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Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) plays an important role in the initiation and progression of breast cancer. DNA promoter methylation status has the potential to be used as a biomarker for predicting the response to immunotherapy. This study aimed to investigate the biological and clinical significance of IDO1 promoter methylation in breast cancer. We analyzed IDO1 promoter methylation and its relationship with survival, patient prognosis, immune cell infiltration, immune-related pathways, and the expression of key immunomodulators via bioinformatics methods in The Cancer Genome Atlas (TCGA) breast cancer cohort (779 samples). Furthermore, the IDO1 promoter methylation status and expression of the IDO1 gene in the basal subtype of breast cancer were investigated in vitro via a methylation-specific PCR (MSP) assay and quantitative polymerase chain reaction (qPCR). The IDO1 promoter was significantly hypomethylated in the basal subtype of breast cancer tissues compared with normal adjacent tissues, and this effect was correlated with high expression of IDO1, resulting in abundant immune cell infiltration, activation of immune-related pathways, and upregulation of key immunomodulators. The influence of IDO1 promoter hypomethylation on the prognosis of patients with breast cancer was also investigated. The promoter hypomethylation of IDO1 in the basal subtype of breast cancer and its correlation with high expression of IDO1 were also investigated in vitro. Our results showed that IDO1 promoter methylation is vital for regulating its expression, which leads to the development of a tumor microenvironment in breast cancer. IDO1 promoter methylation and expression are associated with prognosis, immune cell infiltration, immune-related pathways, and immunomodulator expression in breast cancer. Our findings provide evidence for the validation of IDO1 promoter methylation as a promising biomarker to predict responses to immune checkpoint inhibitors in patients with breast cancer.

Two-dimensional (2D) layered materials with unique physicochemical properties, such as graphene, transition metal dichalcogenides, and hexagonal boron nitride, have shown considerable potential in the electrical and electronics industries as well as society. To realize the practical applications of 2D materials, the size, shape, and edge structures must be refined. Etching is a critical processing step in the semiconducting industry and its potential as an efficient approach for fabricating diverse nanostructures of 2D materials has been demonstrated, broadening their applications in the field of nanoelectronics. In this paper, we present an overview of recent advances in anisotropic etching of various 2D materials. Anisotropic etching and the associated mechanisms are discussed in context of the synthesis, processing, and characterization of 2D materials. An overview of the applications of anisotropic etched 2D materials is provided. Finally, the challenges and future opportunities for anisotropic etching of 2D materials are discussed.

Abstract This study aimed to unveil the central mechanism of moxibustion treating chronic inflammatory visceral pain (CIVP) from the angle of circRNA-miRNA-mRNA networks in the spinal cord. The rat CIVP model was established using a mixture of 5% (w/v) 2,4,6-trinitrobenzene sulfonic acid and 50% ethanol at a volume ratio of 2:1 via enema. Rats in the moxibustion group received herb-partitioned moxibustion at Tianshu (ST25, bilateral) and Qihai (CV6) points. The abdominal withdrawal reflex (AWR), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were adopted for pain behavior observation and pain sensitivity assessment. The circRNA, miRNA, and mRNA expression profiles were detected using the high-throughput sequencing technique. Relevant databases and bioinformatics analysis methods were used to screen for differentially expressed (DE) RNAs and build a circRNA-miRNA-mRNA (competing endogenous RNA) ceRNA regulatory network. The real-time quantitative PCR was employed to verify the sequencing result. CIVP rat models had a significantly higher AWR and lower TWL and MWT than normal rats. Between normal and model rats, there were 103 DE-circRNAs, 16 DE-miRNAs, and 397 DE-mRNAs in the spinal cord. Compared with the model group, the moxibustion group had a lower AWR and higher TWL and MWT; between these two groups, there were 118 DE-circRNAs, 15 DE-miRNAs, and 804 DE-mRNAs in the spinal cord. Two ceRNA networks were chosen to be verified. As a result, moxibustion’s analgesic effect on visceral pain in CIVP rats may be associated with regulating the circRNA_02767/rno-miR-483-3p/Gfap network in the spinal cord and improving central sensitization.

Background: Pegylated liposomal doxorubicin (PLD), epirubicin and pirarubicin are the main anthracyclines widely used in China. PLD demonstrates therapeutic response comparable to epirubicin and pirarubicin in neoadjuvant chemotherapy (NAC) of breast cancer. Objectives: The objectives of our study were to retrospectively assess the real-world effectiveness and prognostic characteristics of PLD as NAC for HR ⩽ 10%/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Design: This was a retrospective study. Methods: Our study enrolled patients with HR ⩽ 10%/HER2-negative breast cancer who received PLD-, epirubicin- or pirarubicin-based NAC from three centres in Hunan Province, China, between 2015 and 2022. We employed inverse probability of treatment weighting to balance the differences in patients’ characteristics among the PLD, epirubicin, and pirarubicin groups. The endpoints were pathological complete response (pCR), event-free survival (EFS), and overall survival (OS). Results: A total of 267 patients were included. After NAC, the pCR rates in PLD group were superior to epirubicin group (PLD, 34.1%; epirubicin, 20.8%, p = 0.038). The differences in EFS (log-rank p = 0.99) and OS (log-rank p = 0.33) among the three groups were not statistically significant. Among the three groups, non-pCR patients had worse EFS than pCR patients (log-rank p = 0.014). For patients with pCR, the differences in EFS (log-rank p = 0.47) and OS (log-rank p = 0.38) were not statistically significant among the three groups, and the EFS (log-rank p = 0.59) and OS (log-rank p = 0.14) of non-pCR patients in the PLD group were similar to those in the epirubicin and pirarubicin groups. Conclusion: PLD had a similar therapeutic response and prognosis compared to epirubicin or pirarubicin in NAC for patients with HR ⩽ 10%/HER2 negative breast cancer, which means that PLD represents a potential NAC option.

Abstract Research on switchable chaotic systems with a large range of parameters is scarce. To explore the chaotic characteristics of such systems, this paper proposes new switchable methods by modifying the nonlinear term in the system, resulting in a chaotic system with different nonlinear terms. The unknown parameters in the nonlinear term exhibit different numerical relationships under various combined conditions, and some parameters may tend towards positive infinity. The chaos characteristics are verified by applying a specific switching method to the unified chaotic system. The pseudo-randomness of the random sequence generated by the dissipative system is verified using the NIST test. Finally, the circuit simulation of the system under various switching conditions is performed by selecting different circuit components and adjusting the resistance values.The switching chaotic system is implemented physically on FPGA and breadboard, and the effectiveness of the system is verified.

Abstract Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.

The usage of Mg–Al–Zn alloys for lithium-ion battery shell is able to achieve further lightweight of electric vehicles, and their corrosion resistance would highly determine the service life. In this work, therefore, a Y-modified AZ91 magnesium alloy (AZ91-0.5Y) was first prepared by conventional casting and following hot extrusion, and the influence of solution treatment (ST) and subsequent pre-deformation (SP) treatments on its electrochemical corrosion and stress corrosion cracking (SCC) resistance in 1 mol/L LiPF6 electrolyte were then investigated. The results indicated that the presence of large lamellar or rod-like β-Mg17Al12 phase in as-extruded AZ91-0.5Y alloy would lead to serious micro-galvanic corrosion and SCC. After solution treatment, the β-Mg17Al12 phase almost completely dissolved into Mg matrix, weakening the micro-galvanic corrosion and anodic dissolution (AD) and hydrogen embrittlement (HE) effect. Further, the subsequent pre-deformation treatment could introduce dislocation, more precipitation of Al2Y phase, massive twins and optimized texture, leading to the improved corrosion resistance and mechanical strength as well as the formation of well-integrated protective corrosion product film MgF2 with low porosity. As a result, the corrosion and SCC resistance of as-extruded, ST and SP specimens is ordered from low to high.

Abstract The presence of stone cells in pears is recognized as a problem for the pear processing industry. Bacillus and mold can degrade stone cells because of their potential to digest cellulose and lignin, but they cannot be used for the degradation test of pear stone cells. In this study Lactoplantibacillus plantarum JYLP‐326 was used in single culture or in the mixed culture with Saccharomyces cerevisiae Y2 to study their potential to degrade stone cells during fermentation and the mechanism of degradation was further explored. Synergy in cellulase activity was observed in the mixed‐culture where the maximum activity was observed at 96th hour of fermentation. Activities of endoglucanase, exoglucanase and β‐glucosidase were 1.75, 4.58, and 2.31. The degradation rate of stone cells in the mixed‐culture was 37.67%, which was significantly higher than that the results obtained for single cultures. The results of scanning electron microscopy (SEM) showed that the surface of the cultured stone cells became rough. Metabolomics studies confirmed the presence of specific metabolites related to the degradation of stone cells after the fermentation. It was concluded that the mixed‐culture fermentation using the above‐mentioned strains could be exploited by the pear processing industry to degrade stone cells.

With the successful application of artificial intelligence technology in various fields, deep reinforcement learning (DRL) algorithms have applied in active corrective control in the power system to improve accuracy and efficiency. However, the “black-box” nature of deep reinforcement learning models reduces their reliability in practical applications, making it difficult for operators to comprehend the decision-making mechanism. process of these models, thus undermining their credibility. In this paper, a DRL model is constructed based on the Markov decision process (MDP) to effectively address active corrective control issues in a 36-bus system. Furthermore, a feature importance explainability method is proposed, validating that the proposed feature importance-based explainability method enhances the transparency and reliability of the DRL model for active corrective control.

Salt stress can affect various physiological processes in plants, ultimately hindering their growth and development. Melatonin (MT) can effectively resist multiple abiotic stresses, improving plant stress resistance. To analyze the mechanism of exogenous MT to enhance salt tolerance in red clover, we conducted a comprehensive study to examine the influence of exogenous MT on various parameters, including seed germination indices, seedling morphological traits, and physiological and photosynthetic indicators, using four distinct red clover varieties (H1, H2, H3, and H4). This investigation was performed under various salt stress conditions with differing pH values, specifically utilizing NaCl, Na2SO4, NaHCO3, and Na2CO3 as the salt stressors. The results showed that MT solution immersion significantly improved the germination indicators of red clover seeds under salt stress. The foliar spraying of 50 μM and 25 μM MT solution significantly increased SOD activity (21–127%), POD activity, soluble sugar content, proline content (22–117%), chlorophyll content (2–66%), and the net photosynthetic rate. It reduced the MDA content (14–55%) and intercellular CO2 concentration of red clover seedlings under salt stress. Gray correlation analysis and the Mantel test further verified that MT is a key factor in enhancing seed germination and seedling growth of red clover under salt stress; the most significant improvement was observed for NaHCO3 stress. MT is demonstrated to improve the salt tolerance of red clover through a variety of mechanisms, including an increase in antioxidant enzyme activity, osmoregulation ability, and cell membrane stability. Additionally, it improves photosynthetic efficiency and plant architecture, promoting energy production, growth, and optimal resource allocation. These mechanisms function synergistically, enabling red clover to sustain normal growth and development under salt stress.

Sulfonamides are not only widely applied in clinics but also highly valued in animal husbandry. Recently, it has become common for sulfonamide residues to exceed the standard limits in food, which can affect human health. Current regulations limit these residues. Therefore, we constructed a new limit test method to rapidly determine the levels of sulfonamide residues. Six sulfonamides were detected using the latest method called TLC-SERS, namely, sulfamethasone (A), sulfamethazine (B), sulfadoxine (C), sulfamethoxydiazine (D), sulfamethoxazole (E), and sulfathiazole (F). The optimal conditions for SERS detection were investigated for these six drugs, and the separation effects of different TLC spreaders on them were compared. Then, we successfully established a separation system using dichloromethane–methanol–ammonia in a ratio of 5:1:0.25 (v/v/v), which provided good separation effects on the six drugs. The residues were preliminarily separated via TLC. A silver sol solution was added to the spot on the silica gel G plate at the corresponding specific shift values, and SERS detection was performed. The sample solution was placed on the spot under a 532 nm laser, and the SERS spectrum was collected and analyzed for the six sulfonamides. The results showed obvious variations in the SERS spectrum among the six sulfonamides, with the LODs being 12.5, 6.4, 6.3, 7.1, 18.8, and 6.2 ng/mL from A to F, respectively, and an RSD of

Salt stress caused by high concentrations of Na+ and Cl- in soil is one of the most important abiotic stresses in agricultural production, which seriously affects grain yield. The alleviation of salt stress through the application of exogenous substances is important for grain production. Melatonin (MT, N-acetyl-5-methoxytryptamine) is an indole-like small molecule that can effectively alleviate the damage caused by adversity stress on crops. Current studies have mainly focused on the effects of MT on the physiology and biochemistry of crops at the seedling stage, with fewer studies on the gene regulatory mechanisms of crops at the germination stage. The aim of this study was to explain the mechanism of MT-induced salt tolerance at physiological, biochemical, and molecular levels and to provide a theoretical basis for the resolution of MT-mediated regulatory mechanisms of plant adaptation to salt stress. In this study, we investigated the germination, physiology, and transcript levels of maize seeds, analyzed the relevant differentially expressed genes (DEGs), and examined salt tolerance-related pathways. The results showed that MT could increase the seed germination rate by 14.28–19.04%, improve seed antioxidant enzyme activities (average increase of 11.61%), and reduce reactive oxygen species accumulation and membrane oxidative damage. In addition, MT was involved in regulating the changes of endogenous hormones during the germination of maize seeds under salt stress. Transcriptome results showed that MT affected the activity of antioxidant enzymes, response to stress, and seed germination-related genes in maize seeds under salt stress and regulated the expression of genes related to starch and sucrose metabolism and phytohormone signal transduction pathways. Taken together, the results indicate that exogenous MT can affect the expression of stress response-related genes in salt-stressed maize seeds, enhance the antioxidant capacity of the seeds, reduce the damage induced by salt stress, and thus promote the germination of maize seeds under salt stress. The results provide a theoretical basis for the MT-mediated regulatory mechanism of plant adaptation to salt stress and screen potential candidate genes for molecular breeding of salt-tolerant maize.

Abstract Telomerase reverse transcriptase (TERT/hTERT) serves as the pivotal catalytic subunit of telomerase, a crucial enzyme responsible for telomere maintenance and human genome stability. The high activation of hTERT, observed in over 90% of tumors, plays a significant role in tumor initiation and progression. An in-depth exploration of hTERT activation mechanisms in cancer holds promise for advancing our understanding of the disease and developing more effective treatment strategies. In breast cancer, the expression of hTERT is regulated by epigenetic, transcriptional, post-translational modification mechanisms and DNA variation. Besides its canonical function in telomere maintenance, hTERT exerts non-canonical roles that contribute to disease progression through telomerase-independent mechanisms. This comprehensive review summarizes the regulatory mechanisms governing hTERT in breast cancer and elucidates the functional implications of its activation. Given the overexpression of hTERT in most breast cancer cells, the detection of hTERT and its associated molecules are potential for enhancing early screening and prognostic evaluation of breast cancer. Although still in its early stages, therapeutic approaches targeting hTERT and its regulatory molecules show promise as viable strategies for breast cancer treatment. These methods are also discussed in this paper. Video Abstract

ObjectiveHormone receptor (HR)-low/HER2-negative breast cancers (BCs) are more likely to be basal-like BCs, with similar molecular features and gene expression profiles to HR-negative (estrogen receptor

Dental fluorosis, resulting from long-term environmental exposure to fluoride, is prevalent among diverse populations worldwide. Severe fluorosis not only compromises the aesthetic appeal of teeth but also impairs their functionality. This study aims to investigate the oral microbiome in dental fluorosis and the health individuals of adolescents living in the endemic fluorosis area of Guizhou, China through full-length 16S rDNA sequencing. Fourty-six individuals meet the sampling criteria, and we divided these samples into the following groups: a healthy group (H = 23) and a dental fluorosis group (F = 23), and two subgroups of Miao ethnicity: a healthy Miao group (Hm = 13) and a dental fluorosis Miao group (Fm = 15). A total of 660,389 high-quality sequences were obtained, and 12,007 Amplicon Sequence Variants (ASVs) were identified, revealing significant variations in oral microbiome between Fm and Hm groups. The composition of oral microbiota was similar between the H and F groups. At the genus level, Pseudopropionibacterium and at the species level, Streptococcus oralis_subsp.dentisani_clade_058 were less abundant in group F than in group H (P < 0.05). Further analysis revealed that the abundance of Capnocytophaga gingivalis and Kingella denitrificans was significantly lower in Fm fluorosis patients than in the Hm group (P < 0.05). Based on the LEfSe analysis, the potential core biomarkers in the oral of Fm fluorosis patients were identified at different taxonomic levels, ranging from phylum to species. These include Gammaproteobacteria, Prevotella sp_HMT_304, Gemella sanguinis, and Gracilibacteria_(GN02). Network analysis revealed that the microbiota in the fluorosis group exhibited more complex interactions with each other than the healthy group. Notably, within the Hm group, the potential biomarkers Capnocytophaga gingivalis and Kingella denitrificans exhibited a positive correlation. Finally, we employed PICRUSt2 analysis to explore the abundance clustering of the top 30 functional units in each sample, and we found that the metabolic pathway compositions of the four groups were similar. In summary, our findings suggest that the microbial composition of plaque in Hm patients with dental fluorosis is significantly altered, and we identified the potential marker microorganisms that contribute to these changes.

Cognitive decline in Alzheimer's disease is associated with electroencephalographic (EEG) biosignatures even at early stages of mild cognitive impairment (MCI). The aim of this work is to provide a unified measure of cognitive decline by aggregating biosignatures from multiple EEG modalities and to evaluate repeatability of the composite measure at an individual level. These modalities included resting state EEG (eyes-closed) and two event-related potential (ERP) tasks on visual memory and attention. We compared individuals with MCI (n = 38) to age-matched healthy controls HC (n = 44). In resting state EEG, the MCI group exhibited higher power in Theta (3-7Hz) and lower power in Beta (13-20Hz) frequency bands. In both ERP tasks, the MCI group exhibited reduced ERP late positive potential (LPP), delayed ERP early component latency, slower reaction time, and decreased response accuracy. Cluster-based permutation analysis revealed significant clusters of difference between the MCI and HC groups in the frequency-channel and time-channel spaces. Cluster-based measures and performance measures (12 biosignatures in total) were selected as predictors of MCI. We trained a support vector machine (SVM) classifier achieving AUC = 0.89, accuracy = 77% in cross-validation using all data. Split-data validation resulted in (AUC = 0.87, accuracy = 76%) and (AUC = 0.75, accuracy = 70%) on testing data at baseline and follow-up visits, respectively. Classification scores at baseline and follow-up visits were correlated (r = 0.72, p

Nine polyglutamine (polyQ) proteins have already been identified that are considered to be associated with the pathologies of neurodegenerative disorders called polyQ diseases, but whether these polyQ proteins mutually interact and synergize in proteinopathies remains to be elucidated. In this study, 4 polyQ-containing proteins, androgen receptor (AR), ataxin-7 (Atx7), huntingtin (Htt) and ataxin-3 (Atx3), are used as model molecules to investigate their heterologous coaggregation and consequent impact on cellular proteostasis. Our data indicate that the N-terminal fragment of polyQ-expanded (PQE) Atx7 or Htt can coaggregate with and sequester AR and Atx3 into insoluble aggregates or inclusions through their respective polyQ tracts. In vitro coprecipitation and NMR titration experiments suggest that this specific coaggregation depends on polyQ lengths and is probably mediated by polyQ-tract interactions. Luciferase reporter assay shows that these coaggregation and sequestration effects can deplete the cellular availability of AR and consequently impair its transactivation function. This study provides valid evidence supporting the viewpoint that coaggregation of polyQ proteins is mediated by polyQ-tract interactions and benefits our understanding of the molecular mechanism underlying the accumulation of different polyQ proteins in inclusions and their copathological causes of polyQ diseases.

We present the design of an Application Specific Integrated Circuit (ASIC) digital clock based on the 0.12 µm deep submicron technology node. The widths of the PMOS and NMOS transistors are 0.72 µm and 0.24 µm, respectively. The clock expresses time based on the 12-hour time notation. The gate-level schematic and the layout of the design are drawn and validated using DSCH3 and Microwind3 Lite. The key feature of the clock is constructed from 18 D-type flip-flops. Two modulo-60 counters and a modulo-12 counter are built from the flip-flops. The modulo-60 counters are used for the second and minute modules, while the modulo-12 flip-flop is for the hour module. The length and width of the layout are, respectively, 153.60 µm and 58.14 µm. This is to say that the size of the die is comparable with that of a human hair. The average static power dissipation is found to be 0.202 mW, which is reasonably low. Since the proposed design is in the form of an ASIC chip, the input and output pins merely require to be connected to an external power source, an oscillator, and displays, to allow the clock to operate properly. With its miniaturized size and low power consumption, the proposed design clearly exhibits advantages over those built using discrete components and general-purpose chips.

Soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP), and total potassium (TK) are important indicators for evaluating soil fertility. Exploring the content and spatial distribution of these indicators is of great significance for optimizing cropland management measures and developing sustainable agriculture. Yunnan Province is one of the most important agricultural regions in southwestern China, characterized by large variations in the topography and an uneven distribution of soil fertility. In this study, the data of 8571 topsoil (0–20 cm) samples selected from Yunnan Province and a portion of related spatial data were used to carry out electronic mapping of the spatial distribution of soil sand content, clay content, silt content, SOC, TN, TP, TK content, and C:N ratio at 1 km resolution using the Random Forest (RF) model. The results indicated that the average measured contents of SOC, TN, TP, TK, and C:N ratio in the topsoil of Yunnan Province were 18.78 ± 0.09 g/kg, 1.78 ± 0.01 g/kg, 0.98 ± 0.01 g/kg, 13.89 ± 0.08 g/kg, and 10.56 ± 0.02, respectively. The spatial analysis showed that higher SOC was mainly distributed in northern and eastern Yunnan, and the spatial distribution pattern of TN and TP was similar to that of SOC. While higher TK was mainly distributed in southwestern Yunnan Province. There was a significant positive correlation between SOC and TN and TP contents with correlation coefficients of 0.889 and 0.463, however, there was a significant negative correlation between SOC and TK content with correlation coefficients of −0.060. It was also indicated that elevation, temperature, precipitation, clay content, sand content, and silt content were the most important factors affecting SOC, TN, TP, and TK content. The present study provided an understanding of soil nutrients characteristics and their affecting factors, which is helpful to optimize agricultural management practices and develop sustainable agriculture according to soil fertility.

The powerful combination of large-scale drug-related interaction networks and deep learning provides new opportunities for accelerating the process of drug discovery. However, chemical structures that play an important role in drug properties and high-order relations that involve a greater number of nodes are not tackled in current biomedical networks. In this study, we present a general hypergraph learning framework, which introduces Drug-Substructures relationship into Molecular interaction Networks to construct the micro-to-macro drug centric heterogeneous network (DSMN), and develop a multi-branches HyperGraph learning model, called HGDrug, for Drug multi-task predictions. HGDrug achieves highly accurate and robust predictions on 4 benchmark tasks (drug-drug, drug-target, drug-disease, and drug-side-effect interactions), outperforming 8 state-of-the-art task specific models and 6 general-purpose conventional models. Experiments analysis verifies the effectiveness and rationality of the HGDrug model architecture as well as the multi-branches setup, and demonstrates that HGDrug is able to capture the relations between drugs associated with the same functional groups. In addition, our proposed drug-substructure interaction networks can help improve the performance of existing network models for drug-related prediction tasks.

Background: Rosmarinic acid (RA) has biological and pharmaceutical properties and shows hepatoprotective potential. However, the hepatoprotective mechanism of RA needs to be further elucidated in vivo and in vitro. Objective: This study was aimed to evaluate the protective effect of RA on carbon tetrachloride (CCl4)-induced liver injury and elucidate the hepatoprotective mechanism of RA in vivo and in vitro. Design: In vivo, the mice were orally administrated with RA (10, 20, and 40 mg/kg bw) daily for 28 consecutive days, and 1% CCl4 (5 mL/kg bw, dissolved in peanut oil) was used to induce liver injury. In vitro, the big rat liver (BRL) hepatocytes were pretreated with RA (0.2, 0.4, and 0.8 mg/mL) for 3 h, and then the hepatocytes were treated with CC14 (final concentration, 14 mM) for 3 h to induce cell injury. The related indexes, including hepatic function, oxidative stress, protein expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) pathway, inflammation, histopathological change, hepatocyte apoptosis, and mitochondrial membrane potential, were evaluated. Results: Oral administration of RA to mice considerably decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), triacylglycerols (TG), total cholesterol (TC), total bilirubin (TBIL), hepatic reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). RA also increased the levels of hepatic glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and the protein expressions of Nrf2, quinine oxidoreductase (NQO1), and heme oxygenease-1 (HO-1). Histopathological examinations indicated that RA (20 and 40 mg/kg bw) alleviated the liver tissue injury induced by CCl4. Moreover, RA inhibited the hepatocyte apoptosis caused by CCl4 based on TUNEL assay. In vitro, RA pretreatment remarkably recovered the cell viability and reduced the CCl4-induced elevation of AST, ALT, lactate dehydrogenase (LDH), ROS, and 8-OHdG. Immunohistochemistry staining demonstrated that pretreatment with RA markedly inhibited the expression of IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and Caspase-3 in CCl4-treated hepatocytes. Additionally, RA pretreatment significantly decreased the elevation of mitochondrial membrane potential in CCl4-treated hepatocytes. Conclusions: RA exerted a protective effect against CCl4-induced liver injury in mice through activating Nrf2 signaling pathway, reducing antioxidant damage, suppressing inflammatory response, and inhibiting hepatocyte apoptosis. RA could attenuate BRL hepatocyte ROS production, DNA oxidative damage, inflammatory response, and apoptosis induced by CCl4 exposure.

Abstract To investigate the role of tracheal wall injury in the development of benign airway stenosis in rabbits. Prospective study. We injured the tracheal walls of 28 New Zealand white rabbits using four different methods. Experimental group: Group A (n = 7, mild injury of tracheal mucosa by ordinary brush under bronchoscopy); Group B (n = 7, severe injury of tracheal mucosa by nylon brush under tracheotomy); Group C (n = 7, tracheal cartilage was injured by vascular clamp after tracheotomy); Group D (n = 7, the tracheal cartilage was injured with vascular forceps and the tracheal mucosa was injured with a nylon brush after tracheotomy). Bronchoscopy was performed on each experimental rabbit at 1, 2, 3 and 4 weeks after operation. High-resolution computed tomography (HRCT) and endobronchial optical coherence tomography (EB-OCT) were performed at 4 weeks, and the rabbits were sacrificed after the examination. Their gross and histological findings were comparatively determined whether the experimental rabbit stenosis was established. No airway stenosis was observed in group A. In group B, 28.57% of experimental rabbits developed tracheal stenosis (granulation tissue proliferation was observed in rabbits No. 2 and No. 6 at 1, 2 and 3 weeks after operation, and the tracheal scar contracture was observed in No.6 rabbit at 4 weeks after operation). Fourteen rabbits in group C and group D had tracheal stenosis caused by granulation tissue proliferation at 1, 2 and 3 weeks after operation. At the fourth week after operation, 71.43% of experimental rabbits had tracheal stenosis due to granulation tissue hyperplasia, 7.14% of experimental rabbits had tracheal stenosis due to scar contracture and granulation hyperplasia, and 21.43% of experimental rabbits had tracheal stenosis due to scar contracture. EB-OCT scan showed that the cartilage layer with low signal reflection band was discontinuous. The injury of cartilage is the key factor of benign airway stenosis. Acute injury of airway mucosa alone is unlikely to cause airway stenosis, but combined with cartilage injury may aggravate airway stenosis. EB-OCT can clearly identify the airway layers of rabbits, which is helpful to evaluate the damage of tracheal cartilage and mucosa. The diagnostic potential of this technique makes EB-OCT a promising approach for the study and monitoring of airway diseases.

ObjectivesAlthough studies have researched the mental effects of intergenerational care, little is known about the impact of transformations in caregiving intensity on depression. This study explores grand-parents’ depressive symptom outcomes in terms of changes over time in grandparental childcare, with considerations for subgroup differences.MethodUsing data from the 2015–2018 China Health and Retirement Longitudinal Study on grandparents aged 45 and older, we adopted generalized estimating equations to estimate the effects of seven category changes [(1) continued to provide high-intensity or (2) low-intensity care at both waves; (3) never provided care; (4) started caregiving; (5) ended caregiving; (6) provided less intensive care; and (7) provided more intensive care] over time in grandparental childcare on depressive symptoms among 17,701 grandparents with at least one grandchild, as well as how the impact varies by gender and urban/rural areas.ResultsGrandparents who decreased the intensity of care, stopped childcare, or offered continuous low-intensity care were associated with a lower level of depression compared with those providing no childcare. In addition, the benefit of continuous caregiving on mental health was especially noticeable in urban grandmothers.ConclusionProviding continuous low-intensity, decreased-intensity grandparenting and the cessation of caregiving were associated with a decreased level of depression for Chinese grandparents; however, there were complex interactions at play. Policies aimed at supporting grandparenting should consider caregiving intensity transitions relevant to gender and urban/rural residence.

In smart cities, bicycle-sharing systems have become an essential component of the transportation services available in major urban centers around the globe. Due to environmental sustainability, research on the power-assisted control of electric bikes has attracted much attention. Recently, fuzzy logic controllers (FLCs) have been successfully applied to such systems. However, most existing FLC approaches have a fixed fuzzy rule base and cannot adapt to environmental changes, such as different riders and roads. In this paper, a modified FLC, named self-tuning FLC (STFLC), is proposed for power-assisted bicycles. In addition to a typical FLC, the presented scheme adds a rule-tuning module to dynamically adjust the rule base during fuzzy inference processes. Simulation and experimental results indicate that the presented self-tuning module leads to comfortable and safe riding as compared with other approaches. The technique established in this paper is thought to have the potential for broader application in public bicycle-sharing systems utilized by a diverse range of riders.

In the present work, the combination of shot peening (SP), low-temperature plasma nitriding (PN) and arc deposition (AD) is proposed to improve the wear performance of Ti6Al4V alloy. The low-temperature rapid nitriding of Ti6Al4V alloy was realized by SP pretreatment to obtain a desired nitrided interlayer. The high-density structural defects produced by SP pretreatment promote the nitriding kinetics at low temperature. The nitrided interlayer consists of an outermost TiN/Ti2N compound layer and an inner diffusion layer, showing a diffusion-typed hardness-profile, which is beneficial for the enhancing of adhesion strength and load-bearing capacity. Moreover, the improvement of adhesion strength is associated closely with TiN/Ti2N compounds which can provide heterogeneous nucleation sites for AD coating with a high hardness of about 3100 HV. The high bearing-load capacity and adhesion strength can ensure the excellent wear resistance of SP-PN-AD-coated sample when compared to single AD or PN-AD samples, especially under intensive wear load conditions. The present work provides a new insight into surface hardening of Ti alloys.

The role of melatonin in plant growth and response to environmental stress has been widely demonstrated. However, the physiological and molecular regulation of salt tolerance in wheat seedlings by melatonin remains unclear. In this study, we investigated changes in phenotype, physiology, photosynthetic parameters, and transcript levels in wheat seedlings to reveal the role of melatonin in the regulation of salt tolerance in wheat. The results indicate that the application of exogenous melatonin significantly alleviates growth inhibition, reactive oxygen species accumulation, and membrane oxidative damage induced by salt stress in wheat. Additionally, exogenous melatonin increased antioxidant enzyme activity and regulated photosynthetic gas exchange. Transcriptomic data showed a significant up-regulation of genes encoding light-harvesting chlorophyll protein complex proteins in photosynthesis and genes related to chlorophyll and carotenoid biosynthesis under the influence of melatonin. These results suggest that exogenous melatonin improves salt tolerance in wheat seedlings by enhancing the antioxidant, photoprotective, and photosynthesis activities.

Folin-Ciocalteu method and sodium nitrite-aluminum chloride method were used to determine total phenolic content and flavonoid content of bound phenolics from the inflorescences, peduncles and leaves of Ottelia acuminata (O. acuminata), respectively. The composition of bound phenolics was analyzed by high performance liquid chromatography (HPLC). The antioxidant activity and protective effect against ROO· mediated DNA damage were also investigated. The results showed that total phenolic content of O. acuminata was in the range of 209.72~366.35 mg GAE/g Extract while total flavonoid content was in the range of 156.69~466.08 mg CAE/g Extract. Five phenolics, namely, caffeic acid, quercetin-3-O-glucoside, luteolin, chlorogenic acid and ferulic acid were identified in bound phenolics of O. acuminata. Trolox equivalent antioxidant activity (TEAC), 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) radical scavenging ability, iron ion reduction antioxidant ability (FRAP) and hydroxyl radical (·OH) scavenging rate IC50 value of different plant parts were in the range of 1.19~1.25 μmol TE/g Extract, 0.74~0.94 mmol/g Extract, 3.61~4.75 mmol Fe2+/g Extract, 0.34~1.26 mg/mL, respectively, among which the leaves displayed the strongest antioxidant activity. In the concentration range of 12.5~500 mg/mL, the percentage of double helix DNA in bound phenolics of inflorescences, peduncles and leaves ranged from 22.74% to 50.07%, 18.25% to 53.28% and 25.93% to 53.60%, respectively, among which the leaves showed the strongest DNA damage protective effect, followed by the peduncles. The results showed that O. acuminata was rich in bound phenolics which possessed strong antioxidant activity and DNA damage protective effect.

Tracheobronchopathia osteoplastica (TO), is an underreported affliction characterized by squamous metaplasia and heterotopic bone formation in trachea and bronchi. Here the authors apply functional, as well as genome-wide transcriptional and epigenetic profiling to identify airway basal cells dysfunction underlying TO.

To investigate the effects of free phenolics from Lycopus lucidus Turcz. on apoptosis, cell cycle and inflammatory factors in CCl4 induced hepatocyte injury by using a in vitro experiment. Apoptosis and the distribution of cell cycle was analyzed by flow cytometry. The contents of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and the activation of Caspase-3 were measured by kits. The protein expression levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6) were also detected by immunohistochemistry. The results showed that compared with the model group, the free phenolics from Lycopus lucidus Turcz. could significantly reduce the apoptosis induced by CCl4 and affect the distribution of cell cycle. In addition, the free phenolics from Lycopus lucidus Turcz. decreased the contents of TNF-α and IL-8 and blocked the activation of Caspase-3 (P

Background & Aims: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV), existing as a stable minichromosome in the hepatocyte, is responsible for persistent HBV infection. Maintenance and sustained replication of cccDNA require its interaction with both viral and host proteins. However, the cccDNA-interacting host factors that limit HBV replication remain elusive. Methods: Minicircle HBV (MC-HBV), a recombinant cccDNA, was constructed based on chimeric intron and minicircle DNA technology. By mass spectrometry based on pull-down with biotinylated MC-HBV, the cccDNA-hepatocyte interaction profile was mapped. HBV replication was assessed in different cell models that support cccDNA formation. Results: MC-HBV supports persistent HBV replication and mimics the cccDNA minichromosome. The MC-HBV–based screen identified cohesin complex as a cccDNA binding host factor, leading to reduced HBV replication. Mechanistically, with the help of CCCTC-binding factor (CTCF), which has specific binding sites on cccDNA, cohesin loads on cccDNA and reshapes cccDNA confirmation to prevent RNA polymerase II enrichment. Interestingly, HBV X protein transcriptionally reduces structural maintenance of chromosomes complex expression to partially relieve the inhibitory role of the cohesin complex on HBV replication. Conclusions: Our data not only provide a feasible approach to explore cccDNA-binding factors, but also identify cohesin/CTCF complex as a critical host restriction factor for cccDNA-driven HBV replication. These findings provide a novel insight into cccDNA–host interaction and targeted therapeutic intervention for HBV infection.

Coumarin derivatives have diverse structures and show various significant biological activities. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. The results indicated that most of the synthesized compounds displayed remarkable inhibitory activity towards cancer cells but low cytotoxicity on normal cells. Among all the compounds, 5d and 6e were the most promising compounds against different cancer cell lines, especially for A549 and KB cells. The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. Furthermore, the combined results of network pharmacology and validation experiments revealed that compound 6e induced mitochondria dependent apoptosis via the PI3K/AKT-mediated Bcl-2 signaling pathway. In summary, our study indicated compound 6e could inhibit cell proliferation, migration, invasion and promote cell apoptosis through inhibition of PI3K/AKT signaling pathway in human oral epidermoid carcinoma cells. These findings demonstrated the potential of 3-(coumarin-3-yl)-acrolein derivatives as novel anticancer chemotherapeutic candidates, providing ideas for further development of drugs for clinical use.

ObjectivesDespite extensive studies about the direct effect of grandchild care on caregiver depression in China, understanding of its internal influencing mechanism has been limited. After controlling for socioeconomic factors, this study investigated whether the experience of caring for grandchildren had a long-term impact on the depression levels of grandparents, either directly or indirectly through generational support from adult children.MethodsThe subjects of this study were a total of 9,219 adults over 45 who participated in the China Health and Retirement Longitudinal Surveys in 2015 and 2018. We adopted a lag-behind variable to examine the impact of grandchild care on depressive symptoms of grandparents. The proposed mediation model was analyzed using bootstrap modeling, and the KHB method was conducted further to examine differences in the effects of generational support.ResultsThe experience of caring for grandchildren had a significant negative correlation with the depression level of Chinese grandparents. Moreover, children's support significantly mediated the impact of parenting experience on grandparents' depression. Significantly, instrumental support mediated the effect to the greatest extent, while emotional support from children contributed the least. The intermediary effect has urban–rural heterogeneity.ConclusionThese findings indicated that grandchild care significantly inhibited the depression level of Chinese grandparents through increased intergenerational support from adult children. The implications of the study's findings were discussed.

Background: Hereditary spherocytosis (HS) is an autosomal dominant (AD) and autosomal recessive (AR) disorder that is mostly caused by mutations of the erythrocyte membrane-related gene ANK1.Methods: Clinical and genetic testing data of 17 HS children with ANK1 gene mutations were retrospectively collected. Clinical manifestations and phenotypic analysis of HS were summarized based on our experience and literature review.Results: A total of 17 mutations of the ANK1 gene were identified from 17 probands (12 sporadic cases and five familial cases), including 15 novel mutations and two previously reported ones. Among the 15 novel variants of ANK1, there were four non-sense mutations, four frameshift mutations, three splicing mutations, three missense mutations and one in-frame deletion of three amino acids. In the present study, HS patients with mutations in membrane binding domains had significantly lower hemoglobin (Hb) levels and higher total bilirubin (T-Bil) levels than those with mutations in regulatory domains. After reviewing and analyzing all available published reports of Chinese HS patients carrying ANK1 mutations in PubMed and Chinese journals, there were no significant differences in Hb, Ret and T-Bil between different mutation types or mutation regions.Conclusion: Mutations of the ANK1 can be inherited or de novo. Clinical manifestations of HS in children caused by ANK1 mutations are similar to those of other types of hemolytic anemia. Our report expands the mutation spectrum of HS, thus providing references for clinical management and genetic counseling of HS.

Background Probiotic lozenges have been developed to harvest the benefits of probiotics for oral health, but their long-term consumption may encourage the transfer of resistance genes from probiotics to commensals, and eventually to disease-causing bacteria. Aim To screen commercial probiotic lozenges for resistance to antibiotics, characterize the resistance determinants, and examine their transferability in vitro. Results Probiotics of all lozenges were resistant to glycopeptide, sulfonamide, and penicillin antibiotics, while some were resistant to aminoglycosides and cephalosporins. High minimum inhibitory concentrations (MICs) were detected for streptomycin (>128 µg/mL) and chloramphenicol (> 512 µg/mL) for all probiotics but only one was resistant to piperacillin (MIC = 32 µg/mL). PCR analysis detected erythromycin (erm(T), ermB or mefA) and fluoroquinolone (parC or gyr(A)) resistance genes in some lozenges although there were no resistant phenotypes. The dfrD, cat-TC, vatE, aadE, vanX, and aph(3”)-III or ant(2”)-I genes conferring resistance to trimethoprim, chloramphenicol, quinupristin/dalfopristin, vancomycin, and streptomycin, respectively, were detected in resistant probiotics. The rifampicin resistance gene rpoB was also present. We found no conjugal transfer of streptomycin resistance genes in our co-incubation experiments. Conclusion Our study represents the first antibiotic resistance profiling of probiotics from oral lozenges, thus highlighting the health risk especially in the prevailing threat of drug resistance globally.

In the context of utilizing BeiDou short-message communication (SMC) for transmitting maritime safety information, challenges arise regarding information redundancy and limited message length. To address these issues, compressing the data content of SMC becomes essential. This paper proposes a dual-stage compression model based on Beidou SMC for compressing maritime safety information, aiming to achieve efficient compression and reduce information redundancy. In the first stage, a binary encoding method (MBE) specifically designed for maritime safety information is proposed to optimize the byte space of the short messages, ensuring the accuracy, integrity, and reliability of the information. In the second stage, we propose a data compression algorithm called XH based on a hash dictionary, which efficiently compresses maritime safety information and reduces information redundancy. Different maritime data have corresponding structures and compositions, which can have a significant impact on the evaluation of compression algorithms. We create a database considering six categories of objects: waves, sea ice, tsunamis, storms, weather, and navigation warnings. Experimental results demonstrate that the proposed model achieves significant compression efficiency and performance on the maritime safety data set, outperforming other benchmark algorithms.

With the rapid growth of wind power penetration into modern power grids, wind speed forecasting plays an increasingly significant role in the planning and operation of electric power and energy systems. However, the existing wind speed forecasting methods are modeled as black boxes, which are very complicated and cannot be written down explicitly due to the complex fluctuation characteristics of wind speed series. To this end, this study proposes a novel direct method based on an explainable neural network (xNN) for deterministic and probabilistic wind speed forecasting. It can theoretically extract the nonlinear mapping features in wind speed, thereby providing a clear explanation of the relationship between the input and the output of the forecasting model. Then, the uncertainties in wind speed are statistically synthesized via the kernel density estimation method. Finally, we use wind speed data from real wind farms in Belgium to verify the feasibility and effectiveness of the proposed method. The simulation results demonstrate that it is not only able to accurately extract the non-stationary feature in the wind speed series but also superior to other benchmark algorithms in prediction accuracy. Therefore, the proposed method has a high potential for practical applications in real electric power and energy systems.

Abstract The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), first broke out in Wuhan, China, in 2019. SARS-CoV-2 develops many types of mutations (such as B.1.1.7), making diagnosis and treatment challenging. Although we now have a preliminary understanding of COVID-19, including pathological changes, clinical manifestations, and treatment measures, we also face new difficulties. The biggest problem is that most COVID-19 patients might face sequelae (e.g., fatigue, sleep disturbance, pulmonary fibrosis) during the recovery phase. We aimed to test six Chinese patent medicines to treat three major abnormal symptoms in COVID-19 patients during the recovery phase, including cardiopulmonary function, sleep disturbance, and digestive function. We launched the “three syndromes and six Chinese patent medicines” randomized, double-blind, placebo-controlled, multicenter clinical trial on April 10, 2020. The results showed that Jinshuibao tablets and Shengmaiyin oral liquid significantly improved the cardiopulmonary function of recovering COVID-19 patients. Shumian capsules, but not Xiaoyao capsules, significantly improved patients’ sleep disorders. This might be because the indication of Xiaoyao capsules is liver qi stagnation rather than psychological or emotional problems. Xiangsha Liujun pills and Ludangshen oral liquid significantly improved digestive function. Our research provides a guideline for treating COVID-19 sequelae in patients during the recovery period based on high-quality evidence.

Robert's uterus is a rare Müllerian malformation first characterized by a French gynecologist Héléne Robert in 1969. It represents an asymmetric division of the uterine cavity. A 45-year-old female patient presented with vaginal bleeding and vague abdominal pain for the course of 20 days, with a blood human chorionic gonadotropin level of 10331.00 mIU/mL, and a gestational sac in the right uterine horn without a fetal heart beat revealed by the ultrasound. Ectopic pregnancy in the right uterine horn seemed to be the most likely diagnosis. Laparoscopic and hysteroscopic attempts to terminate the pregnancy failed. A pelvic magnetic resonance imaging (MRI) performed after the surgery demonstrated Robert's uterus with pregnancy in the blind hemicavity. When a pregnancy sac has been revealed by an ultrasound but nothing has been found by a hysteroscopy, a possibility of uterine malformation should be considered. Radiologists and gynecologists should consider the application of MRI for diagnosis of congenital Müllerian uterine anomalies.

The classification of benign and malignant parotid tumors is very crucial for the selection of surgical methods and their prognoses. The wide application of deep learning technology in the field of medical imaging also provides new ideas for the computer-aided diagnosis of parotid gland tumors. In addition, because the pathological types of parotid gland tumors are very complicated and the computed tomography (CT) images of benign and malignant patients are also very similar, some clinicians may misjudge tumors due to a lack of experience, which affects the effect of surgical treatment and prognosis. Therefore, this research proposes using deep learning methods to solve this problem. This study uses the four classic pretraining models of VGG16, InceptionV3, ResNet and DenseNet to classify parotid CT images using transfer learning methods and uses an improved convolutional neural network (CNN) model to classify parotid CT images. The experimental results show that the improved CNN model achieves an accuracy of 97.78%, and its classification performance is better than those of the other four transfer learning methods. It can effectively diagnose benign and malignant parotid tumors and improve the diagnostic accuracy.

ABSTRACT Although the phosphorothioate (PT) modification, in which the nonbridging oxygen in the DNA sugar-phosphate backbone is replaced by sulfur, has been reported to play versatile roles in multiple cellular processes, very little data have been obtained to define the role of PT in epigenetic regulation. In this study, we report that the PT system in Salmonella enterica serovar Cerro 87 is involved in the transcriptional regulation of the torCAD operon encoding the trimethylamine N-oxide (TMAO) respiration machinery that enables the use of TMAO as a terminal electron acceptor for respiration when oxygen is not available. In vitro, PT enhanced the binding of the transcriptional activator of the torCAD operon, namely, TorR, to its DNA substrate (tor boxes). However, in vivo, the PT modification protein complex DndCDE downregulated torCAD transcription through competing with the binding of TorR to the tor boxes. The altered expression of torCAD caused by PT modification proteins affected cell growth that relied on TMAO respiration. To our knowledge, this is the first report supporting that PT proteins participate in transcriptional regulation, showing a new function of PT systems. IMPORTANCE Since the initial discovery of DNA phosphorothioate (PT) modification systems in Streptomyces lividans in the 1980s, explorations of the biological functions of DNA PT systems have advanced and yielded a number of important findings. However, the functions of PT systems, especially in genetic regulation, remain largely unknown. In this study, we report a case in which the PT system participates in the transcriptional regulation of the torCAD operon in Salmonella enterica serovar Cerro 87. While the PT modification enhanced the binding of TorR, the torCAD operon transcriptional activator, to its DNA substrate in vitro, we found that the PT modification protein complex DndCDE directly competed with TorR binding in vivo and subsequently repressed the expression of torCAD and attenuated cell growth that relied on TMAO respiration. These findings provide a deeper understanding of the characteristics of the PT chemical structure and broaden our understanding of the mechanisms by which PT regulates gene expression.

WHIM syndrome, an extremely rare congenital disease with combined immunodeficiency, is mainly caused by heterozygous gain-of-function mutation in the CXCR4 gene. There have been no previous case reports of WHIM syndrome with Kawasaki disease. We herein report a case of a boy who developed Kawasaki disease at the age of 1 year. After treatment, the number of neutrophils in his peripheral blood decreased continuously. His medical history revealed that he had been suffering from leukopenia, neutropenia and low immunoglobulin since birth, and his neutrophils could return to the normal level in the presence of infection or inflammation. Clinical targeted gene sequencing of 91 genes associated with granulocyte-related disease revealed that the patient had a novel heterozygous NM_003467; c.1032_1033delTG;p.(E345Vfs*12) variant in exon 2 of CXCR4 gene. Family verification analysis by Sanger sequencing showed that his father also had heterozygous variation at this site, while other family members did not. The computer prediction software indicated that the variation had a high pathogenicity. The computational structure analysis of the mutant revealed significant structural and functional changes in the CXCR4 protein. It should be noted that when unexplained persistent neutropenia with low immunoglobulin occurs after birth, especially when there is a family history of neutropenia, immunodeficiency should be investigated with genetic testing.

In the next generation wireless communication paradigm, the number of devices are expected to increase exponentially after the concept of Internet of Things (IoT). These devices are power constrained, with limited processing capability. Therefore, in order to get the maximum advantage from these low power IoT sensing devices, it is of utmost need to empower them. Similarly, the devices are not able to process the computationally intensive applications. In this work, Wireless Power Mobile Edge Cloud (WPMEC) is considered, which is an integration of Wireless Power Transfer (WPT) and Mobile Edge Cloud (MEC) to address low power devices' battery and computational capabilities. The WPMEC is charging the devices in the first phase using the WPT and in the second phase, the devices are offloading their computational intensive data to the MEC. Partial offloading scheme is first time introduced and analyzed with WPMEC. Performance of proposed solution is evaluated in terms of overall network computational energy efficiency. Extensive simulations have been carried out to validate the proposed solution. It is shown that the proposed partial offloading scheme with WPMEC outperforms the binary and local computational schemes.

Background/Aims: The study aimed at investigating the impact of serum magnesium (Mg) baseline level and its variability on mortality in maintenance hemodialysis (MHD) patients. Methods: Eligible patients receiving regular MHD at Ningbo No. 2 Hospital between January 2009 and August 2016 were enrolled and follow-ups were conducted afterwards until death or transplantation. General information, laboratory results, and outcomes of subjects were collected. The relationship between baseline serum Mg level, its coefficient of variation (CV), and all-cause mortality and cardiovascular disease mortality were assessed, respectively. Subjects were divided into groups in 2 manners: by serum Mg level (lower Mg group: serum Mg < 1.00 mmol/L, higher Mg group: serum Mg ≥1.00 mmol/L) and by serum Mg CV (high variation group: CV ≥0.149 mmol/L, middle variation group: 0.114 mmol/L ≤ CV < 0.149 mmol/L, and low variation group: CV < 0.114 mmol/L). Results: 169 MHD patients were recruited in the study, with mean serum Mg 1.00 ± 0.18 mmol/L, average age 60.20 ± 15.64 years, and median dialysis duration 37.00 (18.30, 77.97) months. During the follow-up, 69 (40.83%) patients died, 24 (34.78%) of which died due to cardiovascular disease. Comparing the two groups, patients in the lower Mg group had a higher all-cause mortality (50.00 vs. 29.33%, p = 0.007). The multivariate Cox regression analysis suggested that lower Mg level was an independent factor for all-cause mortality as well as cardiovascular mortality (HR = 13.268, 95% CI 6.234–28.237, p < 0.001; HR = 12.702, 95% CI 3.737–43.174, p < 0.001, respectively). However, there were no significant statistical differences of all-cause and cardiovascular mortality among these three groups concerning Mg variation. And in the univariate and multivariate Cox regression analysis, serum magnesium CV was not the independent factor for all-cause mortality and cardiovascular mortality. Conclusions: The lower baseline serum magnesium level was associated with all-cause and cardiovascular mortality in MHD patients. However, the variability of magnesium level was not independently associated with the risk of death and further studies need to be conducted.

We recently found that SspABCD, catalyzing single-stranded (ss) DNA phosphorothioate (PT) modification, coupled with SspE provides protection against phage infection. SspE performs both PT-simulated NTPase and DNA-nicking nuclease activities to damage phage DNA, rendering SspA-E a PT-sensing defense system.

Olfactory ecto-mesenchymal stem cells (OE-MSCs) are a novel population of resident stem cells in the olfactory lamina propria with strong immunosuppressive function. Exosomes released by MSCs are considered to carry various mRNAs, microRNAs and proteins from cells and function as an extension of MSCs. However, it remains unclear whether exosomes derived from OE-MSCs (OE-MSCs-Exos) possess any immunoregulatory functions. In this study, we found that OE-MSCs-Exos possessed strong suppressive function in CD4+T cell proliferation, accompanied by reduced IL-17, IFN-γ and enhanced TGF-β, IL-10 secreted by T cells. In experimental colitis mice, treatment of OE-MSCs-Exos markedly alleviated the severity of disease, and Th1/Th17 subpopulations were remarkably reduced whereas Treg cells were increased after OE-MSCs-Exos treatment. Mechanistically, OE-MSCs-Exos were demonstrated to inhibit the differentiation of Th1 and Th17 cells, but promote the induction of Treg cells in vitro. Taken together, our findings identified a novel function of OE-MSCs-Exos in regulating T-cell responses, indicating that OE-MSCs-Exos may represent a new cell-free therapy for the treatment of IBD and other inflammatory diseases.

Primary Sjögren’s syndrome (pSS) is a progressive systemic autoimmune disease characterized by lymphocytic infiltrates in exocrine glands, leading to the injury of salivary and lachrymal glands. Mesenchymal stem cells (MSCs) have been demonstrated to exert great potential in the treatment of various autoimmune diseases. Although MSCs have provide an effective therapeutic approach for SS treatment, the underlying mechanisms are still elusive. Our previous study has shown the reduced suppressive capacity of myeloid-derived suppressor cells (MDSCs) advanced the progression of experimental Sjögren’s syndrome (ESS). In this study, we found that BM-MSCs significantly enhanced the suppressive function of MDSCs with high levels of Arginase and NO, decreased the levels of CD40, CD80, CD86, and MHC-II expression on MDSCs, thus attenuating the disease progression in ESS mice. Furthermore, the enhanced suppressive function of MDSCs was mediated by BM-MSC-secreted TGF-β, and the therapeutic effect of BM-MSCs in inhibiting ESS was almost abolished after silencing TGF-β in BM-MSCs. Taken together, our results demonstrated that BM-MSCs alleviated the ESS progression by up-regulating the immunosuppressive effect of MDSCs through TGF-β/Smad pathway, offering a novel mechanism for MSCs in the treatment of pSS.

he right of football clubs to establish local bans (the so-called “blacklists”) depends on a number of reasons. A local ban on visiting football matches can act as a measure to combat the unlawful behaviour of viewers, thus complementing the administrative responsibility of the spectators. In Russian law it is not possible to impose a ban on the sale of tickets to football matches by football clubs. The current wording of the rules of spectators’ behaviour during official sporting events does not, by default, allow supporter identity checks when entering the stadium. That also complicates the identification of spectators for being on the “blacklist”. The practice of civil suits brought by football clubs against supporters, as one of the few legal tools to influence supporters, is currently not widespread. As a result, there are no uniform approaches to resolve these disputes: the courts motivate refusals by various arguments, the validity of which can be reasonably criticised.