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Trehalases (TREs), serving as crucial enzymes regulating trehalose and chitin metabolism in insects, represent prime targets for pest control strategies. We investigated the impact of three thioxothiazolidin compounds (1G, 2G, and 11G) on TRE activity and summarized their effects on the growth and development of Spodoptera frugiperda (Lepidoptera, Noctuidae). The experimental larvae of S. frugiperda were injected with the three thioxothiazolidin compounds (1G, 2G, and 11G), while the control group received an equivalent volume of 2% DMSO as a control. All three compounds had a strong effect on inhibiting TRE activity, significantly prolonging the pre-pupal development stage. However, compared with the 11G-treated group, the survival rate of larvae treated with 1G and 2G was significantly reduced by 31.11% and 27.78% respectively, while the occurrence of phenotypic abnormalities related to growth and development was higher. These results manifest that only the TRE inhibitors, 1G and 2G, modulate trehalose and chitin metabolism pathways of larvae, ultimately resulting in the failure molting and reduction of survival rates. Consequently, the thioxothiazolidin compounds, 1G and 2G, hold potential as environmentally friendly insecticides.

Abstract While canonical Wnt signaling is well recognized for its crucial regulatory functions in cell fate decisions, the role of non-canonical Wnt signaling in adult stem cells remains elusive and contradictory. Here, we identified Mcam, a potential member of the non-canonical Wnt signaling, as an important negative regulator of mammary gland epithelial cells (MECs) by genome-scale CRISPR-Cas9 knockout (GeCKO) library screening. Loss of Mcam increases the clonogenicity and regenerative capacity of MECs, and promotes the proliferation, differentiation, and ductal morphogenesis of mammary epithelial in knockout mice. Mechanically, Mcam knockout recruits and polarizes macrophages through the Il4-Stat6 axis, thereby promoting secretion of the non-canonical Wnt ligand Wnt5a and its binding to the non-canonical Wnt signaling receptor Ryk to induce the above phenotypes. These findings reveal Mcam roles in mammary gland development by orchestrating communications between MECs and macrophages via a Wnt5a/Ryk axis, providing evidences for non-canonical Wnt signaling in mammary development.

Abstract Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.

Optimizing lanthanide catalyst performance with organic ligands often encounters significant challenges, including susceptibility to water or oxygen and complex synthesis pathways. To address these issues, our research focuses on developing inorganic lanthanide clusters with enhanced stability and functionality. In this study, we introduce the [Sm6O(OH)8(H2O)24]I8(H2O)8 cluster (Sm-OC) as a sustainable and efficient catalyst for the aerobic oxidation of thiols under heating conditions. The Sm-OC catalyst demonstrated remarkable stability, outstanding recyclability, and excellent chemoselectivity across a diverse range of functional groups in 38 different tests. Notably, it enables efficient unsymmetrical disulfide synthesis and prevents the formation of over-oxidized by-products, highlighting its superior performance. This Sm-OC catalyst provides a practical and robust tool for the precise construction of versatile disulfides, thus establishing a template for the broader use of lanthanide clusters in organic synthesis.

The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

Spodoptera frugiperda was used to investigate its role as a trehalase inhibitor of three new thiothiazolidone compounds—6d, 6e, and 6f. The development and reproduction of S. frugiperda were investigated to evaluate the potential of these compounds as a novel pesticide for pest control. Compounds 6d, 6e, and 6f were injected into larvae and female pupae. Molecular changes in trehalose and chitin metabolism genes were monitored. Pupal trehalase activity, the female pupal emergence rate, ovarian development, and SfVg and SfVgR gene expression levels were assessed. The results revealed that all three compounds significantly inhibited trehalase activity in the larvae. The expression of TRE was significantly downregulated, and compounds 6d and 6f significantly downregulated the expression of TRE2. Treated larvae exhibited significantly decreased survival rates and a higher incidence of abnormalities. The egg production and hatching rates were markedly diminished by the inhibitors, and the ovaries displayed blackening and clumping. These compounds exhibit promise as eco-friendly insecticides, but further experiments are required to test their multifaceted capabilities.

This study conducted a two-year field artificial intelligence (AI) greenhouse rice planting experiment with different canopy humidity (normal humidity, NH; high humidity, and HH) and irrigation regimes (continuous flooding, CF; drought cultivation, DC; alternate wetting-drying, AWD) to test whether high canopy humidity from heading to maturity deteriorates rice grain quality, whether appropriate water management can alleviate these adverse effects, and the related mechanisms. The results showed that compared with NH, HH significantly decreased the head rice rate while increasing the protein, amino acid, amylopectin, amylose, and chalkiness. Moreover, HH significantly decreased the peak viscosity, breakdown, and number of small starch granules, while increasing the setback, number of large starch granules, relative crystallinity, gelatinization temperature, and enthalpy. Under NH and HH, AWD treatment resulted in a higher head rice rate, peak viscosity, breakdown, key enzyme activities of starch synthesis, amylose, amylopecan, relative crystallinity, small starch granules, gelatinization temperature, and enthalpy than DC and CF treatments, while lower chalkiness, setback, protein, amino acid, and large starch granules were observed. HH increased the chalkiness by promoting the formation of large starch granules, thus reducing the milling quality. The increase in amylose and relative crystallinity further causes HH to deteriorate the cooking and eating quality. AWD could alleviate the deterioration of rice grain milling, appearance, and eating quality caused by HH by improving starch granules.

Abstract Objective The purpose of this study was to estimate the safety and efficacy of spray cryotherapy (SCT) in patients with chronic obstructive pulmonary disease (COPD). Methods We recruited patients aged 40–80 years with a confirmed diagnosis of COPD without serious complications (defined as two consecutive years of chronic cough and cough for at least 3 months with lung function forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC]

Introduction:Spodoptera frugiperda is an omnivorous agricultural pest which is great dangerous for grain output.Methods: In order to investigate the effects of potential trehalase inhibitors, ZK-PI-5 and ZK-PI-9, on the growth and development of S. frugiperda, and to identify new avenues for S. frugiperda control, we measured the content of the trehalose, glucose, glycogen and chitin, enzyme activity, and gene expression levels in trehalose and chitin metabolism of S. frugiperda. Besides, their growth and development were also observed.Results: The results showed that ZK-PI-9 significantly reduced trehalase activity and ZK-PI-5 significantly reduced membraned-bound trehalase activity. Moreover, ZK-PI-5 inhibited the expression of SfTRE2, SfCHS2, and SfCHT, thus affecting the chitin metabolism. In addition, the mortality of S. frugiperda in pupal stage and eclosion stage increased significantly after treatment with ZK-PI-5 and ZK-PI-9, which affected their development stage and caused death phenotype (abnormal pupation and difficulty in breaking pupa).Discussion: These results have provided a theoretical basis for the application of trehalase inhibitors in the control of agricultural pests to promote future global grain yield.

Childhood adversity might impair corticolimbic brain regions, which play a crucial role in emotion processing and the acute stress response. The dimensional model of childhood adversity proposed that deprivation and threat dimensions might associated with individuals’ development through different mechanisms. However, few studies have explored the relationship between different dimensions of childhood stress, emotion processing, and acute stress reactivity despite the overlapping brain regions of the last two. With the aid of the event-related potentials technique, we explore whether negative emotion processing, which might be particularly relevant for adaptive stress responding among individuals with adverse childhood experience, mediates the relationship between dimensional childhood stress and acute stress response. Fifty-one young adults completed a free-viewing task to evaluate neural response to negative stimuli measured by late positive potential (LPP) of ERPs (Event-related potentials). On a separate day, heart rate and salivary cortisol were collected during a social-evaluative stress challenge (i.e. TSST, Trier Social Stress Test). After the TSST, the childhood trauma questionnaire was measured to indicate the level of abuse (as a proxy of threat) and neglect (as a proxy of deprivation) dimensions. Multiple linear regression and mediation analysis were used to explore the relationship among childhood stress, emotion processing, and acute stress response. Higher level of childhood abuse (but not neglect) was distinctly related to smaller LPP amplitudes to negative stimuli, as well as smaller heart rate reactivity to acute stress. For these participants, smaller LPP amplitudes were linked with smaller heart rate reactivity to acute stress. Furthermore, decreased LPP amplitudes to negative stimuli mediated the relationship between higher level of childhood abuse and blunted heart rate reactivity to stress. Consistent with the dimensional model of childhood stress, our study showed that childhood abuse is distinctly associated with neural as well as physiological response to threat. Furthermore, the blunted neural response to negative stimuli might be the underlying mechanism in which childhood abuse leads to the blunted acute stress response. Considering that all the participants are healthy in the present study, the blunted processing of negative stimuli might rather reflect adaptation instead of vulnerability, in order to prevent stress overshooting in the face of early-life threatening experiences.

BackgroundThe diagnostic value of rapid on-site evaluation (ROSE) of cytology during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) remains controversial. The purpose of this study was to validate the value of ROSE during the EUBS-TBNA procedure in the diagnosis of pulmonary lesions (PLs).MethodsEnrolled in this study were 260 patients with nodules, masses, cavities, or inflammatory lesions on pulmonary CT images. They were assigned to undergo EBUS-TBNA with ROSE (n = 134) or without ROSE (n = 126). The diagnostic results of ROSE during EBUS-TBNA and the final pathologic reports were analyzed and compared by utilizing SPSS21.0 software to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, we further explored whether the ROSE method during EBUS-TBNA would improve the diagnostic yield and reduce the incidence of complications.ResultsThe overall diagnostic yield of EBUS-TBNA for malignant diseases in the ROSE and the non-ROSE group were 29.9 and 11.1%, respectively. The sensitivity, specificity, PPV and NPV of the ROSE method during EBUS-TBNA were 97.4, 96.9, 92.5, and 98.90%, respectively. The result of the chi-square test effectively proved that ROSE operation during EBUS-TBNA contributes to the diagnosis of malignancy compared with the non-ROSE group (χ2 = 13.858, P < 0.001). The number of punctures in the ROSE group was significantly lower than that in the non-ROSE group (P < 0.001).ConclusionROSE examination during EBUS-TBNA could effectively improve the diagnostic yield of malignant diseases compared with the non-ROSE group and reduce the number of intraoperative punctures, which is a clinical application worth popularizing.

Iodine is a well-known oxidant that is widely used in organic syntheses. Thiol oxidation by stoichiometric iodine is one of the most commonly employed strategies for the synthesis of valuable disulfides. While recent advancements in catalytic aerobic oxidation conditions have eliminated the need for stoichiometric oxidants, concerns persist regarding the use of toxic or expensive catalysts. In this study, we discovered that iodine can be used as a cheap, low-toxicity catalyst in the aerobic oxidation of thiols. In the catalytic cycle, iodine can be regenerated via HI oxidation by O2 at 70 °C in EtOAc. This protocol harnesses sustainable oxygen as the terminal oxidant, enabling the conversion of primary and secondary thiols with remarkable efficiency. Notably, all 26 tested thiols, encompassing various sensitive functional groups, were successfully converted into their corresponding disulfides with yields ranging from >66% to 98% at a catalyst loading of 5 mol%.

ObjectivesHealth-related physical-fitness (HRPF) involves multi-components of physical functional tests and is reported to be associated with the risk of fall. The study sought to determine whether specific physical fitness components were stronger predictors of falls among elderly people.MethodsThis prospective cohort study involved 299 community residents age ≥60 years from Shanghai, China. The baseline data included comprehensive assessment of sociodemographic, clinical, and HRPF test. Subjects were followed for 1 year and were contacted by telephone to report falls. LASSO regression and Multivariate regression analysis were used to identify risk predictors of fall. In addition, we used receiver operating characteristic (ROC) curve analyses to determine whether the predictors have diagnostic.ResultsDuring the 1-year prospective fall assessment, 11.7% of these subjects experienced one or frequent falls. LASSO models revealed that age (=0.01) and 8-ft up-and-go test score (=0.06) were positively associated with falls, while activity-specific balance confidence (ABC; = −0.007) and 2-min step test score (= −0.005) were inversely related. The Area Under roc Curve (AUC) for a linear combination of age, ABC scale score, 2-min step test and 8-ft up-and-go test was 0.778 (95% confidence interval: 0. 700–0.857), which was superior to any of the variables taken alone.ConclusionAge, activity-specific balance confidence and fitness abnormalities were determined to contribute to the incident of falls. The value of 2-min step test score, and 8-ft up-and-go test score were the key HRPF components in predicting falls among elderly people.

Abstract Background Although traditional diagnostic techniques of infection are mature and price favorable at present, most of them are time-consuming and with a low positivity. Metagenomic next⁃generation sequencing (mNGS) was studied widely because of identification and typing of all pathogens not rely on culture and retrieving all DNA without bias. Based on this background, we aim to detect the difference between mNGS and traditional culture method, and to explore the relationship between mNGS results and the severity, prognosis of infectious patients. Methods 109 adult patients were enrolled in our study in Shanghai Tenth People’s Hospital from October 2018 to December 2019. The diagnostic results, negative predictive values, positive predictive values, false positive rate, false negative rate, pathogen and sample types were analyzed by using both traditional culture and mNGS methods. Then, the samples and clinical information of 93 patients in the infected group (ID) were collected. According to whether mNGS detected pathogens, the patients in ID group were divided into the positive group of 67 cases and the negative group of 26 cases. Peripheral blood leukocytes, C-reactive protein (CRP), procalcitonin (PCT) and neutrophil counts were measured, and the concentrations of IL-2, IL-4, IL-6, TNF-α, IL-17A, IL-10 and INF-γ in the serum were determined by ELISA. The correlation between the positive detection of pathogens by mNGS and the severity of illness, hospitalization days, and mortality were analyzed. Results 109 samples were assigned into infected group (ID, 92/109, 84.4%), non-infected group (NID, 16/109, 14.7%), and unknown group (1/109, 0.9%). Blood was the most abundant type of samples with 37 cases, followed by bronchoalveolar lavage fluid in 36 cases, tissue, sputum, pleural effusion, cerebrospinal fluid (CSF), pus, bone marrow and nasal swab. In the ID group, the majority of patients were diagnosed with lower respiratory system infections (73/109, 67%), followed by bloodstream infections, pleural effusion and central nervous system infections. The sensitivity of mNGS was significantly higher than that of culture method (67.4% vs 23.6%; P

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.

Abstract The mechanism of obesity‐related metabolic dysfunction involves the development of systemic inflammation, largely mediated by macrophages. Switching of M1‐like adipose tissue macrophages (ATMs) to M2‐like ATMs, a population of macrophages associated with weight loss and insulin sensitivity, is considered a viable therapeutic strategy for obesity‐related metabolic syndrome. However, mechanisms for reestablishing the polarization of ATMs remain elusive. This study demonstrates that CD146+ ATMs accumulate in adipose tissue during diet‐induced obesity and are associated with increased body weight, systemic inflammation, and obesity‐induced insulin resistance. Inactivating the macrophage CD146 gene or antibody targeting of CD146 alleviates obesity‐related chronic inflammation and metabolic dysfunction. Macrophage CD146 interacts with Glycoprotein 130 (Gp130), the common subunit of the receptor signaling complex for the interleukin‐6 family of cytokines. CD146/Gp130 interaction promotes pro‐inflammatory polarization of ATMs by activating JNK signaling and inhibiting the activation of STAT3, a transcription factor for M2‐like polarization. Disruption of their interaction by anti‐CD146 antibody or interleukin‐6 steers ATMs toward anti‐inflammatory polarization, thus attenuating obesity‐induced chronic inflammation and metabolic dysfunction in mice. The results suggest that macrophage CD146 is an important determinant of pro‐inflammatory polarization and plays a pivotal role in obesity‐induced metabolic dysfunction. CD146 could constitute a novel therapeutic target for obesity complications.

Abstract Background To investigate the effectiveness of Liuzijue exercise on chronic obstructive pulmonary disease (COPD) in the stable phase. Methods We searched six electronic bibliographic databases (PubMed, EMBASE, The Cochrane Library, Web of Science, CNKI, and Wan Fang Data) from inception to August 2018. Randomized controlled trials (RCTs) were included if they evaluated the effect of Liuzijue exercise on stable COPD. Cochrane Collaboration risk-of-bias tool (Cochrane Handbook 5.1.0) was used to assess the risk of bias of included RCTs. Meta-analysis was performed using the Review Manager software (RevMan V.5.3.5) provided by the Cochrane Collaboration. Outcomes assessed included dyspnea, exercise capacity, lung function, and quality of life. Results Fourteen RCTs involving 920 stable COPD patients were included in this systematic review and meta-analysis. The control groups received usual care. The average number of training sessions per participant was 9.3 per week, and the average length of these training sessions was 31.6 min per week. Training duration varied from 3 to 12 months. Meta-analysis results showed that Liuzijue exercise can effectively improve patients’ Modified Medical Research Council Dyspnea Scale scores (MD = − 0.73, 95% CI: − 1.13 to − 0.33, P

Abstract Background The aim of this study was to investigate the optimal order of radiation therapy in patients affected by stage IIIA pathologic N2 (IIIA/N2) non-small-cell lung cancer (NSCLC) and to identify its potential risk factors. Methods 17,654 (8786 men and 8868 women) diagnosed with NSCLC stage IIIA-N2 from 2004 to 2015 patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Among the relevant clinical parameters, we evaluated overall survival (OS), lung cancer-specific survival (LCSS) and other variables such as age, sex and tumor size in patients who were treated with different combinations of surgery and radiotherapy strategies. Results We discovered that surgery benefit in younger IIIA/N2 NSCLC patients (age ≤ 75), and compared with surgery only, preoperative radiotherapy significantly improved the survival rate most (p 75 years old, who underwent postoperative radiotherapy (PORT) had the highest survival rate (p

Background: Individuals exposed to childhood maltreatment present with a deficiency in emotional processing in later life. Most studies have focused mainly on childhood physical or sexual abuse; however, childhood emotional abuse, a core issue underlying different forms of childhood maltreatment, has received relatively little attention. The current study explored whether childhood emotional abuse is related to the impaired processing of emotional facial expressions in healthy young men.Methods: The emotional facial processing was investigated in a classical gender discrimination task while the event-related potentials (ERPs) data were collected. Childhood emotional abuse was assessed by a Childhood Trauma Questionnaire (CTQ) among 60 healthy young men. The relationship between the score of emotional abuse and the behavioral and the ERP index of emotional facial expression (angry, disgust, and happy) were explored.Results: Participants with a higher score of childhood emotional abuse responded faster on the behavioral level and had a smaller P2 amplitude on the neural level when processing disgust faces compared to neutral faces.Discussion: Individuals with a higher level of childhood emotional abuse may quickly identify negative faces with less cognitive resources consumed, suggesting altered processing of emotional facial expressions in young men with a higher level of childhood emotional abuse.

Abstract Background Chronic obstructive pulmonary disease (COPD) not only affects pulmonary function but also leads to skeletal muscle dysfunction. The various characteristics of different forms of traditional Chinese exercise lead to inconsistent clinical effects in COPD patients. Hence, the present study carefully combined and rearranged liuzijue, wuqinxi, baduanjin, and yijinjing into a pulmonary exercise program targeting COPD patients. Methods/design This study is a single-blind, randomized controlled trial. A random number table will be generated by an independent person. Each number will be placed in a sealed opaque envelop to blind assignment. All outcome assessors will be blinded to group assignment. COPD patients between 40 and 80 years of age, with stable medical treatment and no regular participation in regular exercise in the last 6 months will be included. All participants will be recruited from the Respiratory Medicine Department of Yue-Yang Integrative Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. All participants will continue to follow their medical treatment. They will be randomly assigned to one of four groups in a 1:1:1:1 ratio: (1) usual care (control group, CG), (2) pulmonary exercise group (PG), (3) resistance exercise group (RG), or (4) combined pulmonary exercise and resistance exercise group (PRG). CG participants will receive medical treatment only. PG participants will perform 60 min of exercise twice a day 7 days a week for 3 months, with 1 day’s exercise per week at hospital under guidance and supervision. RG participants will perform 60 min of resistance exercise once a day, three times a week for 3 months, with 1 day’s exercise per week at hospital under guidance and supervision. PRG participants will perform 60 min of prescribed pulmonary exercise combined with resistance exercise for 3 months. The outcomes include the isokinetic strength of peripheral skeletal muscle, surface electromyography, 6-min walking distance, 30-s arm curl test, pulmonary function, respiratory muscle strength, dyspnea, body composition, physical activity, quality of life, and Chronic Disease Self-Efficacy Scale. Discussion The results of this study will compensate for the current inadequate understanding of prescribed pulmonary exercise and may provide a new, simple, convenient, and effective home-based exercise intervention for COPD patients. Trial registration Chinese Clinical Trial Registry, ChiCTR-1800017405. Registered on 28 July 2018.

Neonicotinoids are important insecticides for controlling aphids in agriculture. Growing research suggested that neonicotinoid insecticides are a key factor causing the decline of global pollinator insects, such as bees. Flupyrimin (FLP) is a novel nicotinic insecticide with unique biological properties and no cross-resistance, and is safe for pollinators. Using FLP as the lead compound, a series of novel compounds were designed and synthesized by replacing the amide fragment with a sulfonamideone. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Bioassay results showed that compound 2j had good insecticidal activity against Aphis glycines with an LC50 value of 20.93 mg/L. Meanwhile, compound 2j showed significantly lower acute oral and contact toxicity to Apis mellifera. In addition, compound 2j interacted well with the protein in insect acetylcholine binding protein (AChBP). The molecular docking on honeybee nicotinic acetylcholine receptor (nAChR) indicated that the sulfonamide group of compound 2j did not form a hydrogen bond with Arg173 of the β subunit, which conforms to the reported low bee-toxicity conformation. In general, target compound 2j can be regarded as a bee-friendly insecticide candidate.

Summary: CD146 is an adhesion molecule that plays important roles in angiogenesis, cancer metastasis, and immune response. It exists as a monomer or dimer on the cell surface. AA98 is a monoclonal antibody that binds to CD146, which abrogates the activation of CD146-mediated signaling pathways and shows inhibitory effects on tumor growth. However, how AA98 inhibits the function of CD146 remains unclear. Here, we describe a crystal structure of the CD146/AA98 Fab complex at a resolution of 2.8 Å. Monomeric CD146 is stabilized by AA98 Fab binding to the junction region of CD146 domains 4 and 5. A higher-affinity AA98 variant (here named HA98) was thus rationally designed. Better binding to CD146 and prominent inhibition on cell migration were achieved with HA98. Further experiments on xenografted melanoma in mice with HA98 revealed superior inhibitory effects on tumor growth to those of AA98, which suggested future applications of this antibody in cancer therapy.

Abstract Obesity and its related complications pose an increasing threat to human health; however, targetable obesity‐related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin‐like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element‐binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin‐1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti‐CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity.

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) during androgen deprivation therapy (ADR) in early stages of prostate cancer. Thus, rather than blocking the androgen-related pathway further, docetaxel (DTX)-based therapy has become the most effective and standard first-line chemotherapy for CRPC. Although the therapy is successful in prolonging the survival of patients with CRPC, chemotherapy resistance develops due to the abnormal activation of the androgen receptor (AR) signaling pathway. Thus, to optimize DTX efficacy, continued maximum suppression of androgen levels and AR signaling is required. Here, we designed a prostate-specific membrane antigen (PSMA)-targeted nanosystem to carry both DTX and AR siRNA (Di-PP/AR-siRNA/DTX) for CRPC treatment. Specifically, DTX was encapsulated into the hydrophobic inner layer, and the AR siRNA was then condensed with the cationic PEI block in the hydrophilic outer layer of the PEI-PLGA polymeric micelles. The micelles were further coated with PSMA-targeted anionic polyethylene glycol-polyaspartic acid (Di-PEG-PLD). In vitro and in vivo results demonstrated that the resulting Di-PP/AR-siRNA/DTX exhibited prolonged blood circulation, selective targeting, and enhanced antitumor effects. Consequently, Di-PP/AR-siRNA/DTX holds great potential for efficient CRPC treatment by combining chemotherapy and siRNA silencing of androgen-related signaling pathways.

Introduction Cognitive impairment, an important complication in patients with chronic obstructive pulmonary disease (COPD), seriously affects self-management of the disease and quality of life (QoL). As an exercise-based intervention programme, pulmonary rehabilitation (PR)—especially aerobic exercise (mainly mind–body exercise) and resistance exercise (RE)—has been proposed for its potential effectiveness in improving cognitive function. However, there is still a lack of strong evidence for PR’s effectiveness. In this study, we expect to clarify the effects of pulmonary-based Qigong exercise and elastic band-based RE on cognitive function in patients with COPD and to fill in the relevant evidence blanks.Methods and analysis This study is a single-centre randomised controlled trial with assessor and data analyst blinding. We will recruit 108 participants with stable COPD starting on 23 December 2019, and randomly allocate them into the pulmonary-based Qigong exercise group, elastic band-based RE group, pulmonary-based Qigong exercise and elastic band-based RE combined group, or control group at a 1:1:1:1 ratio. Participants in intervention groups will perform 30 min of exercise two times per day, 5 days a week, for 12 weeks. The primary outcome will be the global cognitive function as assessed by the Montreal Cognitive Assessment and auditory event-related potential P300. Secondary outcomes will include the specific cognitive domains—attention, memory, executive function, verbal fluency and mental-processing speed; psychological functions and QoL. Exploratory outcomes will include grey matter volume and levels of inflammatory mediators. Outcomes will be measured before and after the interventions.Ethics and dissemination Ethics approval has been granted by the Ethics Committee of Yue-Yang Integrative Medicine Hospital, an affiliate of Shanghai University of Traditional Chinese Medicine, Shanghai, China (Grant No. 2019-141). Written informed consent will be obtained from each participant before any procedures are performed. The findings will be published in peer-reviewed journals and presented at academic conferences.Trial registration number ChiCTR1900026869; pre-results.

The University-Enterprise-Cooperation (UEC) has been adopted by many universities globally to effectively utilize the high-quality resources of the construction industry, to improve the general competence, problem-solving skills and innovation capability of graduates of an engineering discipline. There are a limited amount of papers published in international journals on UEC, compared to a significant volume of Chinese published literature. However, based on the best knowledge of the authors, no existing literature has conducted a quantitative statistical analysis on UEC research in Chinese and international journals. In order to fill this knowledge gap, 300 high-quality papers on UEC were derived through the Chinese CNKI database from 2010-2019. The general development trend of UEC research in the past 30 years was also mapped and analyzed. The most popular topics under the UEC theme and the most frequently adopted research methods within the UEC field were also identified. It was found that since the first UEC publication in 1990, the number of UEC publications experienced a steady increase during the last decade, aiding by strong promotion from the government and active practice within universities and from educators in China. Course development (52.94%) and practice resource development (24.89%) were two of the most popular research topics in the UEC field. The elaboration research method was adopted by more than half (55.94%) of UEC papers, followed by case study (21.25%). The findings of this study are valuable for researchers and practitioners globally, to better understand the development status of UEC research in China and embark on future research in this field.

Botrytis cinerea is a destructive plant pathogenic ascomycete that causes serious pre- and post-harvest losses worldwide. The novel sterol 14α-demethylase inhibitor (DMI) pyrisoxazole was recently registered for the control of tomato gray mold caused by B. cinerea in China. Baseline sensitivity of 110 B. cinerea isolates collected from nine provinces in China to pyrisoxazole was demonstrated, with a mean EC50 of 0.057 ± 0.029 μg/ml. Eleven stable mutants resistant to pyrisoxazole were generated via UV irradiation (RU-mutants) and spontaneous selection (RS-mutants) of conidia. The efficacy of pyrisoxazole against the resistant mutants was significantly lower than that of the sensitive isolates. Most of the pyrisoxazole- resistant mutants were less fit than the sensitive isolates, with reduced sporulation, conidia germination, sclerotium production, and pathogenicity, which was confirmed by the competitive ability test. Positive cross-resistance was only observed between pyrisoxazole and the DMIs tebuconazole and prochloraz, but not between pyrisoxazole and non-DMIs iprodione, procymidone, diethofencarb, fluazinam, pyrimethanil, or fludioxonil. A two-point mutation, at G476S and K104E in the RU-mutants, and a one point mutation, M231T, in the RS-mutants, were detected in the CYP51 protein of the resistant mutants. When exposed to pyrisoxazole, the induced expression level of CYP51 increased in the resistant isolates as compared to sensitive ones. Molecular docking suggested that G476S and M231T mutations both led to the loss of electrostatic interactions between CYP51 and pyrisoxazole, while no change was found with the K104E mutation. Thus, two point mutations on CYP51 protein combined with induced expression of its target gene appeared to mediate the pyrisoxazole resistance of B cinerea.

Micelle is mainly used for drug delivery and is prepared from amphiphilic block copolymers. It can be formed into an obvious core-shell structure that can incorporate liposoluble drugs. However, micelles are not suitable for the encapsulation of water-soluble drugs, and it is also difficult to maintain stability in the systemic circulation. To solve these problems, a type of polymer material, Fmoc-Lys-PEG and Fmoc-Lys-PEG-RGD, was designed and synthesized. These copolymers could self-assemble into micelles driven by π–π stacking and the hydrophobic interaction of 9-fluorenylmethoxycarbony (Fmoc) and, at the same time, form a framework for a hydrogen-bonding environment in the core. Mitomycin C (MMC), as a water-soluble drug, can be encapsulated into micelles by hydrogen-bonding interactions. The interaction force between MMC and the polymers was analyzed by molecular docking simulation and Fourier transform infrared (FTIR). It was concluded that the optimal binding conformation can be obtained, and that the main force between the MMC and polymers is hydrogen bonding. Different types of MMC nanoparticles (NPs) were prepared and the physicochemical properties of them were systematically evaluated. The pharmacodynamics of the MMC NPs in vitro and in vivo were also studied. The results show that MMC NPs had a high uptake efficiency, could promote cell apoptosis, and had a strong inhibitory effect on cell proliferation. More importantly, the as-prepared NPs could effectively induce tumor cell apoptosis and inhibit tumor growth and metastasis in vivo.

Abstract VEGF-C is essential for lymphangiogenesis during development and tumor progression. VEGFR-3 is the well-known cognate receptor of VEGF-C to regulate lymphatic migration and proliferation, but the receptor of VEGF-C in regulating lymphatic sprouting, the initiating step of lymphangiogenesis, still remains elusive. Here we use both in vitro and in vivo methods to demonstrate CD146 as a receptor of VEGF-C to regulate lymphangiogenesis, especially at the sprouting step. Mechanistically, CD146 selectively activates the downstream p38 kinase, upon VEGF-C stimulation, to regulate lymphatic sprouting. Moreover, CD146 can also activate ERK to mediate VEGF-C regulation of the subsequent proliferation and migration of lymphatic endothelial cells. In zebrafish embryos, knockdown or dysfunction of CD146 results in similar developmental defects in lymphatic sprouting, capillary network, parachordal lymphangioblast (PL), and thoracic duct (TD) similar to down-regulation of VEGF-C. Altogether, our data reveals a critical role of CD146 to mediate VEGF-C signaling pathway in lymphangiogenesis.

In last decade, there has been a concerted effort to reduce the potential threats of honeybees' population due to exposure to neonicotinoid pesticides. A new perspective was put forward to reduce the potential ecological toxicity of neonicotinoid dinotefuran to honeybee in terms of an enantiomeric level in the study. Toxicity of dinotefuran was enantioselective, and S-dinotefuran was 41.1- to 128.4-fold more toxic than R-dinotefuran to honeybee Apis mellifera (Apis mellifera Linnaeus), whereas R-dinotefuran exhibited comparative insecticidal activities (1.7–2.4 times) to typical sucking pests Aphis gossypii and Apolygus lucorum compared to racemic mixtures. Our data suggested that use of R-dinotefuran could have a good efficacy in controlling target pests while minimizing hazard to honeybees. The mechanism for chiral specific toxicity to honeybee was further characterized by electrophysiological studies and molecular docking. S-dinotefuran appears to be more toxic by binding to α8 subunit of nAChR of Apis mellifera. The α8 also have a more stable, functional binding cavity to S-dinotefuran with a higher binding score of 7.15, primarily due to an extensive hydrogen bond network. Therefore, new chiral products with a high proportion of or an enantiomeric pure R-dinotefuran are recommended to achieve effective pests control reducing hazard to honeybee populations. Keywords: Chiral neonicotinoid, Toxicity reduction, Dinotefuran enantiomers, Enantioselective toxicology, Honeybee

The cortisol awakening response (CAR), a rapid cortisol rise in the morning after awakening, has been proposed to provide energy to cope with daily demands and suggested to be associated with brain functions. Electroencephalogram (EEG) asymmetry studies have implicated asymmetric cortical activation, especially in frontal cortex, in approach-withdrawal motivation. In this study, we examined the relationship between the CAR and lateralized cortical activity under rest in 55 university male students. Saliva samples were collected at 0, 15, 30 and 60 min after awakening on the two consecutive workdays. The lateralized cortical activity at frontocentral sites was examined by alpha asymmetry score. The results showed that a higher CAR was positively associated with alpha asymmetry score, which indicated that the higher CAR is linked with more left-sided cortical activity at frontocentral sites under resting state. This association still existed even after controlling psychological and sleep quality variables. These results suggested that appropriately mobilizing energy resource storage after awakening revealed as CAR might be associated with goal-directed approach tendencies before any eventual stressful situation, characteristic of more left than right resting-state frontocentral cortical activity.

The genus Colletotrichum contains a wide variety of important plant pathogens, and Colletotrichum truncatum is one of the most prevalent species of Colletotrichum on chili in China. Demethylation-inhibitor fungicides (DMIs) are currently registered chemical agents for the management of the anthracnose disease caused by Colletotrichum spp. To assess the risk for DMI resistance development, 112 C. truncatum isolates were collected from infected pepper in 13 regions of China. The sensitivity of C. truncatum isolates to five DMI fungicides was determined based on mycelial growth inhibition assay. C. truncatum was sensitive to prochloraz, epoxiconazole, and difenoconazole, but not to tebuconazole or myclobutanil. Baseline sensitivity using the 112 C. truncatum isolates was established for the first three effective DMIs. Prochloraz, epoxiconazole, and difenoconazole EC50 values were 0.053 ± 0.023, 1.956 ± 0.815, and 1.027 ± 0.644 μg/ml, respectively. Eleven stable DMI-resistant mutants all exhibited lower fitness levels than their wild-type parents, suggesting a low risk of DMI resistance in C. truncatum. By inducing gene expression, CtCYP51 expression increased slightly in the resistant mutants as compared to wild-types when exposed to DMI fungicides and thus contributed at least partially to resistance. Molecular docking with CYP51 structure models was used to explain differential sensitivity of the DMI fungicides in C. truncatum. Our results suggest that the M376L/H373N mutations in CYP51 changed the conformation of DMIs in the binding pocket. These changes prevented the formation of the Fe – N coordinate bond between the heme iron active site and tebuconazole or myclobutanil, and apparently contributed to tebuconazole and myclobutanil insensitivity of C. truncatum.

The latest development in the dimensional structure of posttraumatic stress disorder (PTSD) is a novel 6-factor model, which builds on the newly released DSM-5. One notable gap in the literature is that little is known about how distinct symptom clusters of PTSD are related to hypothalamic-pituitary-adrenal (HPA) axis activity when people perform a relatively less stressful cognitive task. The purpose of this study was to investigate the relationship between cortisol activity when individuals perform cognitive tasks in the laboratory and a contemporary phenotypic model of posttraumatic stress symptomatology in earthquake survivors.Salivary cortisol while performing cognitive tasks was collected and analyzed in 89 adult earthquake survivors. The PTSD Checklist for the DSM-5 (PCL-5) was used to assess the severity of total PTSD as well as six distinct symptom clusters. Regression analyses were conducted to examine the associations between the six distinct PTSD symptom clusters and cortisol profiles.The results showed that the score of the negative affect symptom cluster, but not anhedonia or other clusters, was positively associated with cortisol levels before and during the cognitive tasks.The results showed that higher cortisol levels before and during cognitive tasks might be specifically linked to a distinct symptom cluster of PTSD-negative affect symptomatology. This suggests that a distinction should be made between negative affect and anhedonia symptom clusters, as the 6-factor model proposed.

In order to discover novel eco-friendly compounds with good activity for aphid control, (E)-β-farnesene (EβF), the main component of the aphid alarm pheromone, was chosen as the lead compound. By introducing a 2-nitroimino-hexahydro-1,3,5-triazine moiety (abbreviated NHT) to replace the unstable conjugated double bond system of EβF, a series of novel EβF analogues containing the NHT moiety were synthesized via the reaction of substituted NHT rings with (E)-1-chloro-3,7-dimethylocta-2,6-diene. All the compounds were characterized by 1H-NMR, 13C-NMR, IR, and high resolution mass spectroscopy (HRMS). The bioassay results showed that all the analogues displayed different repellent and aphicidal activities against green peach aphid (Myzus persicae). Particularly, the analogue 4r exhibited obvious repellent activity (repellent proportion: 78.43%) and similar aphicidal activity against M. persicae (mortality: 82.05%) as the commercial compound pymetrozine (80.07%). A preliminary structure-activity relationship (SAR) study was also performed, which offered valuable clues for the design of further new EβF analogues.

The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-A(b) fusion protein (MOG35-55/I-A(b) dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-A(b) dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-β (mTGF-β) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.