Search

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell–cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a ‘seed’ receptor in these tumour cells and a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients’ clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal ‘soil’ receptor of tumour seeding but also a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases.

Abstract Background We aimed to estimate the stage-specific impact of lymph node dissection (LND) on survival for upper urinary tract urothelial carcinoma (UTUC) patients treated with nephroureterectomy (NU). Methods Overall, 7278 UTUC patients undergoing NU within the SEER database from 2004 to 2015 were identified. Kaplan-Meier plots illustrated overall survival (OS) and cancer-specific survival (CSS) rates according to LND status. Multivariable Cox regression analyses assessed the effect of LND on OS and CSS rates stratified by pathological tumor stage. Results LND was performed in 26.9% of patients, and in 18.6, 23.3, 31.2 and 45.9% for pT1, pT2, pT3 and pT4 patients, respectively (P 0.05). LND with 1 to 3 regional lymph nodes removed was prone to a higher OS or CSS only in pT4 compared to no LND (both P

Background: Abnormal lipid accumulation in macrophages may lead to macrophages foaming, which is the most important pathological process of atherosclerosis. Atmospheric PM2.5 could enter the blood circulation and further affect the lipid metabolism of macrophages. But the underlying mechanism is not unclear. This study was undertaken to clarify the effect of PM2.5 on lipid metabolism in macrophages, and to explore the role of inflammatory reaction and JAK2/STAT3 signaling pathway in this process. Method: Macrophages derived from THP-1 cells were exposed to PM2.5 (0,100,200,400 μg/mL) for 6 h and 12 h. STAT3 agonist ColivelinTFA is used to specifically excite STAT3. The survival rate of macrophages was detected by CCK-8. The lipid levels in macrophages were detected by colorimetry. The levels of inflammatory factors secreted by macrophages were detected by ELISA. Q-PCR was used to detect the mRNA expression levels, and Western Blot was used to detect the protein expression levels of JAK2/STAT3 pathway genes. Result: The survival rate of macrophages was reduced by PM2.5, and the levels of TG, T-CHO and LDL-C of macrophages exposed to PM2.5 were increased. PM2.5 led to the increasing level of IL-6 and the decreasing level of IL-4, and the JAK2/STAT3 signaling pathway was inhibited by PM2.5. Colivelin TFA significantly decreased the increasing levels of TG, T-CHO and LDL-C levels, and increased the decreasing mRNA levels of IL-4, and LPL induced by PM2.5 (p

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.

Obesity has been recognized as a major risk factor for the development of chronic cardiomyopathy, which is associated with increased cardiac inflammation, fibrosis, and apoptosis. We previously developed an anti-inflammatory compound C66, which prevented inflammatory diabetic complications via targeting JNK. In the present study, we have tested the hypothesis that C66 could prevent obesity-induced cardiomyopathy by suppressing JNK-mediated inflammation. High-fat diet (HFD)-induced obesity mouse model and palmitic acid (PA)-challenged H9c2 cells were used to develop inflammatory cardiomyopathy and evaluate the protective effects of C66. Our data demonstrate a protective effect of C66 against obesity-induced cardiac inflammation, cardiac hypertrophy, fibrosis, and dysfunction, overall providing cardio-protection. C66 administration attenuates HFD-induced myocardial inflammation by inhibiting NF-κB and JNK activation in mouse hearts. In vitro, C66 prevents PA-induced myocardial injury and apoptosis in H9c2 cells, accompanied with inhibition against PA-induced JNK/NF-κB activation and inflammation. The protective effect of C66 is attributed to its potential to inhibit JNK activation, which led to reduced pro-inflammatory cytokine production and reduced apoptosis in cardiomyocytes both in vitro and in vivo. In summary, C66 provides significant protection against obesity-induced cardiac dysfunction, mainly by inhibiting JNK activation and JNK-mediated inflammation. Our data indicate that inhibition of JNK is able to provide significant protection against obesity-induced cardiac dysfunction.

This study develops a new multi-material topology optimisation framework for design of periodic micro-composites with optimal functional performance and reduced stress concentration. First, multi-material topology optimisation is developed based on the alternating active phase algorithm and inverse homogenisation method with the sensitivity analysis derived for specific property objective i.e., negative Poisson's ratio (NPR) or maximum effective bulk modulus (EBM) and (p-norm macroscopic) stress objective. Then, the effects of initial material distribution and weight ratio (w1, w2 assigned to the property and stress objectives, respectively) are investigated, and the evaluation indices are also developed to obtain the optimal solution. Further, two cases related to the design of micro-composites for maximised either NPR or EBM with reduced maximum stress are performed. The results show that when designing the multi-material NPR micro-composites, the decrease of w1/w2 contributes to a general decease of both NPR and maximum stress. While in designing the maximum EBM, decreasing w1/w2 leads to the reduced maximum stress and simultaneously reduced EBM; hereby, a decision-making method as well as the proposed evaluation index are both applied and compared for acquiring the optimal result. This study provides new methods and solutions to multi-material micro-composites design for future industrial applications.

Abstract Background As a metabolic reprogramming feature, cancer cells derive most of their energy from aerobic glycolysis, while its regulatory mechanisms and therapeutic strategies continue to be illusive. Methods Integrative analysis of publically available expression profile datasets was used to identify critical transcriptional regulators and their target glycolytic enzymes. The functions and acting mechanisms of transcriptional regulators in cancer cells were investigated by using in vitro and in vivo assays. The Kaplan–Meier curve and log‐rank assay were used to conduct the survival study. Results Salmonella pathogenicity island 1 (SPI1/PU.1), a haematopoietic transcription factor, was identified to facilitate glycolytic process, tumourigenesis, invasiveness, as well as metastasis of colon cancer cells, which was interplayed by tumour‐associated neutrophils. Mechanistically, neutrophils delivered SPI1 mRNA via extracellular vesicles, resulting in enhanced SPI1 expression of cancer cells. Through physical interaction with SPI1‐related protein (SPIB), SPI1 drove expression of glycolytic genes within cancer cells, which in turn induced polarization of neutrophils via glycolytic metabolite lactate. Depletion of neutrophils or SPIB–SPI1 interaction in cancer cells significantly inhibited glycolytic process, tumourigenesis and aggressiveness. Upregulation of SPI1 or SPIB was found to be associated with poor prognosis in patients suffering from colon cancer. Conclusions Therapeutic targeting of SPIB/SPI1‐facilitated interplay of cancerous cells and neutrophils suppresses aerobic glycolysis and progression of cancer.

Objective: This study aimed to explore the influence of gratitude on the meaning of life of college students and the mediating effect of family function and peer relationships.Methods: A total of 1,049 college students (mean age: 18.59 ± 0.96 years) were investigated by gratitude scale, family function scale, peer relationship questionnaire, and meaning of life scale.Results: (1) Gratitude was positively correlated with meaning existence (r = 0.39, P < 0.05), meaning seeking (r = 0.23, P < 0.05), and peer relationship (r = 0.32, P < 0.05); meanwhile, it is also positively correlated with family function (r = 0.34, P < 0.05); (2) family function partially mediates the relationship between gratitude and meaning of life. Similarly, peer relationship partially mediates the relationship between gratitude and meaning of life.Conclusion: The mediating model showed that grateful individuals can better sense the meaning of life by perceiving good family function and good peer relationships.

With the expansion of cities, the deterioration of drinking water quality undergoing complex and long-distance distribution is gaining increasing attention. However, spatial variations between free-living bacteria (FLB) and particle-associated bacteria (PAB) in chlorinated drinking water distribution systems (DWDSs) have not been fully explored, especially in complex water supply areas with multiple interconnected DWDSs. To fill this gap, this study utilized 16S rRNA approaches to characterize the spatial patterns of FLB and PAB in DWDSs with intersection regions. Based on distance-decay analysis, transportation distance is a potential driver of bacterial variation for both FLB (Pearson’s r = −0.476, p

Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B is required for airway defense. However, the research on the role of MUC5B in airway inflammation induced by atmospheric PM2.5 remains limited. This study was designed to explore the role of MUC5B in airway inflammation induced by atmospheric PM2.5. In vivo, Wistar rats were exposed to 0, 1.5, 7.5, 37.5 mg/ kg PM2.5 saline suspension via intratracheal instillation. HE staining and AB-PAS staining were used to observe the airway inflammation and goblet cell hyperplasia. In vitro, normal A549 cells and MUC5B-knockdown A549 cells were exposed to 0, 100, 200 and 400 μg/mL PM2.5 for 6 h, 12 h, 24 h and 48 h. ELISA was used to measure the levels of TNF-α and IL-1β in serum and bronchoalveolar lavage fluid of rats and in cell culture. Real time-PCR and ELISA were used to quantify the mRNA and protein levels of MUC5B in trachea and lung of rats and in A549 cells. PM2.5 could cause the infiltration of inflammatory cells and increase the mucus secretions and goblet cell metaplasia. MUC5B is related to rats’ airway inflammation induced by PM2.5. A549 cells exposed to PM2.5 in higher concentration and longer time, the protein level of MUC5B was significantly increased, while the levels of IL-1β, TNF-α and MUC5B mRNA were significantly decreased. Compared with normal A549 cells, the levels of IL-1β and TNF-α were significantly higher in Muc5b-knockdown cells. Atmospheric PM2.5 can induce airway inflammation and mucin secretion. MUC5B played a critical role in controlling the inflammatory response induced by PM2.5.

Small waterbodies are a unique aquatic ecosystem with an increasing recognition for their important role in maintaining regional biodiversity and delivering ecosystem services. However, small waterbodies in Northwest Yunnan, one of the most concerned global biodiversity hot-spots, remain largely unknown. Here, we investigated the community structure of crustacean zooplankton and their relationships with limnological, morphometric and spatial variables in the highland small waterbodies in Northwest Yunnan in both the dry (October 2015) and rainy (June 2016) seasons. A total of 38 species of crustacean zooplankton were identified in our study, which is significantly higher than many other reported waterbodies in the Yunnan–Guizhou plateau as well as in the Yangtze River basin. This suggests that the highland small waterbodies are critical in maintaining regional zooplankton diversity in Northwest Yunnan. Meanwhile, we found limnological variables could explain most variation of crustacean zooplankton community, comparing to the morphometric and spatial variables in both the rainy and dry seasons. Our study revealed the diversity and community structure of crustacean zooplankton in the highland small waterbodies in Northwest Yunnan and highlighted the importance of small waterbodies in maintaining regional biodiversity.

Salicylic acid (SA) is a natural inducer of disease resistance in fruit, but its application in the food industry is limited due to low water solubility. Here, SA was encapsulated in β-cyclodextrin (β-CD) via the host–guest inclusion complexation method, and the efficacy of SA microcapsules (SAM) against blue mold caused by Penicillium expansum in postharvest apple fruit was elucidated. It was observed that SAM was the most effective in inhibiting the mycelial growth of P. expansum in vitro. SAM was also superior to SA for control of blue mold under in vivo conditions. Enzyme activity analysis revealed that both SA and SAM enhanced the activities of superoxide dismutase (SOD) and phenylalanine ammonia lyase (PAL) in apple fruit, whereas SAM led to higher SOD activities than SA. Total phenolic contents in the SAM group were higher than those in the SA group at the early stage of storage. SAM also improved fruit quality by retarding firmness loss and maintaining higher total soluble solids (TSS) contents. These findings indicate that microcapsules can serve as a promising formulation to load SA for increasing P. expansum inhibition activity and improving quality attributes in apple fruit.

Plastics in the environment can be degraded and even broken into pieces under the action of natural factors, and the degraded products with a particle size of less than 5 mm are called microplastics (MPs). MPs exist in a variety of environmental media that come into contact with the human body. It can enter the body through environmental media and food chains. At present, there are many studies investigating the damage of MPs to marine organisms and mammals. The liver is the largest metabolizing organ and plays an important role in the metabolism of MPs in the body. However, there is no available systematic review on the toxic effects of MPs on the liver. This paper summarizes the adverse effects and mechanisms of MPs on the liver, by searching the literature and highlighting the studies that have been published to date, and provides a scenario for the liver toxicity caused by MPs.

Due to the decreasing self-repairing ability, elder people are easier to form chronic wounds and suffer from slow and difficult wound healing. It is desirable to develop a novel wound dressing that can accelerate chronic wound healing in elderly subjects to decrease the pain of patients and save medical resources. In this work, Heparin and basic fibroblast growth factor(bFGF) were dissolved in the mixing solution of 4-arm acrylated polyethylene glycol and dithiothreitol to form hydrogel dressing in vitro at room temperature without any catalysts, which is convenient and easy to handle in clinic application. In vitro re-lease test shows the bFGF could be continuously released for at least 7 days, whereas the dressing surface integrity maintained for 3 days degradation in PBS solution. Three groups of treatments including bFGF-Gel, bFGF-Sol and control without any treatment were applied on the full-thickness wound on the 22 months old mice back. The wound closure rate and histological and immunohistochemical staining all illustrated that bFGF-Gel displayed a better wound healing effect than the other two groups. Thus, as-prepared hydrogel dressing seems supe-rior to current clinical treatment and more effective in elderly subjects, which shows promising potential to be applied in the clinic.

Sending camouflaged audio information for fraud in social networks has become a new means of social networks attack. The hidden acoustic events in the audio scene play an important role in the detection of camouflaged audio information. Therefore, the application of machine learning methods to represent hidden information in audio streams has become a hot issue in the field of network security detection. This study proposes a heuristic mask for empirical mode decomposition (HM-EMD) method for extracting hidden features from audio streams. The method consists of two parts: First, it constructs heuristic mask signals related to the signal’s structure to solve the modal mixing problem in intrinsic mode function (IMF) and obtains a pure IMF related to the signal’s structure. Second, a series of hidden features in environment-oriented audio streams is constructed on the basis of the IMF. A machine learning method and hidden information features are subsequently used for audio stream scene classification. Experimental results show that the hidden information features of audio streams based on HM-EMD are better than the classical mel cepstrum coefficients (MFCC) under different classifiers. Moreover, the classification accuracy achieved with HM-EMD increases by 17.4 percentage points under the three-layer perceptron and by 1.3% under the depth model of TridentResNet. The hidden information features extracted by HM-EMD from audio streams revealed that the proposed method could effectively detect camouflaged audio information in social networks, which provides a new research idea for improving the security of social networks.

Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.

BackgroundScavenger Receptor Class A Member 5 (SCARA5), also known as TESR, is expressed in various tissues and organs and participates in host defense. Recent studies have found SCARA5 to produce an anti-tumor effect for multiple tumors, although the mechanistic basis for the effect is unknown.MethodsBioinformatics, methylation-specific polymerase chain reaction (MSP), quantitative real-time PCR, and immunohistochemistry were used to assess promoter methylation and expression of SCARA5 in lung cancer tissues and cell lines. The biological effect of SCARA5 on lung cancer cells was confirmed by the CCK8 assay, colony formation assay, and flow cytometry. GSEA, Western blot, RNA sequencing, and luciferase-based gene reporter assay were used to explore the mechanistic basis for the anti-tumor effect of SCARA5. Chemosensitivity assays were used to evaluate the anti-tumor effect of SCARA5 in conjunction with chemotherapeutic drugs.ResultsWe found SCARA5 to be downregulated in lung cancer cell lines and tissues with SCARA5 levels negatively related to promoter methylation. Ectopic expression of SCARA5 suppressed proliferation of lung cancer both in vitro and in vivo through upregulation of HSPA5 expression, which inhibited FOXM1 expression resulting in G2/M arrest of the A549 cell line. SCARA5 also improved susceptibility of A549 cells to chemotherapeutic drugs that damage DNA.ConclusionSCARA5 was silenced in NSCLC due to promoter methylation and could be a potential tumor marker in NSCLC.

Stroke is one of the leading causes of death and disability worldwide with limited therapeutic options. Melatonin can attenuate ischemic brain damage with improved functional outcomes. However, the cellular mechanisms of melatonin-driven neuroprotection against post-stroke neuronal death remain unknown. Here, distal middle cerebral artery occlusion (dMCAO) was performed in C57BL/6j mice to develop an ischemic stroke in vivo model. Melatonin was injected intraperitoneally immediately after ischemia, and 24 and 48 hours later. Melatonin treatment, with 5 to 20 mg/kg, elicited a dose-dependent decrease in infarct volume and concomitant increase in sensorimotor function. At the molecular level, phosphorylation of PTEN and Akt were increased, whereas PTEN activity was decreased in melatonin treated animals 72 hours after dMCAO. At the cellular level, oxygenglucose deprivation (OGD) challenge of neuronal cell line Neuro-2a (N2a) and primary neurons supported melatonin’s direct protection against neuronal cell death. Melatonin treatment reduced LDH release and neuronal apoptosis at various time points, markedly increased Akt phosphorylation in neuronal membrane, but significantly suppressed it in the cytoplasm of post-OGD neurons. Mechanistically, melatonin-induced Akt phosphorylation and neuronal survival was blocked by Wortmannin, a potent PIP3 inhibitor, exposing increased PI3K/Akt activation as a central player in melatonin-driven neuroprotection. Finally, PTEN knock-down through siRNA significantly inhibited PI3K/Akt activation and cell survival following melatonin treatment, suggesting that melatonin protection against ischemic brain damage, is at least partially, dependent on modulation of the PTEN/PI3K/Akt signaling axis.

AIM: To study the expressions of TGFBI and microtubule-associated protein 1 light chain 3 alpha(LC3)in granular corneal dystrophy, and the influences of lithium chloride(LiCl)on corneal stromal fibroblast cell proliferation by TGFBI. METHODS: Immunohistochemistry and Western-blot assays were used to detect the expression levels of TGFBI and LC3 in corneal dystrophy and normal corneal tissues. TGFBI overexpression vector was transfected into corneal stromal fibroblasts, and then the cells were treated with 5, 10, 20, 40mmol/L LiCl for different times(0, 1, 6, 12h), and Western-blot assay was performed to evaluate the expression levels of TGFBI and LC3, and CCK-8 assay was carried out to assess cell proliferation activity.RESULTS: TGFBI and LC3 were highly expressed in corneal tissues of patients with corneal dystrophy. TGFBI overexpression inhibited the proliferation ability of corneal stromal fibroblasts(PPCONCLUSION: LiCl promoted the proliferation and autophagy of corneal stromal fibroblasts, and its mechanism may be related to down regulated expressions of TGFBI and LC3.

Abstract Background Epidemiological studies have confirmed atmospheric PM2.5 could affect asthma, and dyslipidemia may be related to pathogenesis of asthma. Recent studies show Notch ligands had lipid combination domains which are responsible for regulating lipid levels. However, the effect of PM2.5 on asthmatic rats’ lipid levels and the role of Notch signaling pathway is unclear. Methods Rats were treat with ovalbumin (OVA) to establish asthma models. Notch signaling pathway inhibitor (DAPT) was injected intraperitoneally. Asthmatic and healthy rats were exposed to different concentrations of PM2.5. Lung tissues were collected and the expression of Hes1 protein was detected by Western Blot. Blood samples were collected to detect the serum lipid levels. Results Hes1 expression levels in healthy and asthma pathway inhibition groups were lower than those in control groups. Compared with control group, rats exposed to PM2.5 in middle and high dose, the levels of TG and TC were decreased. Similar results were observed after exposure to the same concentration of PM2.5 in asthmatic rats. Rats, which were exposed to PM2.5 after being established the asthma model successfully, could exhibit more significant dyslipidemia than those with direct exposure. After Notch signaling pathway inhibited, TC and LDL in asthma pathway inhibition group were lower than those in healthy group. Conclusions PM2.5 can affect the lipid levels of asthmatic rats through the Notch signaling pathway.

Abstract Background Tumor chemo-resistance is a hallmark of malignant tumors as well as the major cause of poor survival rates in lung cancer. Transmembrane-4 L-six family member-1 (TM4SF1), an antigen that serves as an oncogene, mainly affects tumor invasion and metastasis. We investigated the roles of TM4SF1 in non-small-cell lung cancer progression, particularly in the regulation of chemo-sensitivity. Methods TM4SF1 was silenced by small interfering RNA transfection.TM4SF1 expression in cell lines and tissues were determined by Quantitative Real-time PCR. MTS, clonogenic, Transwell assay, Flow cytometry verified cell function. By RT-PCR, Western blot, the mechanisms were studied. Results TM4SF1 was upregulated in both lung cancer cell lines and tissues, compared with 293 T epithelial cells. Analysis of online databases revealed that high expression of TM4SF1 is associated with the older patient age, smoking habits, and poor patient survival and outcome. Knockdown of TM4SF1 substantially inhibited tumor cell growth, migration, and invasion, and enhanced the chemo-sensitivity of the lung cancer cell lines A549 and H1299 to cisplatin and paclitaxel. Furthermore, the silencing of TM4SF1 induced lung cancer cell apoptosis and arrested cells at the G2/M phase. These results suggest that TM4SF1 is associated with lung cancer progression and appears to be required for tumor cell growth, maintenance of chemo-resistance and metastasis. We further found that TM4SF1 exerts these effects in part by regulating the expression of the discoidin domain receptor DDR1 and its downstream target, the Akt/ERK/mTOR pathway, and consequently alters cell sensitivity to chemo-reagents and contributes to invasion and metastasis. Conclusions These findings demonstrate that TM4SF1 may serve as a prognostic factor for lung cancer chemo-response and patient outcome.

Despite the extensive efforts to stabilize Au catalysts for industrial hydrochlorination of acetylene to vinyl chloride the deactivation is not overcome yet. Here, the authors demonstrate that the ceria promotion to Au catalysts affords enhanced activity and stability via formation of Au(0)/Au(I) as new active pairs.

Recent years have witnessed an opportunity to improve trial efficiency and quality by predictive analysis of massive judgment documents. A practical legal judgment prediction (LJP) system should provide a judge with feasible judgment suggestions, including the charges, applicable law articles, and prison term, whereas most existing works focus on only part of the LJP task. Inspired by the impressive success of deep neural networks in a wide range of application scenarios, we propose a multichannel attentive neural network model, MANN, which learns from previous judgment documents and performs the integrated LJP task in a unified framework. In general, MANN takes the textual description of a criminal case as the input for attention-based neural networks to learn its latent feature representations oriented to the case fact, the defendant persona, and relevant law articles. Moreover, we adopt a two-tier structure to empower attentive sequence encoders to hierarchically model the semantic interactions from different parts of case description at both the word and sentence levels. The experiments are conducted on four real-world datasets of criminal cases in mainland China. The experimental results demonstrate that MANN achieves state-of-the-art LJP performance on all evaluation metrics.

Pipeline transportation of crude oil has great advantages over traditional oil transmission methods, in terms of economic and environmental protection. The main costs in the oilfield surface system are the fuel costs for heating the crude oil during transportation and the electricity costs for the pumping units. In the northeast of China, where winter temperatures are extremely low and the oil has a high freezing point and high viscosity, higher temperatures, and pressures are required to transport crude oil. With machine learning widely used in many industries and achieving better results, the digital management of oil pipelines has stored a large amount of production and operation data, which has laid the foundation for the research of oil pipeline process calculation using machine learning methods. In this paper, a crude oil pressure drop calculation of an oil pipeline in Northeast China is carried out based on a neural network. For pipeline pressure drop calculation, the back propagation neural network (BP) pressure drop calculation model and particle swarm optimization for back propagation neuron network (PSO-BP) pressure drop calculation model are established. Two models were used to calculate and compare the measured data, and the average absolute error of the PSO-BP model was the smallest, which was 0.015%. Compared with the BP model, the average relative error is reduced by 13.16%. Therefore, The PSO-BP pressure drop calculation model has high accuracy and is of practical significance for predicting pipeline pressure drop.

LncRNAs play important roles in bladder cancer. However, only a few studies report on the correlation between lncRNAs expression and autophagy in bladder cancer. This study aimed to explore the effect of lncRNA on autophagy in bladder cancer. The findings showed high expression of SNHG1 in the bladder cancer cells and tumor tissues. The high expression of SNHG1 was positively correlated with bladder cancer cell invasion, proliferation, and autophagy. This finding implies that SNHG1 promotes bladder cancer cell invasion and proliferation via autophagy. Further analysis of the mechanism of action of SNHG1 showed that it functions as a sponge of miRNA-493 in bladder cancer. miRNA-493 binds on the 3’ -UTR of ATG14 mRNA thus affecting ATG14 protein expression, which is implicated in autophagy. These findings are supported by previous preclinical studies using multiple Bca cell lines and TCGA, which demonstrate that SNHG1 plays an oncogenic role by acting as a sponge of miR-493-5p or as its ceRNA. Upregulation of SNHG1 promotes proliferation, invasion, and autophagy of bladder cancer cells through the miR-493-5p/ATG14/autophagy pathway. Therefore, SNHG1 may act as a potential therapeutic target for the treatment of bladder cancer.

It is not clear whether D-dimer can be an independent predictor of coronavirus disease 2019 (COVID-19) mortality, and the cut-off of D-dimer for clinical use remains to be determined. Therefore, a comprehensive analysis is still necessary to illuminate the clinical significance of plasma D-dimer in COVID-19 mortality. We searched PubMed, Embase, Cochrane Library, and Scopus databases until November 2020. STATA software was used for all the statistical analyses. The identifier of systematic review registration was PROSPERO CRD42020220927. A total of 66 studies involving 40,614 COVID-19 patients were included in our meta-analysis. Pooled data showed that patients in high D-dimer group had poor prognosis than those in low D-dimer group [OR = 4.52, 95% CI = (3.61, 5.67), P < 0.001; HR = 2.81, 95% CI = (1.85, 4.27), P < 0.001]. Sensitivity analysis, pooled data based on different effect models and the Duval and Tweedie trim-and-fill method did not change the conclusions. Subgroup analyses stratified by different countries, cutoffs, sample size, study design, and analysis of OR/HR still keep consistent conclusions. D-dimer was identified as an independent predictor for COVID-19 mortality. A series of values including 0.5 μg/ml, 1 μg/ml, and 2 μg/ml could be determined as cutoff of D-dimer for clinic use. Measurement and monitoring of D-dimer might assist clinicians to take immediate medical actions and predict the prognosis of COVID-19.

Obesity has been recognized as a major risk factor for the development of chronic kidney disease, which is accompanied by increased renal inflammation, fibrosis, and apoptosis. C66 is a curcumin derivative that exerts anti-inflammatory effects by inhibiting the JNK pathway and prevents diabetic nephropathy. The present study investigates the possible protective effect of C66 on high-fat diet (HFD)-induced obesity-related glomerulopathy. Mice were fed with HFD for 8 weeks while some were treated with C66 every 2 days for 11 weeks. The HFD-fed mice developed renal dysfunction, as well as elevated triglyceride and cholesterol. Kidneys of the HFD-fed mice showed marked glomerular injuries, apoptosis, and inflammation with markedly increased cytokine production. Interestingly, treating HFD-fed mice with C66 remarkably reversed these pathological changes via inhibiting inflammation and NF-κB/JNK activation. In cultured mesangial cells, Palmitic Acid was able to activate the pro-fibrotic mechanisms, apoptosis, inflammatory response, and NF-κB and JNK signaling pathways, all of which could be attenuated by C66 treatment. In all, we demonstrated that curcumin analogue C66 attenuates obesity-induced renal injury by inhibiting chronic inflammation and apoptosis via targeting NF-κB and JNK. Our data suggest that C66 can be potentially used to prevent obesity-associated renal diseases warranting future investigations.

Exposure to adverse events in early life increases the risk of chronic metabolic disease in adulthood. The objective of this study was to determine the significance of milk fat globule membrane (MFGM)-mediated alterations in the gut microbiome to the metabolic health of offspring in the long-term. Female C57BL/6 mice were fed either a high-fat diet (HFD) or a control diet for 3 weeks before pregnancy and throughout pregnancy and lactation. During lactation, pups from the HFD group were breast-fed with or without 1,000 mg/kg BW/day MFGM supplementation (HFD and HFD-MS group, respectively). After weaning, the offspring in each group were divided into male and female subgroups. The weaned mice were then shifted to a control diet for 8 weeks. At the eleventh week, stool samples were collected for 16S rRNA gene sequencing. Serum biochemical parameters were analyzed, and intraperitoneal glucose and insulin tolerance tests were performed. Neonatal supplementation with MFGM ameliorated metabolic disorder and improved glucose tolerance in offspring exposed to maternal HFD in a sex-specific manner. Furthermore, maternal HFD induced gut microbiota perturbation in offspring in adulthood. Neonatal MFGM supplementation significantly enriched g-Parabacteroides, g-Bifidobacterium, g-Faecalibaculum, and g-Lactobacillus in male offspring exposed to maternal HFD, while significantly enriched g-Parabacteroides and g-Alistipes in female offspring exposed to maternal HFD. These bacteria may be associated with the favorable changes in metabolism that occur in adulthood. Sex differences in the changes of metagenomic pathways related to oxidative phosphorylation, citrate cycle, electron transfer carries, and ubiquinone biosynthesis were also observed in the offspring. Maternal HFD has an adverse effect on the metabolism of offspring in later life. Neonatal MFGM supplementation could modulate the structure of gut microbiota communities and may have long-term protective effects on lipid and glucose metabolism, but these effects are sex dimorphic.

Introduction: Coronavirus disease 2019 (COVID-19) has brought great challenges to global public health. However, a comprehensive analysis of the relationship between liver biochemical parameters and COVID-19 mortality is quite limited. Methods: We searched the following electronic databases: PubMed, Embase, Cochrane Library, Web of Science, Scopus, Wanfang and China National Knowledge Infrastructure database until May 5, 2020. STATA software was used for the statistical analyses. Results: A total of 25 studies involving 5971 COVID-19 patients were included in our analysis. Compared with non-survivors, survivors had lower levels of aspartate aminotransferase (AST) (weighted mean difference [WMD] = −16.71 U/L, 95%CI = [−21.03, −12.40], P

Protecting the death of nerve cells is an essential tactic for spinal cord injury (SCI) repair. Recent studies show that nerve growth factors can reduce the death of nerve cells and promote the healing of nerve injury. To investigate the conducive effect of fibroblast growth factor 21 (FGF21) on SCI repair. FGF21 proteins were systemically delivered into rat model of SCI via tail vein injection. We found that administration of FGF21 significantly promoted the functional recovery of SCI as assessed by BBB scale and inclined plane test, and attenuated cell death in the injured area by histopathological examination with Nissl staining. This was accompanied with increased expression of NeuN, GAP43 and NF200, and deceased expression of GFAP. Interestingly, FGF21 was found to attenuate the elevated expression level of the autophagy marker LC3-II (microtubules associated protein 1 light chain 3-II) induced by SCI in a dose-dependent manner. These data show that FGF21 promotes the functional recovery of SCI via restraining injury-induced cell autophagy, suggesting that systemic administration of FGF21 could have a therapeutic potential for SCI repair.

Background: Mono-2-ethylhexyl phthalate (MEHP) is a major metabolite of di (2-ethylhexyl) phthalate (DEHP). Our previous researches have shown that MEHP can induce lipid accumulation in preadipocytes, while, the underlying mechanism is unclear. The present study was undertaken to clarify the effect of Notch pathway on lipid accumulation induced by MEHP. Methods: 3T3-L1 preadipocytes were exposed to MEHP (0, 10, 50, 250 µM and 0.1%DMSO) for the whole differentiation phase. Then the level of TG and cell cycle were detected. RT-PCR was used to detect the mRNA expression and Western blot was used to detect the expression of protein by Notch pathway genes and lipid metabolic related genes. Results: In this study, the level of TG in the 250 µM and 250 µM MEHP groups was significantly higher than that in the control, DMSO and 10 µM MEHP groups (P

Tricothecenes-2 toxin (T-2) is a major mycotoxin that is widely distributed in aquatic feeds and poses a huge challenge to the aquatic industry, but there is scant information on the toxicokinetics of T-2 in aquatic animals. Here, we describe the development of a three-compartment toxicokinetic model for the absorption, distribution, metabolism and elimination (ADME) of T-2 in shrimp. The three compartments were central (the hemolymph), slow metabolizing and fast metabolizing compartments to account for the varying ADME rates of T-2 in different shrimp organs. The toxicokinetic model was solved by the blindfold particle swarm optimization algorithm, and the values for the model equation parameters were obtained by applying the experimental data of T-2 concentrations in shrimp. The model had a good fit with the experimental data. It was revealed through the model that after i.m. administration, T-2 was rapidly absorbed into the hemolymph and distributed into shrimp organs. The hepatopancreas and intestine belonged to the fast and muscle to the slow metabolizing compartments, respectively, while the hemolymph had no capacity to metabolize T-2. The T-2 elimination rates in the hepatopancreas and intestine were similar and quite high while that in the muscle was very low. The methods used in developing and solving the model could be used for similar toxicokinetic and pharmacokinetic studies of other animals.

To enhance the interfacial intermolecular entanglement of the polyethylene/ultrahigh molecular weight polyethylene (PE/UHMWPE) system, the blend was fabricated via a facile melt blending process in presence of UHMWPE with relatively low molecular weight (LUHMWPE). Incorporation of LUHMWPE filled molecular weight gap between PE and UHMWPE, and thus a matched viscosity gradient for the components of blend was constructed. The UHMWPE/LUHMWPE particles with remarkably decreased size and distribution were tightly embedded in PE matrix, and the interface transition area between UHMWPE and PE phase increased dramatically. Meanwhile the molecular entanglement density and viscoelasticity were improved greatly, demonstrating enhanced interfacial adhesion, interfacial intermolecular diffusion and construction of a dense chain entanglement network in blend. An obvious deformation accompanied by lots of pulling-out UHMWPE fibrils was observed on the fractured surfaces of the blend, and the mechanical property was highly enhanced by a roughly 38%/22% increase in tensile strength and a great improvement in impact strength, respectively when compared with neat PE and PE/UHMWPE. The blend was further employed to fabricate pipes, which exhibited significantly improved tensile strength both along hoop and axial direction, and the internal pressure resistance. This work provides a facile method for manufacturing PE/UHMWPE blend and pipe with promising application potentials.

Nerve regeneration and repair still remain a huge challenge for both central nervous and peripheral nervous system. Although some therapeutic substances, including neuroprotective agents, clinical drugs and stem cells, as well as various growth factors, are found to be effective to promote nerve repair, a carrier system that possesses a sustainable release behavior, in order to ensure high on-site concentration during the whole repair and regeneration process, and high bioavailability is still highly desirable. Hydrogel, as an ideal delivery system, has an excellent loading capacity and sustainable release behavior, as well as tunable physical and chemical properties to adapt to various biomedical scenarios; thus, it is thought to be a suitable carrier system for nerve repair. This paper reviews the structure and classification of hydrogels and summarizes the fabrication and processing methods that can prepare a suitable hydrogel carrier with specific physical and chemical properties. Furthermore, the modulation of the physical and chemical properties of hydrogels is also discussed in detail in order to obtain a better therapeutic effect to promote nerve repair. Finally, the future perspectives of hydrogel microsphere carriers for stroke rehabilitation are highlighted.

Aromatic matters are widely present in wastewater, especially industrial wastewater, and may lead to a high abundance of antibiotic resistance genes (ARGs) in wastewater treatment bioreactors and stimulate horizontal transfers of ARGs. Here, we investigated a practical approach that applying ozone pretreatment to mitigate ARGs in bioreactors treating wastewater containing a typical aromatic pollutant, p-aminophenol (PAP). The results showed that ozone pretreatment could effectively reduce the aromaticity of wastewater, and the relative abundance of ARGs in the bioreactor fed with ozone treated wastewater decreased by over 70% compared to the control reactor. Multidrug, quinolone, mupirocin, polymyxin, aminoglycoside, glycopeptide, beta-lactam, and trimethoprim resistance genes were all reduced in the bioreactors receiving wastewater pretreated by ozone. Metagenomic analysis suggested that the reduction of ARGs could be attributed to the co-occurrence of ARGs and aromatic degradation genes in bacteria. Furthermore, we expanded our analysis to investigate 71 metagenomes from different environments, and the results indicated that the impact of aromatics on ARG abundance widely occurs in various ecosystems and confirmed that high levels of aromatics could lead to high abundance of ARGs. Taken together, our work confirmed that the aromatics played critical roles in selecting ARGs and proposed a feasible approach to reduce ARGs in wastewater treatment bioreactors.

Mitophagy is an evolutionarily conserved process to selectively remove damaged or unnecessary mitochondria via the autophagic machinery. In this review, we focus on recent advances in the molecular mechanisms of mitophagy and how mitophagy contributes to cellular homeostasis in physiological and pathological contexts. We also briefly review and discuss the crosstalk between mitophagy and renal disease, highlighting its modulation as a potentially effective therapeutic strategy to treat kidney diseases such as acute kidney injury (AKI), diabetic kidney disease (DKD), and lupus nephritis (LN).

Summary: Exoskeletons of Odontodactylus japonicas, the “smasher-type” mantis shrimp, feature a raptorial appendage comprising a Bouligand architecture of chitin nanofibrils with newly observed voids or defects between the polysaccharide α-chitin and protein interfaces. Here, we use a continuous-fiber 3D printing technology to simulate such materials in carbon fiber-reinforced (helicoidal) composites, complete with the presence of voids due to imperfect printing. The specific impact energies of the 3D printed helicoidal composites are clearly superior and further enhanced by the presence of the voids. To explain the role of the Bouligand architecture, interlaminar stresses are computed and found to yield anti-delamination characteristics, and a theoretical model is derived to evaluate the optimal helicoidal architecture. Finite element modeling indicates that the voids tend to deform and coalesce on loading and appear to guide the fracture into the formation of an ideally twisted crack in the printed helicoidal composites, thereby contributing to the impact toughness.

Pathogenic autoantibodies can cause inflammation and tissue injury in systemic lupus erythematosus (SLE). Although IgG4 is considered non-inflammatory owing to the unique structure of its hinge region, the role of IgG4 autoantibodies in SLE remains largely unknown. The titers of serum anti-nuclear-IgG antibodies (ANA-IgG) and anti-nuclear-IgG4 antibodies (ANA-IgG4) in newly diagnosed SLE patients were detected. The effects of IgG4 purified from SLE patients (SLE IgG4) and healthy controls on complement consumption and inflammatory cytokine production were evaluated in vitro. The therapeutic effects of mouse IgG1 (functionally resembles human IgG4) purified from lupus-prone MRL-lpr/lpr mice (lupus IgG1) and control mice on disease progression were examined in MRL-lpr/lpr mice. The results showed that SLE patients with equal titers of total serum ANA-IgG (1:3,200) were divided into group I with lower ANA-IgG4 titers (≤ 1:10) and group II with higher ANA-IgG4 titers (≥ 1:100), and disease activity, inflammatory cytokine production, complement consumption, and renal-function parameters in group I SLE patients were more severe than those in group II. Further, compared with control IgG4, SLE IgG4 inhibited complement consumption by autoantibody-autoantigen immune complexes, and also inhibited inflammatory cytokines production by SLE PBMCs in vitro. Moreover, compared with control IgG1, lupus IgG1 exhibited a therapeutic effect on lupus by attenuating disease progression in MRL-lpr/lpr mice. These findings, for the first time, suggest that IgG4 autoantibodies can attenuate SLE progression by suppressing complement consumption and inflammatory cytokine production. Hence, this study may provide novel therapeutic strategies against SLE and other autoimmune diseases.

Diabetic retinopathy (DR) is one of the most severe complications of diabetes mellitus, and retinal endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of DR. However, the exact mechanisms by which ERS mediates DR remain unclear. In this study, human retinal vascular endothelial cells (RVECs) were cultured in high-glucose (HG) medium to mimic the environment of DR. The expression of long non-coding RNA (lncRNA)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was determined by quantitative real time PCR. ERS markers (glucose-regulated protein 78 [GRP78] and C/EBP homologous protein [CHOP]) were measured by immunofluorescence and western blotting. Cell viability was analyzed by the CCK-8 assay. The angiogenesis of RVECs was evaluated by tube formation assays. The levels of pro-inflammation cytokines TNF-α and IL-6 in RVECs were determined by ELISA assays. We found that exposure to HG levels upregulated MALAT1 and GRP78 expression in RVECs. While, GRP78 overexpression strengthened CHOP expression, cell proliferation suppression, capillary morphogenesis and inflammation in HG-treated RVECs. Importantly, knockdown of MALAT1 reversed HG-induced cell proliferation suppression, inhibited capillary morphogenesis, and inflammation in RVECs, and those effects were reversed by GRP78 overexpression. These results suggest that MALAT1 promotes HG-induced angiogenesis and inflammation in RVECs by upregulating ER stress, and might be target for treating DR.

Objectives: To estimate the stage-specific impact of perioperative chemotherapy on survival for upper urinary tract urothelial carcinoma (UTUC) patients treated with nephroureterectomy (NU).Methods: Overall, 7,278 UTUC patients treated with NU from 2004 to 2015 were identified within the SEER database. Kaplan–Meier plots were used to elucidate overall survival (OS) and cancer-specific survival (CSS) rates. Multivariable Cox regression analyses were used to test the impact of chemotherapy on survival rates, after stratifying according to pathological stage.Results: Chemotherapy was performed in 17.3% of patients and in 5.7, 11.5, 25.4, and 51.3% of patients with, respectively, pT1, pT2, pT3, and pT4 disease (P < 0.001). In multivariable analyses, perioperative chemotherapy was associated with a lower OS in pT2 patients and a lower CSS in pT1 disease (both P < 0.05), while predisposed to a higher OS in pT3 and pT4 patients (both P < 0.01). Moreover, perioperative chemotherapy was prone to a higher OS or CSS in pN+ disease compared to no chemotherapy (both P < 0.01).Conclusion: Perioperative chemotherapy was more frequently performed in locally advanced UTUC patients. The beneficial effect of chemotherapy on OS was evident in pT3/pT4 and pN+ patients. In addition, a clear CSS benefit was observed in patients who received chemotherapy for pN+ UTUC, while perioperative chemotherapy may reduce CSS for pT1 and OS for pT2 patients following NU.

The existence of local soft interlayer can significantly amplify or attenuate the ground motion and thus might influence the lagged spatial coherency between spatially varying earthquake ground motions. A target site with a local soft interlayer was assumed first, and then two numerical examples were set. In example 1, linear soil behavior was considered and a large amount of quasi-stationary spatially varying earthquake ground motions were generated by combining the one-dimensional wave propagation theory and the classical spectral representation method. The influence regularity of varying shear wave velocity, buried depth, and thickness of the soft interlayer on the characteristics of lagged spatial coherency was investigated. In example 2, non-linear soil behavior was taken into account and fully non-stationary spatially varying earthquake ground motions were thus generated by using time-varying transfer function and spectral representation method. An overall evaluation was carried out to shed light on the differences of characteristics of spatial coherency between non-linear soil and linear soil cases. It showed that: (i) As the shear wave velocity of interlayer declines and as the buried depth and thickness increase, remarkable reduction of spatial coherency showed up; (ii) the reduction of lagged spatial coherency caused by varying buried depth may be more inclined to concentrate in the lower frequency range; (iii) the non-linear soil behavior can cause greater further reduction of lagged spatial coherency in comparison with linear soil behavior, especially in the higher frequency range; (iv) the troughs of lagged spatial coherency curve tend to be located in the variation range of vibration frequency of time-varying spectral ratio.

Background/Aims: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC). Methods: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied. Results: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non-cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T-cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing β-catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/β-catenin pathway. Conclusion: IRF8 acted as a tumor suppressor gene through the transcriptional repression of β-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.

We aimed to identify the potential genes related to blood pressure regulation and screen target genes for high blood pressure (BPH) and low blood pressure (BPL) treatment. The GSE19817 microarray dataset, which included the aorta, liver, heart, and kidney samples from BPH, BPL, and normotensive mice, was downloaded from the Gene Expression Omnibus. Principal component analysis (PCA) was performed based on the entire expression profile. Differentially expressed genes (DEGs) were screened, followed by pathway enrichment analysis. Finally, gene regulatory networks were constructed based on BPH-related and BPL-related DEGs in the aorta, liver, heart, and kidney samples. As a result, DEGs were screened within their respective tissues due to high heterogeneity of different tissues. Totally, 2,726 BPH-related DEGs and 2,472 BPL-related DEGs were screened, which were mainly enriched in pathways such as immune response. The topology data of gene regulatory networks constructed by DEGs in the heart, kidney, and liver were similar than that in aorta. Finally, among BPH-related DEGs, Sept6 and Pigx were found in the top 10 differentially regulated DEGs by comparing the BPH-related DEGs of the aorta with the DEGs of the other 3 tissues in the regulatory network. Although among the top 10 differentially regulated BPL-related DEGs, no common differentially regulated DEGs were found, Wif1, Urb2, and Gtf2ird1 were found among the top ten DEGs in the three tissues other than the kidney tissue. Sept6 and Pigx might participate in the pathogenesis of BPH, whereas Gtf2ird1, Urb2, and Wif1 might be critical target genes for BPL treatment.

Humans are exposed to tens of thousands of chemicals over the course of a lifetime, yet there remains inadequate data on the potential harmful effects of these substances on human health. Using quantitative high-throughput screening (qHTS), we can test these compounds for potential toxicity in a more efficient and cost-effective way compared to traditional animal studies. Tox21 has developed a library of ~10,000 chemicals (Tox21 10K) comprising one-third approved and investigational drugs and two-thirds environmental chemicals. In this study, the Tox21 10K was screened in a qHTS format against a panel of 70 cell-based assays with 213 readouts covering a broad range of biological pathways. Activity profiles were compared with chemical structure to assess their ability to differentiate drugs from environmental chemicals, and structure was found to be a better predictor of which chemicals are likely to be drugs. Drugs and environmental chemicals were further analyzed for diversity in structure and biological response space and showed distinguishable, but not distinct, responses in the Tox21 assays. Inclusion of other targets and pathways to further diversify the biological response space covered by these assays is likely required to better evaluate the safety profile of drugs and environmental chemicals to prioritize for in-depth toxicological studies.

Abstract Background Previous studies have indicated that oxygen uptake ($$VO_2$$ VO2 ) is one of the most accurate indices for assessing the cardiorespiratory response to exercise. In most existing studies, the response of $$VO_2$$ VO2 is often roughly modelled as a first-order system due to the inadequate stimulation and low signal to noise ratio. To overcome this difficulty, this paper proposes a novel nonparametric kernel-based method for the dynamic modelling of $$VO_2$$ VO2 response to provide a more robust estimation. Methods Twenty healthy non-athlete participants conducted treadmill exercises with monotonous stimulation (e.g., single step function as input). During the exercise, $$VO_2$$ VO2 was measured and recorded by a popular portable gas analyser ($$K4b^2$$ K4b2 , COSMED). Based on the recorded data, a kernel-based estimation method was proposed to perform the nonparametric modelling of $$VO_2$$ VO2 . For the proposed method, a properly selected kernel can represent the prior modelling information to reduce the dependence of comprehensive stimulations. Furthermore, due to the special elastic net formed by $$\mathcal {L}_1$$ L1 norm and kernelised $$\mathcal {L}_2$$ L2 norm, the estimations are smooth and concise. Additionally, the finite impulse response based nonparametric model which estimated by the proposed method can optimally select the order and fit better in terms of goodness-of-fit comparing to classical methods. Results Several kernels were introduced for the kernel-based $$VO_2$$ VO2 modelling method. The results clearly indicated that the stable spline (SS) kernel has the best performance for $$VO_2$$ VO2 modelling. Particularly, based on the experimental data from 20 participants, the estimated response from the proposed method with SS kernel was significantly better than the results from the benchmark method [i.e., prediction error method (PEM)] ($$76.0\pm 5.72$$ 76.0±5.72 vs $$71.4\pm 7.24\%$$ 71.4±7.24% ). Conclusions The proposed nonparametric modelling method is an effective method for the estimation of the impulse response of VO 2—Speed system. Furthermore, the identified average nonparametric model method can dynamically predict $$VO_2$$ VO2 response with acceptable accuracy during treadmill exercise.

Background/Aims: Massive proteinuria, a significant sign of nephrotic syndrome (NS), has the potential to injure tubular epithelial cells (TECs). Furosemide is widely used for the treatment of edema, a common manifestation of NS. However, whether furosemide treatment affects massive proteinuria-induced TEC injury in patients with NS is unknown. Methods: The effect of furosemide on TEC damage was investigated in vitro. In addition, a clinical study was conducted to study whether the short-term treatment of nephrotic edema with furosemide could exacerbate TEC injury. Results: The proliferation of in vitro human kidney-2 (HK-2) cells exposed to massive urinary protein (8 mg/mL) significantly decreased (P0.05). In addition, serum levels of BUN, Scr, Cys C, and urinary Kim-1 and NGAL were not significantly different between the two groups (all P>0.05). Twenty-three patients underwent a renal biopsy. Of these, 22 patients exhibited vacuolar degeneration of the TECs; 8 patients showed brush border membrane shedding of the TECs; and 12 patients showed protein casts. However, there were no significant differences between the two groups (all P>0.05). Conclusion: In summary, massive proteinuria induced the injury of TECs in patients with NS, and furosemide treatment did not aggravate this injury.

With the advancement of cloud computing, the control flow integrity (CFI) of virtual machines' kernel becomes more and more important for the security of cloud services. Many CFI checking and protecting approaches have been proposed. Among them, dynamic analysis approaches have the best detection capability, but they are rarely used because of the high overhead introduced to the virtual machines to be monitored. In this paper, we propose a function-level kernel CFI checking approach to meet the performance requirements in the cloud. By combining the static memory analysis and the dynamic tracing, our system can achieve high detection capability with low overhead. Since the analysis and tracing targets of our system are kernel functions, our system incurs lower overhead to the monitored virtual machines than the instruction-level monitors. We propose two models to describe the kernel control flows. After building the secure control flow database by learning the normal behaviors, we can detect abnormal control flows in real time. With the help of virtualization and virtual machine introspection techniques, we implement a prototype system in the hardware virtualization environment. From the evaluation, our system has high detection capability with reasonable overhead.