toxin (BFT), which is thought to be the only recognized virulence factor in ETBF. ETBF can cause acute diarrhea, inflammatory bowel disease (IBD), colorectal cancer, and breast cancer. BFT is divided into three subtypes, BFT1, BFT2, and BFT3. BFT1 is the most widely distributed in human B. fragilis isolates. BFT can be used as a biomarker for predicting the inflammation-cancer transformation of intestine and breast. Nanobodies have the advantages of small structure, complete antigen recognition capacity, rapid selection via phage display technology, and can be massively produced in microbial expression systems. Nanobodies have become a powerful tool for medical diagnosis and treatment. This study focuses on screening and structural characterization of nanobodies targeting full length and active BFT. By constructing prokaryotic expression systems to obtain recombinant BFT1 protein, high purity BFT1 protein was used to immunize alpacas. Phage display technology was used to construct a phage display library. The positive clones were selected by bio-panning, and the isothermal titration calorimetry was used to select high-affinity nanobodies. Then the three-dimensional structures of BFT1:Nb2.82 and BFT1:Nb3.27 were solved by crystal X-ray diffraction. We got two kinds of nanobodies, Nb2.82 targeting the BFT1 prodomain and Nb3.27 recognizing the BFT1 catalytic domain. This study provides a new strategy for the early diagnosis of ETBF and the possibility for BFT as a biomarker for diagnosing diseases.

Abstract Background Immune‐based combination therapies have revolutionized the first‐line treatment for advanced non‐small cell lung cancer (NSCLC). However, for the efficacy and safety, the best treatment option is still uncertain. Methods We conducted a Bayesian network meta‐analysis of randomized controlled trials (RCTs) to evaluate first‐line immune‐based combination therapies for advanced NSCLC. Results Fourteen trials involving 8467 patients were included. For the programmed cell death‐ligand 1 (PD‐L1) expression non‐selective patients, there were no significant differences among all the treatment modes for overall survival (OS), but the ranking profiles indicated that Immunotherapy + Immunotherapy + Chemotherapy (IO + IO + Chemo) was most likely to be the best mode (probability = 68%). Immunotherapy + Immunotherapy + Anti‐angiogenic therapy + Chemotherapy (IO + Anti‐angio + Chemo) was significantly better than most other treatment modes for progression‐free survival (PFS) with better objective response rate (ORR) and more obvious grade ≥3 treatment‐related adverse events (TRAEs). In PD‐L1‐high cohort, IO + Anti‐angio + Chemo seemed to be the best mode for OS, PFS, and ORR according to the ranking profiles. In PD‐L1‐intermediate and PD‐L1‐negative cohort, IO + IO + Chemo was inclined to be ranked first for prolonging OS (probability = 78%; 37%) and IO + Anti‐angio + Chemo was most likely to provide best PFS (probability = 96%; 100%). Conclusion IO + IO + Chemo has great potential to improve the OS regardless of histology type, especially in PD‐L1‐intermediate and PD‐L1‐negative cohort. IO + Anti‐angio + Chemo shows great superiority in improving the short‐term survival accompanied by increasing grade ≥3 TRAEs.

PurposeRecent studies have revealed the contrasting prognostic roles of body mass index (BMI) and tumor location in colorectal cancer (CRC). Given that right- and left-sided CRC may exhibit inverse effects on outcome and body weight, the present study aimed to examine whether the prognostic value of BMI and tumor location could be reciprocally stratified.MethodsThis prospective, observational study recruited 4,086 patients diagnosed with stage III CRC from five independent clinical centers in China. The association of patients’ outcomes with BMI and tumor location was evaluated hierarchically by Kaplan–Meier and Cox proportional-hazards models.ResultsAlthough BMI was not associated with overall outcome, the association was significantly modified by tumor location. Among left-sided tumors, obesity and overweight were significantly associated with adverse overall survival (OS) and disease-specific survival (DSS). In contrast, among right-sided tumors, overweight was significantly associated with more favorable OS and DSS compared with the normal-weight group. The association of survival with tumor location did not reach statistical significance. However, hierarchical analysis by BMI revealed that left-sided tumors were associated with more favorable outcomes in the normal-weight group, while there was no statistically significant difference in the overweight or obese group.ConclusionsBMI and tumor location may have opposing effects on CRC prognosis, when stratified by each other, after adjusting for other known prognostic factors. These findings are the first to show the interactive prognostic impact of BMI and tumor location, which could be relevant to the stratification of patient management.

Karst ecosystems represent a typical heterogeneous habitat, and it is ubiquitous with varying interactive patches of rock and soil associated with differential weathering patterns of carbonate rocks. Arbuscular mycorrhizae fungi (AMF) play an important role in regulating plant growth and nutrition in heterogeneous karst habitats. However, it remains unclear how AMF affects the growth and nutrition of plants in heterogeneous karst soil with varying patches and weathering gravel. A heterogeneous experiment with Bidens pilosa L. was conducted in a grid microcosm through patching karst soil with different gravel contents. The experimental treatments included the AMF treatments inoculated with (M+) or without (M-) fungus Glomus etunicatum; the substrate patchiness treatments involved different sizes of the homogeneous patch (Homo), the heterogeneous large patch (Hetl), and the heterogeneous small patch (Hets); the substrate gravel treatments in the inner patch involved the free gravel (FG), the low gravel (LG) 20% in 80% soil, and the high gravel (HG) 40% in 60% soil. Plant traits related to growth and nutrients were analyzed by comparing substrate gravel content and patch size. The results showed that AMF was more beneficial in increasing the aboveground biomass of B. pilosa under the LG and HG substrates with a higher root mycorrhizal colonization rate than under the FG substrate with a lower root mycorrhizal colonization rate. AMF enhanced higher growth and nutrients for B. pilosa under the LG and HG substrates than under the FG substrate and under the Hets than under the Hetl. Moreover, AMF alleviated the limited supply of N for B. pilosa under all heterogeneous treatments. Furthermore, the response ratio LnRR of B. pilosa presented that the substrate gravel promoted the highest growth, N and P absorption than the substrate patchiness with M+ treatment, and the gravel content had a more effect on plant growth and nutrition as compared to the patch size. Overall, this study suggests that plant growth and nutrition regulated by AMF mainly depend on the substrate gravel content rather than the spatial patchiness in the heterogeneous karst habitat.

Phenylacetic acid (PAA) is a central intermediate metabolite involved in bacterial degradation of aromatic components. The bacterial PAA pathway mainly contains 12 enzymes and a transcriptional regulator, which are involved in biofilm formation and antimicrobial activity. They are present in approximately 16% of the sequenced bacterial genome. In this review, we have summarized the PAA distribution in microbes, recent structural and functional study progress of the enzyme families of the bacterial PAA pathway, and their role in bacterial pathogenicity and antibiotic resistance. The enzymes of the bacterial PAA pathway have shown potential as an antimicrobial drug target for biotechnological applications in metabolic engineering.

Plant invasion has severely damaged ecosystem stability and species diversity worldwide. The cooperation between arbuscular mycorrhizal fungi (AMF) and plant roots is often affected by changes in the external environment. Exogenous phosphorus (P) addition can alter the root absorption of soil resources, thus regulating the root growth and development of exotic and native plants. However, it remains unclear how exogenous P addition regulates the root growth and development of exotic and native plants mediated by AMF, affecting the exotic plant invasion. In this experiment, the invasive plant Eupatorium adenophorum and native plant Eupatorium lindleyanum were selected and cultured under intraspecific (Intra-) competition and interspecific (Inter-) competition conditions, involving inoculation with (M+) and without AMF (M−) and three different levels of P addition including no addition (P0), addition with 15 mg P kg−1 soil (P15), and addition with 25 mg P kg−1 soil (P25) for the two species. Root traits of the two species were analyzed to study the response of the two species’ roots to AMF inoculation and P addition. The results showed that AMF significantly promoted the root biomass, length, surface area, volume, tips, branching points, and carbon (C), nitrogen (N), and P accumulation of the two species. Under M+ treatment, the Inter- competition decreased the root growth and nutrient accumulation of invasive E. adenophorum but increased the root growth and nutrient accumulation of native E. lindleyanum relative to the Intra- competition. Meanwhile, the exotic and native plants responded differently to P addition, exhibiting root growth and nutrient accumulation of invasive E. adenophorum increased with P addition, whereas native E. lindleyanum reduced with P addition. Further, the root growth and nutrition accumulation of native E. lindleyanum were higher than invasive E. adenophorum under Inter- competition. In conclusion, exogenous P addition promoted the invasive plant but reduced the native plant in root growth and nutrient accumulation regulated by AMF, although the native plant outcompeted the invasive plant when the two species competed. The findings provide a critical perspective that the anthropogenic P fertilizer addition might potentially contribute to the successful invasion of exotic plants.

IntroductionCheckpoint inhibitor pneumonitis (CIP) is a common serious adverse event caused by immune checkpoint inhibitors (ICIs), and severe CIP can be life-threatening. We aimed to investigate the role of peripheral blood cells in diagnosis, prediction, and prognosis evaluation for all and severe CIP.Materials and methodsPatients with lung cancer receiving ICIs were enrolled in this retrospective study. Baseline was defined as the time of ICI initiation, endpoint was defined as the time of clinical diagnosis of CIP or the last ICI treatment, and follow-up point was defined as 1 week after CIP. Eosinophil percentages at baseline, endpoint, and follow-up point were shortened to “Ebas”, “Eend and “Efol”, respectively.ResultsAmong 430 patients included, the incidence of CIP was 15.6%, and severe CIP was 3.7%. The Eend/Ebas value was lower in patients with CIP (p = 0.001), especially severe CIP (p = 0.036). Receiver operating characteristic curves revealed that Eend/Ebas could serve as a biomarker to diagnose CIP (p = 0.004) and severe CIP (p < 0.001). For severe CIP, the eosinophil percentage declined before the symptoms appeared and CT diagnosis. The eosinophil percentage significantly elevated at the follow-up point in the recovery group but not in the non-recovery group. The CIP patients with Efol/Ebas ≥1.0 had significantly prolonged overall survival (p = 0.024) and after-CIP survival (AS) (p = 0.043). The same results were found in severe CIP but without a statistical difference.ConclusionsEosinophil percentage was associated with the diagnosis, prediction, and prognosis of CIP and severe CIP.

During the COVID-19 pandemic, urban forest parks are becoming increasingly significant for recreation and relaxation, not just for urban residents but also for tourists. This study empirically examined the structural relationships among first-time visitors’ perceptions of destination image, perceived value and destination loyalty through structural equation modeling. Additionally, the mediating influence of perceived value and the moderating effect of gender were investigated as well. The Grand Canal Forest Park in Beijing was selected as the case study. In total, 486 questionnaires that were considered to be legitimate were gathered and afterwards analyzed. The results revealed that first-time visitors’ perceptions of destination image can positively and significantly affect their perceived value and destination loyalty. In addition, perceived value partially mediates the relationship between first-time visitors’ perceptions of destination image and destination loyalty. Moreover, the findings of the examination of the moderating effects showed that gender has substantial moderating effects on the relationships described above. The theoretical and practical implications, limitations and future research of the current study are also discussed.

In this study, a novel intelligent nanoplatform to integrate multiple imaging and therapeutic functions for targeted cancer theranostics. The nanoplatform, DOX@Gd-MFe3O4 NPs, was constructed Gd-doped mesoporous Fe3O4 nanoparticles following with the doxorubicin (DOX) loading in the mesopores of the NPs. The DOX@Gd-MFe3O4 NPs exhibited good properties in colloidal dispersity, photothermal conversion, NIR triggered drug release, and high T1/T2 relaxicity rate (r1=9.64 mM−1s−1, r2= 177.71 mM−1s−1). Benefiting from the high MR contrast, DOX@Gd-MFe3O4 NPs enabled simultaneous T1/T2 dual-modal MR imagining on 4T1 bearing mice in vivo and the MR contrast effect was further strengthened by external magnetic field. In addition, the DOX@Gd-MFe3O4 NPs revealed the strongest inhibition to the growth of 4T1 in vitro and in vivo under NIR irradiation and guidance of external magnetic field. Moreover, biosafety was also validated by in vitro and in vivo tests. Thus, the prepared DOX@Gd-MFe3O4 NPs would provide a promising intelligent nanoplatform for dual-modal MR imagining guided synergistic therapy in cancer theranostics.

BackgroundDrug–drug interactions (DDIs) pose new challenges beyond traditional pharmacodynamics in the context of optimizing the treatment options with immune checkpoint inhibitors (ICIs). To alleviate cancer-related pain, analgesics are of absolute vital importance as chronic medications used by cancer patients. However, the possible outcome of ICI treatment concomitant with analgesics remains unclear.MethodsOriginal articles describing the possible influence of analgesics use on ICI treatment published before December 1, 2021 were retrieved from PubMed, Embase, and the Cochrane Library. Odds ratio (OR) with 95% confidence interval (CI) for objective response rate (ORR), hazard ratio (HR) with 95% CI for progression-free survival (PFS), and overall survival (OS) were calculated using the random-effects or fixed-effects model, and heterogeneity was assessed using the χ2-based Q-test. Publication bias was examined by funnel plot analysis.ResultsA total of 11 studies involving 4,404 patients were included. The pooled OR showed that opioid use decreased the response of opioid users to ICIs compared to non-opioid users (OR = 0.49, 95% CI = 0.37–0.65, p < 0.001). Compared to patients who did not receive opioids, opioid users had an increased risk of progression and mortality (HR = 1.61, 95% CI = 1.37–1.89, p < 0.001; HR = 1.67, 95% CI =1.30–2.14, p < 0.001, respectively). Furthermore, the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) was not significantly associated with differences in ORR, PFS, and OS in patients treated with ICIs (OR = 1.40, 95% CI = 0.84–2.32, p = 0.190; HR = 0.90, 95% CI = 0.77–1.06, p = 0.186; HR = 0.90, 95% CI = 0.71–1.14, p = 0.384, respectively).ConclusionThe concomitant use of opioids during ICI treatment has an adverse effect on patient prognosis, while the use of NSAIDs is not significantly associated with the prognosis in patients treated with ICIs.

Background: Anti-silencing function 1B (ASF1B), a histone H3-H4 chaperone, is crucial for S-phase progression and cell proliferation. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. However, the prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear.Methods: We analyzed the expression of ASF1B and its prognostic value using The Cancer Genome Atlas (TCGA) database (as a training set) and other databases, and we validated the findings by immunohistochemistry in our clinical database, containing 141 HCC patients (as a validation set). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to probe the tumor-associated biological processes of ASF1B in HCC. The interrelationships between ASF1B expression and tumor immunological characteristics were analyzed by multiple databases. The Imvigor210 cohort was retrieved to assess the ability of ASF1B to predict immunotherapy efficacy.Results: ASF1B was highly expressed in tumor tissue compared to paracancerous tissue. High ASF1B expression was associated with worse overall survival (OS) and progression-free survival (PFS) in the training set (p = 0.005, p < 0.001) and validation set (p < 0.001, p < 0.001). Multivariate analysis revealed that ASF1B was an independent prognostic factor associated with OS and PFS. GSEA and GSVA suggested that ASF1B was involved in tumor-associated biological processes, including the cell cycle, DNA replication, base excision repair, mismatch repair, RNA degradation, ubiquitin-mediated proteolysis, and nucleotide excision repair. Further analysis revealed that the levels of ASF1B were positively correlated with the immune cells infiltration of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells. However, ASF1B was positively correlated with Treg cell infiltration and inhibitory immune checkpoints in exhausted T cells. Patients who received anti-PD-L1 immunotherapy with high ASF1B expression had a higher objective response.Conclusion: The ASF1B level is an independent prognostic factor and may serve as a potential immunotherapeutic target.

BackgroundNivolumab + ipilimumab + two cycles chemotherapy (N-I + chemo, intensive immunotherapy but chemo-light) and pembrolizumab + chemotherapy (Pem + chemo) were both recommended as first-line treatment for metastatic non-small cell lung carcinoma (NSCLC) patients. We conducted this indirect comparison to compare the efficacy of and safety between these two treatments for providing reference for decision making.MethodsRelevant databases were searched for eligible trials. A well-accepted adjusted indirect treatment comparison (ITC) approach was selected to pool efficacy results and safety outcomes. Subgroup analyses were stratified according to PD-L1 expression and clinical characteristics.ResultsFour eligible randomized trials (CheckMate9LA, KEYNOTE-021G, KEYNOTE 189, KEYNOTE 407) involving 2017 patients were available to analyze. The ITC results suggested that N-I + chemo is comparable to Pem + chemo in OS (HR 1.03, 95% CI 0.82-1.30) and ORR (RR 0.81, 95% CI 0.62-1.06), but tended to yield inferior PFS (HR 1.28, 95% CI 1.04-1.59) than did Pem + chemo. As for safety profiles, N-I + chemo showed no significant difference relative to Pem + chemo in any grade adverse events: (RR 1.03, 95% CI 0.99-1.10), but demonstrated reduced toxicity in chemo-related adverse events, such as anemia (RR 0.63, 95% CI 0.49-0.81), neutropenia (RR0.51, 95% CI 0.33-0.79), and thrombocytopenia (RR 0.38, 95% CI 0.21-0.69).ConclusionsN-I + chemo is a promising treatment option for providing comparable OS related to Pem + chemo. However, for never smoker female patients, Pem + chemo is preferable to choose for demonstrating favorable OS benefit than N-I + chemo.

The synthesis of a novel versatile nanomedicine platform integrating multiple imaging and therapeutic functions has always been a great challenge for efficient cancer diagnosis and therapy. Herein, in this study, a novel versatile carbon monoxide (CO) delivery nanoplatform was constructed with hollow mesoporous CuS NPs carrying manganese carbonyl (MnCO) to realize MR imaging-guided PTT and CO combined anticancer therapy. The MnCO@CuS nanoplatform revealed superior properties in colloidal stability, photothermal conversion, H2O2/NIR-stimulated CO release and tumoral accumulation. More importantly, the enriched H2O2 in the tumor microenvironment (TME) triggered MnCO to release CO in situ, and this process was further strengthened by the NIR irradiation. Subsequently, the intermediate products MnOx was degraded into Mn2+ by the mild acidic tumor microenvironment to enable T1-weighted MR imaging. Simultaneously, the in situ-released CO combined with NIR irradiation exhibited strongest inhibition to the growth of MV3 tumor in vitro and in vivo. Moreover, the multifunctional nanoplatform also exhibited low toxicity and good biocompatibility in vitro and in vivo. Hence, these results suggested the MnCO@CuS nanoplatform possessed significant potential in realizing TME/NIR stimulated CO/Mn2+ generation and photothermal conversion for MR imaging-guided synergistic PTT and CO anticancer therapy.

Urban trees provide a range of ecological services for urban dwellers. This is particularly true in residential areas where these services are known and valued. The abundance and diversity of trees determine and indicate the provision of ecological services by trees, while various characteristics of residential areas determine and indicate the abundance and diversity of trees within those areas. Exploring the abundance and diversity of trees in residential areas and their major driving and indicative factors is important for evaluating, predicting, and thus improving the ecological services provided by trees. Here, we selected 87 residential areas in Beijing through spatially stratified random sampling. Unlike the quadrat survey that is usually used, we conducted a detailed investigation of the abundance and diversity of trees in residential areas through a tree-by-tree survey and explored the major driving and indicative factors of the abundance and diversity of the trees. In the 87 sampled residential areas, 69 tree taxa belonging to 34 families were identified, and we found that the 10 most common species accounted for 55.9% of all trees. Trees in the residential areas had both high allergenic risk and high ornamental value. In newly built residential areas, the allergenic risk decreased but the ornamental value remained high. Average building height and distance to the city center were the two major driving and indicative factors of residential tree abundance, both of which were positive indicators, and the former played a larger role than that of the latter. In this study, distance to the city center was the only predicator of tree species diversity, and was also a positive indicator. The size of residential area did not show any relationship with tree abundance or diversity. Even though housing age and housing price were not included in the forecasting model, both showed a negative correlation with tree abundance, i.e., an opposite legacy effect and luxury effect. The results of this study can help in understanding tree abundance and diversity and their driving and indicative factors in residential areas in highly urbanized cities and can provide potential guidance for future residential tree planning and management.

Abstract Hepatocellular carcinoma (HCC) is a common malignant tumor with insidious onset and rapid progression. Its treatment is often difficult owing to tumor resistance. In this study, we aimed to understand the different biological characteristics, gene expression profiles, and drug resistance mechanisms of HCC cells cultured under different conditions. A conventional adherence method and a liquid overlay technique were used to prepare two‐ and three‐dimensional cultures of Bel‐7402 and 5‐fluorouracil (5‐Fu)‐resistant Bel‐7402 (Bel‐7402/5‐Fu) cells. Morphological characteristics were assessed via microscopy, and cell cycle distribution and apoptotic rate were obtained using flow cytometry. Cell sensitivity to different concentrations of drugs was detected with 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays. Gene expression profiles and signal transduction pathways of Bel‐7402 and Bel‐7402/5‐Fu cells under different culture conditions were determined using gene chips. Cells in three‐dimensional culture were suspended and they grew into dense multicellular spheroid (MCS) structures, aggregating with each other. In contrast to cells in the two‐dimensional culture, cell cycle arrest was observed in MCSs. The sensitivity of Bel‐7402 cells in the two‐dimensional culture to drugs at high concentrations was significantly higher than that of cells in the three‐dimensional culture (p

The development of multifunctional nanoplatforms that are safe and have multiple therapeutic functions integrated with dual- or multi-imaging modality is one of the most urgent medical requirements for active cancer therapy. In our study, we prepared multifunctional magnetic nanobubbles (MF-MNBs) by co-encapsulating superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin into polylactideco–glycolide–polyethylene glycol–folate (PLGA-PEG-FA) polymer-based nanobubbles for tumor-targeted ultrasound (US)/magnetic resonance (MR) imaging and focused ultrasound (FUS)-triggered drug delivery. Hydrophobic SPIONs were successfully embedded into MF-MNBs by a typical double emulsion process. The MF-MNBs were highly dispersed with well-defined spherical morphology and an average diameter of 208.4 ± 12.58 nm. The potential of MF-MNB as a dual-modal contrast agent for US and MR imaging was investigated via in vitro study, and the MF-MNB exhibits promising US/MR contrast ability. Moreover, tumor targeting ability was further enhanced by folate conjugation and assessed through in vitro cell test. Furthermore, FUS, as a non-invasive and remote-control technique, was adopted to trigger the release of doxorubicin from MF-MNB and generate the sonoporation effect to enhance drug release and cellular uptake of MF-MNBs. The 4T1 cell viability was significantly decreased by FA ligand-receptor-mediated targeting and FUS sonication. In addition, the developed MF-MNB also exhibits enhanced accumulation in tumor site by FA ligand-receptor-mediated tumor targeting, in which the accumulation of MF-MNB was further enhanced by FUS sonication. Hence, we believe that the MF-MNB could be a promising drug nanocarrier for US/MR-guided anticancer drug delivery to improve cancer treatment efficacy.

Clear cell renal cell carcinoma (ccRCC), the most frequent subtype of renal cell carcinoma (RCC), is characterized by high relapse rate and mortality. Long non-coding RNAs (lncRNAs) are critical participants during cancer development. LncRNA DARS antisense RNA 1 (DARS-AS1), a newly-found lncRNA, is not specifically reported in ccRCC. However, Gene Expression Profiling Interactive Analysis (GEPIA) and starBase databases revealed the up-regulation of DARS-AS1 in ccRCC. Current study investigated the function and mechanism of DARS-AS1 in ccRCC. Functional assays including colony formation assay, EdU assay, caspase-3 activity detection, flow cytometry analysis and JC-1 assay were implemented to identify the role of DARS-AS1 in ccRCC. As a result, silencing of DARS-AS1 retarded proliferation and facilitated apoptosis in ccRCC cells. Moreover, mainly a cytoplasmic localization of lncRNA DARS-AS1 was verified in ccRCC cells. Then, we demonstrated that DARS-AS1 positively regulated its nearby gene, aspartyl-tRNA synthetase (DARS), by sequestering miR-194−5p. Moreover, DARS was testified as the oncogene in ccRCC and DARS-AS1 worked as a tumor-facilitator in ccRCC through miR-194−5p/DARS signaling. In a summary, this study firstly uncovered that DARS-AS1 boosted DARS expression via absorbing miR-194−5p, therefore contributing to malignancy in ccRCC. Our findings may be helpful for opening new strategies for ccRCC treatment.

BackgroundCoronary artery disease (CAD) is a type of cardiovascular disease that greatly hurts the health of human beings. Diabetic status is one of the largest clinical factors affecting CAD-associated gene expression changes. Most of the studies focus on diabetic patients, whereas few have been done for non-diabetic patients. Since the pathophysiological processes may vary among these patients, we cannot simply follow the standard based on the data from diabetic patients. Therefore, the prognostic and predictive diagnostic biomarkers for CAD in non-diabetic patient need to be fully recognized.Materials and MethodsTo screen out candidate genes associated with CAD in non-diabetic patients, weighted gene co-expression network analysis (WGCNA) was constructed to conduct an analysis of microarray expression profiling in patients with CAD. First, the microarray data GSE20680 and GSE20681 were downloaded from NCBI. We constructed co-expression modules via WGCNA after excluding the diabetic patients. As a result, 18 co-expression modules were screened out, including 1,225 differentially expressed genes (DEGs) that were obtained from 152 patients (luminal stenosis ≥50% in at least one major vessel) and 170 patients (stenosis of

Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.

Based on the NCEP/NCAR daily reanalysis product, NOAA monthly sea surface temperature (SST) dataset, and daily precipitation data collected at observational stations provided by Meteorological Information Center of China Meteorological Administration, the present study analyzes characteristic circulation anomalies conducive to regional extreme daily precipitation in the summer over Northeast China. Results indicate that 26 extreme precipitation events occurred during the 36-year period of 1979–2014. The precipitation threshold for the 99th percentile is 22.2 mm/d, and the maximum extreme daily precipitation occurred in Liaoning Province. When extreme precipitation occurs, Northeast China is located to the southeast of an anomalous cyclonic circulation and northwest of an anomalous anticyclonic circulation, where a strong convergence zone is formed in the lower troposphere. The low-level convergence and upper-level divergence as well as the baroclinic circulation structure are favorable for the development of extreme daily precipitation. Meanwhile, there exist two symmetrical meridional circulations to the north and south of Northeast China. The two meridional circulations share the same ascending branch, which is conducive to the occurrence of precipitation. Located in the strong convergence zone to the southeast of the abnormal cyclonic circulation and northwest of the abnormal anticyclonic circulation, huge amounts of water vapor from the Inner Mongolia, Russia, the Japan Sea, and the mid-high latitudes of the Northwest Pacific are transported to Northeast China, providing sufficient water vapor condition for the occurrence of extreme daily precipitation in this region. In addition, daily extreme precipitation in Northeast China is also closely related to the accumulation and convergence of disturbance energy in Northeast China. It may also be related to the abnormal SST distribution that is high in the north and low in the south. Corresponding to extreme daily precipitation, SST anomaly in the Pacific Ocean is roughly characterized by the feature of “positive-north and negative- south” with the equator as the boundary.

Wheat stripe rust, caused by Puccina striiformis f. sp. tritici (Pst), is one of the most devastating diseases of wheat in China. Rapid change to virulence following release of resistant cultivars necessitates ongoing discovery and exploitation of new resistance resources. Considerable effort has been directed at nonhost resistance (NHR) which is believed to be durable. In the present study we identified rice mutant crr1 (compromised resistance to rust 1) that exhibited compromised NHR to Pst. Compared with wild type rice variety Nipponbare, crr1 mutant displayed a three-fold increase in penetration rates by Pst, and enhanced hyphal growth. The pathogen also developed haustoria in crr1 mesophyll cells, but failed to sporulate. The response to the adapted rice pathogen Magnaporthe oryzae was unchanged in crr1 relative to the wild type. Several defense-related genes involved in the SA- and JA-mediated defense pathways response and in phytoalexin synthesis (such as OsPR1a, OsLOX1, and OsCPS4) were more rapidly and strongly induced in infected crr1 leaves than in the wild type, suggesting that other layers of defense still in effect. Genetic analysis and mapping located the mutant loci at a region between markers ID14 and RM25792, which cover about 290 kb genome sequence on chromosome 10. Further fine mapping and cloning of the locus should provide further insights into NHR to rust fungi in rice, and may reveal new strategies for improving rust resistance in wheat.

Puccinia striiformis f. sp. tritici (Pst), the causal fungus of wheat stripe rust, was previously reported to be infected by Lecanicillium lecanii, Microdochium nivale and Typhula idahoensis. Here, we report a novel hyperparasite on Pst. This hyperparasitic fungus was identified as Cladosporium cladosporioides (Fresen.) GA de Vries based on morphological characteristics observed by light and scanning electron microscopy together with molecular data. The hyperparasite reduced the production and viability of urediniospores and, therefore, could potentially be used for biological control of wheat stripe rust.

Background and Aims Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. Methods TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT–qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. Results VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout Apoe KO mice (Apoe KO Trap1 SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. Conclusions This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis. [ABSTRACT FROM AUTHOR]