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Abstract The Staphylococcus aureus (S. aureus) SaeRS two-component system (TCS) regulates over 20 virulence factors. While its impact on chronic infection has been thoroughly discussed, its role in the early stage of infection remains elusive. Since macrophages serve as the primary immune defenders at the onset of infection, this study investigates the influence of SaeRS on macrophage functions and elucidates the underlying mechanisms. Macrophage expression of inflammatory and chemotactic factors, phagocytosis, and bactericidal activity against S. aureus were assessed, along with the evaluation of cellular oxidative stress. SaeRS was found to impair macrophage function. Mechanistically, SaeRS inhibited NF-κB pathway activation via toll-like receptor 2 (TLR2). Its immune-modulating effect could partially be explained by the strengthened biofilm formation. More importantly, we found SaeRS compromised macrophage immune functions at early infection stages even prior to biofilm formation. These early immune evasion effects were dependent on bacterial clumping as cytokine secretion, phagocytosis, and bactericidal activity were repaired when clumping was inhibited. We speculate that the bacterial clumping-mediated antigen mask is responsible for SaeRS-mediated immune evasion at the early infection stage. In vivo, ΔsaeRS infection was cleared earlier, accompanied by early pro-inflammatory cytokines production, and increased tissue oxidative stress. Subsequently, macrophages transitioned to an anti-inflammatory state, thereby promoting tissue repair. In summary, our findings underscore the critical role of the SaeRS TCS in S. aureus pathogenicity, particularly during early infection, which is likely initiated by SaeRS-mediated bacterial clumping.

Abstract Background Ischemic stroke (IS) is known for its high morbidity, disability and mortality rates, and studies designed to explore its pathophysiological mechanisms and identify novel therapeutic strategies are urgently needed. We aimed to probe the effects of the deubiquitinase OTUD3-IRP2-p53/PTGS2 pathway on cerebral ischemia‒reperfusion (I/R) injury and hippocampal neuron ferroptosis. Methods A cerebral I/R mouse model was established. Furthermore, lentiviral vectors that overexpressed OTUD3 and knocked down IRP2 were constructed, and a series of assays were performed to probe the OTUD3/IRP2/p53/PTGS2 mechanism. An oxygen‒glucose deprivation and reoxygenation (OGD/R) model of mouse hippocampal neurons was constructed. Then, OTUD3 and IRP2 were knocked down and overexpressed, and p53 was overexpressed to explore the mechanism of the OTUD3/IRP2/p53/PTGS2 pathway. Results OTUD3 and IRP2 were expressed at low levels in cerebral I/R models. OTUD3 promoted IRP2 expression to protect damaged hippocampal neurons. Moreover, IRP2 affected ferroptosis in hippocampal neurons. In addition, IRP2 inhibited p53. After IRP2 and p53 were overexpressed, IRP2 regulated the p53/PTGS2 pathway and affected ferroptosis in hippocampal neurons. In vivo, after overexpressing OTUD3 and knocking down IRP2, we found that overexpression of OTUD3 promoted IRP2 expression to reduce ferroptosis in hippocampal neurons and improve cerebral I/R injury via the inhibition of the p53/PTGS2 pathway. Conclusions The deubiquitinase OTUD3 stabilized IRP2 expression to reduce hippocampal neuron ferroptosis via the p53/PTGS2 pathway to subsequently ameliorate cerebral I/R injury.

Effective hurricane preparedness and response demand a thorough understanding of the impact on mobility patterns. While existing studies have explored mobility disruptions caused by hurricanes, very few have delved into the impact, considering both mobility vulnerability and recovery, on a state level. Utilising mobile phone location data, this research examines the mobility patterns of Florida residents throughout Hurricane Ian. The findings reveal that the hurricane profoundly disturbed the mobility patterns of Floridians. The state experienced a maximum average daily mobility reduction of 63.41%, with certain neighbourhoods coming to a complete standstill at 100% cessation in mobility. On average, Florida neighbourhoods needed 2.61 days for mobility recovery, though this period stretched to as long as 92 days in the most severely affected areas. The bivariate map highlights a prevailing trend: neighbourhoods with prolonged recovery periods also witnessed more substantial reductions in mobility. This dual disadvantage underscores the critical need for increased focus on these neighbourhoods. Furthermore, our findings highlight the significance of factoring in forecasted hurricane paths when analysing mobility impacts, as we noted more substantial effects on neighbourhoods along the predicted trajectory.

BackgroundBreast cancer, despite significant advancements in treatment, remains a major cause of cancer-related deaths among women. Immunotherapy, an emerging therapeutic strategy, offers promise for better outcomes, particularly through the modulation of immune functions. Glioma-Associated Oncogene Homolog 1 (GLI1), a transcription factor implicated in cancer biology, has shown varying roles in different cancers. However, its immunoregulatory functions in breast invasive carcinoma (BRCA) remain elusive. The current study aimed to unravel the expression patterns and immune-regulatory roles of GLI1 in BRCA.MethodsUtilizing multiple bioinformatic platforms (TIMER2.0, GEPIA2, and R packages) based on The Cancer Genome Atlas (TCGA) and/or Genotype-Tissue Expression (GTEx) databases, we analyzed the expression of GLI1 in BRCA and its pan-cancer expression profiles. We further validated these findings by conducting qPCR and immunohistochemical staining on clinical BRCA samples. Kaplan-Meier analysis and Cox proportional hazards regression were performed to assess the prognostic value of GLI1. Additionally, the association between GLI1 expression and immune infiltration within the tumor immune microenvironment (TMIE) was examined.ResultsThe findings reveal dysregulated expression of GLI1 in numerous cancers, with a significant decrease observed in BRCA. High GLI1 expression indicated better survival outcomes and was correlated with the age and stage of BRCA patients. GLI1 was involved in immune status, as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Meanwhile, GLI1 was co-expressed with multiple immune-related genes, and high GLI1 expression was associated with the activation of immune-related pathways, such as binding to proteasome and mismatch repair and retinol metabolism signaling pathways. Additionally, the differential expression of GLI1 may be related to the effect of immunotherapy on CTLA-4, PD-1, and other signals, and can effectively predict the immune efficacy.ConclusionOur study underscores the critical role of GLI1 in BRCA, both as a potential tumor suppressor and an immune regulator. The association between GLI1 expression and favorable prognosis suggests its potential as a prognostic biomarker and immunotherapeutic target in BRCA.

Abstract Introduction An increasing body of evidence suggests a close association between COVID‐19 infection and the safety of PD‐1/PD‐L1 inhibitor therapy in cancer patients. However, the available data concerning these impacts remain limited and occasionally contradictory. Material and Methods We conducted a retrospective analysis of cancer patients who received PD‐1/PD‐L1 inhibitor therapy at the same institution from November 2022 to May 2023. After excluding patients with missing information, a total of 224 cases were included. In our study, immune‐related adverse events (irAEs) that occurred during the hospitalization of patients were included in the analysis. Further analysis of inter‐subgroup differences was conducted following a 1:2 propensity score matching. Statistical analyses were performed using the Fisher's exact, chi‐squared, and Mann–Whitney U‐tests. Result The results showed that no statistically significant differences between the two subgroups in the incidence of irAEs, changes in immune function before and after using PD‐1/PD‐L1 inhibitors, and alterations in hepatic and renal function (p > 0.05). Conclusion Our findings suggest that infection with COVID‐19 does not significantly impact the safety of PD‐1/PD‐L1 inhibitors in cancer patients. Most cancer patients used PD‐1/PD‐L1 inhibitors during COVID‐19 infection (asymptomatic or mild infection) did not experience exacerbation of their underlying condition, nor did they exhibit a substantial increase in toxic side effects.

Abstract Understanding human mobility patterns amid natural hazards is crucial for enhancing urban emergency responses and rescue operations. Existing research on human mobility has delineated two primary types of individuals: returners, who exhibit a tendency to frequent a limited number of locations, and explorers, characterized by a more diverse range of movement across various places. Yet, whether this mobility dichotomy endures in the context of natural hazards remains underexplored. This study addresses this gap by examining anonymized high-resolution mobile phone location data from Lee County, Florida residents, aiming to unravel the dynamics of these distinct mobility groups throughout different phases of Hurricane Ian. The results indicate that returners and explorers maintained their distinct mobility characteristics even during the hurricane, showing increased separability. Before the hurricane, returners favored shorter trips, while explorers embarked on longer journeys, a trend that continued during the hurricane. However, the hurricane heightened people’s inclination to explore, leading to a notable increase in longer-distance travel for both groups, likely influenced by evacuation considerations. Spatially, both groups exhibited an uptick in trips towards the southern regions, away from the hurricane’s path, particularly converging on major destinations such as Miami, Fort Lauderdale, Naples, and West Palm Beach during the hurricane.

Given the deficiencies in the definition of connotation, the construction of index systems, and the coordination of targets within the research on sustainable development in the manufacturing industry, an evaluation index system for sustainable development has been established. This system includes economic benefits, social benefits, resource management, and environmental goals and is built upon a clear definition of the concept’s connotation. The CRITIC–entropy–TOPSIS–CCDM approach is employed for the computation of the coordinated development level of the manufacturing industry. To identify the main factors influencing the coupling coordination degree (CCD) from a mechanistic and compositional point of view, a logarithmic mean divisia index (LMDI) is used. Furthermore, the obstacle degree model analyzes the factors that restrict subsystem development. The results show the following. (1) The coordinated development level of the Chinese manufacturing industry has been maintained at 0.6–0.7, while the CCD of Hainan, Qinghai, and Xinjiang remains to be enhanced. (2) The key factor affecting the CCD is the coupling degree. The evaluation value of the economy and employment system determines the trend of coordinated development in the regional manufacturing industry. (3) The economic and employment scenarios in most provinces (cities) led to a significant decrease in the CCD compared to the baseline scenario, with average growth rates of −10.55% and −12.69%. This suggests that policymakers’ priorities significantly influence the CCD. The research presents a theoretical framework for assessing the sustainability of the manufacturing industry, offering valuable insights to guide the industry towards more sustainable practices.

Background: Microglia-mediated inflammation is a critical factor in the progression of ischemic stroke. Consequently, mitigating excessive microglial activation represents a potential therapeutic strategy for ischemic injury. Thymol, a monophenol derived from plant essential oils, exhibits diverse beneficial biological activities, including anti-inflammatory and antioxidant properties, with demonstrated protective effects in various disease models. However, its specific effects on ischemic stroke and microglial inflammation remain unexplored. Methods: Rodent transient middle cerebral artery occlusion (tMCAO) model was established to simulate ischemic stroke. TTC staining, modified neurological function score (mNSS), and behavioral tests were used to assess the severity of neurological damage. Then immunofluorescence staining and cytoskeleton analysis were used to determine activation of microglia. Lipopolysaccharide (LPS) was utilized to induce the inflammatory response of primary microglia in vitro. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to exam the expression of inflammatory cytokines. And western blot was used to investigate the mechanism of the anti-inflammatory effect of thymol. Results: In this study, we found that thymol treatment could ameliorate post-stroke neurological impairment and reduce infarct volume by mitigating microglial activation and pro-inflammatory response (IL-1β, IL-6, and TNF-α). Mechanically, thymol could inhibit the phosphorylation of phosphatidylinositol-3-kinase (PI3K), sink serine/threonine kinase (Akt), and mammalian target of rapamycin (mTOR), thereby suppressing the activation of nuclear factor-κB (NF-κB). Conclusions: Our study demonstrated that thymol could reduce the microglial inflammation by targeting PI3K/Akt/mTOR/NF-κB signaling pathway, ultimately alleviating ischemic brain injury. These findings suggest that thymol is a promising candidate as a neuroprotective agent against ischemic stroke.

Abstract Background In recent years, accelerated transcranial magnetic stimulation (aTMS) has been developed, which has a shortened treatment period. The aim of this study was to evaluate the efficacy and long-term maintenance effects of aTMS in patients with major depressive disorder (MDD). Methods We systematically searched online databases for aTMS studies in patients with MDD published before February 2023 and performed a meta-analysis on the extracted data. Results Four randomized controlled trials (RCTs) and 10 before-and-after controlled studies were included. The findings showed that depression scores significantly decreased following the intervention (SMD = 1.80, 95% CI (1.31, 2.30), p

Abstract Sharing of genetic elements among different pathogens and commensals inhabiting same hosts and environments has significant implications for antimicrobial resistance (AMR), especially in settings with high antimicrobial exposure. We analysed 661 Escherichia coli and Salmonella enterica isolates collected within and across hosts and environments, in 10 Chinese chicken farms over 2.5 years using data-mining methods. Most isolates within same hosts possessed the same clinically relevant AMR-carrying mobile genetic elements (plasmids: 70.6%, transposons: 78%), which also showed recent common evolution. Supervised machine learning classifiers revealed known and novel AMR-associated mutations and genes underlying resistance to 28 antimicrobials, primarily associated with resistance in E. coli and susceptibility in S. enterica. Many were essential and affected same metabolic processes in both species, albeit with varying degrees of phylogenetic penetration. Multi-modal strategies are crucial to investigate the interplay of mobilome, resistance and metabolism in cohabiting bacteria, especially in ecological settings where community-driven resistance selection occurs.

Fluoride contamination in drinking water poses a health threat. Activated carbon suffers from low fluoride adsorption capacity, which can be enhanced by loading with nitrogen-rich compounds. In this study, graphitic carbon nitride (g-C3N4) nanosheets were loaded onto activated carbon using ultrasonic irradiation to synthesize a g-C3N4-activated carbon composite. The ultrasonically synthesized composite exhibited significantly higher fluoride removal capacity of 92.7 mg/g compared to 2.1 mg/g for activated carbon alone. The adsorption followed the Langmuir isotherm model. Thermodynamic analysis revealed the adsorption was spontaneous and exothermic. Characterization confirmed the role of surface complexation between fluoride ions and C-N/CN groups in g-C3N4 for the enhanced adsorption. The composite achieved 82–90% defluoridation of real wastewater samples containing initially 8.7–12 mg/L fluoride. The composite could be regenerated using NaOH and reused for multiple cycles. The study demonstrates the potential of a simple ultrasonic irradiation method for synthesizing a g-C3N4-activated carbon composite with remarkably enhanced defluoridation capacity. The composite is promising for practical decentralized water defluoridation applications, especially in regions affected by high fluoride levels.

Indigenous microbial stimulation is considered as a highly promising technology for enhanced oil recovery (EOR) of low-permeability reservoirs. In this paper, oil components and microbial communities of indigenous microorganisms before and after bio-stimulation in the largest low-permeability oil field of China were discussed. The results showed that Pseudomonas aeruginosa was dominant in the original samples, followed by some sulfate-reducing bacteria (SRB) and iron-reducing bacteria (IRB), such as Desulfovibrio oxyclinae, and Methylopila capsulata, Deferribacter abyssi. After bio-stimulation, the species of microorganisms gradually decreased, the content of Pseudomonas aeruginosa reached 2∼3 times than that of the original samples. The harmful bacteria, such as SRB and IRB, gradually disappeared. The Pr/Ph of the oil decreased, whereas the Pr/nC 17, Ph/nC 18, and ∑nC 21−/∑nC 22+increased. The average molecular weight of oil decreased after the microorganisms were stimulated, in which the contents of N1-containing compounds increased, and that of O1-containing compounds decreased. The contents of biphenyls, naphthalene, and its derivatives decreased. Whereas those of aromatic compounds, such as phenanthrene, quaternary, fluorene, and their homologs increased. Pilot study was applied in LD field block, the average water cut of 27–47 well group decreased from 87.60% to 74.86%, the oil production increased from 12.18 t/d to 29.58 t/d.

Objective: To explore the effect and mechanism of action of the Wenjing Zhitong recipe (WZR) in primary dysmenorrhea (PD) treatment. Methods: Uterine contractions were induced by estradiol benzoate and oxytocin in a PD model and WZR was administrated. The rate of change in uterine contractility and the writhing test were used to evaluate the effects of WZR. The serum levels of prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2), and the activity of cyclooxygenase-2 (COX2) were detected by enzyme-linked immunosorbent assay (ELISA). The changes in phosphor-phospholipase C (pPLC/PLC), phosphor-protein kinase C (pPKC/PKC), and connexin 43 (CX43) expression were detected using immunohistochemistry and western blot. Results: WZR significantly reduced the rate of change in uterine contractility and writhing times in the PD model. WZR treatment inhibited the enzymatic activity of COX2 and reduced the levels of PGF2α, PGF2α/PGE2 and COX2 in the PD model. WZR also significantly reduced the expression of pPLC/PLC, pPKC/PKC and CX43. Targeting the inhibition of COX2 activity, caffeic acid and 1-acetyl-β-carboline were validated as the active ingredients in WZR responsible for reducing uterine contractions. Conclusion: WZR attenuated PD by inhibiting COX2 activity, downregulating PGF2α/PGE2 expression, and inhibiting the PKC signaling pathway.

Objective Campylobacter species are the main causes of foodborne illness worldwide, posing significant threats to public health. This study aimed to investigate the antibiotic resistance and genomic characterization of C. jejuni/C.coli from retail chickens in Beijing. Methods Antimicrobial susceptibility testing was conducted on 126 C. jejuni/C. coli isolated from retail chickens in Beijing, following CLSI protocols. Whole genomes of all isolates were sequenced using the Illumina platform. Results More C. coli (83.82%) showed multi-drug resistance than C. jejuni (8.62%). Genomic analysis demonstrated 42 sequence types (STs) and 12 clonal complexes (CCs), from which CC828 and CC52 were dominant. cdtA, cdtB and cdtC encoding cytotoxic protein were present spontaneously in most C. jejuni but not found in any C. coli isolates. The abundances of antibiotic resistance genes (ARGs) and virulence genes (VGs) in C. jejuni and C. coli were significantly different, with ARGs numbered in C. coli and VGs in C. jejuni. Conclusions High prevalence of multi-drug resistance C. coli and C. jejuni isolated from Beijing chickens were challenging clinical antibiotic usages in the treatment of Campylobacter infection. The surveillance of particular C. jejuni and C. coli STs correlated with higher resistance and virulence needs to be strengthened in the future.

ABSTRACTThis paper presents a new method for predictive crime hotspot analysis that further improves the kernel density estimation (KDE) method and the spatio-temporal kernel density estimation (STKDE) method by accounting for temporal crime cycles and is therefore termed the ‘cyclically adjusted STKDE (cSTKDE) method’. The case study on robbery incidents in Baton Rouge, Louisiana, shows a temporal cycle with a 6-month period of statistical significance from January 2010 to May 2018. This identified period is incorporated into the temporal kernel function of the new cSTKDE method. For validation, the Forecast Accuracy Index (FAI) and Forecast Precision Index (FPI) are used to evaluate the performance across 52 weeks in 2013. For 11 consecutive weeks since the beginning of 2013, the cSTKDE method outperforms the STKDE by 89% lower average abs(1-FAI) and 17% higher average FPI, and outperforms the KDE by 90% lower average abs(1-FAI) and 8% higher average FPI. Overall, the scenario with the best predictive accuracy by the cSTKDE is recommended over the traditional KDE or STKDE method as most feasible and effective in implementation of hotspot policing in practice.

Salmonella, especially antimicrobial resistant strains, remains one of the leading causes of foodborne bacterial disease. Retail chicken is a major source of human salmonellosis. Here, we investigated the prevalence, antimicrobial resistance (AMR), and genomic characteristics of Salmonella in 88 out of 360 (24.4%) chilled chicken carcasses, together with 86 Salmonella from humans with diarrhea in Qingdao, China in 2020. The most common serotypes were Enteritidis and Typhimurium (including the serotype I 4,[5],12:i:-) among Salmonella from both chicken and humans. The sequence types were consistent with serotypes, with ST11, ST34 and ST19 the most dominantly identified. Resistance to nalidixic acid, ampicillin, tetracycline and chloramphenicol were the top four detected in Salmonella from both chicken and human sources. High multi-drug resistance (MDR) and resistance to third-generation cephalosporins resistance were found in Salmonella from chicken (53.4%) and humans (75.6%). In total, 149 of 174 (85.6%) Salmonella isolates could be categorized into 60 known SNP clusters, with 8 SNP clusters detected in both sources. Furthermore, high prevalence of plasmid replicons and prophages were observed among the studied isolates. A total of 79 antimicrobial resistant genes (ARGs) were found, with aac(6′)-Iaa, blaTEM-1B, tet(A), aph(6)-Id, aph(3″)-Ib, sul2, floR and qnrS1 being the dominant ARGs. Moreover, nine CTX-M-type ESBL genes and the genes blaNMD-1, mcr-1.1, and mcr-9.1 were detected. The high incidence of MDR Salmonella, especially possessing lots of mobile genetic elements (MGEs) in this study posed a severe risk to food safety and public health, highlighting the importance of improving food hygiene measures to reduce the contamination and transmission of this bacterium. Overall, it is essential to continue monitoring the Salmonella serotypes, implement the necessary prevention and strategic control plans, and conduct an epidemiological surveillance system based on whole-genome sequencing.

ABSTRACTThe virulence factors of Staphylococcus aureus are tightly controlled by two-component systems (TCSs) and small RNA (sRNA). TCSs have been well studied over the past several decades, but our understanding of sRNA functions lags far behind that of TCS functions. Here, we studied the biological role of sRNA from 506 S. aureus RNA-seq datasets using independent component analysis (ICA). We found that a previously neglected sRNA, Sau-41, functions in the Agr system. Sau-41 is located within the PSMα operon and controlled by the Agr system. It was predicted to share 22-base complementarity with RNAIII, a major regulator of S. aureus virulence. The EMSA results demonstrated that Sau-41 directly binds to RNAIII. Furthermore, our results found that Sau-41 is capable of repressing S. aureus haemolysin activity by downregulating α-haemolysin and δ-toxin. The repression of α-haemolysin was attributed to the competition between the 5’ UTR of hla and Sau-41 for binding RNAIII. We observed that Sau-41 mitigated S. aureus virulence in an orthopaedic implant infection mouse model and alleviated osteolysis. Together, our results indicate that Sau-41 is a virulence-regulating RNA and suggest that Sau-41 might be involved in a negative feedback mechanism to control the Agr system. This work is a demonstration of using ICA in sRNA identification by mining high-throughput data and could be extended to other organisms as well.

As a new alternative fuel vehicle for energy reserve strategy, the development of methanol vehicles in China has been at the forefront. Completed pilot projects have demonstrated that methanol vehicles can effectively reduce fuel costs and pollutant emissions during driving. In addition to methanol vehicles, alternative fuel vehicles such as electric vehicles and compressed natural gas vehicles also maintain a sound development momentum in China. It is essential to understand which one has more advantages from sustainable development. This paper uses the Energy, Environment, and Economy (3E) evaluation method to analyze the energy consumption, environmental emission, and economy of methanol, electric, gas, and gasoline vehicles from the whole life cycle perspective. A comprehensive index evaluation model was constructed, and the development potential of the three alternative fuel vehicles was ranked under four different scenarios (energy-oriented, environment-oriented, economic-oriented, and equilibrium scenarios). This research shows that methanol vehicles have higher total energy consumption than gasoline vehicles in the whole life cycle. In terms of greenhouse gas emissions, compared with gasoline vehicles, methanol, and compressed natural gas vehicles decreased by 8.79 tons and 12.45 tons, respectively. At the same time, methanol vehicles have a better economic benefit than gasoline vehicles (37%), which is the same as the completed pilot projects. In addition, results also show that due to the advantages of low renovation cost and fuel price, the user’s cost of methanol vehicles is more down than blade electric vehicles, which makes them have better development potential compared with electric and compressed natural gas vehicles in the economic-oriented and equilibrium scenario. Therefore, methanol vehicles can be used as alternative fuel vehicles for long-term development in China.

Abstract Sleep deprivation (SD) can lead to cognitive impairment caused by neuroinflammation. MiR-181c-5p/HMGB1 axis plays a part in anti-inflammation effects. However, the mechanism that miR-181c-5p facilitates learning and memory in SD mice remains unclear. So we investigated the role of miR-181c-5p in learning and memory impairment induced by SD. We overexpressed miR-181c-5p in the mice hippocampus by injecting lentivirus vector-miR-181c-5p (LV-miR-181c-5p) particles. Mice were divided into four groups: control (Ctrl), SD, SD + miR-181c-5p and SD + vector. We found that mice in the third group showed ameliorated learning and memory compared with the fourth group. The content of ionized calcium binding adaptor molecule 1 (IBA-1) in the third group was decreased compared with the fourth group. Moreover, the expression levels of HMGB1, TLR4 and p-NF-κB in the hippocampus of overexpressed miR-181c-5p mice were reduced. In total, miR-181c-5p ameliorated learning and memory in SD mice via the HMGB1/TLR4/NF-κB pathway.

Abstract The tumor microenvironment is proposed to contribute substantially to the progression of cancers, including breast cancer. Cancer‐associated fibroblasts (CAFs) are the most abundant components of the tumor microenvironment. Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors, generating exosomes, releasing nutrients, reshaping the extracellular matrix, and suppressing the function of immune cells. CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers. Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials. Here, we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer. We hope that summarizing CAF‐related studies from a historical perspective will help to accelerate the development of CAF‐targeted therapeutic strategies for breast cancer.

ABSTRACT: As an essential way to enhance farmers’ self-development ability, off-farm employment plays an indispensable role in farmers’ multidimensional poverty reduction in many countries. Employing a survey of 1926 farmers in five provinces of the Yellow River Basin in China, this paper examined the multi-dimensional poverty reduction effect of off-farm employment and the heterogeneous influence of different dimensions of off-farm employment (modes, levels, distances and frequency). The results showed that (1) although absolute poverty in the income dimension was largely eliminated in the Yellow River Basin, the poverty in social resources, transportation facilities, employment security were the key bottlenecks restricting farmers’ self-development. (2) The province with the best multidimensional poverty reduction effect for non-farm employment was Shaanxi, with the largest contribution to employment security. (3) Improving off-farm employment level, distance and time can significantly alleviate the multi-dimensional poverty of farmers. Therefore, to lessen the multi-dimensional poverty of farmers in the Yellow River Basin, it is necessary to focus on the governance of multi-dimensional key poverty-stricken areas, such as the middle and upper courses of the Yellow River, adopting multidimensional poverty alleviation strategy of off-farm employment according to local conditions, working on the farmers’ deficiencies in social resources, mobility, employment security, and deepening the effect of off-farm employment on benefiting farmers and helping the poor.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide and often diagnosed at advanced stages with poor prognosis. Combination of radiotherapy and immunotherapy seems to be a promising approach for treating ESCC. This comprehensive review article summarizes the current state of combination of radiotherapy and immunotherapy in locally advanced/metastatic ESCC, delineates the clinical trials that merit attention, and outlines unresolved issues and future research directions in this field. The clinical trial findings suggest that radio-immunotherapy combination may improve tumor response and overall survival with manageable side effects, highlighting the importance of patient selection and the necessity for further research to optimize treatment strategies. Issues such as irradiation dosage, fractionation regimen, irradiation site and technique of radiotherapy, as well as the timing, sequence and duration of combination therapy will all affect treatment outcomes, justifying further in-depth investigation.

The Palaeocene-Eocene thermal maximum is a global warming period (∼56 Ma), which is marked by a sharp negative carbon isotope excursion (CIE) that caused by the injection of massive isotopically-light carbon into the ocean-atmosphere. It is generally considered that the carbon injection caused global warming. However, several studies have suggested that warming and environmental perturbations precede the onset of the CIE. Here we present Granger test to investigate the detailed mechanisms of this event. We show a shift from climate-warming driving carbon-emission scenario to a scheme in which carbon-injection causing global-warming during the CIE. The initial carbon emission might be from methane hydrates dissociation and/or permafrost thawing, possibly linked with astronomical paced warming. This change of causal direction may result from the warming feedback of the emitted carbon and additional carbon from other sources, such as volcanism, bolide impact, oxidation of marine organic matter, and wildfires burning peatlands.

Abstract Purpose To investigate the mechanism underlying the regulatory effect of melatonin on chronic sleep deprivation‐related cognitive impairment. Methods Chronic sleep deprivation (CSD) model was established using the MMPM method. After the model was established, melatonin receptor agonist and inhibitor were given, respectively. Water maze was conducted to record the escape latency and the duration of crossing the platform of space exploration. The concentration of TNF‐α, IL‐6, MDA, and SOD was measured by ELISA. Immunofluorescence was used to determine the expression level of CD86 and CD206, while the mRNA expression of Bax, Bcl‐2, P65, IκB, and BMAL1 was detected by qPCR. Western blotting assay was utilized to determine the protein expression of Bax, Bcl‐2, P65, p‐P65, IκB, p‐I κB, and BMAL1. Results Compared with the control, the escape latency was greatly increased on the second and third day, accompanied by the increased expression of TNF‐α, IL‐6, MDA, and SOD in serum. Furthermore, dramatically upregulated Bax, Bcl‐2, P65, IκB, and CD86 were observed in the model group, accompanied by the declined expression level of BMAL1 and CD206. Compared with the model group, the escape latency was declined, the concentration of TNF‐α, IL‐6, MDA, and SOD was decreased, the expression level of Bax, Bcl‐2, P65, IκB, and CD86 was declined, and the level of BMAL1 and CD206 was promoted by the treatment of the melatonin agonist, while the opposite results were observed under the treatment of the melatonin inhibitor. Conclusion Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation‐related cognitive impairment by alleviating oxidative stress.

Objective: Erchen Decoction (ECD), a well-known traditional Chinese medicine, exerts metabolism-regulatory, immunoregulation, and anti-tumor effects. However, the action and pharmacological mechanism of ECD remain largely unclear. In the present study, we explored the effects and mechanisms of ECD in the treatment of CRC using network pharmacology, molecular docking, and systematic experimental validation.Methods: The active components of ECD were obtained from the TCMSP database and the potential targets of them were annotated by the STRING database. The CRC-related targets were identified from different databases (OMIM, DisGeNet, GeneCards, and DrugBank). The interactive targets of ECD and CRC were screened and the protein-protein interaction (PPI) networks were constructed. Then, the hub interactive targets were calculated and visualized from the PPI network using the Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. In addition, the molecular docking was performed. Finally, systematic in vitro, in vivo and molecular biology experiments were performed to further explore the anti-tumor effects and underlying mechanisms of ECD in CRC.Results: A total of 116 active components and 246 targets of ECD were predicted based on the component-target network analysis. 2406 CRC-related targets were obtained from different databases and 140 intersective targets were identified between ECD and CRC. 12 hub molecules (STAT3, JUN, MAPK3, TP53, MAPK1, RELA, FOS, ESR1, IL6, MAPK14, MYC, and CDKN1A) were finally screened from PPI network. GO and KEGG pathway enrichment analyses demonstrated that the biological discrepancy was mainly focused on the tumorigenesis-, immune-, and mechanism-related pathways. Based on the experimental validation, ECD could suppress the proliferation of CRC cells by inhibiting cell cycle and promoting cell apoptosis. In addition, ECD could inhibit tumor growth in mice. Finally, the results of molecular biology experiments suggested ECD could regulate the transcriptional levels of several hub molecules during the development of CRC, including MAPKs, PPARs, TP53, and STATs.Conclusion: This study revealed the potential pharmacodynamic material basis and underlying molecular mechanisms of ECD in the treatment of CRC, providing a novel insight for us to find more effective anti-CRC drugs.

Salmonella enterica serotype Indiana (S. Indiana) in Chinese poultry meat has aroused widespread concern because of its high prevalence and strong antimicrobial resistance. In consideration of the relationship in our previous study between S. Indiana and co-resistance to ciprofloxacin and cefotaxime (CIP-CTX), which were the first-line drug which were used in Salmonella infection in clinical, the antimicrobial resistance (AMR) of 224 CIP-CTX co-resistant S. Indiana isolated from retail chicken samples in China were investigated, with the aim of characterizing the AMR profiles and related resistance mechanisms to ciprofloxacin and cefotaxime among these CIP-CTX co-resistant S. Indiana isolates, all of which showed multi-drug-resistant (MDR) phenotypes. GyrA (S83F and D87N/G) with ParC (T57S and S80R) were the dominant amino acid substitution types, with oqxA, oqxB, and aac (6′)-Ib-cr identified as common plasmid-mediated quinolone resistance (PMQR)-encoding genes. Five blaCTX-M gene subtypes were identified with blaCTX-M-65 ranking at the top. Equally important, we obtained one isolate CFSA664 harboring the mcr-1 gene was ESBL producer with co-resistance to nine in ten classes of tested drugs inclduing colistin. A single circular chromosome and 3 circular plasmids were found in its genome. Among the 26 AMR genes identified, 24 were located on plasmid pCFSA664-1, including three ESBL genes, while plasmid pCFSA664-3 owning only the mcr-1 gene and sharing the same backbone structure with plasmids from Enterobacteriaceae. No insertion sequences were found near the mcr-1 gene but a relaxase-encoding gene in the flank, which could transfer into E. coli J53 at a relatively high frequency. S. Indiana in this study exhibited highly drug-resistant phenotypes, contributing to the acceleration of the dissemination and emergence of this pathogen among different sources. Surveillance and a One Health strategy are needed to limit the emergence of S. Indiana along the food chain.

Background: Type 2 diabetes (T2D) is considered as one of the most significant metabolic syndromes worldwide, and the long-term use of the drugs already on the market for T2D often gives rise to some side effects. The mulberry leaf (ML), Morus alba L., has advantages in terms of its comprehensive therapeutic efficacy, which are characterized as multicomponent, multitarget, multipathway, and matching with the complex pathological mechanisms of diabetes.Methods: T2D rats were established by a high-fat diet combined with an intraperitoneal injection of streptozotocin; an evaluation of the hypoglycemic effects of the ML in combination with fasting blood glucose and other indicators, in addition to the utilization of metabolomics technology, was performed to analysis the metabolite changes in serum of rats.Results: MLs significantly reduced the fasting blood glucose of T2D rats, while improving the symptoms of polyphagia and polyuria. ML treatment altered the levels of various metabolites in the serum of T2D rats, which are involved in multiple metabolic pathways (amino acid metabolism, carbohydrate metabolism, and lipid metabolism), played a role in antioxidative stress and anti-inflammation, modulated immune and gluconeogenesis processes, and improved obesity as well as insulin resistance (IR).Conclusion: The ML contains a variety of chemical components, and metabolomic results have shown that MLs regulate multiple metabolic pathways to exert hypoglycemic effects, suggesting that MLs may have great promise in the development of new hypoglycemic drugs.

Coordinating dynamic interceptive actions in sports like badminton requires skilled performance in getting the racket into the right place at the right time. For this reason, the strategic movement and placement of one's feet, or footwork, is an important part of competitive performance. Developing an automated, efficient, and economical method to record individual movement characteristics of players is critical and can benefit athletes and motor control specialists. Here, we propose new methods for recording data on the footwork of individual badminton players, in which deep learning is used to obtain image coordinates (2D) of their shoes and binocular positioning to reconstruct the 3D coordinates of the shoes. Results show that the final positioning accuracy is 74.7%. Using the proposed methods, we revealed inter-individual adaptations in the footwork of several participants during competitive performance. The data provided insights on how individual participants coordinated footwork to intercept the projectile, by varying the distance traveled on court and jump height. Compared with visual observations by biomechanists and motor control specialists, the proposed methods can obtain quantitative data, provide analysis and evaluation of each participant's performance, revealing personal characteristics that could be targeted to shape the individualized training programs of players to refine their badminton footwork.

Epimedii Folium is widely used worldwide as an herbal supplement, and the risk of its induced liver damage has emerged in recent years. Our preliminary study has found that, among several Epimedii Folium species specified in the Chinese Pharmacopoeia, Epimedium koreanum Nakai has a more severe propensity for hepatotoxicity. However, the mechanism of hepatotoxicity of Epimedium koreanum Nakai is still unclear. In this study, untargeted metabolomics was performed to analyze the serum and liver tissue to explore the mechanism of hepatotoxicity of Epimedium koreanum Nakai. The results of experiments in vivo showed that, after 28 days of exposure to Epimedium koreanum Nakai ethanol extract (EEE), the liver weight, levels of AST, ALP, TBIL, etc. in serum of rats in the EEE group were significantly increased, as well as severe cytoplasmic vacuolation appeared in the liver tissue, which suggested that EEE has significant hepatotoxicity. Subsequently, the results of metabolomics revealed significant changes in the metabolic profile in the liver and serum of rats after EEE exposure, in which metabolites in serum such as flavin mononucleotide, phenylacetylglycine, glutathione, l-tryptophan, and sphingomyelin were able to accurately identify liver injury caused by EEE and could be used as serum markers to reflect EEE-induced liver injury. The KEGG pathway enrichment analysis revealed that EEE caused extensive effects on rats' metabolic pathways. Some of the most affected pathways included glutathione metabolism, glutamate metabolism pathway, primary bile acid biosynthesis pathway, and sphingolipid metabolism pathway, which were all directed to the biological process of ferroptosis. Then, the main markers related to ferroptosis in the liver were examined, and the results demonstrated that the content of malondialdehyde was significantly increased, the activity of superoxide dismutase was significantly reduced, the ferroptosis inhibitory proteins GPX4 and System xc− were significantly downregulated, and the ferroptosis-promoting protein ACSL4 was significantly up-regulated. Judging from these results, we concluded that the mechanism of hepatotoxicity of Epimedium koreanum Nakai was probably related to the induction of ferroptosis in hepatocytes.

Migraine is a major cause of disability worldwide, particularly in young adults and middle-aged women. Xiongshao Zhitong Recipe (XZR) is a traditional Chinese medicine prescription used for treating migraine, but its bioactive components and therapeutic mechanisms remain unclear. We aimed to confirm the therapeutic effect of XZR on migraine and to determine the possible mechanism and bioactive components of XZR. Here, a sensitive UHPLC-LTQ-Orbitrap MS assay was carried out to analyze the ingredients of XZR, and a total of 62 components were identified, including coumarins, phenolic acids, phthalides, flavonoids, and terpenoids; among them, 15 components were identified in the serum samples after XZR treatment. We established a rat model of migraine via nitroglycerin (NTG) injection. The in vivo experiments demonstrated that XZR attenuated allodynia and photophobia in rats with NTG-induced migraine, and XZR also demonstrated analgesic effects. XZR reversed the abnormal levels of nitric oxide, 5-hydroxytryptamine (5-HT), calcitonin gene-related peptide (CGRP), and substance P (SP) to normal levels. XZR also downregulated inflammatory reactions, including mast cell degranulation and serum IL-1β, IL-6, and TNF-α levels. In terms of mechanism, we revealed that XZR treated NTG-induced migraine through the inhibition of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in both the trigeminal nucleus caudalis (TNC) and periaqueductal gray matter (PAG), as well as the total NOS enzyme activity, which regulated the NF-κB signaling pathway. Additionally, imperatorin and xanthotoxin, two major ingredients of XZR, showed a high binding affinity to nNOS (Gly468-Leu616). In vitro, XZR, imperatorin, and xanthotoxin inhibited the nNOS expression and the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated PC12 cells. In conclusion, we demonstrated the therapeutic effects of XZR and provided evidence that XZR played a critical anti-inflammatory role by suppressing NOS and NF-κB signaling pathway activation. Imperatorin and xanthotoxin were potential bioactive components of XZR. The findings from this study supported that XZR was a candidate herbal drug for migraine therapy.

Abstract Background Detection of somatic mutations in tumor tissues helps to understand tumor biology and guide treatment selection. Methods such as quantitative PCR can analyze a few mutations with high efficiency, while next generation sequencing (NGS) based methods can analyze hundreds to thousands of mutations. However, there is a lack of cost-effective method for quantitatively analyzing tens to a few hundred mutations of potential biological and clinical significance. Methods Through a comprehensive database and literature review we selected 299 mutations associated with colorectal cancer. We then designed a highly multiplexed assay panel (8-wells covering 299 mutations in 109 genes) based on an automated MADLI-TOF mass spectrometry (MS) platform. The multiplex panel was tested with a total of 319 freshly frozen tissues and 92 FFPE samples from 229 colorectal cancer patients, with 13 samples also analyzed by a targeted NGS method covering 532 genes. Results Multiplex somatic mutation panel based on MALDI-TOF MS detected and quantified at least one somatic mutation in 142 patients, with KRAS, TP53 and APC being the most frequently mutated genes. Extensive validation by both capillary sequencing and targeted NGS demonstrated high accuracy of the multiplex MS assay. Out of 35 mutations tested with plasmid constructs, sensitivities of 5 and 10% mutant allele frequency were achieved for 19 and 16 mutations, respectively. Conclusions Automated MALDI-TOF MS offers an efficient and cost-effective platform for highly multiplexed quantitation of 299 somatic mutations, which may be useful in studying the biological and clinical significance of somatic mutations with large numbers of cancer tissues.

Immune checkpoint inhibitors (ICIs) are a revolutionary breakthrough in the field of cancer by modulating patient’s own immune system to exert anti-tumor effects. The clinical application of ICIs is still in its infancy, and their dosing regimens need to be continuously adjusted. Pharmacokinetic/pharmacodynamic studies showed a significant plateau in the exposure-response curve, with high receptor occupancy and plasma concentrations achieved at low dose levels. Coupled with concerns about drug toxicity and heavy economic costs, there has been an ongoing quest to reevaluate the current ICI dosing regimens while preserving maximum clinical efficacy. Many clinical data showed remarkable anticancer effects with ICIs at the doses far below the approved regimens, indicating the possibility of dose reduction. Our review attempts to summarize the clinical evidence for ICIs regimens with lower-dose, less-frequency, shorter-course, and provide clues for further ICIs regimen optimization.

ABSTRACT A novel plant growth-promoting rhizobacterium (PGPR), which was designated strain BY2G20, was isolated from saline-alkaline soil in Dongying, China. Strain BY2G20 can grow at a NaCl range from 0 to 7% and a pH range from 7 to 9 and can prevent the growth of the phytopathogen Ralstonia solanacearum. Based on its phenotypic and genomic characteristics and phylogenetic analysis, strain BY2G20 represents a novel species of the genus Metabacillus, for which the name Metabacillus dongyingensis sp. nov. is proposed. Comparative genomic analysis of strain BY2G20 with its closely related species exhibited a high level of evolutionary plasticity derived by horizontal gene transfer, which facilitated adaptative evolution. Different evolutionary constraints have operated on the diverse functions of BY2G20, with the gene adapted to saline-alkaline ecosystems experiencing functional constraints. We determined the genetic properties of saline-alkaline tolerance and plant growth promotion, such as cation-proton antiporters, cation transporters, osmoprotectant synthesis and transport, H+-transporting F1F0-ATPase, indole-3-acetic acid production, and secondary metabolite synthesis. We also evaluated the effects of strain BY2G20 on the growth of Zea mays L. (maize) under salt stress. The physiological parameters of maize such as plant height, stem diameter, dry biomass, and fresh biomass were significantly higher after inoculating strain BY2G20 under salt stress, indicating that inoculation with BY2G20 enhanced the growth of maize in saline areas. This study demonstrates that M. dongyingensis sp. nov. BY2G20 is a potential candidate for organic agriculture biofertilizers in saline-alkaline areas. IMPORTANCE Plant growth and yield are adversely affected by soil salinity. PGPRs can promote plant growth and enhance plant tolerance to salt stress. In this study, a saline-alkaline tolerant PGPR strain BY2G20 was isolated from the rhizosphere of Ulmus pumila in Dongying, China. Strain BY2G20 represents a novel species within the genus Metabacillus based on phenotypic, genomic, and phylogenetic analysis. Genomic components have undergone different functional constraints, and the disparity in the evolutionary rate may be associated with the adaptation to a specific niche. Genomic analysis revealed numerous adaptive features of strain BY2G20 to a saline-alkaline environment and rhizosphere, especially genes related to salt tolerance, pH adaptability, and plant growth promotion. Our work also exhibited that inoculation of strain BY2G20 enhanced the growth of maize under salt stress. This study demonstrates that PGPRs play an important role in stimulating salt tolerance in plants and can be used as biofertilizers to enhance the growth of crops in saline-alkaline areas.

Non-typhoidal Salmonella (NTS) is a major cause of human salmonellosis globally. Food animals are major NTS reservoirs. An increase in antimicrobial resistance (AMR) in foodborne NTS has led to clinical treatment failures. Here, to examine the prevalence and perform characterization of foodborne NTS with AMR in China, we tested the antimicrobial susceptibility of 1,256 NTS isolates cultured from retail foods in 2020 in China. The antimicrobial susceptibility of 26 antimicrobial agents representing 12 classes was evaluated with the broth-microdilution method; the presence of ten mcr genes was screened with multi-PCR. The complete closed genomes of mcr -gene-carrying isolates were generated by hybrid assembly through whole genome sequencing on both the PacBio and Illumina platforms. Genomic features and genetic environments of the mcr-1 gene were analysed. The overall drug resistance rate was 92.28%, and the multi-drug resistance (MDR) rate was 76.53%. A total of 341 AMR profiles were determined, and resistance was highest to nalidixic acid (63.38%). Among 887 NTS isolates with MDR, 232 showed co-resistance to cefotaxime and ciprofloxacin, and 25 were resistant to ten classes of antimicrobial agents. The resistance of NTS isolated from different regions varied. Isolates from raw chicken sources most frequently showed resistance. Four NTS carried the mcr-1 gene and represented four different serotypes. Four mcr-1 gene-bearing plasmids from the four Salmonella isolates were classified into two replicon types (IncI2 and IncHI2A). Two mcr-1 genes in IncI2 type plasmids were found to be located between a PAP2 family protein-encoding gene and a relaxase-encoding gene, whereas the other two mcr-1 gene structures in IncHI2A type plasmids showed variations in the presence of insertion sequences. Our data demonstrated severe AMR among foodborne NTS isolated from food in China, thus highlighting the importance of antimicrobial susceptibility surveillance to decrease the spread of AMR, particularly to critical drugs in human medicine.

To enhance domestic energy security and reduce air pollution, China has accelerated the deployment of alternative fuel vehicles including methanol vehicles since the 2010s. Already completed pilot projects have demonstrated that methanol vehicles (commercial fleet) are economical, environmentally friendly, and technically mature. Therefore, the Chinese government aims to continually deploy methanol vehicles in coal-rich provinces. There are more than 20,000 methanol taxis in operation in China, it is important to evaluate the existing consumer acceptance of such commercial fleet before commercialization in a wider range. This paper proposes a conceptual model to identify consumer acceptance of methanol taxis. The model generates hypotheses that have been tested using surveys completed by taxi drivers of methanol vehicles in the cities of Xi’an (Shaanxi province) and Guiyang (Guizhou province). Results demonstrate that market, economic, and technological concerns strongly determine the consumer acceptance of the commercial fleet of methanol vehicles in China.

In shale vanadium ore, vanadium is mainly formed as a low-V(III) homogeneous phase to partially replace Si and exists in the lattice structure of aluminosilicate minerals such as biotite. During the acid leaching of shale vanadium ore, an activator is needed to effectively extract vanadium. Using biotite as a tetrahedral structure doped with Aluminum-Silicon tetrahedron structure, the interaction between leaching-agent ions (H+), activator ions (F−), and vanadium-containing biotite surface was discussed by DFT quantum chemical calculations. The dissolution behavior of activator fluoride ions on the surface of vanadium-bearing biotite during sulfuric acid leaching was revealed. According to the simulated leaching results, the oxygen on the biotite surface first absorbed hydrogen ions to undergo complete hydroxylation, and then combined with hydrogen ions to form water molecules. However, in the presence of activator (NaF), fluoride ions were adsorbed on the surface cations, which catalyzed the formation of water molecules and promoted the dissolution of surface cations. SEM–EDS analysis showed that the surface of vanadium-bearing minerals became very irregular, and the number of voids and cracks greatly increased. At the same time, XPS showed that the addition of activator fluoride ions destroyed the Al-O tetrahedron structure. Many Al and V atoms dissolved in the solution, which improved the leaching rate of vanadium.

Tea plants prefer NH4+-N to NO3−-N, and thus nitrification would be detrimental to the N uptake of tea. However, the effects of different stand ages on nitrification and nitrogen oxide (NO and N2O) emissions in tropical and subtropical regions remain unclear. We performed an incubation experiment with tea field soils from different stand ages (5, 15, and 30 years) under different water contents in subtropical (Changsha, Hunan; C5L, C15L, C30L, C5H, C15H, C30H) and tropical regions (Baisha, Hainan; B5L, B15L, B30L, B5H, B15H, B30H). The results showed that the highest net nitrification rate was in C15L and B15. The results indicated that there was more NO3−-N loss in the 15-y tea field soil in both regions. The highest nitrogen oxide emissions from the subtropical and tropical plots were in C15H and B30H. Available K was the key variable for NO and N2O emissions in Changsha county, whereas SOM, pH, and available P were the key factors affecting NO and N2O emissions in Baisha county. Our findings suggest that more attention should be paid to NO3−-N loss in middle-aged (10–30 years) tea fields. Similarly, the focus should be given to nitrogen oxide emissions from middle-aged tea plantations in subtropical regions and old tea plantations (≥30 stand years) in tropical regions.

The mcr-1 gene mediating mobile colistin resistance in Escherichia coli was first reported in China in 2016 followed by reports among different species worldwide, especially in E. coli and Klebsiella. However, data on its transmission in Salmonella are still lacking. This study analyzed the antimicrobial resistance (AMR) profiles and the mcr-1 gene presence in 755 foodborne Salmonella from 26 provinces of mainland, China in 2016. Genomic features of two mcr-1-carrying isolates, genome sequencing, serotypes and further resistance profiles were studied. Among the 755 Salmonella tested, 72.6% were found to be resistant to at least one antimicrobial agent and 10% were defined as multi-drug resistant (MDR). Salmonella Derby CFSA231 and Salmonella Typhimurium CFSA629 were mcr-1-harboring isolates. Both expressed an MDR phenotype and included a single circular chromosome and one plasmid. Among the 22 AMR genes identified in S. Derby CFSA231, only the mcr-1 gene was localized on the IncX4 type plasmid pCFSA231 while 20 chromosomal AMR genes, including four plasmid-mediated quinolone resistance (PMQR) genes, were mapped within a 64 kb Salmonella genomic island (SGI) like region. S. Typhimurium CFSA629 possessed 11 resistance genes including an mcr-1.19 variant and two ESBL genes. Two IS26-flanked composite-like transposons were identified. Additionally, 153 and 152 virulence factors were separately identified in these two isolates with secretion system and fimbrial adherence determinants as the dominant virulence classes. Our study extends our concern on mcr-1-carrying Salmonella in regards to antimicrobial resistance and virulence factors, and highlight the importance of surveillance to mitigate dissemination of mcr-encoding genes among foodborne Salmonella.

The power gap between supply and demand in the microgrid caused by the uncertainty of wind and solar output and users’ electricity consumption needs to be absorbed by the hybrid energy storage devices and the demand-side electricity price response. To maximize the service life of the lithium battery pack, this paper optimizes a reasonable ratio of the supercapacitor pack’s daily charge and discharge times to the daily cycle times of the lithium battery pack. The model construction includes two parts: power prediction and multi-objective optimization modeling. In the case study, a microgrid district under the Guizhou Power Grid is analyzed and discussed. Based on the predicted wind output, solar output, and load demand on a certain day, the optimal scheduling results have been obtained. On the one hand, a reasonable ratio regarding the daily charge and discharge times of hybrid energy storage devices has been obtained under the optimized parameter k in the model. Correspondingly, the daily operation and maintenance of the lithium battery pack is minimum. On the other hand, when the hybrid energy storage devices and demand-side electricity price response are included and not, the changes on the supply and demand sides (a) and of three evaluation indicators (b) are compared, respectively. Thus, the effectiveness of the model in this paper is verified.

Abstract Background The bla NDM-1 gene in Salmonella species is mostly reported in clinical cases, but is rarely isolated from red and white meat in China. Methods A Salmonella Indiana (S. Indiana) isolate was cultured from a chicken carcass procured from a slaughterhouse in China. Antimicrobial susceptibility was tested against a panel of agents. Whole-genome sequencing of the isolate was carried out and data was analyzed. Results A large plasmid, denoted as plasmid pC629 (210,106 bp), containing a composite cassette, consisting of IS26-bla NDM-1-ble MBL -△trpF-tat-cutA-ISCR1-sul1-qacE△1-aadA2-dfrA12-intI1-IS26 was identified. The latter locus was physically linked with bla OXA-1, bla CTX-M-65, bla TEM-1-encoding genes. A mercury resistance operon merACDEPTR was also identified; it was flanked on the proximal side, among IS26 element and the distally located on the bla NDM-1 gene. Plasmid pC629 also contained 21 other antimicrobial resistance-encoding genes, such as aac(6′)-Ib-cr, aac(3)-VI, aadA5, aph(4)-Ia, arr-3, blmS, brp, catB3, dfrA17, floR, fosA, mph(A), mphR, mrx, nimC/nimA, oqxA, oqxB, oqxR, rmtB, sul1, sul2. Two virulence genes were also identified on plasmid pC629. Conclusion To the best of our knowledge, this is the first report of bla NDM-1 gene being identified from a plasmid in a S. Indiana isolate cultured from chicken carcass in China.

This study is aimed at exploring the mechanism by which the −254C>G single nucleotide polymorphism (SNP) on the transient receptor potential cation channel 6 (TRPC6) gene promoter could increase its activation in steroid-resistant nephrotic syndrome children of China. Plasmids containing the TRPC6 promoter region (with the −254C or G allele) were constructed and then transfected into human embryonic kidney (HEK) 293T cells and human podocytes. Luciferase assays were used to test the promoter activity in both cell lines with or without tumor necrosis factor-α (TNF-α) treatment, and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) analysis was used to verify the transcription factor that could bind to this mutant sequence. Luciferase results indicate that the activity of the mutant promoter was greater than that of the normal promoter of the TRPC6 gene in both cell lines. We further predicted and verified that this variation was mediated by the nuclear factor kappa B (NF-κB) subunit RELA, and TNF-α significantly enhanced the transcription activity of TRPC6 with the −254G allele. In conclusion, the −254C>G SNP is a gain-of-function variation of the TRPC6 gene, and it is also an early and effective factor for predicting steroid-resistant nephrotic syndrome (SRNS) in Chinese children.

The stay-green leaf phenotype is typically associated with increased yields and improved stress resistance in maize breeding, due to higher nitrogen (N) nutrient levels that prolong greenness. The application of N fertilizer can regulate the N status of plants, and furthermore, impact the photosynthetic rates of leaves at the productive stage; however, N deficiencies and N excesses will reduce maize yields. Consequently, it is necessary to develop N fertilizer management strategies for different types of stay-green maize. For this study, the senescent cultivar Lianchuang 808 (LC808), moderate-stay-green cultivar Zhengdan 958 (ZD958), and over stay-green cultivar Denghai 685 (DH685) were selected as experimental models. Our results revealed that yields of ZD958 were slightly higher than DH685 and notably improved over than LC808. Compared with a non-stay-green cultivar LC808, ZD958 and DH685 still maintained higher chlorophyll contents and cell activities following the silking stage, while efficiently slowing the senescence rate. The supply of N fertilizer significantly prolonged leaf greenness and delayed senescence for ZD958 and DH685; however, the effect was not obvious for LC808. The stem remobilization efficiency of N was higher in the moderate-stay-green cultivar ZD958, in contrast to LC808, while the transfer of leaf N was lower than LC808, which guaranteed high leaf N levels, and that sufficient N was transferred to grains in ZD958. To obtain the highest yields, the optimal N fertilizer rates were 228.1 kg hm−2 for LC0808, 180 kg hm−2 for ZD958, and 203.8 kg hm−2 for DH685. In future, the selection of stay-green type crops might serve as an important agricultural strategy to reduce the quantity of N fertilizer and increase N efficiency.

One mcr-1-carrying ST34-type Salmonella Typhimurium WW012 was cultured from 3,200 ready-to-eat (RTE) pork samples in 2014 in China. Broth dilution method was applied to obtain the antimicrobial susceptibility of Salmonella Typhimurium WW012. Broth matting assays were carried out to detect transferability of this phenotype and whole-genome sequencing was performed to analyze its genomic characteristic. Thirty out of 3,200 RTE samples were positive for Salmonella and the three most frequent serotypes were identified as S. Derby (n = 8), S. Typhimurium (n = 6), and S. Enteritidis (n = 6). One S. Typhimurium isolate (S. Typhimurium WW012) cultured from RTE prepared pork was found to contain the mcr-1 gene. S. Typhimurium WW012 expressed a level of high resistance to seven different antimicrobial compounds in addition to colistin (MIC = 8 mg/L). A single plasmid, pWW012 (151,609-bp) was identified and found to be of an IncHI2/HI2A type that encoded a mcr-1 gene along with six additional antimicrobial resistance genes. Plasmid pWW012 contained an IS30-mcr-1-orf-orf-IS30 composite transposon that can be successfully transferred to Escherichia coli J53. When assessed further, the latter demonstrated considerable similarity to three plasmids pHYEC7-mcr-1, pSCC4, and pHNSHP45-2, respectively. Furthermore, plasmid pWW012 also contained a multidrug resistance (MDR) genetic structure IS26-aadA2-cmlA2-aadA1-IS406-sul3-IS26-dfrA12-aadA2-IS26, which showed high similarity to two plasmids, pHNLDF400 and pHNSHP45-2, respectively. Moreover, genes mapping to the chromosome (4,991,167-bp) were found to carry 28 mutations, related to two component regulatory systems (pmrAB, phoPQ) leading to modifications of lipid A component of the lipopolysaccharide structure. Additionally, one mutation (D87N) in the quinolone resistance determining region (QRDR) gene of gyrA was identified in this mcr-1 harboring S. Typhimurium. In addition, various virulence factors and heavy metal resistance-encoding genes were also identified on the genome of S. Typhimurium WW012. This is the first report of the complete nucleotide sequence of mcr-1-carrying MDR S. Typhimurium strain from RTE pork in China.

Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long-term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3β-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO) until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3β-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein.

Carbon nanotubes (CNTs) with homogeneous diameters have been proven to transform into new carbon allotropes under pressure but no studies on the compression of inhomogeneous CNTs have been reported. In this study, we propose to build new carbon allotropes from the bottom-up by applying pressure on symmetry-matched inhomogeneous CNTs. We find that the (3,0) CNT with point group C3v and the (6,0) CNT with point group C6v form an all sp3 hybridized hexagonal 3060-Carbon crystal, but the (4,0) CNT with point group D4h and the (8,0) CNT with point group D8h polymerize into a sp2+sp3 hybridized tetragonal 4080-Carbon structure. Their thermodynamic, mechanical and dynamic stabilities show that they are potential carbon allotropes to be experimentally synthesized. The multiporous structures, excellently mechanical properties and special electronic structures (semiconductive 3060-Carbon and semimetallic 4080-Carbon) imply their many potential applications, such as gases purification, hydrogen storage and lightweight semiconductor devices. In addition, we simulate their feature XRD patterns which are helpful for identifying the two carbon crystals in future experimental studies.

This study investigates the effects of rt-PA thrombolytic therapy at varying times on neurological function and complications in acute cerebral infarction (ACI) patients. A total of 120 ACI patients admitted between August 2019 and July 2021 were divided into three groups based on the timing of rt-PA treatment: <3h (40 patients), 3–4.5h (55 patients), and >4.5h (25 patients). All received standard treatment and rt-PA IV thrombolysis. Key comparisons included cerebral oxygen metabolism, oxidative stress, neural markers, hemodynamics, coagulation function, NIHSS scores, ADL, clinical efficacy, and complications. Results showed that 48 hours post-treatment, SjvO2 levels were significantly higher in the <3h and 3-4.5h groups compared to the >4.5h group. SOD levels were also higher in the earlier groups, while MDA levels were lower. Three months after treatment, NIHSS scores were significantly lower and ADL scores higher in the <3h and 3-4.5h groups, with lower complication rates. Efficacy was similar within 3 hours and 3–4.5 hours, but complications increased significantly after 4.5 hours. [ABSTRACT FROM AUTHOR]