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Abstract Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

Abstract Translational control is crucial for protein production in various biological contexts. Here, we use Ribo-seq and RNA-seq to show that genes related to oxidative phosphorylation are translationally downregulated during heart regeneration. We find that Nat10 regulates the expression of Uqcr11 and Uqcrb mRNAs in mouse and human cardiomyocytes. In mice, overexpression of Nat10 in cardiomyocytes promotes cardiac regeneration and improves cardiac function after injury. Conversely, treating neonatal mice with Remodelin—a Nat10 pharmacological inhibitor—or genetically removing Nat10 from their cardiomyocytes both inhibit heart regeneration. Mechanistically, Nat10 suppresses the expression of Uqcr11 and Uqcrb independently of its ac4C enzyme activity. This suppression weakens mitochondrial respiration and enhances the glycolytic capacity of the cardiomyocytes, leading to metabolic reprogramming. We also observe that the expression of Nat10 is downregulated in the cardiomyocytes of P7 male pig hearts compared to P1 controls. The levels of Nat10 are also lower in female human failing hearts than non-failing hearts. We further identify the specific binding regions of Nat10, and validate the pro-proliferative effects of Nat10 in cardiomyocytes derived from human embryonic stem cells. Our findings indicate that Nat10 is an epigenetic regulator during heart regeneration and could potentially become a clinical target.

ObjectivesThis manuscript undertakes a systematic examination of the research landscape concerning global Cryptococcus species and their dynamism with the host immune system spanning the past decade. It furnishes a detailed survey of leading knowledge institutions and critical focal points in this area, utilizing bibliometric analysis.MethodsVOSviewer and CiteSpace software platforms were employed to systematically analyze and graphically depict the relevant literature indexed in the WoSCC database over the preceding ten years.ResultsIn the interval between October 1, 2013, and October 1, 2023, a corpus of 795 publications was amassed. The primary research institutions involved in this study include Duke University, the University of Minnesota, and the University of Sydney. The leading trio of nations, in terms of publication volume, comprises the United States, China, and Brazil. Among the most prolific authors are Casadevall, Arturo; Wormley, Floyd L., Jr.; and Olszewski, Michal A., with the most highly cited author being Perfect, Jr. The most esteemed journal is Mbio, while Infection and Immunity commands the highest citation frequency, and the Journal of Clinical Microbiology boasts the most significant impact factor. Present research foci encompass the intricate interactions between Cryptococcus pathogenesis and host immunity, alongside immune mechanisms, complications, and immunotherapies.ConclusionThis represents the first exhaustive scholarly review and bibliometric scrutiny of the evolving landscapes in Cryptococcus research and its interactions with the host immune system. The analyses delineated herein provide insights into prevailing research foci and trajectories, thus furnishing critical directions for subsequent inquiries in this domain.

Abstract Objective The objective of this study was to investigate the relationship between lipoprotein (a) (Lp(a)), triglyceride/high‐density lipoprotein cholesterol (TG/HDL‐C), and the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke. Methods A total of 142 patients with acute ischemic stroke were selected and divided into group A (59 cases of stable plaque formation) and group B (83 cases of unstable plaque formation) according to the characteristics of carotid artery plaque formation detected by carotid color Doppler ultrasound. The serum Lp(a), lipid metabolism indexes, peripheral blood routine indexes, and related serum inflammatory factors indexes were compared between the two groups. Receiver operating characteristic curve and multivariate logistic regression model were used to analyze the relationship between each index and the formation of carotid unstable plaque. Results There were no significant differences in serum total cholesterol (TC), HDL‐C, and low‐density lipoprotein cholesterol (LDL‐C) between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL‐C in group B were higher than those in group A, and the differences were statistically significant (p < .05). There were no significant differences in serum TC, HDL‐C, and LDL‐C between groups A and B (p > .05). The values of Lp(a), TG, and TG/HDL‐C in group B were higher than those in group A, and the differences were statistically significant (p < .05). The values of HBA1C, Lp‐PLA2, CRP, CysC, Hcy, TNF‐α, neutrophils, and NLR in group B were higher than those in group A, and the differences were statistically significant (p < .05). There was no significant difference in FPG, systolic blood pressure, diastolic blood pressure, Hb, white blood cells, platelets, and lymphocytes between groups A and B (p > .05). The results of logistic regression model showed that the increase of Lp(a), TG/HDL‐C, HBA1C, Lp‐PLA2, CRP, CysC, Hcy, and NLR could increase the risk of carotid artery unstable plaque in patients with ischemic stroke (p < .05). Conclusion Lp(a) and TG/HDL‐C have certain value in evaluating the stability of carotid atherosclerotic plaque in patients with acute ischemic stroke, and the increased levels of LP (a) and TG/HDL‐C will significantly increase the risk of carotid unstable plaque in patients.

Insulin secretion from pancreatic β cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that β-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced β-cell injury in aging. β-cell-specific-Ghsr-deficient (Ghsr-βKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected β-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-βKO mice were subjected to STZ. We found that middle-aged and old Ghsr-βKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that β-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced β-cell injury in aging.

Background: Coronary artery calcification (CAC), a surrogate of atherosclerosis, is related to stent underexpansion and adverse cardiac events. However, the effect of CAC on plaque stability is still controversial and the morphological significance of CAC has yet to be elucidated. Methods: A retrospective series of 419 patients with acute coronary syndrome (ACS) who underwent optical coherence tomography (OCT) were enrolled. Patients were classified into three groups based on the calcification size in culprit plaques and the features of the culprit and non-culprit plaques among these groups were compared. Logistic regression was used to analyze independent risk factors for culprit plaque rupture and the nonlinear relationship between calcification parameters and culprit plaque rupture. Furthermore, we compared the detailed calcification parameters of different kinds of plaques. Results: A total of 419 culprit plaques and 364 non-culprit plaques were identified. The incidence of calcification was 53.9 % in culprit plaques and 50.3 % in non-culprit plaques. Compared with culprit plaques without calcification, plaque rupture, macrophages and cholesterol crystals were more frequently observed in the spotty calcification group, and the lipid length was longer; the incidence of macrophages and cholesterol crystals was higher in the macrocalcification group. Calcification tended to be smaller in ruptured plaques than in non-ruptured plaques. Moreover, the arc and length of calcification were greater in culprit plaques than in non-culprit plaques. Conclusions: Vulnerable features were more frequently observed in culprit plaques with spotty calcification, whereas the presence of macrocalcification calcifications did not significantly increase plaque vulnerability. Calcification tends to be larger in culprit plaques than in non-culprit plaques.

Pigeon paramyxovirus 1 (PPMV-1) is an antigenic host variant of avian paramyxovirus 1. Sporadic outbreaks of PPMV-1 infection have occurred in pigeons in China; however, few cases of human PPMV-1 infection have been reported. The purpose of this article is to report a case of severe human PPMV-1 infection in an individual with probable post-COVID-19 syndrome (long COVID) who presented with rapidly progressing pulmonary infection. The patient was a 66-year-old man who was admitted to the intensive care unit 11 days after onset of pneumonia and recovered 64 days after onset. PPMV-1 was isolated from the patient’s sputum and in cloacal smear samples from domesticated pigeons belonging to the patient’s neighbour. Residual severe acute respiratory syndrome coronavirus 2 was detected in respiratory and anal swab samples from the patient. Sequencing analyses revealed that the PPMV-1 genome belonged to genotype VI.2.1.1.2.2 and had the 112RRQKRF117 motif in the cleavage site of the fusion protein, which is indicative of high virulence. This case of cross-species transmission of PPMV-1 from a pigeon to a human highlights the risk of severe PPMV-1 infection in immunocompromised patients, especially those with long COVID. Enhanced surveillance for increased risk of severe viral infection is warranted in this population.

In recent studies, the tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy. We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on the median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. CYBA and SMPD3 were significantly related to the prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC. In this study, a prognostic model constructed based on two redox-related genes (CYBA and SMPD3) were proved to be independent prognostic factors of EC and associated with tumour immune microenvironment. The redox signature genes have the potential to predict the prognosis and the immunotherapy efficacy of patients with EC.

Existing target detection models are large and have multiple network parameters, which can severely slow down the detection speed when deployed on small, low-cost GPU-free Industrial Personal Computers (IPC). As a result, this study proposes a lightweight real-time tomato detection and point-picking integrated network model based on YOLOv5 (TDPPL-Net). Firstly, the algorithm replaces the YOLOv5 backbone with a four-group lightweight downsampling model consisting of Ghost Conv and Ghost Bottleneck to reduce the model size, while adding the attention mechanism SimAM module to improve detection accuracy after each scale’s feature map. Secondly, the Spatial Pyramid Pooling-Fast (SPPF) network structure is used and the convolutional layers in the (Feature Pyramid Network and Path Aggregation Network) FPN+PAN structure are replaced with a depth-separable convolution to reduce the computational effort. Finally, the center of the bounding box is used as the picking point, and the corresponding depth information is obtained in combination with the Intel RealSense D435 camera, which is converted into 3D coordinates under the robot arm coordinate system after hand-eye calibration. The experimental results show that TDPPL-Net reduces the number of parameters by 59.84% compared with the original YOLOv5, the model volume is only 40% of the original, the mAP is 93.36, and the real-time detection speed on the IPC without GPU acceleration is 31.41 FPS, which is 170.31% higher than YOLOv5. The TDPPL-Net increases detection speed on low-performance equipment without compromising detection accuracy. It can detect and locate tomato picking points in real-time in the complex natural environment, which can meet the working requirements of harvesting robots.

To address the current problems of poor seed-filling performance and seed leakage of the pneumatic seed filler for cabbage, we designed a pneumatic disturbing precision seed filler for cabbage based on the auxiliary disturbing seed-filling method. This seeder can completely perturb the seed population entering the bottom of the seed box casing during the seed-filling process, thereby increasing the initial velocity of the cabbage seeds, and facilitating the smooth progress of the seed-filling process. Firstly, we carried out a theoretical analysis based on the particle dynamics of the seed-filling process of the seeder and obtained the influencing factors affecting the seed-filling performance of the seeder. Secondly, through EDEM discrete element simulation, the average speed of the seed population, the disturbance frequency, and the degree of disturbance were used as the indicators to select the seed discharge disk structure with the best seed-filling performance. In the experimental aspect, a four-factor three-level orthogonal standardized test was conducted to evaluate the seed filling performance of the planter, using the seed suction qualification rate and the seed leakage rate as the evaluation indexes. The optimal structure of the seed discharge tray was selected through polarity analysis and ANOVA. The optimal combination of parameters for the seed-filling process of the planter was obtained; linear serrated disk, 40 rpm disk rotation speed, −2500 Pa negative fan pressure, and 1.2 mm aperture diameter. After comparative validation tests, the seed suction qualification rate of the seed absorber was 95.32%, and the leakage rate was 3.11%, which was in line with the agronomic planting of Chinese cabbage seeds.

This article analyzes the problems existing in the domestic hydrogen peroxide production plant, and introduces slurry-bed production technology developed by SINOPEC from various aspects, including anthraquinone hydrogenation catalysts, slurry-bed hydrogenation reactor, high-throughput filtering, oxidation process intensification, efficient extraction, safe and environmentally friendly working solution regeneration technique. The operation of the pilot plant and industrial production plant shows that the technical indicators of the developed technology are significantly better than those of the traditional technology, with high intrinsic safety and easy to large-scale production. The slurry-bed production technology developed by SINOPEC greatly improves the level of hydrogen peroxide production technology in China and provides raw material guarantee for the development of downstream green chemical industry.

A series of novel derivatives of isaindigotone, which comes from the root of isaits indinatca Fort, were synthesised (Compound 1–26). Four human gastrointestinal cancer cells (HCT116, PANC-1, SMMC-7721, and AGS) were employed to evaluate the anti-proliferative activity. Among them, Compound 6 displayed the most effective inhibitory activity on AGS cells with an IC50 (50% inhibitory concentration) value of 2.2 μM. The potential mechanism study suggested that Compound 6 induced apoptosis in AGS cells. The collapse of mitochondrial membrane potential (MMP) in AGS cells was proved. In docking analysis, good affinity interaction between Compound 6 and AKT1 was discovered. Treatment of AGS cells with Compound 6 also resulted in significant suppression of PI3K/AKT/mTOR signal pathway. The collapse of MMP and suppression of PI3K/AKT/mTOR signal pathway may be responsible for induction of apoptosis. This derivative Compound 6 could be useful as an underlying anti-tumour agent for treatment of gastric cancer.

Uncovering the mechanism underlying the pathogenesis of Edwardsiella piscicida-induced enteritis is essential for global aquaculture. In the present study, we identified E. piscicida as a lethal pathogen of the big-belly seahorse (Hippocampus abdominalis) and revealed its pathogenic pattern and characteristics by updating our established bacterial enteritis model and evaluation system. Conjoint analysis of metagenomic and metabolomic data showed that 15 core virulence factors could mutually coordinate the remodeling of intestinal microorganisms and host metabolism and induce enteritis in the big-belly seahorse. Specifically, the Flagella, Type IV pili, and Lap could significantly increase the activities of the representative functional pathways of both flagella assembly and bacterial chemotaxis in the intestinal microbiota (P < 0.01) to promote pathogen motility, adherence, and invasion. Legiobactin, IraAB, and Hpt could increase ABC transporter activity (P < 0.01) to compete for host nutrition and promote self-replication. Capsule1, HP-NAP, and FarAB could help the pathogen to avoid phagocytosis. Upon entering epithelial cells and phagocytes, Bsa T3SS and Dot/Icm could significantly increase bacterial secretion system activity (P < 0.01) to promote the intracellular survival and replication of the pathogen and the subsequent invasion of the neighboring tissues. Finally, LPS3 could significantly increase lipopolysaccharide biosynthesis (P < 0.01) to release toxins and kill the host. Throughout the pathogenic process, BopD, PhoP, and BfmRS significantly activated the two-component system (P < 0.01) to coordinate with other VFs to promote deep invasion. In addition, the levels of seven key metabolic biomarkers, Taurine, L-Proline, Uridine, L-Glutamate, Glutathione, Xanthosine, and L-Malic acid, significantly decreased (P < 0.01), and they can be used for characterizing E. piscicida infection. Overall, the present study systematically revealed how a combination of virulence factors mediate E. piscicida-induced enteritis in fish for the first time, providing a theoretical reference for preventing and controlling this disease in the aquaculture of seahorses and other fishes.

Chemotherapy is commonly used clinically to treat colorectal cancer, but it is usually prone to drug resistance, so novel drugs need to be developed continuously to treat colorectal cancer. Neocryptolepine derivatives have attracted a lot of attention because of their good cytotoxic activity; however, cytotoxicity studies on colorectal cancer cells are scarce. In this study, the cytotoxicity of 8-methoxy-2,5-dimethyl-5H-indolo[2,3-b] quinoline (MMNC) in colorectal cells was evaluated. The results showed that MMNC inhibits the proliferation of HCT116 and Caco-2 cells, blocks the cell cycle in the G2/M phase, decreases the cell mitochondrial membrane potential and induces apoptosis. In addition, the results of western blot experiments suggest that MMNC exerts cytotoxicity by inhibiting the expression of PI3K/AKT/mTOR signaling pathway-related proteins. Based on these results, MMNC is a promising lead compound for anticancer activity in the treatment of human colorectal cancer.

Diet conversion is a key stage of seahorse aquaculture. Herein, we set up five groups to evaluate the probiotic effects of Enterococcus faecium supplementation on the growth, development, intestinal health, and immunity of big-belly seahorses (Hippocampus abdominalis) during this stage, including control (C) (no E. faecium), H2 (1 ×107 CFU mL−1, every 2 d), H4 (1 ×107 CFU mL−1, every 4 d), L2 (1 ×105 CFU mL−1, every 2 d), and L4 (1 × 105 CFU mL−1, every 4 d) groups. After 48 d culture, concentration and frequency of E. faecium supplementation, as well as their interaction, were confirmed to have significant effects on growth performance of seahorses (P < 0.05). Body weight, specific growth rate, body weight increase, standard length and standard length increase of H4 and L4 groups were significantly higher (P < 0.05); Ovary weight but not testis weight and brood pouch length significantly increased in H4 group (P

Background: Cervical cancer (CC), the fourth most common cancer among women worldwide, has high morbidity and mortality. Necroptosis is a newly discovered form of cell death that plays an important role in cancer development, progression, and metastasis. However, the expression of necroptosis-related genes (NRGs) in CC and their relationship with CC prognosis remain unclear. Therefore, we screened the signature NRGs in CC and constructed a risk prognostic model.Methods: We downloaded gene data and clinical information of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) from The Cancer Genome Atlas (TCGA) database. We performed functional enrichment analysis on the differentially expressed NRGs (DENRGs). We constructed prognostic models and evaluated them by Cox and LASSO regressions for DENRGs, and validated them using the International Cancer Genome Consortium (ICGC) dataset. We used the obtained risk score to classify patients into high- and low-risk groups. We employed the ESTIMATE and single sample gene set enrichment analysis (ssGSEA) algorithms to explore the relationship between the risk score and the clinical phenotype and the tumor immune microenvironment.Results: With LASSO regression, we established a prognostic model of CC including 16 signature DENRGs (TMP3, CHMP4C, EEF1A1, FASN, TNF, S100A10, IL1A, H1.2, SLC25A5, GLTP, IFNG, H2AC13, TUBB4B, AKNA, TYK2, and H1.5). The risk score was associated with poor prognosis in CC. Survival was lower in the high-risk group than the low-risk group. The nomogram based on the risk score, T stage, and N stage showed good prognostic predictive power. We found significant differences in immune scores, immune infiltration analysis, and immune checkpoints between the high- and low-risk groups (p < 0.05).Conclusion: We screened for DENRGs based on the TCGA database by using bioinformatics methods, and constructed prognostic models based on the signature DENRGs, which we confirmed as possibly having important biological functions in CC. Our study provides a new perspective on CC prognosis and immunity, and offers a series of new targets for future treatment.

Swainsonine-containing plants contain swainsonine which has been shown to cause neurological signs and pathological changes in farm animals. It causes a large number of livestock poisonings every year resulting in economic losses to the livestock industry. At present, “Jifang E” is used in the prevention of swainsonine-containing plants poisoning livestock, and the preventive effects have been well-documented. However, “Jifang E” is typically administered in drinking water, making it difficult to control the administered dosage, because of feeding difficulties and it may cause certain side effects that are unique to the water-dissolved powder. To overcome these difficulties, we developed a temperature-sensitive gel for injection and the optimal ratio of each formula of sustained-release injection is P407 (24%), P188 (6%), Vitamin C (1%), PEG4000 (0.5%), and “Jifang E” (10%). Our results suggest that novel formulation makes the micellar system more stable and the particles are uniformly dispersed. Colloidal morphological studies showed that each group formed a homogeneous pore structure after gelling, and the structure became more dense with the addition of “Jifang E”. The rheological study shows that “Jifang E” is a pseudoplastic fluid, and the addition of “Jifang E” reduces the viscosity of the formula, which is beneficial to the injection. In vitro and in vivo release rate studies have shown that the effective concentration of “Jifang E” can be maintained for 3 to 5 days. The acute toxicity test in SPF Kunming mice showed that its LD50 was 828.323 mg/kg, with confidence limits of 676.706–1013.911 mg/kg, which is a safe dosage (LD50 > 200 mg/kg). There were no observed reactions of muscle irritation or subcutaneous tissue irritation with the dosage used for New Zealand rabbits. In summary, we successfully developed the sustained-release injection formulation of “Jifang E” for the prevention of swainsonine-containing plants poisoning livestock, which provides the basis for subsequent field extension trials and the further study of its detoxification mechanism.

Abstract The aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil-to-lymphocyte*platelet ratio (NLRP) are novel indices that simultaneously reflect the inflammatory and immune status. However, the role of these indices in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) remains unclear. We aimed to elucidate the predictive value of AISI, SIRI, and NLRP in patients with ACS undergoing PCI. A total of 1558 patients with ACS undergoing PCI were consecutively enrolled from January 2016 to December 2018. The AISI, SIRI, NLRP, systemic immune-inflammatory index, derived neutrophil-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio cutoff values for predicting major adverse cardiovascular events (MACE) were calculated using receiver-operating characteristic curves, and Spearman's test was used to analyze correlations between these indices. Kaplan–Meier curves and Cox regression models were used for survival analyses, and the endpoint was a MACE, which included all-cause mortality and rehospitalization for severe heart failure during the follow-up period. The Kaplan–Meier curves showed that higher AISI, SIRI, and NLRP values were associated with a higher risk of MACE (all P .05). Increasing tertiles of AISI, SIRI, and NLRP significantly increased the MACE risk ( P for trend < .05). AISI, SIRI, and NLRP may be suitable laboratory markers for identifying high-risk patients with ACS after PCI.

Background and aims Novel pro- and anti-inflammatory adipocytokines affect inflammation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. We evaluated the diagnostic and risk predictive value of such adipocytokines for ACS. Methods We enrolled 168 consecutive inpatients with suspected ACS and detected serum PLIN1, PLIN2, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, FAM19A5, TNF-α, and adiponectin levels. Multivariate logistic regression analysis and Spearman's test were used to assess risk factors for ACS and correlations between serum adipocytokines and continuous variables, respectively. Results Serum levels of the adipocytokines differed between ACS and Non-ACS groups ( p

BackgroundThe C1q/TNF-related protein (CTRP) family affects inflammation regulation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. In this cross-sectional study, we aimed to investigate the association between CTRP family and ACS.MethodsWe enrolled 289 consecutive inpatients with suspected ACS. Serum CTRP family, tumor necrosis factor-α (TNF-α), and adiponectin (ADP) levels were assessed using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and subgroup analyses were used to assess risk factors for ACS. Spearman's tests were used to analyze correlations between CTRP family and continuous variables.ResultsSerum CTRP family levels differed significantly between ACS and Control groups (p < 0.05). After adjusting for confounding factors, CTRP family were independently associated with ACS (p < 0.05). The association between serum CTRP family levels and ACS was stable in various subgroups according to sex, age, diabetes mellitus, and dyslipidemia status (p for interaction > 0.05). Increasing tertiles of serum CTRP1 levels, significantly increased ACS risks, which decreased gradually with increasing CTRP2, CTRP12, and CTRP13 tertiles (p for trend < 0.05). Additionally, serum CTRP1, CTRP2, CTRP13, and CTRP15 levels were weakly correlated with the severity of coronary artery stenosis.ConclusionCTRP1 and CTRP5 were identified as independent ACS risk factors, whereas CTRP2, CTRP3, CTRP9, CTRP12, CTRP13, and CTRP15 were independent protective factors for ACS. CTRP family, especially CTRP1 and CTRP3 could be novel potential clinical biomarkers of ACS.

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly reduced ROS level in macrophages and other cell types and increased glutathione/oxidized glutathione (GSH/GSSG) ratio in macrophages, suggesting an increased antioxidant capacity. We showed a mechanism for MALAT1 ablation leading to enhanced antioxidant capacity is through activation of methionine cycle by epitranscriptomical regulation of methionine adenosyltransferase 2A (MAT2A). MAT2A 3′UTR can be methylated by METTL16 which was known to directly bind to MALAT1. MALAT1 ablation was found to reduce methylation in MAT2A hairpin1 and increase MAT2A protein levels. Our results suggest a MALAT1-METTL16-MAT2A interactive axis which may be targeted for treatments of sepsis.

Using a 2009–2019 sample of Chinese bond issuers, we examine the effect of carbon risk on bond financing costs. Relative to low carbon risk issuers, high carbon risk issuers have substantially larger bond credit spreads, mainly because their credit risk is greater and they invest the funds in non-green projects. This positive relationship is more pronounced for issuers with financing constraints, those not making a green transition and those in cities with stringent environmental regulations. We find a reversed effect during the COVID-19 pandemic. However, China’s carbon peak and carbon neutral goals have renewed the focus on carbon risk. Carbon risk also causes bond issuers to scale back production and negatively affects their likelihood of receiving long-term financial support. Our findings suggest that investors consider carbon risk and charge a corresponding risk premium.

Artificial intelligence can train the related known drug data into deep learning models for drug design, while classical algorithms can design drugs through established and predefined procedures. Both deep learning and classical algorithms have their merits for drug design. Here, the webserver WADDAICA is built to employ the advantage of deep learning model and classical algorithms for drug design. The WADDAICA mainly contains two modules. In the first module, WADDAICA provides deep learning models for scaffold hopping of compounds to modify or design new novel drugs. The deep learning model which is used in WADDAICA shows a good scoring power based on the PDBbind database. In the second module, WADDAICA supplies functions for modifying or designing new novel drugs by classical algorithms. WADDAICA shows better Pearson and Spearman correlations of binding affinity than Autodock Vina that is considered to have the best scoring power. Besides, WADDAICA supplies a friendly and convenient web interface for users to submit drug design jobs. We believe that WADDAICA is a useful and effective tool to help researchers to modify or design novel drugs by deep learning models and classical algorithms. WADDAICA is free and accessible at https://bqflab.github.io or https://heisenberg.ucam.edu:5000.

A stable and reliable cloud detection algorithm is an important step of optical satellite data preprocessing. Existing threshold methods are mostly based on classifying spectral features of isolated individual pixels and do not contain or incorporate the spatial information. This often leads to misclassifications of bright surfaces, such as human-made structures or snow/ice. Multi-temporal methods can alleviate this problem, but cloud-free images of the scene are difficult to obtain. To deal with this issue, we extended four deep-learning Convolutional Neural Network (CNN) models to improve the global cloud detection accuracy for Landsat imagery. The inputs are simplified as all discrete spectral channels from visible to short wave infrared wavelengths through radiometric calibration, and the United States Geological Survey (USGS) global Landsat 8 Biome cloud-cover assessment dataset is randomly divided for model training and validation independently. Experiments demonstrate that the cloud mask of the extended U-net model (i.e., UNmask) yields the best performance among all the models in estimating the cloud amounts (cloud amount difference, CAD = −0.35%) and capturing the cloud distributions (overall accuracy = 94.9%) for Landsat 8 imagery compared with the real validation masks; in particular, it runs fast and only takes about 41 ± 5.5 s for each scene. Our model can also actually detect broken and thin clouds over both dark and bright surfaces (e.g., urban and barren). Last, the UNmask model trained for Landsat 8 imagery is successfully applied in cloud detections for the Sentinel-2 imagery (overall accuracy = 90.1%) via transfer learning. These prove the great potential of our model in future applications such as remote sensing satellite data preprocessing.

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4+ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4+ and CD8+ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

Objective. Inflammatory cascades and hematomas after intracerebral hemorrhage (ICH) cause brain tissue and neuronal damage. Interleukin-12 (IL-12) promotes brain inflammation, and regulates coagulation mediated by red blood cells and platelets. This study was designed to investigate the relationship of serum IL-12 to inflammation, hematoma volume, and prognosis in ICH patients. Methods. We recruited patients with ICH within 12 hours of symptom onset (n = 209) and measured their serum IL-12 levels. Patients with an increased National Institute of Health stroke scale (NIHSS) score ≥4 were defined as early neurological deterioration, and modified rankin scale (mRS) score >2 at 3 months after intracerebral hemorrhage was defined as poor prognosis. Results. Levels of serum IL-12 was positively correlated with the admission of NIHSS scores (r = 0.535, P

Abstract Background Interleukin-8 (IL-8) plays a vital role in the invasion and metastasis of hepatocellular carcinoma (HCC), and is closely associated with poor prognosis of HCC patients. Integrin αvβ3, a member of the integrin family, has been reported to be overexpressed in cancer tissues and mediate the invasion and metastasis of HCC cells. However, the relationship between IL-8 and integrin αvβ3 in HCC and the underlying mechanism of IL-8 and integrin αvβ3 in the invasion of HCC remains unclear. Methods The expression of IL-8, integrin αv and integrin β3 in HCC cells and tissues was detected by quantitative real-time PCR, Western blot and immunohistochemistry. Transwell assay and Western blot was used to detect the invasiveness, the expression of integrin β3 and the activation of PI3K/Akt pathway of HCC cells pretreated with IL-8 knockdown or exogenous IL-8. Results IL-8, integrin αv and integrin β3 were overexpressed in highly metastatic HCC cell lines compared with low metastatic cell lines. There was a positive correlation between integrin β3 and IL-8 expression in HCC tissues. IL-8 siRNA transfection reduced HCC cell invasion and the levels of integrin β3, p-PI3K and p-Akt. IL-8 induced HCC cell invasion and integrin β3 expression was significantly inhibited by transfection with CXCR1 siRNA or CXCR2 siRNA. When we stimulated HCC cells with exogenous IL-8, cell invasion and the levels of integrin β3, p-PI3K, and p-Akt increased, which could be effectively reversed by adding PI3K inhibitor LY294002. Conclusions Our results suggest that IL-8 promotes integrin β3 upregulation and the invasion of HCC cells through activation of the PI3K/Akt pathway. The IL-8/CXCR1/CXCR2/PI3K/Akt/integrin β3 axis may serve as a potential treatment target for patients with HCC.

Forests are the most important part of terrestrial ecosystems. In the context of China’s industrialization and urbanization, mining activities have caused huge damage to the forest ecology. In the Ulan Mulun River Basin (Ordos, China), afforestation is standard method for reclamation of coal mine degraded land. In order to understand, manage and utilize forests, it is necessary to collect local mining area’s tree information. This paper proposed an improved Faster R-CNN model to identify individual trees. There were three major improved parts in this model. First, the model applied supervised multi-policy data augmentation (DA) to address the unmanned aerial vehicle (UAV) sample label size imbalance phenomenon. Second, we proposed Dense Enhance Feature Pyramid Network (DE-FPN) to improve the detection accuracy of small sample. Third, we modified the state-of-the-art Alpha Intersection over Union (Alpha-IoU) loss function. In the regression stage, this part effectively improved the bounding box accuracy. Compared with the original model, the improved model had the faster effect and higher accuracy. The result shows that the data augmentation strategy increased AP by 1.26%, DE-FPN increased AP by 2.82%, and the improved Alpha-IoU increased AP by 2.60%. Compared with popular target detection algorithms, our improved Faster R-CNN algorithm had the highest accuracy for tree detection in mining areas. AP was 89.89%. It also had a good generalization, and it can accurately identify trees in a complex background. Our algorithm detected correct trees accounted for 91.61%. In the surrounding area of coal mines, the higher the stand density is, the smaller the remote sensing index value is. Remote sensing indices included Green Leaf Index (GLI), Red Green Blue Vegetation Index (RGBVI), Visible Atmospheric Resistance Index (VARI), and Normalized Green Red Difference Index (NGRDI). In the drone zone, the western area of Bulianta Coal Mine (Area A) had the highest stand density, which was 203.95 trees ha−1. GLI mean value was 0.09, RGBVI mean value was 0.17, VARI mean value was 0.04, and NGRDI mean value was 0.04. The southern area of Bulianta Coal Mine (Area D) was 105.09 trees ha−1 of stand density. Four remote sensing indices were all the highest. GLI mean value was 0.15, RGBVI mean value was 0.43, VARI mean value was 0.12, and NGRDI mean value was 0.09. This study provided a sustainable development theoretical guidance for the Ulan Mulun River Basin. It is crucial information for local ecological environment and economic development.

Paclitaxel (PTX) is one of the most efficient drugs for late-stage non-small cell lung cancer (NSCLC) patients. However, most patients gradually develop resistance to PTX with long-term treatments. The identification of new strategies to reverse PTX resistance in NSCLC is crucially important for the treatment. PTX is an agonist for the pregnane X receptor (PXR) which regulates PTX metabolism. Antagonizing PXR, therefore, may render the NSCLC more sensitive to the PTX treatment. In this study, we investigated the PXR antagonist SPA70 and its role in PTX treatment of NSCLC. In vitro, SPA70 and PTX synergistically inhibited cell growth, migration and invasion in both paclitaxel-sensitive and paclitaxel-resistant A549 and H460 lung cancer cells. Mechanistically, we found PTX and SPA70 cotreatment disassociated PXR from ABCB1 (MDR1, P-gp) promoter, thus inhibiting P-gp expression. Furthermore, the combination regimen synergistically enhanced the interaction between PXR and Tip60, which abrogated Tip60-mediated α-tubulin acetylation, leading to mitosis defect, S-phase arrest and necroptosis/apoptosis. Combination of PXT and SPA70 dramatically inhibited tumor growth in a paclitaxel-resistant A549/TR xenograft tumor model. Taken together, we showed that SPA70 reduced the paclitaxel resistance of NSCLC. The combination regimen of PTX and SPA70 could be potential novel candidates for the treatment of taxane-resistant lung cancer.

Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from Cryptolepis sanguinolent. The cytotoxicity of neocryptolepine to gastric cancer cells AGS, MKN45, HGC27, and SGC7901 was not very strong, and it also had certain toxicity to gastric mucosa cells GES-1. Therefore, a series of neocryptolepine derivatives were synthesized by the modification of the structure of neocryptolepine, and their cytotoxicity was evaluated. The results showed that compounds C5 and C8 exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds C5 and C8 could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds C5 and C8 did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound C5 had no significant effect on AGS and HGC27 cell cycles at low concentration. After treatment with AGS cells for 24 h at high concentration, compound C5 could significantly arrest the AGS cell cycle in the G2/M phase. Compound C8 had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds C5 and C8 might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds C5 and C8 may be promising lead compounds for the treatment of gastric cancer.

Isaindigotone is an alkaloid containing a pyrrolo-[2,1-b]quinazoline moiety conjugated with a benzylidene group and isolated from the root of Isatis indigotca Fort. However, further anticancer activities of this alkaloid and its derivatives have not been fully explored. In this work, a novel isaindigotone derivative was synthesized and three different gastric cell lines and one human epithelial gastric cell line were used to study the anti-proliferation effects of the novel isaindigotone derivative BLG26. HGC27 cells and AGS cells were used to further explore the potential mechanisms. BLG26 exhibited better anti-proliferation activities in AGS cells with a half-maximal inhibitory concentration (IC50) of 1.45 μM. BLG26 caused mitochondrial membrane potential loss and induced apoptosis in both HGC27 cells and AGS cells by suppressing mitochondrial apoptotic pathway and PI3K/AKT/mTOR axis. Acute toxicity experiment showed that LD50 (median lethal dose) of BLG26 was above 1000.0 mg/kg. This research suggested that BLG26 can be a potential candidate for the treatment of gastric cancer.

Objective This study aimed to investigate the predictive value of inflammatory cells in peripheral blood on the prognosis of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Methods Patients (n=1558) were consecutively enrolled and the median follow-up was 1142 days. Patients were divided into the major adverse cardiac events (MACE) 1 group (n=63) (all-cause mortality [n=58] and rehospitalization for severe heart failure [n=5], no MACE1 group (n=1495), MACE2 group (n=38) (cardiac mortality [n=33] and rehospitalization for severe heart failure [n=5]), and no MACE2 group (n=1520). The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) were analyzed. Results The NLR, MLR, and PLR were higher in the MACE groups than in the no MACE groups. Different subsets of inflammatory cells had similar diagnostic values for MACE. Kaplan–Meier curves showed that the survival time gradually decreased with an increase in the degree of risk as determined by the NLR, MLR, and PLR. The risk of MACE was highest in the extremely high-risk group. Conclusion Peripheral blood inflammatory cell subsets can predict MACE in patients with ACS undergoing PCI. These cell subsets could be important laboratory markers for the prognosis and clinical treatment of these patients.

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor (Pgr) promoter. Our results showed reduced tumor burden in Ptend/d; Ezh2d/d mice compared with that of Ptend/d mice during early carcinogenesis. The decreased Ki67 index in EZH2 and PTEN-depleted uteri versus that in PTEN-depleted uteri indicated an oncogenic role of EZH2 during early tumor development. However, mice harboring uterine deletion of both Ezh2 and Pten developed unfavorable disease outcome, accompanied by exacerbated epithelial stratification and heightened inflammatory response. The observed effect was non-cell autonomous and mediated by altered immune response evidenced by massive accumulation of intraluminal neutrophils, a hallmark of endometrial carcinoma in Ptend/d; Ezh2d/d mice during disease progression. Hence, these results reveal dual roles of EZH2 in endometrial cancer development.

In this study, we analyzed the role of mammalian STE20-like protein kinase 2 (Mst2), a serine-threonine protein kinase, in Lipopolysaccharides (LPS)-mediated inflammation and apoptosis in the H9C2 cardiomyocytes. Mst2 mRNA and protein levels were significantly upregulated in the LPS-treated H9C2 cardiomyocytes. LPS treatment induced expression of IL-2, IL-8, and MMP9 mRNA and proteins in the H9C2 cardiomyocytes, and this was accompanied by increased caspase-3/9 mediating H9C2 cardiomyocyte apoptosis. LPS treatment also increased mitochondrial reactive oxygen species (ROS) and the levels of antioxidant enzymes, such as GSH, SOD, and GPX, in the H9C2 cardiomyocytes. The LPS-treated H9C2 cardiomyocytes showed lower cellular ATP levels and mitochondrial state-3/4 respiration but increased mitochondrial fragmentation, including upregulation of the mitochondrial fission genes Drp1, Mff, and Fis1. LPS-induced inflammation, mitochondrial ROS, mitochondrial fission, and apoptosis were all significantly suppressed by pre-treating the H9C2 cardiomyocytes with the Mst2 inhibitor, XMU-MP1. However, the beneficial effects of Mst2 inhibition by XMU-MP1 were abolished by carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), a potent activator of mitochondrial fission. These findings demonstrate that Mst2 mediates LPS-induced cardiomyocyte inflammation and apoptosis by increasing mitochondrial fission.

The kisspeptin system is a central modulator of the hypothalamic-pituitary-gonadal axis in vertebrates. Its existence outside the vertebrate lineage remains largely unknown. Here, we report the identification and characterization of the kisspeptin system in the sea cucumber Apostichopus japonicus. The gene encoding the kisspeptin precursor generates two mature neuropeptides, AjKiss1a and AjKiss1b. The receptors for these neuropeptides, AjKissR1 and AjKissR2, are strongly activated by synthetic A. japonicus and vertebrate kisspeptins, triggering a rapid intracellular mobilization of Ca2+, followed by receptor internalization. AjKissR1 and AjKissR2 share similar intracellular signaling pathways via Gαq/PLC/PKC/MAPK cascade, when activated by C-terminal decapeptide. The A. japonicus kisspeptin system functions in multiple tissues that are closely related to seasonal reproduction and metabolism. Overall, our findings uncover for the first time the existence and function of the kisspeptin system in a non-chordate species and provide new evidence to support the ancient origin of intracellular signaling and physiological functions that are mediated by this molecular system.

Procyanidins B2 (PB2) was found to block T-2 toxin-induced reproductive toxicity and may be used as a dietary preventive agent. We investigated the mechanism of PB2 in blocking the T-2 toxin-induced apoptosis in Leydig cells in conjunction with analysis of T-2 toxin induced proapoptotic responses in Leydig cells including induction of oxidative stresses. The stress inducible proteins ASK, p38 and JNK were increased in response to T-2 toxin and the induction was attenuated by PB2. Furthermore, we showed that T-2 toxin suppressed mitochondrial membrane potential, reduced the levels of the mitochondrial respiratory chain complex I-V, adversely affected the level of mitochondrial proteins CypD, Bax, Bak, Bcl-2, Bcl-xl, Bax/Bcl-2 and cyt c and these adverse effects were counteracted by PB2 in dose-dependent manner. In summary, our results showed great potential of PB2 in preventing T-2 toxin-induced toxicity in Leydig cells through its potent antioxidant property.

Accurate channel information is usually required in under-ice acoustic (UIA) communication, which exhibits a sparse characteristic. A type of norm-constrained least mean square (LMS) algorithm performs well in estimating the real-valued (passband) channels but cannot be directly applied to complex-valued (baseband) channels. This paper generalizes norm-constrained complex LMS. Complex-valued zero-attracting LMS and l0-norm LMS (C l0-LMS) are mentioned first. These two algorithms render a fixed penalty to each coefficient, which may deteriorate the performance. Then, we propose a complex-valued adaption penalized LMS (CAP-LMS) to further utilize the sparsity of the UIA channels. The adaption penalty is achieved by dividingp-norm-like constraints into two separate groups according to the l1norm of each coefficient. For the dominant coefficients in the large group, the norm constraint disappears to reduce the estimation bias. For the small coefficients, the adaption penalty aims to accelerate the convergence speed. Simulation results are presented to demonstrate the superior performance of the CAP-LMS algorithm. Data processing results from two under-ice experiments show the feasibility and validity of the proposed algorithms in practical UIA applications.

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

Nitrogen (N) is an important element for plant growth, and a suitable N supply is crucial to ensure optimal yields from fruit trees. Frequently, application of N fertilizers to fruit trees is often excessive, which not only leads to environmental pollution, but also reduces the output from fruit trees through N toxicity. To evaluate the effects of different concentrations of nitrate on plant growth, root-morphological traits, and other nutritional element’s responses in pear, pear seedlings (Pyrus betulifolia Bunge) were treated with five levels of N. Both N-deficiency and an excess of N inhibited the growth and development of pear rootstocks. However, different visible symptoms were observed among treated leaves and roots. Leaf yellowing, the stimulation of root elongation, a decrease in nitrate reductase activity and chlorophyll content were observed under N-deficiency conditions. On the other hand, dark green leaves accompanied by coking, the suppression of root elongation, and a decrease in nitrate reductase activity and chlorophyll content were displayed under regimes of excess N. In addition, not only the N content, but also the content of other mineral nutrients was influenced by nitrate treatments. Taken together, these results suggested that a careful choice of N fertilizer supply is crucial to ensure normal growth and development in pear trees.

Several studies have revealed that MFG-E8 (milk fat globule–epidermal growth factor 8) is related to tumour development and progression. However, the relationship between MFG-E8 expression and metastasis in colorectal cancer patients and the role of MFG-E8 in colorectal cancer invasion and progression remain unknown. In this study, we performed immunohistochemistry and quantitative real-time polymerase chain reaction to assess MFG-E8 expression in colorectal cancer and adjacent non-cancerous tissues. Colorectal cancer RNAseq data from The Cancer Genome Atlas project were downloaded and MFG-E8 expression was analysed. Gene set enrichment analysis was performed for gene ontology and pathway analysis associated with MFG-E8 expression. For in vitro studies, we used lentivirus-mediated MFG-E8 RNA interference and commercialized recombinant human MFG-E8 to investigate its role in colorectal cancer cell growth, migration and invasion. It seems that MFG-E8 was overexpressed in advanced colorectal cancer tissues compared with early-stage colorectal cancer tissues and adjacent non-cancerous tissues. Correlation analysis revealed that MFG-E8 expression was significantly related to plasma membrane invasion, lymph node metastasis, distant metastasis and tumour–node–metastasis stage. Survival analysis revealed that high MFG-E8 expression predicted a poorer prognosis than low MFG-E8 expression group both in our colorectal cancer cohort and The Cancer Genome Atlas colorectal cancer cohort. In vitro study suggested that MFG-E8 knockdown can suppress the growth of colorectal cancer cells without affecting the expression of the proliferation-related gene Ki67. MFG-E8 knockdown also suppressed colorectal cancer cell migration and invasion, a change accompanied by MMP-2 and MMP-9 downregulation. Moreover, MFG-E8 knockdown induced a shift from mesenchymal makers to epithelial makers, while pretreatment with rhMFG-E8 had the opposite effect. The effect of MFG-E8 on colorectal cancer cell migration, invasion and epithelial-to-mesenchymal was partially dependent on the PI3K/AKT signalling pathway. These findings provide a better understanding of the molecular mechanism underlying colorectal cancer progression and suggest a predictive role for MFG-E8 in colorectal cancer metastasis and prognosis.

T-2 toxin is a mycotoxin generated by Fusarium species which has been shown to be highly toxic to human and animals. T-2 toxin induces apoptosis in various tissues/organs. Apoptosis and autophagy are two closely interconnected processes, which are important for maintaining physiological homeostasis as well as pathogenesis. Here, for the first time, we demonstrated that T-2 toxins induce autophagy in human liver cells (L02). We demonstrated that T-2 toxin induce acidic vesicular organelles formation, concomitant with the alterations in p62/SQSTM1 and LC3-phosphatidylethanolamine conjugate (LC3-II) and the enhancement of the autophagic flux. Using mRFP-GFP-LC3 by lentiviral transduction, we showed T-2 toxin-mediated lysosomal fusion and the formation of autophagosomes in L02 cells. The formation of autophagosomes was further confirmed by transmission electron microcopy. While T-2 toxin induced both autophagy and apoptosis, autophagy appears to be a leading event in the response to T-2 toxin treatment, reflecting its protective role in cells against cellular damage. Activating autophagy by rapamycin (RAPA) inhibited apoptosis, while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis, suggesting the crosstalk between autophagy and apoptosis. Taken together, these results indicate that autophagy plays a role in protecting cells from T-2 toxin-induced apoptosis suggesting that autophagy may be manipulated for the alleviation of toxic responses induced by T-2 toxin.