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Lipid metabolism dysregulation is an important characteristic of tumor cells. Increased lipid metabolism provides a vital material and energy source for tumor growth, thereby promoting tumor invasion and metastasis. In the current work, we carried out a series of in vivo and in vitro studies to explore the relationship between miR-29 and lung cancer. The results showed that miR-29 was down-regulated in lung cancer, and overexpression of miR-29 inhibited the proliferation and migration of lung cancer cells (in vitro). Anti-lung cancer effect of miR-29 in vivo was evaluated, and results indicated that transfection of miR-29b/c markedly inhibited lung tumor growth (in vivo). We further explored the potential mechanism by which miR-29 could inhibit the cell proliferation of lung cancer. It is well known that lipid metabolism dysregulation is an important characteristic of tumor cells. Increased lipid metabolism provides a vital material and energy source for tumor growth, thereby promoting tumor invasion and metastasis, and sterol regulatory element-binding protein 1 (SREBP) is involved in liposome metabolism. Therefore, we analyzed the interaction between miR-29C and SREBP-1 in lung cancer cells. Bioinformatics analysis showed that the miR-29 has the potential binding site on SCAP and SREBP mRNA, and Luciferase reporter gene assays revealed the interaction between 3′UTR of SREBP-1 mRNA and miR-29c. Further study showed that miR-29 suppressed (SREBP-1) expression by interacting with 3′UTR of SREBP-1. Further work indicated that miR-29 transfection strongly inhibited lung cancer cell proliferation, which was rescued by the overexpression of SREBP-1. These findings demonstrate that transfection of miR-29 suppressed lung cancer proliferation via inhibiting SREBP-1 expression. The current study provides a basis for exploring the targeted agents against lung cancer.

Objective This study aimed to describe the characteristics of plasma D-dimer level with increasing age and establish a new age-adjusted D-dimer cutoff value for excluding preoperative lower limb deep vein thrombosis (DVT) in elderly patients with hip fractures. Methods This was a retrospective study of elderly patients who presented with acute hip fracture in our institution between June 2016 and June 2019. All patients underwent D-dimer test and duplex ultrasound. Patients were divided into six 5-year-apart age groups. The optimal cutoff value for each group was calculated by using receiver operating characteristic (ROC) curves, whereby the new age-adjusted D-dimer cutoff value was determined. The sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) were calculated and compared when different D-dimer cutoff values were applied, i.e., conventional 0.5 mg/L, previously well-established age-adjusted cutoff value (age × 0.01 mg/L) and the new age-adjusted D-dimer cutoff value herein. Results There were 2759 patients included, 887 males and 1872 females, with an average age of 78 years. In total, 280 patients were diagnosed with preoperative DVT. The optimal cutoff values for the six age groups were 0.715 mg/L, 1.17 mg/L, 1.62 mg/L, 1.665 mg/L, 1.69 mg/L and 1.985 mg/L, respectively, and the calculated age-adjusted coefficient was 0.02 mg/L. With this new coefficient applied, the specificity was 61%, clearly higher than those for conventional threshold (0.5 mg/L, 37%) or previously established age-adjusted D-dimer threshold (age × 0.01 mg/L, 22%). In contrast, the sensitivity was lower than that (59% vs 85% or 77%) when D-dimer threshold of 0.5 mg/L or age-adjusted cutoff value (age × 0.01 mg/L) was used. The other indexes as PPV (15%, 11% and 12%) and NPV (93%, 93% and 94%) were comparable when three different D-dimer thresholds were applied. Conclusions We developed a new age-adjusted D-dimer cutoff value (age × 0.02 mg/L) for a specified high-risk population of patients aged 65 years or older with hip fractures, and demonstrated the improved utility of the D-dimer test for exclusion of DVT. This formula can be considered for use in elderly hip fracture patients who meet the applicable standards as preoperative DVT screening, after its validity is confirmed by more well-evidenced studies.

Maintaining foot comfort is important as it influences the overall comfort of the human body. Shoe microclimate and foot skin temperature have been suggested to contribute to the thermal sensation of the foot. Considering the thermal environment and personal protective equipment (PPE) used for structural and proximity firefighting, climatic chamber tests with 13 male participants were conducted during standing and walking. Four test conditions – unloaded with training shoes, loaded with training shoes, unloaded with firefighting boots, and loaded with firefighting boots – were designed to investigate the effects of firefighting boots and PPE load on the thermal comfort of the human foot. Physiological variables of in-shoe and foot skin temperature at the whole and local regions of the foot were measured and subjective responses were gathered using psychological scales. The results showed that wearing firefighting boots may elevate the thermal sensation of wearers. The PPE load increased the in-shoe and foot skin temperature as well as subjective ratings. Subjective sensations of the foot were strongly correlated with in-shoe and skin temperature in the plantar regions. Correlation analysis of thermal sensation at the whole and local foot regions indicated that the sensation at the forefoot was closest to the whole foot, followed by the midfoot and heel. The findings address the relationship of physiological and subjective variables as well as the thermal sensation of whole and local foot regions, which can be considered for footwear design and thermal comfort prediction of the foot and whole body.

Primary adrenal angiosarcoma is a rare, malignant, vascular neoplasm. These neoplasms typically arise in middle age (median age of 60 years) and are more common in males (65%) than in females. Although rare, these neoplasms are aggressive with a propensity for local recurrence and metastasis and a median survival of 18 months. We present 2 cases of primary adrenal angiosarcoma with synchronous, ipsilateral adrenocortical adenomas. We review the cases of adrenal angiosarcoma reported since 1988 and discuss their clinical and histopathologic characteristics.

Neuroprotection is critical to rescue injured neural tissues and prevent secondary injuries but current clinical neuroprotection options are alarmingly limited. Following neural injury, reactive oxygen species (ROS) are aberrantly accumulated due to overactivation of glutamate, a major neurotransmitter in the vertebrate nervous system, leading to massive neural cell death. Antioxidant defense of neuronal cells is inherently repressed and poorly compensated by current pharmacological antioxidants. Here, we explore whether cold atmospheric plasma (CAP) with its ROS tuned near their physiological concentrations may be neuroprotective. Using a neural cell model, we show that a single treatment of a helium CAP jet for 4–10 s induces a pulsed elevation by 220% of reduced glutathione, the main ROS-scavenging system in cells, and substantially increase the viability of glutamate-damaged cells, demonstrating neuroprotection against glutamate excitotoxicity. By correlating peroxynitrite, hydrogen peroxide and nitric oxide produced by CAP to literature evidence of their neuroprotective activity when acting alone, we suggest that micromolar-level peroxynitrite and 30–70-µM hydrogen peroxide produced from the CAP jet trigger their known and dose-dependent pathways for activating the cellular antioxidant defense. Collectively, our data show that CAP offers a novel and potentially potent strategy to neuroprotection.

Influenza A virus is a single-stranded RNA virus that can cause great mortality and economic loss worldwide. Circular RNAs (circRNAs) are non-coding RNAs that have been shown to have important functions in the regulation of biological processes. However, their functions during the influenza A virus infection process remain unclear. Herein, RNA sequencing technology was used to identify circRNAs expressed in mouse lungs during infection with H7N9/PB2-627 K/701D (H7N9/Wild-type) virus and PB2 mutant viruses (H7N9/PB2-627E/701D and H7N9/PB2-627E/701 N). We identified 7126 circRNAs at different genomic locations during H7N9 influenza virus and its mutant virus infections, of which 186 were differentially expressed. Enrichment analysis revealed that the differentially expressed circRNAs were associated with the viral infection process. Our study shows that circRNA expression profiles were altered following H7N9 influenza A virus infection and the differentially expressed circRNAs may have an important immune-regulating function during viral infection.

Aims G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. Methods and results We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. Conclusion GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

Biodiesel biosynthesis with enzymatic transesterification is considered green, sustainable, and environmentally friendly method. Lipase from Burkholderia cepacia G63 has excellent catalytic properties in biodiesel production. Lipase chaperones promote secretion and folding of enzymes, thereby enhancing enzymatic activity. In the current study, heterologous co-expression of lipase (lipA) and chaperone (lipB) was achieved in Escherichia coli through codon optimization. The enzymatic activity of purified and renatured lipAB was 2080.23 ± 19.18 U/g at 50 °C and pH 8.0. Moreover, lipAB showed increased resistance to pH and temperature changes, and lipAB retained stable catalytic properties after treatment with metal ions, organic solvents, and surfactants, namely Mg2+, methanol, and Triton-100X. Besides, using recombinant lipase lipAB as catalysts, biodiesel was synthesized using rapeseed oil under 50 °C for 72 h with a yield of 90.23%. Thus, the current study confirmed that co-expression of lipase and its chaperone is an effective strategy to enhance enzyme activity and improve the biochemical profile, meanwhile, showing that lipAB is a promising biocatalyst for biodiesel production.

Subarachnoid hemorrhage (SAH) patients’ surgery is performed to prevent extravasation of blood into the subarachnoid space. Cerebral vasospasm (CVS; narrowing of cerebral arteries) occurs following SAH and represents a major cause of associated mortality and morbidity. To improve postsurgery care of SAH patients and their prognosis, the ability to predict CVS onset is critical. We report a long noncoding RNA (lncRNA) signature to distinguish SAH patients with CVS from SAH patients without CVS. Cerebrospinal fluid (CSF) was obtained from SAH patients without CVS (n = 10) and SAH patients with CVS (n = 10). lncRNAs ZFAS1 and MALAT1 were significantly upregulated (p < 0.05), whereas lncRNAs LINC00261 and LINC01619 were significantly downregulated in SAH patients with CVS (p < 0.05) compared to SAH patients without CVS. We applied this lncRNA signature to retrospectively predict CVS in SAH patients (n = 38 for SAH patients without CVS, and n = 27 for SAH patients with CVS). The 4-lncRNA signature was found to be predictive in >40% of samples and the 2-lncRNA comprising MALAT1 and LINC01619 accurately predicted CVS in ∼90% cases. These results are initial steps toward personalized management of SAH patients in clinics and provide novel CSF biomarkers that can substantially improve the clinical management of SAH patients., Graphical Abstract, Cerebral vasospasm (CVS) is a major cause of subarachnoid hemorrhage (SAH) mortality and morbidity. However, the prediction of CVS remains a clinical challenge. Yun-Feng Cui and colleagues report that lncRNAs MALAT1 and LINC01619 can predict CVS occurrence with remarkable precision. This work is a step toward personalized treatment and management of SAH patients.

Author(s): Christine, Chadwick W; Auinger, Peggy; Saleh, Nasrin; Tian, Miao; Bottiglieri, Teodoro; Arning, Erland; Tran, Nam K; Ueland, Per Magne; Green, Ralph; Parkinson Study Group-DATATOP Investigators | Abstract: BackgroundUsing blood specimens from untreated early Parkinson's disease (PD) patients from the DATATOP trial, we found that subjects in the low serum vitamin B12 tertile experienced greater annualized change in ambulatory capacity score, whereas those with moderately elevated (g15 μmol/L) total homocysteine had greater annualized declines in the Mini-Mental State Exam.MethodsIn this this study we sought to determine whether levels of cerebrospinal fluid (CSF) B12 markers were also associated with progression of PD.ResultsThe annualized change in the UPDRS "walking" item, a component of the ambulatory capacity score, was worse in the low B12 tertile. No association with change in the Mini-Mental State Exam was seen for those 7% with the highest baseline CSF total homocysteine.ConclusionsIn these untreated early-PD subjects, low CSF B12 predicted greater worsening of the UPDRS "walking" item, whereas CSF total homocysteine was not associated with progression of cognitive impairment. These findings extend and partially support our findings in serum. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Stress-induced α-synuclein aggregation, especially the most toxic species (oligomers), may precede synaptic and cognitive dysfunction. Under pathological conditions, α-synuclein is degraded primarily through the autophagic/lysosomal pathway. We assessed the involvement of autophagy in α-synuclein aggregation and cognitive impairment following general anesthesia and surgical stress. Autophagy was found to be suppressed in the aged rat hippocampus after either 4-h propofol anesthesia alone or 2-h propofol anesthesia during a laparotomy surgery. This inhibition of autophagy was accompanied by profound α-synuclein oligomer aggregation and neurotransmitter imbalances in the hippocampus, along with hippocampus-dependent cognitive deficits. These events were not observed 18 weeks after propofol exposure with or without surgical stress. The pharmacological induction of autophagy using rapamycin markedly suppressed α-synuclein oligomerization, restored neurotransmitter equilibrium, and improved cognitive behavior after prolonged anesthesia or anesthesia combined with surgery. Thus, both prolonged propofol anesthesia alone and propofol anesthesia during surgery impaired autophagy, which may have induced abnormal hippocampal α-synuclein aggregation and neurobehavioral deficits in aged rats. These findings suggest that the activation of autophagy and the clearance of pathological α-synuclein oligomers may be novel strategies to ameliorate the common occurrence of postoperative cognitive dysfunction.

Two kinds of evaluation methods were applied to gain insight into how fabrics affect the perception of wetness under dynamic skin contact at different velocities. In a previous study, the stimulus intensity rating was tested by applying a fixed amount of water to fabric samples to determine the quantitative ratings for the intensity of the perception of wetness. In this study, the perceived threshold was determined by supplying water continually until the level of wetness was just-detectable. The results indicated positive correlations between the fabric coefficient of friction, the water spreading speed, and the wetness perception threshold, and there were negative correlations between fabric wetting time, skin cooling rate, and wetness perception threshold. However, no correlation between wetness threshold and maximum transient thermal flow ( Qmax) was found in this study. The wetness threshold can be predicted by wetting time and coefficient of friction ( R2 = .70, p < .001). The threshold detection was qualified to evaluate the sensitivity to wetness at the initial detection of moisture on the skin, while the stimulus intensity rating would give a better prediction at the moisture absorption stage. This study provided the evaluation technology for designing sportswear, leisurewear, and health-care products with desirable wetness levels.

Early detection of the pulmonary nodule is critical to increase the five-year survival rate of lung cancer. Many computer-aided diagnosis (CAD) systems have been proposed for nodule detection to assist radiologists in diagnosis. Along this direction, this paper proposes a novel automated pulmonary nodule detection model using the modified V-Nets and a high-level descriptor based support vector machine (SVM) classifier. The former is for nodule candidate detection and the latter is for false positive (FP) reduction. A hard mining scheme for retraining is devised to improve the FP reduction performance. The proposed SVM classifier, which employs more critical features of CT images, performs superior in FP reduction than other SVM based classifiers and CNN classifiers. Experimental results using the LIDC-IDRI dataset are presented to demonstrate the effectiveness of the proposed CAD model.

Objective: Our objective was to assess the incidence and quality of reporting of published health economic evaluations in mainland China and compare the quality of peer-reviewed articles in Chinese and English. Methods: A comprehensive search was conducted for economic evaluations pertaining to China published from 2006 to 2015 using the PubMed, CBM, CMCC, CNKI, VIP, and Wanfang databases. All studies in English that met the inclusion criteria were included. For studies in Chinese, 200 sampled studies were included according to the random seeds method, and the same number of the most-cited studies in Chinese as those in English were included according to the number of citations and journal grades. Researchers independently assessed the quality of the studies using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: After literature search and screening, a total of 310 studies were identified. The majority of these studies were cost-effectiveness studies (82.26%). Scores among different CHEERS items varied greatly. There was a gap between the average quality scores of the studies published in Chinese and those published in English (49.78 ± 9.31 vs. 82.48 ± 17.69) and between the average quality scores of the included most-cited studies in Chinese and English, which was slightly smaller (54.08 ± 10.27 vs. 82.48 ± 17.69). The methods, results, and discussion sections of studies published in Chinese were of low quality. Conclusion: The quality of reporting of health economic evaluations in mainland China has developed slowly. Most of the included studies were incomplete in the presentation of content, making the results less reliable. It is important to standardize and improve the quality of Chinese health economic research.

Background Under normal physiological conditions, insulin exhibited a series of important biological functions. However, more and more evidence indicate that insulin is closely related to the occurrence and development of tumors. Recent studies have shown that insulin is also closely related to the occurrence and development of lung cancer. However, until now, the cellular properties of insulin/insulin receptors on lung cancer have not been fully revealed. Methods Indirect immunofluorescence, western-blot and other techniques have been used to identify the biological activity of insulin on lung cancer cell lines. Results The biological activity of insulin is closely related to its cell behavior. therefore we used lung cancer cell lines as a model to explore the cellular behavior and properties of insulin/IR in the current study, and the results showed that the IR can internalize into lung cancer cells, and it can also transport into the nucleus under insulin treatment. further study showed nuclear-localized IR could promote the proliferation of lung cancer cells. Taken together, this study shows that IR’s nuclear localization is closely related to cell proliferation. Conclusions This work lays the foundation for further research on relationship between insulin and the occurrence and development of lung cancer.

Metastasis is regarded as the fatal hallmark for colon cancer, but molecular mechanisms responsible for it have remained poorly defined. Glucocorticoid receptor (GR) within the tumor microenvironment mediates the effects of stress hormones which are used in clinics for their inflammation-modulatory and immunosuppressive properties. Further, epigenetic activation of GR promotes tumor heterogeneity and metastasis. Here, we sought to investigate the correlation between GR activation and proliferation and invasion in metastatic colon cancer microenvironment. We used proliferation/invasion assays, western blot, RT-qPCR, immunofluorescence staining and quantitative methylation to study glucocorticoid-GR signaling, including the involvement of CDK1, in human colon adenocarcinoma cell lines HT29 and T84 (a representative metastatic cell line). Nuclear expression levels of GR were significantly upregulated in metastatic T84 cells, and glucocorticoid derivative, dexamethasone (DEX) treatment caused increased proliferation and invasion in T84 cell, compared to HT29 cell. DEX treatment induced CDK1 expression which was accompanied by reduced CDK1 methylation, indicating epigenetic regulation. Depletion of GR suppressed proliferation of metastatic colon carcinoma cells and depletion of CDK1 had similar suppressing effects on proliferation as well as invasion of metastatic cells. Our study suggests that glucocorticoid-GR-CDK1 signaling induces proliferation and invasion of colon cancer cells and therapies involving the use of glucocorticoids need to exercise caution and re-evaluation.

Cervical cancer is a deadly gynecological malignancy in need of innovative treatment strategies. Emerging preclinical data has suggested the benefits of nanocarriers over the traditional chemotherapy for cancer treatment. In particular, gold nanoparticles are gaining popularity due to gold's inert nature, limited side effects, good cytocompatibility, and flexibility in preparation/modification. We conjugated polyethylene glycol (PEG) with hollow gold nanospheres (HGNs) and loaded the pegylated HGNs with an anticancer drug, cisplatin to target cervical cancer. HGNs were irradiated with noninfrared laser to increase the penetration of drug into tumor tissue and improve the delivery of cisplatin. We investigated the comparative characterization studies of prepared cisplatin loaded pegylated HGNs (cis PEG-HGNs), free cisplatin, cisplatin loaded HGNs (cis-HGNs), cis PEG-HGNs without laser, and cis PEG-HGNs with laser and its effects over cervical cancer cells. Transmission electron microscopy photomicrographs confirmed the integrity of prepared HGNs. While no significant difference was observed between encapsulation efficiency and drug loading of cis-HGNs (84.6%) and cis PEG-HGNs (86.7%), the encapsulation efficiency increased almost twice in HGNs, compared with control gold nanoparticles (GNs) because of the hollow cavity in HGNs. In-vitro cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa cells. With irradiation, HGNs induced much elevated cytotoxicity. Not only HGNs were internalized by HeLa cells, they were retained in the cellular compartment. We also tested formulations in vivo and observed that the irradiated cis-HGNs and cis PEG-HGNs were most effective in regressing tumors in mice.

BACKGROUND: Genetic variants of coding genes related to blood pressure regulation participate in the pathogenesis of hypertension and determines the response to specific antihypertensive drugs. G protein-coupled receptor kinase 4 (GRK4) and its variants are of great importance in pathogenesis of hypertension. However, little is known about role of GRK4 variants in determine circadian rhythm of blood pressure and response to candesartan in hypertension. The aim of this study was to analyze the correlation of GRK4 variants and circadian rhythm of blood pressure, and to explore their effect on antihypertensive efficiency of candestartan. METHODS: In this study, a total of 1239 cases were eligible, completed ambulatory blood pressure monitoring (ABPm) observation and exon sequencing of G protein-coupled receptor kinase 4 (GRK4). ABPm was obtained before and after 4-week treatment of candesartan. Diurnal variation of systolic blood pressure and antihypertensive effect of candesartan were then assessed. RESULTS: Compared to GRK4 wild type (GRK4-WT), patients with GRK4 variants were more likely to be non-dippers (odds ratio (OR) 6.672, 95% confidence interval (CI) 5.124–8.688, P < .001), with GRK4 A142V (OR 5.888, 95% CI 4.332–8.003, P < .001), A486V (OR 7.102, 95% CI 5.334–9.455, P < .001) and GRK4 R65L (OR 3.273, 95% CI 2.271–4.718, P < .001), respectively. Correlation analysis revealed that non-dippers rhythm of blood pressure were associated with GRK4 variants (r = .420, P < .001), with GRK4 A142V (r = .416, P < .001), A486V (r = .465, P < .001) and GRK4 R65L (r = .266, P < .001), respectively. When given 4-week candesartan, patients with GRK4 variants showed better antihypertensive effect as to drop in blood pressure (24 h mSBP, 21.21 ± 4.99 vs 12.34 ± 4.78 mmHg, P < .001) and morning peak (MP-SBP, 16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001), as well as greater increase in trough to peak ratio (SBP-T/P, .71 ± .07 vs .58 ± .07, P < .001) and smoothness index (SBP-SI, 1.44 ± .16 vs 1.17 ± .11, P < .001) than those with GRK4 WT. CONCLUSION: This study indicates that hypertensive patients with GRK4 variants are more likely to be non-dippers. What’s more, patients with GRK4 variants possess a significantly better antihypertensive response to candesartan than those with GRK4 WT.

One avian H3N2 influenza virus, providing its PB1 and HA segments, reassorted with one human H2N2 virus and caused a pandemic outbreak in 1968, killing over 1 million people. After its introduction to humanity, the pandemic H3N2 virus continued adapting to humans and has resulted in epidemic outbreaks every influenza season. To understand the functional roles of the originally avian PB1 gene in the circulating strains of human H3N2 influenza viruses, we analyzed the evolution of the PB1 gene in all human H3N2 isolates from 1968 to 2019. We found several specific residues dramatically changed around 2002-2009 and remained stable through to 2019. Then, we verified the functions of these PB1 mutations in the genetic background of the early pandemic virus, A/Hong Kong/1/1968(HK/68), as well as a recent seasonal strain, A/Jiangsu/34/2016 (JS/16). The PB1 V709I or PB1 V113A/K586R/D619N/V709I induced higher polymerase activity of HK/68 in human cells. And the four mutations acted cooperatively that had an increased replication capacity in vitro and in vivo at an early stage of infection. In contrast, the backward mutant, A113V/R586K/N619D/I709V, reduced polymerase activity in human cells. The PB1 I709V decreased viral replication in vitro, but this mutant only showed less effect on mice infection experiment, which suggested influenza A virus evolved in human host was not always consisted with highly replication efficiency and pathogenicity in other mammalian host. Overall, our results demonstrated that the identified PB1 mutations contributed to the viral evolution of human influenza A (H3N2) viruses.

Ethnopharmacological relevance Zuojin Pill (ZJP) is a classic prescription composed of Coptis chinensis and Tetradium ruticarpum (A.Juss.) T.G.Hartley, which is often used in the treatment of digestive system diseases. Aim of this study The purpose of this study was to explore the therapeutic effect and potential mechanism of ZJP on chronic atrophic gastritis (CAG) induced by MNNG. Materials and methods The GES-1 and rat model of CAG was established by MNNG. Detection of cell viability, morphological changes and proliferation of GES-1 by CCK-8 and high content screening (HCS) assay. G-17, IL-8 and TNF-α in rat serum were detected by ELISA kit. The expression of related mRNA and protein on TGF-β1/PI3K/Akt signal axis were detected by RT-PCR and Western blot. Results The results showed that ZJP could significantly improve the GES-1 damage induced by MNNG and improve the gastric histomorphology of CAG rats. The intervention of ZJP could significantly reduce the content of G-17 and inflammatory factors IL-8, TNF- α, IL-6 and IL-1β, inhibit the expression of TGF-β1, PI3K and their downstream signals p-Akt, p-mTOR, P70S6K, and promote the expression level of PTEN, LC3-II and Beclin-1. Conclusion ZJP has a good therapeutic effect on CAG induced by MNNG, which may be closely related to the inhibition of TGF-β1/PI3K/Akt signal pathway.

Background Hesperidin, a natural flavanone, has been proven to have multiple protective effects in diabetic rats, such as antioxidant, anti-inflammatory and anti-apoptotic effects. However, the molecular mechanisms underlying the effects of hesperidin are not well elucidated. Methods LO2 cells were stimulated with high glucose (HG, 33 mM) for 24 h to establish a model of oxidative stress. Then, cell viability was determined using the MTT assay. The antioxidant activities, including the reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels, mitochondrial membrane potential (MMP) and adenosine-triphosphate (ATP) production, were measured with the corresponding kits. The levels of gene expression, protein expression and methylation were detected using qRT-PCR, western blotting and methylation-specific PCR (MSP) assays, respectively. Results Compared to the NG treatment, hesperidin treatment increased the viability and improved the oxidative stress, mitochondrial dysfunction and insulin resistance of HG-treated LO2 cells, and these effects were correlated with heightened SOD and GPx activities, increased MMP level and ATP generation, reduced MDA, ROS and glucose levels, and activated GSK3β/AKT and inactivated IRS1 signals. Mechanistically, hesperidin treatment enhanced the miR-149 expression level by reducing its promoter methylation by inhibiting DNMT1. Importantly, knockdown of miR-149 obviously abolished the biological roles of hesperidin. Conclusions Our findings demonstrated that hesperidin treatment ameliorated HG-induced insulin resistance by reducing oxidative stress and mitochondrial dysfunction partly by suppressing DNMT1-mediated miR-149 silencing.

Occurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis., The alternative mechanisms of innate immunity in tumorigenesis of colorectal cancers are unclear. Here, the authors report a non-canonical function of IRF3, a mediator of innate immune signalling, in the suppression of colorectal tumorigenesis and this is via the inhibition of Wnt/β-catenin pathway.

Background Influenza virus remains a continuous and severe threat to public health worldwide, and its prevention and treatment have always been a major international issue. Because of its ability to evade immune surveillance through rapid antigenic drift and antigenic shift, broad-spectrum vaccines seem increasingly important. Methods A mAb named 3C12 from an immortalized hybrid cell was generated via immunizing mice with HA2 protein from A/chicken/Anhui/BRI99/2016 (AH/BRI99/16, H9N2) generated by prokaryotic expression. Then, its broad-spectrum activity was analyzed by WB and IFA. Next, the minimal linear epitope was identified via analyzing the reaction of a series of HA truncations with 3C12. Finally, the protective effects of 3C12 were evaluated in vitro and in vivo infection experiments. Results The mAb could react with the viruses of subtypes H1, H2, H5, H8, H9, H12, H13, H16, and HA protein of H18 in group 1, but failed to react with viruses in group 2. The minimal linear epitope targeted by the mAb was 433NAELLVL439 in full length of HA and localized in the C-helix region of HA2 (residue 95-101, HA2 numbering). What’s more, the mAb 3C12 inhibited H1, H2, H5, H8, H9, H12, H13 and H16 virus-replication in vitro and also has shown effectiveness in preventing and treating disease in mice challenged with lethal dose of AH/BRI99/16 (H9N2) virus in vivo. These results suggested that the broadly reactive anti-HA stem mAb 3C12 exhibited prophylactic and therapeutic efficacy. Conclusions Here, we have demonstrated that the linear epitope identified in this study could be a novel target for developing broad-spectrum influenza diagnostics or vaccine design, and the HA2-based monoclonal antibody is indeed a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.

AIM The aim of this study was to use a metabonomics approach to identify potential biomarkers of exhaled breath condensate (EBC) for predicting the prognosis of acute-on-chronic liver failure (ACLF). METHODS Using liquid chromatography mass spectrometry, EBC metabolites of ACLF patients surviving without liver transplantation (n = 57) and those with worse outcomes (n = 45), and controls (n = 15) were profiled from a specialized liver disease center in Beijing. The metabolites were used to identify candidate biomarkers, and the predicted performance of potential biomarkers was tested. RESULTS Forty-one metabolites, involving glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, and amino acid metabolism, as candidate biomarkers for discriminating the different outcomes of ACLF were selected. A prognostic model was constructed by a panel of four metabolites including phosphatidylinositol [20:4(5Z,8Z,11Z,14Z)/13:0], phosphatidyl ethanolamine (12:0/22:0), L-metanephrine and ethylbenzene, which could predict the worse prognosis in ACLF patients with sensitivity (84.4%) and specificity (89.5%) (area under the receiver operating characteristic curve [AUC] = 0.859, 95% confidence interval [CI] = 0.787-0.931). Compared with Model for End-Stage Liver Disease (MELD) score (AUC = 0.639, 95% CI = 0.526-0.753) and MELD-sodium (MELD-Na) score (AUC = 0.692, 95% CI = 0.582-0.803), EBC-associated metabolite signature model could better predict worse outcomes in patients with ACLF (p

Because molecules, atoms, electrons and chemical bonds all have vibrational properties, all organisms will be affected by the vibrational energy field...

A recently developed humanized mouse has been used to assess the immune response evoked against the isolated attenuated C9 parasite clone (C9-M; carrying a single insertion disrupting the open reading frame (ORF) of PF3D7_1305500) of Plasmodium falciparum. Significant human RBC engraftment was achieved by ameliorating the residual non-adaptive immune response using clodronate-loaded liposome treatment. Controlled reactive professional phagocytic leukocytes in immunodeficient mice allowed for sizeable human blood chimerism and injected huRBCs acted as bona fide host cells for P. falciparum. huRBC-reconstituted immunodeficient mice received infectious challenge with attenuated P. falciparum C9 parasite mutants (C9-M), complemented (C9-C), and wild type (NF54) progenitors to study the role of immune effectors in the clearance of the parasite from mouse circulation. C9-M and NF54 parasites grew and developed in the huRBC-reconstituted humanized NSG mice. Further, the presence of mutant parasites in deep-seated tissues suggests the escape of parasites from the host's immune responses and thus extended the survival of the parasite. Our results suggest an evasion mechanism that may have been employed by the parasite to survive the mouse's residual non-adaptive immune responses. Collectively, our data suggest that huRBCs reconstituted NSG mice infected with attenuated P. falciparum is a valuable tool to explore the role of C9 mutation in the growth and survival of parasite mutants and their response to the host's immune responses. This mouse might help in identifying novel chemotherapeutic targets to develop new anti-malarial drugs.

Propofol, a common intravenous anesthetic, has been found to exert anti-cancer effects with inhibition of cancer cell proliferation, migration and invasion. We tested its possible action against HER2-overexpressing breast cancer cells that developed resistance against trastuzumab. Cell viability assay, ELISA for cytokines, mammosphere formation, quantitative RT-PCR for EMT/IL-6-targeting miRNAs and the in vivo experimental pulmonary metastasis model were performed to understand the epigenetic action of propofol. Propofol sensitized HER2 overexpressing cells to trastuzumab but such action was even more pronounced in resistant cells. Increased cytokines IL-6 as well as IL-8 were released by resistant cells, along with increased mammospheres and induction of EMT, all of which was inhibited by propofol. IL-6 targeting tumor suppressor miR-149-5p was found to be the novel miRNA that was up-regulated by propofol, resulting in the observed effects on cell viability, IL-6 production, mammospheres generation as well as EMT induction. Further, antagonizing miR-149-5p attenuated the propofol effects confirming the epigenetic activity of propofol through miR-149-5p regulation. Finally, in vivo validation in an experimental metastasis model conformed an inhibitory action of propofol against experimental lung metastasis and the essential mechanistic role of miR-149-5p/IL-6 loop. These results present a novel role of general anesthetic propofol against resistant breast cancer cells and the underlying epigenetic regulation of a tumor suppressor miRNA.

Background Berberine has been established as a potential drug for inflammation and metabolic disorder. Here, we aimed to explore the effects and the underlying mechanisms of berberine on obesity-induced chronic inflammation. Methods Mice were fed with high-fat diet to induce obesity. Inflammation in adipocytes were induced with treatment of free fatty acids. The expression of IL-4, CD206, ARG1 and other markers were used to identify M1 and M2 polarization. The expression of GPR78 and CHOP were used to evaluate endoplasmic reticulum stress. H&E staining was used to reveal the adipose tissue macrophage and adipocytes enlargement. Results Berberine treatment attenuated endoplasmic reticulum stress and inflammation in obese mice and free fatty acids-treated adipocytes. Overexpression of lncRNA Gomafu partially blocked the protective effects of berberine in free fatty acids-treated adipocytes by increasing endoplasmic reticulum stress. Moreover, Gomafu overexpression partly reversed berberine-induced enhancement of M2 polarization in macrophages. Finally, Gomafu overexpression induced ER stress and inflammation in mice, which were improved by berberine administration. Conclusions Berberine improves obesity-induced chronic inflammation by alleviating endoplasmic reticulum stress and consequently promoting macrophage M2 polarization. And these protective effects were mediated at least partly by the suppression of lncRNA Gomafu.

Aim To investigate the factors associated with the duration of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) RNA shedding in patients with coronavirus disease 2019 (COVID‐19). Methods A retrospective cohort of COVID‐19 patients admitted to a designated hospital in Beijing was analyzed to study the factors affecting the duration of viral shedding. Results The median duration of viral shedding was 11 days (IQR, 8‐14.3 days) as measured from illness onset. Univariate regression analysis showed that disease severity, corticosteroid therapy, fever (temperature>38.5℃), and time from onset to hospitalization were associated with prolonged duration of viral shedding (p38.5℃) (OR 5.1, 95%CI: 1.5‐18.1), corticosteroid therapy (OR 6.3, 95%CI: 1.5‐27.8), and time from onset to hospitalization (OR 1.8, 95%CI: 1.19‐2.7) were associated with increased odds of prolonged duration of viral shedding. Conclusions Corticosteroid treatment, fever (temperature>38.5℃), and longer time from onset to hospitalization were associated with prolonged viral shedding in COVID‐19 patients. This article is protected by copyright. All rights reserved.

Recent discoveries have led to the development of novel ideas and techniques that have helped elucidate the correlation between epigenetics and tumor biology. Nowadays, the field of tumor genetics has evolved to include a new type of regulation by epigenetics. An increasing number of studies have demonstrated the importance of DNA methylation and hydroxymethylation in specific genes in the progression of cervical cancer. Determining the methylation and hydroxymethylation profiles of these genes will help in the early prevention and diagnosis, monitoring recurrence, prognosis, and treatment of patients with cervical cancer. In this review, we focus on the significance of aberrant DNA methylation and hydroxymethylation in cervical cancer and the use of these epigenetic signatures in clinical settings.

Tobacco smoking was one of the important adverse factors for congenital heart disease. The effects of nicotine, the main component of tobacco, on human embryonic cardiogenesis and related mechanisms remain poorly understood. This work used single-cell RNA sequencing to investigate the effects of nicotine on human embryonic stem cell (hESC) line H9 and its underlying mechanisms during cardiac differentiation. H9 was cultured in feeder-free medium and differentiated in cardiac condition medium when cells reached 90% confluent. Cell viability was detected by MTT after different concentration of nicotine treatment. Different expressed genes during cardiac differentiation was analyzed by single-cell RNA sequencing (scRNA-seq). Key gene expressions were confirmed by qPCR and Western blot. Results showed that 0.1μM–10μM nicotine did not affect H9 cell proliferation. Nicotine 1 μM down-regulated cardiac progenitor cell, mesoderm cell, smooth muscle cell and neural crest cell relatively. Snail1/2 regulating endocardial cushion development were downregulated apparently at differention day 6. Nicotine didn’t affect bry-1 and mesp-1 but inhibited cardiac transcript factors. Consequently, the expression of cTnI, a marker of cardiomyocytes was decreased significantly. The data suggest direct adverse effects of nicotine on heart development at the single-cell level and offer a new approach for estimate drug and environmental toxicity on the pathogenesis of the embryonic cardiovascular system development.

Diabetic retinopathy (DR) is the most severe microvascular complication of diabetes and a major cause of visual impairment and blindness. However, the treatment for DR is still limited. Our study aimed to explore the role of circular RNA_0002570 in DR. First, we predicted the potential microRNA and mRNA that could bind to circ_0002570 and identified the miR-1243 and angiomotin gene; then, we used RT-PCR and Western blot to measure their expression. Next, we evaluated the abilities of proliferation, migration, and angiogenesis in vitro in human retinal microvascular endothelial cells (hRMECs) by CCK-8, transwell assay, and tube formation assay, respectively. To analyze the relationship among miR-1243, circ_0002570, and angiomotin, RNA pull-down and luciferase assay were performed. Our results showed that, in DR patients and high-glucose–induced hRMECs, miR-1243, circ_0002570, and angiomotin were all abnormally expressed. MiR-1243 could directly and competitively bind to both circ_0002570 and angiomotin mRNA to inhibit their expression. Moreover, circ_0002570 suppressed the abilities of proliferation, migration, and angiogenesis in hRMECs induced by high glucose, which was dependent on miR-1243-angiomotin axis. Furthermore, circ_0002570 could upregulate angiomotin by targeting miR-1243 to mediate the dysfunction of hRMECs induced by high glucose. In conclusion, circ_0002570 might serve as a potential target for diagnosis and treatment for DR.

Background: Adenovirus(AdV) infection, which distributes globally when regional epidemics are reported throughout the year, has no specific treatment yet. As the significance of the oral microbiome has been increasingly recognized in virus infection, this study aims to explore the characteristics of the tongue coating microbiome in AdV infected patients for the first time. Methods: 26 patients with AdV infection and 34 matched healthy controls were enrolled to collect tongue coating samples for 16S rRNA gene sequencing. Information on the tongue coating microbiome was annotated by the Human Oral Microbiome Database(HOMD). Results: The characteristics of AdV infection include decreased abundance and evenness of microbiome among individuals (p

For the lung nodule screening, one of the commonly testing methods is the chest radiograph. However, it is difficult to judge with the naked eye with the initial nodule size is usually less than one centimeter. It is known that skilled pulmonary radiologists have a high degree of accuracy in diagnosis, but there remain problems in disease diagnosis. These problems include the miss rate for diagnosis of small nodules and the diagnosis of change in preexisting interstitial lung disease. The recent studies have found that 68% lung cancer nodules in radiographs can be detected by one reader and 82% by two readers. In order to solve this problem, we proposed a 3D-CNN predicting model to differ malignant nodules from all nodules in computed tomography scan. In the experiment results, the model was able to achieve a training accuracy of 100% and a testing accuracy of 94.52%. It shows the proposed model is able to be used for improving the accuracy of detecting nodules.

Chronic mild stress (CMS) has been demonstrated to contribute to atherosclerosis. 6-gingerol (6-Gin), a phenolic component of ginger (Zingiber officinale), has been shown to exert numerous pharmacological properties, such as anti-inflammatory and cardioprotective effects. Here we investigated the role of CMS in the development of atherosclerosis in high-fat diet (HFD)-fed ApoE−/− mice and evaluated the potential therapeutic effects of 6-Gin. Mice were exposed to CMS for 20 weeks, at week 5, they were fed with a high-fat diet (HFD), then received 6-Gin (20 mg/kg/day, intragastrically) treatment. Antiatherosclerotic simvastatin (Sim) and antidepressant lorazepam (Lor) were used for positive drugs. The behavioral and atherosclerotic changes, plasma lipid profiles as well as inflammatory cytokine levels were measured. Our results showed that CMS-exposed mice exhibited reduced body weight gain, sucrose preference and locomotor activity, which are representative of some of the core symptoms of depression. Furthermore, CMS challenge aggravated atherosclerotic lesions, as indicated by increased plaque formation, elevation of plasma total cholesterol, triglyceride, low-density lipoprotein cholesterin, and proinflammatory cytokines including TNF-α, IL-1β, and IL-6. In addition, the expression levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), acetyl-CoA carboxylase (ACC), hHMG-CoA reductase (HMGCR), fatty acid synthase (FAS), sterol regulatory element binding protein (SREBP)-1 and SREBP-2 in the liver tissues were altered after CMS exposure. 6-Gin not only improved the behavioral changes, but also alleviated atherosclerotic lesions, and reversed the expression levels of lipid profiles and inflammatory cytokines in stressed mice. Moreover, the antiatherosclerotic effects of 6-Gin is mediated in part by the AMPK signaling pathway, which is closely associated with cholesterol synthesis and lipid accumulation. Together, these results suggest that 6-Gin attenuates arteriosclerosis in ApoE−/− mice exposed to CMS and HFD, and it may be a potential therapeutic agent for the treatment of atherosclerosis.