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Abstract Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SLC7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SLC7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SLC7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SLC7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SLC7A11 expression levels were negatively associated with lung cancer patients’ survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.

Abstract Background Fusarium head blight (FHB) significantly impacts wheat yield and quality. Understanding the intricate interaction mechanisms between Fusarium graminearum (the main pathogen of FHB) and wheat is crucial for developing effective strategies to manage and this disease. Our previous studies had shown that the absence of the cell wall mannoprotein FgCWM1, located at the outermost layer of the cell wall, led to a decrease in the pathogenicity of F. graminearum and induced the accumulation of salicylic acid (SA) in wheat. Hence, we propose that FgCWM1 may play a role in interacting between F. graminearum and wheat, as its physical location facilitates interaction effects. Results In this study, we have identified that the C-terminal region of NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) could interact with FgCWM1 through the yeast two-hybrid assay. The interaction was further confirmed through the combination of Co-IP and BiFC analyses. Consistently, the results of subcellular localization indicated that TaNDUFA9 was localized in the cytoplasm adjacent to the cell membrane and chloroplasts. The protein was also detected to be associated with mitochondria and positively regulated complex I activity. The loss-of-function mutant of TaNDUFA9 exhibited a delay in flowering, decreased seed setting rate, and reduced pollen fertility. However, it exhibited elevated levels of SA and increased resistance to FHB caused by F. graminearum infection. Meanwhile, inoculation with the FgCWM1 deletion mutant strain led to increased synthesis of SA in wheat. Conclusions These findings suggest that TaNDUFA9 inhibits SA synthesis and FHB resistance in wheat. FgCWM1 enhances this inhibition by interacting with the C-terminal region of TaNDUFA9, ultimately facilitating F. graminearum infection in wheat. This study provides new insights into the interaction mechanism between F. graminearum and wheat. TaNDUFA9 could serve as a target gene for enhancing wheat resistance to FHB.

Abstract Background Prediabetes mellitus (PreDM) is a high-risk state for developing type 2 diabetes mellitus (T2DM) and often goes undiagnosed, which is closely associated with obesity and characterized by insulin resistance that urgently needs to be treated. Purpose To obtain a better understanding of the biological processes associated with both "spleen-dampness" syndrome individuals and those with dysglycaemic control at its earliest stages, we performed a detailed metabolomic analysis of individuals with various early impairments in glycaemic control, the results can facilitate clinicians’ decision making and benefit individuals at risk. Methods According to the diagnostic criteria of TCM patterns and PreDM, patients were divided into 4 groups with 20 cases, patients with syndrome of spleen deficiency with dampness encumbrance and PreDM (PDMPXSK group), patients with syndrome of dampness-heat in the spleen and PreDM (PDMSRYP group), patients with syndrome of spleen deficiency with dampness encumbrance and normal blood glucose (NDMPXSK group), and patients with syndrome of dampness-heat in the spleen and normal blood glucose (NDMSRYP group). Plasma samples from patients were collected for clinical index assessment and untargeted metabolomics using liquid chromatography-mass spectrometry. Results Among patients with the syndrome of spleen deficiency with dampness encumbrance (PXSK), those with PreDM (PDMPXSK group) had elevated levels of 2-hour post-load blood glucose (2-h PG), glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (SBP) than those in the normal blood glucose group (NDMPXSK group, P

Background: The relationship between serum lipids and sarcopenia remains unclear due to conflicting results in previous studies. Objective: To explore the associations and potential causality between serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), and sarcopenia. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) were analysed using multivariable regression and restricted cubic splines (RCSs) to assess the associations between serum lipids and sarcopenia. Bidirectional Mendelian randomization (MR) was employed to investigate the causal relationships with sarcopenia-related traits such as appendicular lean mass (ALM), hand grip strength, and usual walking pace. Results: Serum HDL-C and TG levels were inversely associated with ALMBMI, with each 1-unit increase linked to a 0.13 % and 1.32 % decrease, respectively. Elevated TG, but not HDL-C, LDL-C, or TC levels, was significantly associated with an increased risk of sarcopenia (P for trend = 0.001). RCS analysis revealed a log-shaped dose-response relationship between TG and sarcopenia risk (P overall

Lithium (Li) metal batteries though with high energy density are still facing issues like Li dendrite growth, dead Li formation, and thick solid electrolyte interphase (SEI) formation, hindering their long-term stability. Recently, Li-Ag alloys have been reported to potentially address these challenges possibly due to their superior conductivity, lithiophilicity, and mechanical stability. In the pursuit of high-energy-density batteries, Li-Ag alloys typically employ a high Li content phase (γ1). In this study, we applied density functional theory (DFT) calculations to compare the thermodynamic stability, Li adsorption, and Li diffusion of Ag-rich Li-Ag alloy within the γ1 phase (AR-γ1), Ag-poor Li-Ag alloy within the γ1 phase (AP-γ1), and pure Li. AR-γ1 showed better thermodynamic stability and improved Li adsorption and diffusion properties compared to AP-γ1 and pure Li. Electrochemical tests further confirmed the advantages of AR-γ1 in terms of electrode kinetics and cell stability compared to AP-γ1 and pure Li. Our study offers guidance for the selection of the most suitable Li-Ag alloys that can be utilized in high-energy-density lithium batteries.

The paper focused on the distributed tracking problem for a specific class of multi-agent systems, characterized by bandwidth constraint and dead zone actuators, where the bandwidth limitations exist in neighbor agents and the dead zone nonlinearity refers to a generalized mathematical model. Initially, a series of event-triggered mechanisms with relative thresholds were established for neighbor agents, ensuring that control signals were transmitted only when necessary. Next, the generalized dead zone models were decomposed into two parts: indefinite terms with control coefficients and disturbance-like terms, resulting in unpredictability and damaging effects. Subsequently, based on the backstepping procedure, final consensus controllers with multiple polynomial compensators were constructed. These controllers offset the coupling coefficients caused by event-triggered mechanisms and dead zone non-smooth. Stability analysis was given to substantiate the theoretical correctness of this method and support the claim of Zeno behavior avoidance. Finally, simulation studies were performed for the feasibility of our proposed methodology.

Deep learning methods have achieved great success in the field of remote sensing image segmentation in recent years, but building a lightweight segmentation model with comprehensive local and global feature extraction capabilities remains a challenging task. In this article, we propose a convolutional neural network (CNN) and cross-shaped transformer hybrid network (CCTNet) for semantic segmentation of high-resolution remote sensing images. This model follows an encoder–decoder structure. It employs ResNet18 as an encoder to extract hierarchical feature information, and constructs a transformer decoder based on efficient cross-shaped self-attention to fully model local and global feature information and achieve lightweighting of the network. Moreover, the transformer block introduces a mixed-scale convolutional feedforward network to further enhance multiscale information extraction. Furthermore, a simplified and efficient feature aggregation module is leveraged to gradually aggregate local and global information at different stages. Extensive comparison experiments on the ISPRS Vaihingen and Potsdam datasets reveal that our method obtains superior performance compared with state-of-the-art lightweight methods.

Blood is vital to sustain human life, to ensure that hospitals or blood centers have sufficient blood reserves, this paper is based on Long- and Short-Term Temporal Patterns with Deep Neural Networks (LSTNET) and Attention Mechanism, uses Gaussian Process Bayesian Optimization (GPBO) to optimize the model, and propose GPBO-LST-Attention network model. Based on the clinical blood transfusion data of a medical institution in Harbin in the past 10 years, the clinical blood transfusion volume was modeled and the blood usage in the future was predicted. The model proposed in this paper was subjected to ablation experiments and compared with other models, using the Root Mean Square Error (RMSE), the Mean Absolute Error (MAE) and the Mean Absolute Percentage Error (MAPE) analyses to evaluate the model performance, and Akaike Information Criterion corrected (AICc) was used to analyze the model performance. It is shown that when the attention module and the GPBO algorithm are used in the GPBO-LST-Attention model proposed in this paper, the RMSE is reduced by 0.789, the MAE by 0.592, and the MAPE by 0.49. The prediction error values of error indexes and the AICc value are lower than the other models. It shows that the model established in this paper can accurately predict blood consumption in a future time and has excellent model performance, which can provide data reference for the blood reserve of hospitals or blood centers.

Background and objective In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. Methods A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. Results MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P

The objective of this study was to investigate the structural and antioxidative properties of royal jelly protein (RJP) at different degrees of hydrolysis (DH) by partial enzymatic hydrolysis. RJP was hydrolyzed by alcalase for 0 min, 15 min, 1 h, 5 h and 8 h to obtain hydrolysates at DH of 5.34 %, 11.65 %, 15.19 %, 21.38 % and 23.91 %, respectively. With the increased DH, the RJP hydrolysates showed elevated antioxidative activities. The molecular weight of RJP hydrolysates was significantly decreased but their primary backbone kept unchanged. Analysis of circular dichroism spectra revealed that the enzymolysis reduced the content of α-helix but increased the contents of β-sheet, β-turn and random coil. Meanwhile, the surface hydrophobicity and fluorescence intensity of RJP hydrolysates were decreased and a red shift occurred. As the enzymolysis continued, the surface morphology of RJP was gradually changed from a sheet-like structure into microparticles. Changes in antioxidative activities and structures generally followed a DH-dependent manner, however these changes became insignificant for samples at DH beyond 20 %. Taking into consideration of both effectiveness and productivity, the optimum enzymatic duration was determined at 5 h.

Introduction: Transplant renal artery stenosis (TRAS) is a common post-renal transplant complication. Although endovascular treatment is widely used to treat TRAS, previous research has been limited by small sample sizes. This article aimed to present the clinical outcomes of endovascular treatment for TRAS in a large sample. Methods: Between January 2010 and December 2019, this study included patients with TRAS who were admitted to our center. All patients’ clinical symptoms, comorbidities, imaging data, treatment, and follow-up results were reviewed retrospectively. Results: Seventy two patients participated in this study. The median time between renal transplantation and TRAS was 5.25 months. Out of 72 patients, 55 (76.4%) received balloon dilatation in conjunction with stent deployment, 10 (13.9%) received drug-coated balloon dilatation alone, and 7 (9.7%) received balloon dilatation alone. The median follow-up period was 27 months. Primary patency rates were 100%, 81.8%, 74.5%, 64.6%, and 61.8% at 1, 3, 6, 12, and 24 months. A total of 23 patients were found to have restenosis during follow-up, with 6 (26.1%) requiring reintervention and none remaining restenosis after the second treatment. In the subgroup analysis of the three types of stenosis, patients with transplant renal stenosis at the anastomosis had a significantly higher rate of primary patency. Between endovascular treatments, the primary patency rate, postoperative creatinine clearance, and mean systolic blood pressure did not differ significantly. Conclusion: Endovascular treatment resulted in favorable short-term patency as well as effective relief of renal dysfunction and renal hypertension in TRAS patients.

Fatty acids are the key active components in royal jelly (RJ) with various biological activities. In this study, a novel ultrasound-assisted extraction (UAE) method was established to extract fatty acids from RJ and their structural and antioxidant property were further evaluated. The optimum extraction conditions were as follows: liquid-to-solid ratio of 10:1, ultrasonic power of 450 W and ultrasonic duration of 20 min, resulting in a better extraction yield of 16.48 % and 10-hydroxy-2(E)-decenoic acid (10-HDA) content of 4.12 %. Furthermore, compared with the solvent extraction method, the antioxidant activity of extract by ultrasound was enhanced significantly by at least 448 %. GC–MS showed that ultrasound didn’t change the chemical composition of fatty acids, while it significantly increased the content of fatty acids. SEM image illustrated that extracts by UAE showed a rougher, looser microstructure compared to the solvent method. Overall, UAE is a promising method to obtain fatty acids in RJ with high efficiency.

This paper explores the impact of government environmental protection subsidies on corporate green innovation using panel data of listed companies from 2007 to 2019. The results show that such subsidies can significantly promote corporate green innovation, and the results are robust. Financing constraints, research and development (R&D) willingness, and resource allocation efficiency are important variables for government environmental protection subsidies to promote corporate green innovation. Further analysis shows that compared with industrial policies at the provincial level, the key supportive industrial policies at the central level have a more obvious reinforcing effect on government environmental subsidies to promote enterprise green innovation. Furthermore, government environmental subsidies in the eastern, middle, and western regions benefit the promotion of enterprise green innovation, and the promotional effect is stronger in the middle and western regions. Compared with state-owned enterprises, government environmental subsidies have a more obvious promotional effect on promoting green innovation of non-state-owned enterprises. This paper provides strong theoretical inspiration for better playing the positive incentive role of government intervention with the help of government environmental protection subsidies.

Dendrite formation, contact loss, and continuous formation of the solid electrolyte interphase (SEI) preclude the practical use of the energy-dense lithium (Li) metal. Li–Ag alloys have the potential to address these issues due to their exceptional lithiophilicity, outstanding mechanical stability, and moderate chemical stability. This study evaluates all phases in the Li–Ag phase diagram based on lithiation capacity, Li insertion, mechanical property, and chemical stability. Our findings suggest that Li4Ag is the most promising phase, and the Gibbs free energy of nucleation (∆Gnucle) for Li–Ag alloys is 3 to 5 orders of magnitude smaller compared to pure Li, resulting in uniform nucleation and deposition behavior. We proposed practical applications within the Li4Ag phases or from the Li9Ag4 to the Li4Ag phases, which may provide a usable capacity of 409 to 696 mAh/g, respectively. Experiments indicate that Li4Ag exhibits not only the smallest impedance but also the highest capacity retention compared to Li9Ag4 and pure Li. The study provides valuable guidance for the selection and application of Li-containing alloys in future battery development.

Abstract Since the identification of the first case of pneumonia of unknown cause in 2019, the COVID‐19 pandemic has spread the globe for over 3 years. As the most populous country in the world, China's disease prevention policies and response plans concern the health of the country's 1.4 billion people and beyond. During the course of the pandemic, scientific research has been accumulated and given evidence‐based support to the official guidance of COVID‐19 management. The National Health Commission of China have compiled, published, and updated a total of 10 versions of the “Diagnosis and Treatment Protocol for COVID‐19 Patients” to better inform clinical practitioners and staff to effectively screen, diagnose, manage, treat, and care for cases of severe acute respiratory syndrome coronavirus 2 infection. This paper compares and summarizes each version of the protocol in terms of etiology and epidemiology, clinical manifestation and diagnosis, treatment and nursing, disease control and management, presenting detailed changes, additions, deletions, and refinement of the protocols.

Background and objective The morbidity and mortality rates of lung cancer remain high worldwide, and lung adenocarcinoma is one of the most important tissue subtypes of lung cancer. Epidermal growth factor receptor (EGFR) mutation is an important driver gene mutation for lung adenocarcinoma. In recent years, immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, have achieved remarkable efficacy in some lung cancer patients. Patients with EGFR mutations enjoyed limited benefits from immunotherapy according to recent studies. This study aimed to explore the relationship between EGFR mutation status and the spatial distribution as well as infiltration number of various immune cells in patients with EGFR mutant lung adenocarcinoma. Methods This study included 62 lung adenocarcinoma patients who underwent surgery. Through multi-point sampling of surgically removed tumor tissues in different areas, 223 tumor tissue samples were finally obtained. We aquired EGFR mutations status including variant allele frequency (VAF) and mutation subtype in each tumor tissue by genetic test. Afterwards, hematoxylin-eosin (HE) staining, immunohistochemical staining and multiplex fluorescence immunohistochemistry staining have been performed, therefore the infiltration of various immune cells and the distribution of tertiary lymphoid structure (TLS) in tumor tissues were obtained by calculating the immunohistochemical score. Results Compared with EGFR wild-type patients, patients with EGFR-mutant lung adenocarcinoma had more infiltration of CD68+ macrophages and major histocompatibility complex (MHC) class II antigen-presenting cells and higher spatial distribution heterogeneity of MHC class II antigen presenting cells in tumor tissues, while CD56+ natural killer cells and CD8+ T cells had lower infiltration. Tumor tissues with higher EGFR VAF were associated with lower cell infiltration such as CD3+ T cells, CD20+ B cells, CD56+ natural killer cells, CD68+ macrophages, CD8+ T cells, and only CD3+ T cells showed a lower spatial distribution heterogeneity. For the two common subtypes of EGFR mutations in Chinese population, tumor tissues with EGFR exon 19 deletion mutations have lower immune cell infiltration but higher spatial distribution heterogeneity of CD3+ T cells, CD56+ natural killer cells, CD68+ macrophages, and CD8+ T cells than that in EGFR exon 21 L858R mutant tumor tissues. Prognostic analysis found that patients with EGFR mutations with high degree of CD3+ T cells, CD20+ B cell infiltration and larger numbers of TLS formation and high spatial distribution heterogeneity of CD8+ T cell had longer disease-free survival. Conclusion EGFR-mutated lung adenocarcinoma had a unique "non-inflammatory" tumor microenvironment with low infiltration of immune cells, and there was also heterogeneity in the tumor microenvironment among the tumors with different mutation subtypes and mutation abundance. These differences were not only reflected in the number but also the spatial distribution of immune cell infiltration. Hence, further studies on the immune microenvironment of EGFR-mutant lung adenocarcinoma were of great significance for improving the efficacy of immunotherapy in EGFR-mutant lung adenocarcinoma patients in the future.

Royal jelly is a yellowish, creamy and acidic substance secreted by mandibular and hypopharyngeal glands of young worker bees. Fatty acids including (E)-10-hydroxy-2-decenoic acid, 10-hydroxydecanoic acid, 3,10-dihydroxydecanoic acid, 8-hydroxyoctanoic acid, sebacic acid and so on are one of the major components of royal jelly with a variety of biological activities, such as anti-inflammation, anti-bacteria and anti-tumor. Fatty acids are one of the main active components of royal jelly which are considered an important indicator in quality control. This article summarizes the identification methods of the royal jelly fatty acid including the principle of the method, the comparisons of technology and application features of methods, as well as the future research prospects. This review will provide a reference for the development of determining methods for fatty acids and pave the way for quality control of royal jelly.

BackgroundDibutyl phthalate (DBP) is a common plasticizer in daily life and has been proved to be related to the exacerbation of allergic asthma. Domestic and foreign studies have shown that lipid peroxidation is closely related to the severity of asthma, which can be used as a basis for the diagnosis and treatment of asthma. Whether DBP can induce lipid peroxidation in allergic asthma remains to be further studied.ObjectiveTo investigate whether DBP aggravates allergic asthma by inducing lipid peroxidation in allergic asthma mice.MethodsEighty male BALB/c mice were randomly divided into 4 groups, namely control group, DBP group (40 mg·kg−1), 50 μg ovalbumin (OVA) group (allergic asthma model group), and DBP+OVA group. The DBP group and the DBP+OVA group were given DBP by gavage from Day 1 to 28, and the OVA group and the DBP+OVA group were sensitized by intraperitoneal injection of OVA, once every 3 d, a total of 5 injections, from Day 9 to 21. From Day 29 to 35, the OVA group and the DBP+OVA group were challenged by OVA atomization. After the exposure, samples of blood and lung were collected. The airway hyperresponsiveness of mice was observed by lung function analysis. The serum contents of immunoglobulin E (IgE), OVA-specific immunoglobulin E (OVA-IgE), and lung homogenate levels of interleukin 4 (IL-4) were detected by enzyme-linked immunosorbent assay (ELISA) to evaluate airway allergic inflammation. The pathological changes of lung tissues were observed after hematoxylin-eosin (HE) staining and collagen fiber (Masson) staining. The contents of reactive oxygen species (ROS), lipid ROS, glutathione peroxidase 4 (GPX4), reduced glutathione (GSH), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) in lung homogenates were detected by ELISA to evaluate lipid peroxidation.ResultsThe results of lung function analysis showed that compared with the control group, the inspiratory resistance (Ri) and expiratory resistance (Re) of the OVA group and the DBP+OVA group were increased, and the lung compliance (Cldyn) was decreased. The DBP + OVA group was more severe, and the difference between the OVA group and the DBP + OVA group was statistically significant (P

Royal jelly (RJ) is a milk-like secretion produced by honey bees that is used to nourish larvae in the honeycomb. It contains many nutrients, including proteins, carbohydrates, fatty acids, and minerals. Fatty acids from RJ are gaining popularity owing to their antioxidant, anti-inflammatory, immunoregulatory, and antibacterial properties. Solvent and Soxhlet extraction are the most commonly used methods for fatty acid extraction from RJ. Owing to the inherent limitations of these methods, the development of a rapid and efficient method for fatty acid extraction from RJ is challenging. This review summarizes the current knowledge on the chemical composition, extraction methods, and biological activities of RJ fatty acids to provide a theoretical basis for expanding the prospective applications of RJ in human health.

Corynebacterium glutamicum represents an emerging recombinant protein expression factory due to its ideal features for protein secretion, but its applicability is harmed by the lack of an autoinduction system with tight regulation and high yield. Here, we propose a new recombinant protein manufacturing platform that leverages ethanol as both a delayed carbon source and an inducer. First, we reanalysed the native inducible promoter PICL from the acetate uptake operon and found that its limited capacity is the result of the inadequate translation initial architecture. The two strategies of bicistronic design and ribozyme-based insulator can ensure the high activity of this promoter. Next, through transcriptional engineering that alters transcription factor binding sites (TFBSs) and the first transcribed sequence, the truncated promoter PA256 with a dramatically higher transcription level was generated. When producing the superfolder green fluorescent protein (sfGFP) under 1% ethanol conditions, PA256 exhibited substantially lower protein accumulation in prophase but an approximately 2.5-fold greater final yield than the strong promoter PH36. This superior expression mode was further validated using two secreted proteins, camelid antibody fragment (VHH) and endoxylanase (XynA). Furthermore, utilizing CRISPRi technology, ethanol utilization blocking strains were created, and PA256 was shown to be impaired in the phosphotransacetylase (PTA) knockdown strains, indicating that ethanol metabolism into the tricarboxylic acid cycle is required for PA256 upregulation. Finally, this platform was applied to produce the “de novo design” protein NEO-2/15, and by introducing the N-propeptide of CspB, NEO-2/15 was effectively secreted with the accumulation 281 mg/L obtained after 24 h of shake-flask fermentation. To the best of our knowledge, this is the first report of NEO-2/15 secretory overexpression.

Introduction: The nuclear factor kB (NF-κB) pathway emerges as a critical regulator of immune responses and is often dysregulated in human cancers. It consists of a family of transcription factors involved in many biological responses. Activated NF-κB subunits results in the nuclear translocation and activation of transcription, and the NF-κB pathway is known to influence the transcription of many genes. Noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Besides, NF-κB signaling had diverse and complicated roles in cancer with studies that NF-κB could both contribute to tumor promotion and suppression of oncogenesis relying on the cellular context. RelB, a member of noncanonical NF-κB was abnormally regulated in most cancer types, however the molecular features and clinical signature of RelB expression, as well as its role in cancer immunity in human pan-cancer remains to be elucidated.Methods: We used the open databases to explore RelB expression, clinical features and the association with tumor-infiltration cells in human pan-cancer. In this study, we investigated the aberration expression and prognostic significance of RelB, and the correlation with clinicopathological characters and immune cells infiltration in various cancers. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to analyze the mRNA expression level in different cancer types. Kaplan-Meier analysis and Cox regression were used to explore the prognostic significance of RelB in human pan-cancer. Then we took advantage of the TCGA database to analyze the relationship between RelB expression and DNA methylation, the infiltration of immune cells, immune checkpoint genes, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MSS).Results: Higher expression of RelB was significantly detected in human cancer tissues and a high level of RelB expression was significantly linked with a worse outcome in LGG, KIPAN, ACC, UVM, LUAD,THYM, GBM, LIHC and TGCT but associated with a favorable overall survival (OS) in SARC, SKCM and BRCA. According to the Human Protein Altas database, RelB was considered as an independent factor in breast cancer and renal cancer prognosis. GSEA results revealed that RelB was involved in many oncogenesisrelated processes and immunity-related pathways. RelB was significantly correlated with DNA methylation in 13 types of cancer. Meanwhile, RelB expression was associated with TMB in 5 types of cancer and MSI in 8 types of cancer. In the final, we analyzed the relationship between RelB expression and immune-infiltration cells in human pan-cancer, which suggested RelB could be a promising therapeutic target for cancer immunotherapy.Discussion: Our study further provided insights into a deeper understanding of RelB as a prognostic biomarker.

Intracardiac foreign bodies (IFB) are rare clinical conditions. There are now several reports on the percutaneous retrieval of IFB under fluoroscopy. However, some IFB are not radiopaque, and retrieval requires combined fluoroscopic and ultrasound guidance. We report the case of a bedridden 23-year-old male patient with T-lymphoblastic lymphoma treated with long-term chemotherapy. Ultrasound examination diagnosed a huge thrombus in the right atrium near the opening of the inferior vena cava which affected the patency of his PICC line. Ten days of anticoagulant therapy did not modify the thrombus size. Open heart surgery was not feasible because of the patient clinical condition. Snare-capture of the non-opaque thrombus was done from the femoral vein under fluoroscopic and ultrasound guidance with excellent outcomes. We also present a systematic review of IFB. We found out that percutaneous removal of IFBs is a safe and effective procedure. The youngest patient who received percutaneous IFB retrieval was 10 days old and weighed only 800 g, while the oldest patient was 70 years old. Port catheters (43.5%) and PICC lines (42.3%) were the most commonly found IFBs. Snare catheters and forceps were the most commonly used instruments.

Summary: The emergence and spread of artemisinin-tolerant malaria parasites threatens malaria control programmes worldwide. Mutations in the propeller domain of the Kelch13 protein confer Plasmodium falciparum artemisinin resistance (ART-R). ART-R is linked to the reduced susceptibility of temporary growth-arrested ring-stage parasites, but the metabolic mechanisms remain elusive. We generated two PfKelch13 mutant lines via CRISPR-Cas9 gene editing which displayed a reduced susceptibility accompanied by an extended ring stage. The metabolome of ART-induced ring-stage growth arrest parasites carrying PfKelch13 mutations showed significant alterations in the tricarboxylic acid (TCA) cycle, glycolysis, and amino acids metabolism, pointing to altered energy and porphyrin metabolism with metabolic plasticity. The critical role of these pathways was further confirmed by altering metabolic flow or through chemical inhibition. Our findings uncover that the growth arrestment associated with ART-R is potentially attributed to the adaptative metabolic plasticity, indicating that the defined metabolic remodeling turns out to be the trigger for ART-R.

Plasmodium ovale curtisi and P. ovale wallikeri are both endemic in sub-Saharan Africa, the Middle East and Southeast Asia. Molecular surveillance data for drug resistance in P. ovale spp. is limited at present. We analysed polymorphisms in the podhfr, pocrt and pocytb genes of P. ovale spp. in 147 samples collected from travelers returning to China from Africa. Two podhfr mutations, S58R and S113N/T were detected in P. ovale curtisi with high/moderate frequencies of 52.17% and 17.39%, respectively. Evidence of positive selection (dN/dS = 2.41) was found for podhfr in P. ovale curtisi and decreased diversity (He) of microsatellite markers flanking the mutant alleles suggests that selective sweeps have occurred for both. Mutations E34G (1.50%) and L43V (1.50%) in pocrt of P. ovale curtisi, and E34G (3.70%), I102M (1.80%) and V111F (1.80%) of P. ovale wallikeri were found at low frequencies. Mutations R66K (6.20%), R75K (11.63%) and R95K (3.88%) of pocytb were found in both P. ovale curtisi and P. ovale wallikeri. These results suggest that the podhfr gene of P. ovale curtisi may be subject to drug selection in Africa, warranting further attention. We observed significant differences in the prevalence and distribution of podhfr mutations between the two P. ovale species, suggestive of fundamental biological differences between them.

Growing evidence links DNA methylation to tumor immunity. The impact of DNA methylation (5 mC) on the microenvironment surrounding tumors and immunotherapy remains to be clarified. Through clustering gene expression of 20 DNA methylation regulators, this study aimed at systematically analyzing DNA methylation regulator patterns and tumor microenvironment characteristics of TCGA-GBM patients. Various subtypes of glioblastoma exhibit different tumor microenvironments and DNA methylation patterns. Each DNA methylation modification was then assigned a DNA methylation score (DMS). High DMS was associated with a good prognosis. In contrast, the low DMS group had a relatively low survival rate. A correlation was also found between high DMS and enhanced immunotherapy efficacy in two immune checkpoint blocking treatment cohorts. To conclude, identifying DNA methylation regulation patterns may prove critical to understanding glioblastoma progression and differentiation, as well as future therapeutic targets.

This randomized, double-blind trial assessed the efficacy and safety of Pueraria lobata radix (PLR) and Pueraria thomsonii radix (PTR) for dyslipidemia. We randomly assigned 174 patients with mildly elevated low-density lipoprotein cholesterol (LDL-C) levels to receive 15 g/day PLR, PTR, or a placebo for 12 weeks. Changes in baseline LDL-C levels after PLR or PTR treatments compared with placebo treatment were not significant. High-density lipoprotein cholesterol (HDL-C) levels increased more significantly after PLR treatment than placebo treatment (+3.05 mg/dl, 95 % confidence interval = 0.75–5.35), whereas this effect was not observed for PTR treatment. Regarding PLR treatment, increases in HDL-C levels were mainly observed in the female, >50 years old, and nondrinker subgroups. The treatments did not show significant effects on other outcomes. No PLR- or PTR-related adverse events were reported. Given its effect on HDL-C, daily consumption of PLR, but not PTR, may represent an edible, medicinal remedy to manage dyslipidemia.

Surface fine particulate matter (PM) with a diameter of less than 2.5 microns (PM2.5) negatively impacts human health and the economy. However, due to data and model limitations, obtaining high-quality, high-spatial-resolution surface PM2.5 concentration data is a challenging task, and it is difficult to accurately assess the temporal and spatial changes in PM2.5 levels at a small regional scale. Here, we combined multi-angle implementation of atmospheric correction (MAIAC) aerosol products, ERA5 reanalysis data, etc., to construct an STW-LightGBM model that considers the spatiotemporal characteristics of air pollution and estimate the PM2.5 concentration of China’s surface at 1 km resolution from 2015 to 2020. Our model performed well, and the fitting accuracy of the 10-fold cross-validation between years was 0.877–0.917. The fitting accuracy of the model was >0.85 at different time scales (month, season, and year). The average slope of the regression prediction was 0.9 annually. The results showed that PM2.5 pollution improved from 2015 to 2020. The average PM2.5 concentration decreased by 4.55 μg/m3, and the maximum decrease reached 90.51 μg/m3. The areas with high PM2.5 concentrations were predominantly in the North China Plain, Sichuan Basin, and Xinjiang in the west, and the levels in areas with elevated PM2.5 levels were consistent across most study years. The standard deviation ellipse for PM2.5 in China showed a ‘northeast–southwest’ spatial distribution. From an interannual perspective, the average values of the four seasonal stations in the country showed a downward trend from 2015 to 2020, with the most obvious decline in winter, from 70.67 μg/m3 in 2015 to 46.75 μg/m3 in 2020. Compared to earlier inversion studies, this work provides a more stable and accurate method for obtaining high-resolution PM2.5 data, which is necessary for local air governance and environmental ecological construction at a fine scale.

Abstract Ischemia–reperfusion injury (IRI) remains the major reason for impaired donor graft function and increased mortality post-liver transplantation. The mechanism of IRI involves multiple pathophysiological processes and numerous types of cells. However, a systematic and comprehensive single-cell transcriptional profile of intrahepatic cells during liver transplantation is still unclear. We performed a single-cell transcriptome analysis of 14,313 cells from liver tissues collected from pre-procurement, at the end of preservation and 2 h post-reperfusion. We made detailed annotations of mononuclear phagocyte, endothelial cell, NK/T, B and plasma cell clusters, and we described the dynamic changes of the transcriptome of these clusters during IRI and the interaction between mononuclear phagocyte clusters and other cell clusters. In addition, we found that TNFAIP3 interacting protein 3 (TNIP3), specifically and highly expressed in Kupffer cell clusters post-reperfusion, may have a protective effect on IRI. In summary, our study provides the first dynamic transcriptome map of intrahepatic cell clusters during liver transplantation at single-cell resolution.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is an acute and sometimes fatal cerebrovascular disease. The chronobiological patterns of aSAH are still unclear worldwide. This 15-year time-series study aims to clarify the chronobiological patterns including seasonal, monthly, weekly, and circadian distributions of aSAH. Methods: We retrospectively analyzed the medical records of aSAH patients in central China. To investigate seasonal and weekly distributions, we used the χ2 goodness-of-fit test to analyze the uniformity of the onset time. To explore monthly and circadian distributions, we established Fourier models to show the rhythmicity in chronobiological patterns. Subgroup analyses were conducted to assess the impact of age, gender, hypertension statuses, and aneurysmal characteristics (number, size, and location) on the chronobiological patterns of aSAH. Results: A total of 1469 patients with aSAH were recruited in the study. The seasonal and monthly distribution exhibited significantly higher incidence in winter and January/December and lower incidence in summer and July. The weekly distribution of aSAH onset showed no significant uneven variation. The circadian distribution of aSAH exhibited a significant pattern (p = 0.0145), with a morning peak around 8:00, and a late afternoon peak at 16:00–20.00. The circadian rhythmicity varied in subgroups of different ages, genders, and aneurysmal locations. Conclusion: The occurrence of aSAH exhibits significant circannual and circadian patterns among the Chinese population. Patients with aSAH of different ages, genders, and aneurysmal locations would present different chronobiological patterns.

Flower breeders are continually refining their methods for producing high-quality flowers. Phalaenopsis species are considered the most important commercially grown orchids. Advances in genetic engineering technology have provided researchers with new tools that can be used along with traditional breeding methods to enhance floral traits and quality. However, the application of molecular techniques for the breeding of new Phalaenopsis species has been relatively rare. In this study, we constructed recombinant plasmids carrying flower color-related genes, Phalaenopsis Chalcone synthase (PhCHS5) and/or Flavonoid 3′,5′-hydroxylase (PhF3′5′H). These genes were transformed into both Petunia and Phalaenopsis plants using a gene gun or an Agrobacterium tumefaciens-based method. Compared with WT, 35S::PhCHS5 and 35S::PhF3′5′H both had deeper color and higher anthocyanin content in Petunia plants. Additionally, a phenotypic comparison with wild-type controls indicated the PhCHS5 or PhF3′5′H-transgenic Phalaenopsis produced more branches, petals, and labial petals. Moreover, PhCHS5 or PhF3′5′H-transgenic Phalaenopsis both showed deepened lip color, compared with the control. However, the intensity of the coloration of the Phalaenopsis lips decreased when protocorms were co-transformed with both PhCHS5 and PhF3′5′H. The results of this study confirm that PhCHS5 and PhF3′5′H affect flower color in Phalaenopsis and may be relevant for the breeding of new orchid varieties with desirable flowering traits.

Proteins are the basic substances that undertake human life activities, and they often perform their biological functions through interactions with other biological macromolecules, such as cell transmission and signal transduction. Predicting the interaction sites between proteins can deepen the understanding of the principle of protein interactions, but traditional experimental methods are time-consuming and labor-intensive. In this study, a new hierarchical attention network structure, named HANPPIS, by adding six effective features of protein sequence, position-specific scoring matrix (PSSM), secondary structure, pre-training vector, hydrophilic, and amino acid position, is proposed to predict protein–protein interaction (PPI) sites. The experiment proved that our model has obtained very effective results, which was better than the existing advanced calculation methods. More importantly, we used the double-layer attention mechanism to improve the interpretability of the model and to a certain extent solved the problem of the “black box” of deep neural networks, which can be used as a reference for location positioning on the biological level.

Background and Purpose Patients with aortic disease might have an increased risk of intracranial aneurysm (IA). We conducted this research to assess the prevalence of IA in patients with aortopathy, considering the impact of gender, age, and cardiovascular risk factors. Methods We searched PubMed and Scopus from inception to August 2019 for epidemiological studies reporting the prevalence of IA in patients with aortopathy. Random-effect meta-analyses were performed to calculate the overall prevalence, and the effect of risk factors on the prevalence was also evaluated. Anatomical location of IAs in patients suffered from distinct aortic disease was extracted and further analyzed. Results Thirteen cross-sectional studies involving 4,041 participants were included in this systematic review. We reported an estimated prevalence of 12% (95% confidence interval [CI], 9% to 14%) of IA in patients with aortopathy. The pooled prevalence of IA in patients with bicuspid aortic valve, coarctation of the aorta, aortic aneurysm, and aortic dissection was 8% (95% CI, 6% to 10%), 10% (95% CI, 7% to 14%), 12% (95% CI, 9% to 15%), and 23% (95% CI, 12% to 34%), respectively. Gender (female) and smoking are risk factors related to an increased risk of IA. The anatomical distribution of IAs was heterogeneously between participants with different aortic disease. Conclusions According to current epidemiological evidence, the prevalence of IA in patients with aortic disease is quadrupled compared to that in the general population, which suggests that an early IA screening should be considered among patients with aortic disease for timely diagnosis and treatment of IA.

Abstract Background Tuberculosis (TB) remains one of the infectious diseases with a leading cause of death among adults worldwide. Metformin, a first-line medication for the treatment of type 2 diabetes, may have potential for treating TB. The aims of the present systematic review were to evaluate the impact of metformin prescription on the risk of tuberculosis diseases, the risk of latent TB infection (LTBI) and treatment outcomes of tuberculosis among patients with diabetic mellitus. Methods Databases were searched through March 2019. Observational studies reporting the effect of metformin prescription on the risk and treatment outcomes of TB were included in the systematic review. We qualitatively analyzed results of included studies, and then pooled estimate effects with 95% confidence intervals (CIs) of different outcome using random-effect meta-analyses. Results This systematic review included 6980 cases from 12 observational studies. The meta-analysis suggested that metformin prescription could decrease the risk of TB among diabetics (pooled odds ratio [OR], 0.38; 95%CI, 0.21 to 0.66). Metformin prescription was not related to a lower risk of LTBI (OR, 0.73; 95%CI, 0.30 to 1.79) in patients with diabetes. Metformin medication during the anti-tuberculosis treatment is significantly associated with a smaller TB mortality (OR, 0.47; 95%CI, 0.27 to 0.83), and a higher probability of sputum culture conversion at 2 months of TB disease (OR, 2.72; 95%CI, 1.11 to 6.69) among patients with diabetes. The relapse of TB was not statistically reduced by metformin prescription (OR, 0.55; 95%CI, 0.04 to 8.25) in diabetics. Conclusions According to current observational evidence, metformin prescription significantly reduced the risk of TB in patients with diabetes mellitus. Treatment outcomes of TB disease could also be improved by the metformin medication among diabetics.

This study analyzes seasonal characteristics and long-term variations in aerosol optical parameters in Hong Kong from 2006 to 2021 using AERONET data and satellite-based observations based on the extreme-point symmetric mode decomposition (ESMD) model. The dominant aerosol types in Hong Kong are mixed aerosols and urban/industrial aerosols with fine-mode sizes, and slightly absorbing or non-absorbing properties. Aerosol optical depth (AOD), Angstrom exponent (AE) and single scattering albedo (SSA) varied seasonally with a lower AOD but higher AE and SSA in summer, and elevated AOD but lower AE and SSA in spring and winter. The long-term variations show the year 2012 to be a turning point, with an upward trend in AOD and AE before 2012 and then downwards after 2012. However, for SSA, a rising trend was exhibited in both pre- and post-2012 periods, but with a larger gradient in the first period. The ESMD analysis shows shorter-term, non-linear fluctuations in aerosol optical parameters, with alternating increasing and declining trends. The examination of the relationships between AOD and meteorological factors based on the extreme gradient boosting (XGBoost) method shows that the effects of weather conditions on AOD are complex and non-monotonic. A lower relative humidity, higher wind speed in southwest directions and lower temperature are beneficial to the abatement of aerosol loads in Hong Kong. In conclusion, the findings of this study enhance the understanding of aerosol properties and the interactions between aerosol loading and meteorological factors.

Background The association between ambient temperature and cardiovascular diseases has been well established, but evidence of temporal changes in the risk of acute aortic dissection (AAD) onset is lacking. Methods and Results We conducted an 8‐year time‐series study based on data from 2120 patients diagnosed with AAD at Tongji Hospital (Wuhan, China). Daily meteorological parameters were measured in the study area. Spearman's rank correlation analysis was applied to measure the associations between daily meteorological data and air pollution indicators. A distributed lag nonlinear model following quasi‐Poisson regression was used to express the nonlinear exposure‐response relationships and lag effects of daily mean temperature and temperature variability on the occurrence of AAD. Considering a 25‐day lag effect, lower or higher temperatures with reference to 25°C did not alter the onset risk of AAD. The lag effect of daily mean temperature on the incidence of AAD is statistically significant within 2 days, and the impact of daily mean temperature on the risk is most influential on the day. The exposure‐response curve between daily mean temperature and onset risks of AAD at lag 0 showed that the extremely cold temperature (2.5th percentile, 0.5°C) significantly increased the AAD risk for the total (relative risk, 1.733; 95% CI, 1.130–2.658) and type A dissection (relative risk, 3.951; 95% CI, 1.657–9.418). Temperature variability within 1 week did not affect the onset risks of AAD for the total. Conclusions We confirmed that extremely cold temperatures significantly increased the AAD risk, which could contribute to early prevention and timely diagnosis of the disease.

Oenococcus oeni is the main microorganism that undergoes malolactic fermentation (MLF) in the winemaking industry due to its excellent adaptability to harsh wine environments. The start of MLF is often delayed or even fails, and low pH appears to be a crucial parameter. To study the function of the trxA gene in acid stress, a plasmid containing the trxA gene of O. oeni SD-2a was heterologously expressed in Lactiplantibacillus plantarum WCFS1. The recombinant strain (WCFS1-trxA) grew better than the control strain (WCFS1-Vector) under acid stress. The expression of thioredoxin system genes was much higher in the recombinant strain compared with the control strain under acid stress. In addition, a series of physiological and biochemical assays were conducted. The ATP content was lower in the recombinant strain, while the cell membrane fluidity and integrity improved in the recombinant strain. Moreover, reactive oxygen species (ROS) accumulation, intracellular GSH level, and superoxide dismutase (SOD) activity assays showed that the recombinant strain decreased the intracellular reactive oxygen species (ROS) accumulation by improving the SOD activity. In conclusion, heterologous expression of trxA improves the SOD activity of L. plantarum WCFS1, reducing bacterial ROS and increasing cell membrane fluidity and integrity, enhancing the tolerance of Lactiplantibacillus plantarum WCFS1 under acid stress.

Accurately identifying the peak value of impact load acting on the helicopter structure during weapon launch is of great significance to the design and finalization of weapon pylons. Firstly, a method of standardized preprocessing load signal is proposed by analyzing the vibration response and the characteristics of the impact load. Then, the test model of the weapon pylon is designed, and the position of the strain gauge is determined; the static load calibration test and the ground impact test are carried out on the test model. Next, the time-domain response measured by the strain gauge is filtered and de-noised. Impact load is processed by a standardized method. The response and load are used to train BP neural network and the mapping relationship between response and load is established. The impact load generated by a specific weapon is statistically processed to obtain the normalized average load time history, and the identified standard load is converted back to the original load pattern. Finally, the network that meets the error requirements is tested. Both the standardized pattern and the original pattern have high identification accuracy, which shows that an effective load identification model can be established based on the time-domain response signal and the standardized processed load signal.

Objective: To evaluate the association between aspirin use and the risks of unruptured intracranial aneurysm (UIA) growth and aneurysmal subarachnoid hemorrhage (aSAH).Methods: We searched PubMed and Scopus from inception to 1 September 2020. Studies evaluating the associations between aspirin prescription and the risk of UIA growth or the risk of aSAH were included. The study only included patients with intracranial aneurysms. We assessed the quality of included studies using the Newcastle-Ottawa scale. Random-effects meta-analysis was conducted to pool the estimates of effect size quantitatively. Sensitivity analyses using the leave-one-out strategy were performed to identify any potential source of heterogeneity.Results: After a review of 2,226 citations, five cohort studies, two case-control studies, and one nested case-control study involving 8,898 participants were included. Pooled analyses showed that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth (OR 0.25, 95% CI 0.11–0.54; I2 = 0.0%, p = 0.604) and aSAH (OR, 0.37, 95% CI, 0.23–0.58; I2 = 79.3%, p = 0.001) in patients presented with intracranial aneurysms. The results did not significantly change in sensitivity analyses.Conclusions: Summarizing available evidence in the literature, our findings indicate that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth and aSAH in patients with UIA. Well-designed and large-scale clinical trials are needed to help define the role of aspirin as a protective pharmaceutical for UIAs.

Advances in research over the past few decades have greatly improved metabolomics-based approaches in studying parasite biology and disease etiology. This improves the investigation of varied metabolic requirements during life stages or when following transmission to their hosts, and fulfills the demand for improved diagnostics and precise therapeutics. Therefore, this review highlights the progress of metabolomics in malaria research, including metabolic mapping of Plasmodium vertebrate life cycle stages to investigate antimalarials mode of actions and underlying complex host-parasite interactions. Also, we discuss current limitations as well as make several practical suggestions for methodological improvements which could drive metabolomics progress for malaria from a comprehensive perspective.

ABSTRACT The heterochromatin environment plays a central role in silencing genes associated with the malaria parasite’s development, survival in the host, and transmission to the mosquito vector. However, the underlying mechanism regulating the dynamic chromatin structure is not understood yet. Here, we have uncovered that Plasmodium falciparum Rrp6, an orthologue of eukaryotic RNA exosome-associated RNase, controls the silencing of heterochromatic genes. PfRrp6 knockdown disrupted the singular expression of the GC-rich ncRNA RUF6 family, a known critical regulator of virulence gene expression, through the stabilization of the nascent transcripts. Mechanistic investigation showed that the accumulation of the multiple RUF6 ncRNAs triggered local chromatin remodeling in situ, which activated their adjacent var genes. Strikingly, chromatin isolation by RNA purification analysis (ChIRP-seq) revealed that a remarkable RUF6 ncRNA had interacted with distal heterochromatin regions directly and stimulated a global derepression effect on heterochromatic genes, including all variant gene families and the sexual commitment-associated regulator ap2-g gene. Collectively, Rrp6 appears to conduct the epigenetic surveillance of heterochromatic gene expression through controlling RUF6 levels, thereby securing antigenic variation and sexual commitment of malaria parasites during the infection of the host. IMPORTANCE Malaria remains a major public health and economic burden. The heterochromatin environment controls the silencing of genes associated with the fate of malaria parasites. Previous studies have demonstrated that a group of GC-rich ncRNAs (RUF6) is associated with the mutually exclusive expression of var genes, but the underlying mechanisms remain elusive. Here, through a series of genetic manipulation and genome-wide multiomics analysis, we have identified the plasmodial orthologue of RNA exosome-associated Rrp6 as an upstream regulator of RUF6 expression and revealed that the dysregulation of RUF6 upon Rrp6 knockdown triggered local chromatin alteration, thereby activating most heterochromatic genes via direct interaction of RUF6 and distal gene loci. This finding not only uncovered the in-depth mechanism of RUF6-mediated regulation of heterochromatic genes but also identified Rrp6 as a novel regulator of gene expression in human malaria parasites, which provides a new target for developing intervention strategies against malaria.

Impact load is a kind of aperiodic excitation with a short action time and large amplitude, it had more significant effect on the structure than static load. The reconstruction (or identification namely) of impact load is of great importance for validating the structural strength. The aim of this article was to reconstruct the impact load accurately. An impact load identification method based on impulse response theory (IRT) and BP (Back Propagation) neural network is proposed. The excitation and response signals were transformed to the same length by extracting the peak value (amplitude of sine wave) in the rising oscillation period of the response. First, we deduced that there was an approximate linear relationship between the discrete-time integral of impact load and the amplitude of the oscillation period of the response. Secondly, a BP neural network was used to establish a linear relationship between the discrete-time integral of the impact load and the peak value in the rising oscillation period of the response. Thirdly, the network was trained and verified. The error between the actual maximum amplitude of impact load and the identification value was 2.22%. The error between the actual equivalent impulse and the identification value was 0.67%. The results showed that this method had high accuracy and application potential.

Bionic algorithms are established by imitating human neural structures and animal social behaviors. As an important part of bionic technology, bionic algorithms are often used to solve the control problems of complex nonlinear systems, such as the rotor aeroelasticity dynamics model used in the helicopter individual blade control (IBC) optimization process. Two control methods based on bionic intelligent algorithms are introduced, respectively. The first method is to combine the fuzzy neural network and the classical PID control together. Compared with traditional PID control, the combined one was able to adjust the PID control parameters automatically by using the learning ability of the fuzzy neural network. The second method is to directly search the optimal control parameters by using the particle swarm algorithm. Both two methods demonstrate higher efficiency and accuracy; according to the results obtained by the algorithms, the vibration level was 80% less than without the applied high order harmonics. This indicates great application prospects for bionic intelligent algorithms in solving complex nonlinear system problems.

Abstract This paper proposes a novel hybrid multilevel converter with DC fault-blocking capability, i.e., the neutral-point clamped hybrid multilevel converter (NHMC). By employing two types of unipolar full-bridge submodules along with director switches, which are composed of series-connected insulated-gate bipolar transistors, the NHMC combines the features and advantages of the neutral-point clamped converter and the modular multilevel converter. The basic topology, operating principles, modulation scheme, and energy-balancing scheme of the NHMC are presented. The DC fault-blocking capability of the NHMC is investigated. The number of power electronic devices used by the NHMC is calculated and compared with other multilevel converters, showing that the proposed NHMC can be an economical and feasible option for medium-voltage DC transmission with overhead lines. Simulation results demonstrate the features and operating scheme of the proposed NHMC.

The novel coronavirus disease (COVID-19) has become a public health problem at a global scale because of its high infection and mortality rate. It has affected most countries in the world, and the number of confirmed cases and death toll is still growing rapidly. Susceptibility studies have been conducted in specific countries, where COVID-19 infection and mortality rates were highly related to demographics and air pollution, especially PM2.5, but there are few studies on a global scale. This paper is an exploratory study of the relationship between confirmed COVID-19 cases and death toll per million population, population density, and PM2.5 concentration on a worldwide basis. A multivariate linear regression based on Moran eigenvector spatial filtering model and Geographically weighted regression model were undertaken to analyze the relationship between population density, PM2.5 concentration, and COVID-19 infection and mortality rate, and a geostatistical method with bivariate local spatial association analysis was adopted to explore their spatial correlations. The results show that there is a statistically significant positive relationship between COVID-19 confirmed cases and death toll per million population, population density, and PM2.5 concentration, but the relationship displays obvious spatial heterogeneity. While some adjacent countries are likely to have similar characteristics, it suggests that the countries with close contacts/sharing borders and similar spatial pattern of population density and PM2.5 concentration tend to have similar patterns of COVID-19 risk. The analysis provides an interpretation of the statistical and spatial association of COVID-19 with population density and PM2.5 concentration, which has implications for the control and abatement of COVID-19 in terms of both infection and mortality.

Understanding the relationship between the built environment and the risk of COVID-19 transmission is essential to respond to the pandemic. This study explores the relationship between the built environment and COVID-19 risk using the confirmed cases data collected in Hong Kong. Using the information on the residential buildings and places visited for each case from the dataset, we assess the risk of COVID-19 and explore their geographic patterns at the level of Tertiary Planning Unit (TPU) based on incidence rate (R1) and venue density (R2). We then investigate the associations between several built-environment variables (e.g., nodal accessibility and green space density) and COVID-19 risk using global Poisson regression (GPR) and geographically weighted Poisson regression (GWPR) models. The results indicate that COVID-19 risk tends to be concentrated in particular areas of Hong Kong. Using the incidence rate as an indicator to assess COVID-19 risk may underestimate the risk of COVID-19 transmission in some suburban areas. The GPR and GWPR models suggest a close and spatially heterogeneous relationship between the selected built-environment variables and the risk of COVID-19 transmission. The study provides useful insights that support policymakers in responding to the COVID-19 pandemic and future epidemics.

The triple network model, consisting of the central executive network, salience network and default mode network, has been recently employed to understand dysfunction in core networks across various disorders. Here we used the triple network model to investigate the large-scale brain networks in cognitively normal APOE4 carriers who are at risk of Alzheimer’s disease (AD). To explore the functional connectivity for each of the three networks and the effective connectivity among them, we evaluated 17 cognitively normal individuals with a family history of AD and at least one copy of the apolipoprotein e4 (APOE4) allele and compared the findings to those of 12 individuals who did not carry the APOE4 gene or have a family history of AD, using independent component analysis and Bayesian network approach. Our findings indicated altered within-network connectivity that suggests future cognitive decline risk, and preserved between-network connectivity that may support their current preserved cognition in the cognitively normal APOE4 allele carries. The study provides novel sights into our understanding of the risk factors for AD and their influence on the triple network model of major psychopathology.