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Terrestrial mosses are tracers for studying atmospheric trace metal deposition and pollution. Here, Al, Fe, Zn, Mn, Ba, Cu, V, Cr, Pb, Ni, Co, and Cd concentrations in mosses from Huai'an, China, were measured to investigate their contamination level, spatial distribution, and sources. The average concentration of all the metals (except Ni) was much higher than those in Albania, a "hotspot" of toxic metal contamination in Europe. The pollution degree of the metals varied significantly: moderate contamination by Al, Fe, Mn, Zn, Cr, V, and Cd; slight contamination by Ba, Cu, Ni, and Pb; and suspected contamination by Co. Based on the Nemerow index (P

With the improvement of industrialization, numerous rural laborers migrate to urban areas in search of off-farm jobs. Farmers change agricultural production decisions to adapt to the change of labor force, which will inevitably affect the crop planting structure. However, few studies have explored the sustainability of crop planting structure. Based on the calculation of the multiple cropping index (MCI), grain crops planting rate (GCR), economic crops planting rate (ECR), and ecological sustainability index (ESI) of crop planting structure, this study analyzes the impact of labor transfer rate (LTR) and labor cost (LC) on the sustainability of crop planting structure using a geographically and temporally weighted regression (GTWR) model. The results show that the scale of rural labor transfer and labor cost in China remains on the rise, but the growth rate has slowed down. The total carbon absorption of crops in China shows a U-shape trend, and the rice and maize have the largest carbon absorption. The impact of LTR on MCI is mainly positive, especially in the North China Plain in the early stage and some provinces in the Southwest China in the later stage. The impact of LTR on ECR and ESI is negative in most provinces. And the negative influence of LC on MCI is increasing, showing the spatial distribution characteristics of large influence in the southeast and small influence in the northwest. The impact of LC on ESI shows a negative effect in most provinces in the early stage, and the negative effect is more concentrated in some provinces in the southwest in the later stage.

Degradation of methylene blue is a critical procedure in its wastewater remediation, thus has inspired wide catalysis research with semiconductors such as Titanium dioxide (TiO2) and rare metals such as gold (Au). In this study we report bacterial cells assisting biosynthesis for Au@TiO2 as an efficient catalyst for the degradation of methylene blue. Multiple complementary characterization for bio-Aux@TiO2 evidenced the evenly distributed Au NPs on the bio-TiO2 layers. Meanwhile, bio-Au2@TiO2 displayed the superior catalytic activity in the degradation of methylene blue with the highest k value of 0.195 min-1. The origin of the catalytic activity was explored by the hydroxyl radical fluorescence quantitative analysis. In the bio-Au2@TiO2 catalytic system, Au NPs decreased the band gap energy of TiO2, increased charge separation between the excited (h+)–(e-) pairs, enabling the generation of a large amount of photogeneration hydroxyl radicals, resulting in an enhanced photocatalytic activity. Our microbial synthesized bio-TiO2 and bio-Aux@TiO2 study would be useful for developing green synthesis catalyst technologies.

Melanocortin-4 receptor (MC4R) plays an important role in energy balance regulation and insulin secretion. It has been demonstrated that in the pancreas, it is expressed in islet α and β cells, wherein it is significantly correlated with insulin and glucagon-like peptide-1 (GLP-1) secretion. However, the molecular mechanism by which it regulates islet function is still unclear. Therefore, in this study, our aim was to clarify the signaling and target genes involved in the regulation of insulin and GLP-1 secretion by islet MC4R. The results obtained showed that in islet cells, the expression of prohormone convertase 1/3 (PC1/3), which is correlated with islet GLP-1 and insulin secretion, increased significantly under the action of the MC4R agonist, NDP-α-MSH, but decreased under the action of the MC4R antagonist, AgRP. Additionally, we observed that to exert their regulatory functions in the islets, cAMP and β-arrestin-1 acted as important signaling mediators of MC4R, and compared with control islets, the cAMP, PKA, and β-arrestin-1 levels corresponding to NDP-α-MSH-treated islets were significantly elevated; however, in AgRP-treated islets, their levels decreased significantly. Islets treated with the PKA inhibitor, H89, and the ERK1/2 inhibitor, PD98059, also showed significant decreases in PC1/3 expression level, indicating that the cAMP and β-arrestin-1 pathways are significantly correlated with PC1/3 expression. These findings suggest that islet MC4R possibly affects PC1/3 expression via the cAMP and β-arrestin-1 pathways to regulate GLP-1 and insulin secretion. These results provide a new theoretical basis for targeting the molecular mechanism of type 2 diabetes mellitus.

Quorum cheating, a socio-microbiological process that is based on mutations in cell density-sensing (quorum-sensing) systems, has emerged as an important contributor to biofilm-associated infection in the leading human pathogen Staphylococcus aureus. This is because inactivation of the staphylococcal Agr quorum-sensing system leads to pronounced biofilm formation, increasing resistance to antibiotics and immune defense mechanisms. Since biofilm infections in the clinic usually progress under antibiotic treatment, we here investigated whether such treatment promotes biofilm infection via the promotion of quorum cheating. Quorum cheater development was stimulated by several antibiotics used in the treatment of staphylococcal biofilm infections more strongly in biofilm than in the planktonic mode of growth. Sub-inhibitory concentrations of levofloxacin and vancomycin were investigated for their impact on biofilm-associated (subcutaneous catheter-associated and prosthetic joint-associated infection), where in contrast to a non-biofilm-associated subcutaneous skin infection model, a significant increase of the bacterial load and development of agr mutants was observed. Our results directly demonstrate the development of Agr dysfunctionality in animal biofilm-associated infection models and reveal that inappropriate antibiotic treatment can be counterproductive for such infections as it promotes quorum cheating and the associated development of biofilms.

Background While adjuvant endocrine therapy (ET) may decrease the mortality rate of estrogen receptor-positive (ER+) breast cancer (BC), the likelihood of relapse and metastasis due to ET resistance remains high. Cuproptosis is a recently discovered regulated cell death (RCD), whose role in tumors has yet to be elucidated. Thus, there is a need to study its specific regulatory mechanism in resistance to ET in BC, to identify novel therapeutic targets. Methods The prognostic cuproptosis-related genes (CRGs) in ER+ BC were filtered by undergoing Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses in TCGA-BRCA, and a CRGs risk signature was constructed using the correlation coefficient. Immune infiltration analysis, immune function analysis, tumor microenvironment (TME) analysis, immune checkpoint analysis, immunotherapy response analysis, drug sensitivity analysis, and pathway activation analysis were carried out among the high- and low-risk groups in turn. The central CRG of cuproptosis in ER+ BC resistance to ET was acquired through the intersection of protein interaction network (PPI) analysis, genes differentially expressed (DEGs) between human BC cells LCC9 and MCF-7 (GSE159968), and CRGs with prognostic significance in TCGA-BRCA ER+ BC. The miRNAs upstream of the core CRGs were predicted based on the intersection of 4 databases, miRDB, RNA22, miRWalk, and RNAlnter. Candidate miRNAs consisted of the intersection of predicted miRNAs and miRNAs differentially expressed in the LCC9 and MCF-7 cell lines (GSE159979). Candidate lncRNAs were the intersection of the differential lncRNAs from the LCC9 and MCF-7 cell lines and the survival-related lncRNAs obtained from a univariate Cox regression analysis. Pearson's correlation analysis was performed between mRNA-miRNA, miRNA-lncRNA, and mRNA-lncRNA expression separately. Results We constructed A risk signature of 4-CRGs to predict the prognosis of ER+ BC in TCGA-BRCA, a risk score = DLD*0.378 + DBT*0.201 + DLAT*0.380 + ATP7A*0.447 was used as the definition of the formula. There were significant differences between the high- and low-risk groups based on the risk score of 4-CRGs in aspects of immune infiltration, immune function, expression levels of immune checkpoint genes, and signaling pathways. DLD was determined to be the central CRG of cuproptosis in ER+ BC resistance to ET through the intersection of the PPI network analysis, DEGs between LCC9 and MCF-7 and 4-CRGs. Two miRNAs hsa-miR-370-3p and hsa-miR-432-5p were found taking DLD mRNA as a target, and the lncRNA C6orf99 has been hypothesized to be a competitive endogenous RNA that regulates DLD mRNA expression by sponging off hsa-miR-370-3p and hsa-miR-432-5p. Conclusion This study built a prognostic model based on genes related to cuproptosis in ER+ BC. We considered DLD to be the core gene associated with resistance to ET in ER+ BC via copper metabolism. The search for promising therapeutic targets led to the establishment of a cuproptosis-related ceRNA network C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD.

Background Multimorbidity has become one of the main challenges in health care system. The association between prevalence, patterns of multimorbidity and health care utilization is less often discussed in China. The purpose of this study is to examine this association among Chinese middle-aged and older adults and take into account different sociodemographic, behavioral and health characteristics. Based on this, implications of current evidence and effective intervention on multimorbidity and health care utilization can be identified and put into practice. Methods The wave 4 in 2018 of the China Health and Retirement Longitudinal Study (CHARLS) was used in the study. Multimorbidity was defined as the co-occurrence of two or more chronic medical condition of a list of fourteen chronic diseases in one person. The presence of chronic diseases was assessed through self-report. Health care utilization include whether the respondents received outpatient service last month and inpatient service in the past year. Latent Class Analysis was conducted to identify the clustering pattern of chronic diseases. Logistic regressions were employed to explore the association between prevalence, patterns of multimorbidity and health care utilization. Analyses were weighted using individual sample weights, adjusted for non-response of individual and household. Results Among 19,559 participants aged 45 and older, 23.10% were aged above 70 years and 52.42% were female. The prevalence of multimorbidity was 56.73%. Four patterns were identified: relatively healthy class, respiratory class, stomach-arthritis class and vascular class. Multimorbid individuals used more outpatient services (OR = 1.89, 95%CI = 1.65–2.17) and more inpatient services (OR = 2.52, 95%CI = 2.22–2.86) compared to their no-multimorbid counterparts. Compared to relatively healthy class, the respondents classified into respiratory class, stomach-arthritis class and vascular class used more outpatient services (OR = 1.90, 95%CI = 1.57–2.30; OR = 2.39, 95%CI = 2.06–2.78; OR = 1.53, 95%CI = 1.32–1.79 respectively) and more inpatient services (OR = 2.19, 95%CI = 1.83–2.62; OR = 2.93, 95%CI = 2.53–3.40; OR = 1.90, 95%CI = 1.65–2.19 respectively). Conclusion Our study provided evidence that multimorbidity is high among Chinese older adults and is associated substantially higher health care utilization in China. Four multimorbidity patters were identified. Policy should prioritize improving the management of individuals with multimorbidity to increase healthcare efficiency. Further research is necessary with special emphasis on the trajectory of multimorbidity and the role of health system in satisfying needs of multimorbid individuals.

Alkynols semi-hydrogenation is a critical industrial process as the product, alkenols, have extensive applications in chemistry and life sciences. However, this class of reactions is plagued by the use of high-pressure hydrogen, Pd-based catalysts, and low efficiency of the contemporary thermocatalytic process. Here, we report an electrocatalytic approach for selectively hydrogenating alkynols to alkenols under ambient conditions. For representative 2-methyl-3-butene-2-ol, Cu nanoarrays derived electrochemically from CuO, achieve a high partial current density of 750 mA cm−2 and specific selectivity of 97% at −0.88 V vs. reversible hydrogen electrode in alkaline solution. Even in a large two-electrode flow electrolyser, the Cu nanoarrays deliver a single-pass alkynol conversion of 93% with continuous production of 2-methyl-3-butene-2-ol at a rate of ~169 g gCu−1 h−1. Theoretical and in situ electrochemical infrared investigations reveal that the semi-hydrogenation performance is enhanced by exothermic alkynol adsorption and alkenol desorption on the Cu surfaces. Furthermore, this electrocatalytic semi-hydrogenation strategy is shown to be applicable to a variety of alkynol substrates.

Background Hemorrhagic transformation (HT) is a common complication of acute ischemic stroke (AIS), and may develop into parenchyma hemorrhage (PH). We aimed to investigate the association between serum homocysteine levels and HT as well as PH in all AIS patients, and in those with and without thrombolysis by subgroup analysis. Methods AIS patients who were admitted within 24 h after onset were enrolled and categorized into the higher homocysteine level group (≥ 15.5 µmol/L) and the lower homocysteine level group ( Results Of the 427 included patients (mean age 67.35 years, 60.0% males), 56 (13.11%) developed HT and 28 (6.56%) had PH. Serum homocysteine levels were significantly associated with HT (adjusted OR 1.029, 95%CI 1.003–1.055) and PH (adjusted OR 1.041, 95%CI 1.013–1.070). The higher homocysteine group was more likely to have HT (adjusted OR 1.902, 95% CI 1.022–3.539) and PH (adjusted OR 3.073, 95% CI 1.327–7.120) than the lower homocysteine group. Subgroup analysis of patients without thrombolysis also showed the significant differences in HT (adjusted OR 2.064, 95% CI 1.043–4.082) and PH (adjusted OR 2.926, 95% CI 1.196–7.156) between the two groups. Conclusion Higher serum homocysteine levels are associated with an increased risk of HT and PH in AIS patients, especially in those without thrombolysis. Monitoring the serum homocysteine may be conducive to determining individuals at a high risk of HT.

Background Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. Methods Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. Results Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8+ T cells. Conclusions Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.

Background To explore the correlation of tumor necrosis factor-α-induced protein 8-like protein 3 (TIPE3) expressions in colorectal cancer (CRC) with tumor-immune infiltration and patient prognosis. Methods Formalin-fixed paraffin-embedded tumor samples from CRC patients (n = 110) were used in this study. Immunohistochemistry staining of TIPE3 and three prognostic immune biomarkers (CD8, CD20, and CD66b) was conducted in the tumor tissues and adjacent normal tissues. A Cox regression analysis of univariate and multivariate variables was performed to assess the correlation between TIPE3 and patient prognosis. Result We found that TIPE3 was mainly expressed in the cytoplasm, with a small amount in the nucleus. The expression of TIPE3 in tumor tissues is significantly higher than in adjacent normal tissues, and it is significantly correlated with the survival rate of patients in tumor tissues (p = 0.0038) and adjacent normal tissues (pp = 0.007), the TIPE3 expression in adjacent normal tissues (pp = 0.020), the number of CD20+ B cells in tumor tissues (p = 0.023), the number of CD20+ B cells in adjacent normal tissues (p = 0.023), the number of CD66b+ neutrophils in tumor tissues (p = 0.005), the number of CD66b+ neutrophils in adjacent normal tissues (pp = 0.010), TNM stage (p = 0.013), and tumor grade (p = 0.027) were significantly correlated with overall survival (OS). These prognostic factors were then subjected to multivariate regression analysis, and the results showed that the expression of TIPE3, the number of CD8+ T cells, and the number of CD66b+ neutrophils were prognostic factors affecting the OS rate of CRC patients. Conclusion We found that the TIPE3 protein is upregulated in CRC cancer tissues and is correlated with survival rate.

This study aimed to improve the catalytic activity of aspartate kinase (AK), the first key rate-limiting enzyme in the aspartic acid metabolism pathway, by site-directed saturation mutagenesis, and to weaken the synergistic feedback inhibition of metabolites and analyze its mechanism using molecular dynamics simulation (MD). The key residual sites around the inhibitor lysine (Lys) were selected to construct the mutant strains. The mutant A380M with significantly increased enzyme activity was obtained through enzyme activity screening. Kinetic analysis showed that the V

Background Asthma is an important non-communicable disease worldwide. DNA methylation is associated with the occurrence and development of asthma. We are aimed at assuring differential expressed genes (DEGs) modified by aberrantly methylated genes (DMGs) and pathways related to asthma by integrating bioinformatics analysis. Methods One mRNA dataset (GSE64913) and one gene methylation dataset (GSE137716) were selected from the Gene Expression Omnibus (GEO) database. Functional enrichment analysis was performed using GeneCodies 4.0 database. All gene expression matrices were analyzed by Gene set enrichment analysis (GSEA) software. STRING was applied to construct a protein-protein interaction (PPI) network to find the hub genes. Then, electronic validation was performed to verify the hub genes, followed by the evaluation of diagnostic value. Eventually, quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression of hub genes. Results In total, 14 hypomethylated/high-expression genes and 10 hypermethylated/low-expression genes were obtained in asthma. Among them, 10 hub genes were identified in the PPI network. Functional analysis demonstrated that the differentially methylated/expressed genes were primarily associated with the lung development, cytosol and protein binding. Notably, HLA-DOA was enriched in asthma. FKBP5, WNT5A, TM4SF1, PDK4, EPAS1 and GMPR had potential diagnostic value for asthma. Conclusion The project explored the pathogenesis of asthma, which may provide a research basis for the prediction and the drug development of asthma.

Tumour cell metabolic plasticity is essential for tumour progression and therapeutic responses, yet the underlying mechanisms remain poorly understood. Here, we identify Prospero-related homeobox 1 (PROX1) as a crucial factor for tumour metabolic plasticity. Notably, PROX1 is reduced by glucose starvation or AMP-activated protein kinase (AMPK) activation and is elevated in liver kinase B1 (LKB1)-deficient tumours. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. Downregulation of PROX1 activates branched-chain amino acids (BCAA) degradation through mediating epigenetic modifications and inhibits mammalian target-of-rapamycin (mTOR) signalling. Importantly, PROX1 deficiency or Ser79 phosphorylation in liver tumour shows therapeutic resistance to metformin. Clinically, the AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that deficiency of the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signalling, and facilitating tumourigenesis and aggressiveness.

In this paper, the diversity of complicated dendrite microstructure and its evolution behavior during solidification in different magnesium alloys under various processing conditions were illustrated using synchrotron X-ray imaging technique. A variety of dendritic morphologies and branching structures were revealed, i.e., sixfold plate-like symmetric structure in Mg–Al-based structure, 12-branch structure in Mg–Zn-based alloys and 18-branch structure in Mg–Sn- and Mg–Ca-based alloys as well as seaweed like hyper-branched structure in Mg-38wt%Zn alloy. In addition, a dendrite morphology and orientation transition with increasing addition of Zn content were also observed in Mg–Zn alloy, with dendrite growth pattern transform from anisotropy (low Zn addition) with sixfold symmetric snow-flake structure to relative isotropy (intermediate Zn addition) where seaweed morphology presented and then back to anisotropy (high Zn addition) when only 12 branches with preferred orientations were observed. The phase-field model representing the typical dendritic morphologies and branching structures under various conditions was also depicted and discussed. Further, the two-dimensional (2D) real-time dendrite growth dynamics in different Mg-based alloys captured using synchrotron X-ray radiography for unveiling the originate of the α-Mg dendrite was reviewed. Following this, the four-dimensional (3D + time) synchrotron X-ray tomographic in situ observation of dendritic morphology evolution indicating the formation mechanism of the diverse dendritic morphology during Mg–Sn- and Mg–Zn-based alloys was also summarized. Finally, the future study on exploring the complicated dendritic morphologies and their origination during solidification of Mg-based alloys is prospected.

To explore the prognostic value of the systemic inflammation response index (SIRI) defined as neutrophil count × monocyte count/lymphocyte count in the patients with early stage hepatocellular carcinoma (HCC) within the Milan criteria after radiofrequency ablation (RFA). The prognostic value of SIRI was evaluated in a primary cohort (n = 403) and then further validated in an independent test cohort (n = 140). A novel preoperative prognostic nomogram was constructed from a multivariate analysis and validated in an external validation cohort. The optimal cutoff value of SIRI for patient stratification into a low SIRI group and a high SIRI group was 1.36. Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly higher in patients with a low SIRI compared to those with a high SIRI. The alpha-fetoprotein (AFP), SIRI, tumor number and size were independent predictors of RFS based on multivariate analysis. The nomogram including the SIRI, tumor number, tumor size, AFP could more accurately determine the prognosis of HCC patients than BCLC stage (0.74 vs. 0.62, P 75% had a better prognosis. Preoperative SIRI was an independent predictor for RFS in patients with early stage HCC within the Milan criteria. The comprehensive nomogram can objectively and reliably help clinicians identify high-risk patients and develop individualized treatment plans.

Mineral-associated soil organic matter (MAOM) is seen as the key to soil carbon sequestration, but its stability often varies with types of exogenous organic materials. Fulvic acid and manure are ones of the exogenous organic materials used for the improvement of degraded soil. However, little is known about if and how fulvic acid and manure affect the stability of MAOM. Using a field experiment of four fertilization treatments (no fertilization, mineral fertilizers, fulvic acid, and manure) and a comprehensive meta-analysis using relevant studies published prior to January 2020, we investigated effects of exogenous fulvic acid and manure applications on four MAOM stability indexes: association intensity, humus stabilization index, iron oxide complex coefficient, and aluminum oxide complex coefficient. Exogenous fulvic acid and manure applications increased soil organic carbon fractions by 26.04-48.47%, MAOM stability by 12.26-387.41%, and complexed iron/aluminum contents by 16.12-20.01%. Fulvic acid application increased MAOM stability by promoting mineral oxide complexation by 20.33% and manure application improved MAOM stability via increasing humus stabilization by 21-25%. Association intensity was positively correlated with contents of soil carbon fractions and the metal oxide complex coefficients were positively correlated with iron/aluminum oxide contents. Moreover, stable-humus exerted significantly positive direct and indirect effects on association intensity and humus stabilization index, while amorphous iron/aluminum content had significantly negative influences on metal oxide complex coefficients. The meta-analysis verified that long-term fulvic acid application improved MAOM stability more so than manure application in acidic soils. We recommend that strategies aiming to prevent land degradation should focus on the potential of fulvic acid as a soil amendment because it can significantly increase MAOM stability.

Over the past few decades, co-amorphous solids have been used as a promising approach for delivering poorly water-soluble drugs. Co-amorphous solids, comprising pharmacologically relevant drug substances or excipients, improve physical stability, solubility, dissolution, and bioavailability compared with single amorphous ingredients. In this review, we have summarized recent advances in physical stability and in vitro and in vivo performances of co-amorphous solids. We have highlighted the role of molar ratio, molecular interaction, and mobility that affects the physical stability of co-amorphous solids. This review delves deep as to how co-amorphous solids affect the physicochemical properties in vitro and in vivo. We also described the challenges to the formulation of co-amorphous solids. A better understanding of the mechanisms of the physical stability, in vitro and in vivo performance of co-amorphous solids, and proper selection of the co-former is likely to expedite the development of robust co-amorphous-based pharmaceutical formulations and can address the challenges associated with the delivery of poorly soluble drugs.

Background Circulating tumour DNA (ctDNA)-based sequencing might provide a simple test for the stratified model of non-small cell lung cancer (NSCLC). Here, we aimed to assess the ctDNA sequencing-based tumour mutation index (TMI) model for screening responders (from non-responders) among NSCLC patients who received monotherapy with docetaxel or atezolizumab. Methods We performed a retrospective analysis of the POPLAR (NCT01903993) and OAK (NCT02008227) trials. We identified three biomarkers, blood tumour mutation burden (bTMB), sensitive blood tumour mutation burden (sbTMB) and unfavourable mutation score (UMS), of the ctDNA profiles. After integrating the advantages and disadvantages of the three independent biomarkers, we developed the TMI model and identified NSCLC patients who may benefit from monotherapy with docetaxel or atezolizumab in terms of overall survival (OS). Results The TMI model as a stratified biomarker for docetaxel responders provided a median OS duration of 5.55 months longer than non-responders in the OAK cohort, with a significantly decreased hazard ratio (HR). Moreover, atezolizumab responders had a 10.21-month OS advantage over atezolizumab non-responders in the OAK cohort via TMI stratification, and the HR was also decreased significantly. The TMI demonstrated effectiveness for stratifying responders in the POPLAR cohort. Importantly, we found that the TMI model could screen additional responders upon combining the cohorts from the POPLAR and OAK trials after adjustment. Conclusion In the present study, we provide a novel TMI model for screening responders (from non-responders) among NSCLC patients who received the 2nd-line monotherapy with docetaxel or atezolizumab. We believe that the biomarker TMI will potentially be effective for the clinical treatment of NSCLC in the future.

Background Migraine is a highly prevalent neurological disorder. It is the third most prevalent disorder and the seventh highest cause of disability worldwide. Acupuncture may be a viable prophylactic treatment option for frequent or uncontrolled migraine. Clinical studies comparing acupuncture and placebo acupuncture have not reached a consistent conclusion in confirming whether acupuncture is effective in migraine prophylaxis. The effect of acupuncture mainly depends on acupoints and needles operation. We found that the design of the placebo acupuncture in previous studies included shallow needling at sham acupoints, non-penetrating needling at sham acupoints, and needling at inactive acupuncture points to achieve the inert effect of control group, but the non-penetrating needling at true acupoints was ignored. This randomized controlled trial aims to use true acupoints for non-penetrating acupuncture as control to evaluate the efficacy of manual acupuncture for the prophylaxis of migraine without aura (MWoA). Methods/design This is a single-blinded, randomized, controlled, prospective, multi-center trial with two parallel treatment groups. A total of 198 eligible patients with MWoA will be randomly divided into two groups (1:1 allocation ratio). The intervention group will receive manual acupuncture and the control group will receive placebo acupuncture (non-penetrating). Patients will receive three acupuncture treatment sessions per week for 4 consecutive weeks. All patients will then receive a 12-week follow-up. Discussion In this study, we are evaluating the efficacy and safety of manual acupuncture in the prophylaxis of MWoA. The placebo control is using non-penetrating needling verum acupoints. It is essential to determine an appropriate control method to ensure the methodological quality of a randomized controlled trial. Trial registration The trial has been registered in the Chinese Clinical Trial Registry (approval no. ChiCTR2000032308) in April 2020.

Necroptosis is a novel manner of programmed cell death and important for tissue development, homeostasis, damage, and repair. Activation of receptor-interacting protein kinase 3 (RIPK3), a key member of receptor-interacting protein family in contributing significantly to necroptosis, in tissues is a hallmark of cells dying by necroptosis. However, there are few studies that examine the expression of RIPK3 in the glandular cells of stomachs under physiological condition. We have therefore conducted this study to immunohistochemically characterize the key element of necroptosis, RIPK3, in the mouse and human stomach. Results showed that RIPK3 positive cells could be observed in the surface mucosal cells, granular cells, and lamina propria cells in both mouse and human stomach tissues. Ratios of PCNA/RIPK3 positive cells in the glandular cells were ~ 2.1 in mouse and ~ 4.15 in human sections respectively. Morphological and double immunofluorescence analysis confirmed that these RIPK3 positive cells were mucous, parietal and lamina propria cells. Our results indicate that the expression of RIPK3 in different cell types might contribute to cell turnover of gastric mucosa in the mouse and human stomach under physiological condition.

Inhibitors of apoptosis (IAPs) are regulators of cell death and may play a role in the salivary glands of ticks during blood-feeding. We cloned the open reading frame (ORF) sequence of the IAP gene in Rhipicephalus haemaphysaloides (RhIAP). The RhIAP ORF of 1887 bp encodes a predicted protein of 607 amino acids, which contains three baculovirus IAP repeat domains and a RING finger motif. A real-time PCR assay showed that RhIAP mRNA was expressed in all the tick developmental stages (eggs, larvae, nymphs, and adults) and in all tissues examined (midgut, ovary, salivary glands, fat body, and hemolymph). Western blot showed that the protein level of RhIAP in salivary glands increased during tick blood-feeding and decreased towards the end of tick engorgement. RhIAP gene silencing in vitro experiments with salivary glands demonstrated that RhIAP could be effectively knocked down within 48 h after dsRNA treatment, and as a consequence, salivary glands displayed apoptotic morphology. RhIAP gene silencing also inhibited tick blood-feeding and decreased the engorgement rate. These data suggest that RhIAP might be a suitable RNAi target for tick control.

To investigate the prognostic value of pre-procedure neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and construct a nomogram to predict disease-free survival (DFS) in patients receiving radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) within Milan criteria. The data of 515 patients of HCC within Milan criteria receiving RFA were retrospectively collected. The patients were divided into two groups: the training group (n = 382) and the validation group (n = 133). Several preprocedural variables were analyzed in the two groups to determine the prognostic factors. The median DFS time of the training and validation group was 28.4 months and 24.5 months, respectively. Multivariate analyses showed that number of lesions, alpha-feto protein levels, NLR and PLR were independent risk factors of DFS. According to the time-dependent receiver operating characteristic curve (t-ROC), the optimal cutoff value of the NLR and PLR was 1.55 and 75.30, respectively, with sensitivity of 0.737 and 0.648 and specificity of 0.541 and 0.508, respectively. The area under curve (AUC) of the t-ROC curves for the NLR was 0.662 and PLR was 0.597. The DFS was significantly higher in the NLR ≤ 1.55 group compared to NLR > 1.55 group and the PLR ≤ 75.30 group compared to PLR > 75.30 group in both training and validation datasets. Nomogram was developed based on the prognostic factors indicated by the Cox regression to predict 1-, 2-, 3- and 5-year DFS probabilities. The cutoff value of the NLR and PLR was 1.55 and 75.30. This new nomogram based on NLR and PLR may provide good and individualized prediction of recurrence for HCC patients within Milan criteria after RFA.

The dramatic increase of microbial resistances against conventional available antibiotics is a huge challenge to the effective treatment of infectious disease and thus becoming a daunting global threat of major concern, which necessitates the development of innovative therapeutics. Nanomaterial-based antimicrobial strategies have emerged as novel and promising tools to combat lethal bacteria and recalcitrant biofilm, featuring the abilities to evade existing drug resistance-related mechanisms. In this review, recent advances in “state-of-the-art” nanosystems which acting either as inherent therapeutics or nanocarriers for the precise delivery of antibiotics, are comprehensively summarized. Those nanosystems can effectively accumulate at the infectious sites, achieve multifunctional synergistic antibacterial efficacy, and provide controlled release of antibiotics in response to endogenous or exogenous stimulus (e.g., low pH, enzymes, or illumination). Especially, the nanoplatform that integrated with photothermal/photodynamic therapy (PTT/PDT) can enhance the bacterial destruction and biofilm penetration or ablation. In addition, nanoparticle-based approaches with enzymatically promoting bacterial killing, anti-virulence, and other mechanisms were also involved. Overall, this review provides crucial insights into the recent progress and remaining limitations of various antimicrobial nanotherapeutic strategies, and enlightens the further developments in this field simultaneously, which eventually benefiting public health.

Gastric cancer is one of the deadliest cancers worldwide. An accurate prognosis is essential for effective clinical assessment and treatment. Spatial patterns in the tumor microenvironment (TME) are conceptually indicative of the staging and progression of gastric cancer patients. Using spatial patterns of the TME by integrating and transforming the multiplexed immunohistochemistry (mIHC) images as Cell-Graphs, we propose a graph neural network-based approach, termed Cell−GraphSignatureorCGSignature, powered by artificial intelligence, for the digital staging of TME and precise prediction of patient survival in gastric cancer. In this study, patient survival prediction is formulated as either a binary (short-term and long-term) or ternary (short-term, medium-term, and long-term) classification task. Extensive benchmarking experiments demonstrate that the CGSignature achieves outstanding model performance, with Area Under the Receiver Operating Characteristic curve of 0.960 ± 0.01, and 0.771 ± 0.024 to 0.904 ± 0.012 for the binary- and ternary-classification, respectively. Moreover, Kaplan–Meier survival analysis indicates that the “digital grade” cancer staging produced by CGSignature provides a remarkable capability in discriminating both binary and ternary classes with statistical significance (P value CGSignature improves the assessment of the link between the TME spatial patterns and patient prognosis. Our study suggests the feasibility and benefits of such an artificial intelligence-powered digital staging system in diagnostic pathology and precision oncology.

Background mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Methods Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients’ survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. Results We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. Conclusions These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings.

The conversion of CO2 by renewable power-generated hydrogen is a promising approach to a sustainable production of long-chain olefins (C4+=) which are currently produced from petroleum resources. The decentralized small-scale electrolysis for hydrogen generation requires the operation of CO2 hydrogenation in ambient-pressure units to match the manufacturing scales and flexible on-demand production. Herein, we report a Cu-Fe catalyst which is operated under ambient pressure with comparable C4+= selectivity (66.9%) to that of the state-of-the-art catalysts (66.8%) optimized under high pressure (35 bar). The catalyst is composed of copper, iron oxides, and iron carbides. Iron oxides enable reverse-water-gas-shift to produce CO. The synergy of carbide path over iron carbides and CO insertion path over interfacial sites between copper and iron carbides leads to efficient C-C coupling into C4+=. This work contributes to the development of small-scale low-pressure devices for CO2 hydrogenation compatible with sustainable hydrogen production.