Abstract Introduction: Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. Telomerase RNA component (TERC) plays an important role in maintaining TL. We proposed a hypothesis that propofol dose in general anesthesia can be predicted by measuring TL before operation, which greatly reduced the risk of anesthesia, especially the elderly. Methods: The association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight; sex; difference of the Bispectral Index (BIS) before and after anesthesia induction in patients was evaluated by multivariable linear regression analyses. The mutation at the 5’end or 3’end of TERC was detected. We recruited 100 patients of elective surgery. Results: We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p < 0.001), body weight (r = 0.84, p = 0.004), sex (r = 0.83, p= 0.84, p = 0.004), sex (r = 0.83, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.21, 0.19, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, the mutation at the 5’ end or 3’ end of TERC was not found. Conclusions: These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications.

Abstract Objective: To investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients. Methods: KD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis. Results: There were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%. Conclusions: IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.

Abstract Phenols from wheat bran play an important role in improving the physiological function of human body because of their potential antioxidant capacity. However, most of the phenols in wheat bran exist in the form of insoluble binding, which limits their application in the field of food and medicine. In this paper, the modification of wheat bran by Penicillium solid-state fermentation (SSF) was studied. It was found that the content of free phenolic acids in wheat bran was significantly correlated with the activity of key hydrolytic enzymes in the fermentation process. On the fifth day of Penicillium fermentation, the content of free phenolic acids was the highest, which was 750.98 μg/g, which was 1.78 times higher than that of the control. The release of free phenolic acids was highest when wheat bran was treated with compound enzyme at 300 U/mL. Furthermore, the structure of wheat bran was significantly changed by fermentation with enzyme addition. On the 5th day of fermentation, the content of free phenolic acids was as high as 1500 μg/g, which was twice as much as that of fermented bran and 3.56 times that of unfermented bran.

Abstract Introduction/objectives Systemic lupus erythematosus (SLE) is a classic prototype of the multisystem autoimmune disease and follows a relapsing and remitting course. Triptolide is a diterpene triepoxide extracted from Chinese medicine Tripterygium wilfordii Hook F, with potent immunosuppressive and anti-inflammatory properties. Our previous work observed that triptolide alleviated lupus in MRL/lpr lupus mice with the upregulation of regulatory T cells (Treg) proportion in previous study. In this study, we explored the proportion of follicular T regulatory (Tfr), follicular T helper (Tfh) and germinal center (GC) B cells in lupus mice and evaluated the efficacy of triptolide for lupus treatment in vivo. Methods 20 female MRL/lpr mice were randomly divided into 2 treatment groups and treated orally with vehicle or triptolide. C3H mice were all housed as controlled group and treated orally with vehicle. The percentage of Tfr cells, Tfh cells and GC B cells in spleen of mice were detected by Flow cytometric analysis and immunohistochemistry after 13 weeks of treatment. Results We found that the percentage of Tfr cells decreased in MRL/lpr mice compared with controlled mice. The percentage of Tfh cells in MRL/lpr mice was significantly higher compared with that in controlled mice. The ratio of Tfr/Tfh is also decreased in lupus mice. After treated with triptolide in MRL/Lpr mice in vivo, the percentage of Tfr cells and ratio of Tfr/Tfh increased. The proportion of GC B cells also decreased in mice treated with triptolide by FACS and immunohistochemistry. Conclusions Our results demonstrate that the effect of triptolide in alleviating lupus is partly by reversing immune imbalance with increased percentage of Tfr cells and ratio of Tfr/Tfh. Triptolide might also has effect on immune response through inhibiting proliferating GC B cells.

Clinical indicators do not adequately predict the long-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) following percutaneous coronary intervention (PCI). The low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio is expected to be a reliable predictor of the long-term prognosis of these patients. This study aimed to explore the correlation between the LDL/HDL ratio and long-term prognosis in STEMI patients undergoing PCI. Patients with confirmed STEMI who underwent PCI in 7 hospitals in China from January 2009 to December 2011 were enrolled. Information about clinical endpoints, including all-cause death and major adverse cardiovascular events, was collected. Overall, 915 patients were included for analysis, the average follow-up time was 112.2 months. According to the LDL/HDL ratio, the patients were divided into 3 groups using the three-quantile method: low (LDL/HDL≤1.963), medium (1.963<LDL/HDL<2.595), and high (LDL/HDL≥2.595) LDL/HDL groups. The rate of coronary revascularization was higher in the high LDL/HDL group (28.52%) than in the low (17.38%, P=0.001) and medium (19.34%, P=0.010) LDL/HDL groups. The hazard ratio of coronary revascularization was significantly higher in the high LDL/HDL group than in the low (P=0.007) and medium (P=0.004) LDL/HDL groups. Increased LDL/HDL ratio was an independent risk factor for long-term coronary revascularization in STEMI patients undergoing PCI (HR=1.231, 95%CI: 1.023-1.482, P=0.028). These findings suggest that an increased LDL/HDL ratio was an independent risk factor for long-term coronary revascularization in STEMI patients undergoing PCI. The risk of coronary revascularization was significantly increased in patients with LDL/HDL≥2.595.

Abstract Bacteria play the most important role in the fermentation process of Dongcai. At present, the flora in the fermentation process of Dazu Dongcai have not been detected. The physicochemical indexes association with microbiota changes during fermentation have not yet been evaluated. Therefore, it is necessary to explored the correlations between microbial communities and physicochemical indexes during Dazu Dongcai fermentation. Dazu Dongcai samples including five time points were prepared for four year during the spontaneous fermentation process. Microbial community dynamics and associated biochemical changes were characterized using metagenomics sequencing technology and physiochemical properties determination to identify associations between microorganisms and fermentation characteristics. These results indicated that Staphylococcus, Lactobacillus, Terrisporobacter, Blautia, Romboutsia, Bifidobacterium and Streptococcus dominated the whole fermentation process, which were strongly correlated with the physical and chemical indexes. These flora have promoting function during fermentation and may affect the quality of Dongcai. This study provides new detailed insights into the succession of microbial communities and their potential roles in Dazu Dongcai fermentation, so as to establish a correlation analysis model of key factors in the pickling process of Dazu Dongcai, which can lay a foundation for the standardized production of Dazu Dongcai.

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.

ABSTRACT Purpose: Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability with a huge economic burden worldwide. Cerebrolysin (CBL) has been previously used as a nootropic drug. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the precise role of necroptosis in CBL neuroprotection following ICH has not been confirmed. Methods: In the present study, we aimed to investigate the neuroprotective effects and potential molecular mechanisms of CBL in ICH-induced early brain injury (EBI) by regulating neural necroptosis in the C57BL/6 mice model. Mortality, neurological score, brain water content, and neuronal death were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Evans blue extravasation, Western blotting, and quantitative real-time polymerase chain reaction (PCR). Results: The results show that CBL treatment markedly increased the survival rate, neurological score, and neuron survival, and downregulated the protein expression of RIP1 and RIP3, which indicated that CBL-mediated inhibition of necroptosis, and ameliorated neuronal death after ICH. The neuroprotective capacity of CBL is partly dependent on the Akt/GSK3β signaling pathway. Conclusions: CBL improves neurological outcomes in mice and reduces neuronal death by protecting against neural necroptosis.

Resumo: A indústria florestal desempenha um papel importante na economia global e tem influências significativas em nossas vidas e no meio ambiente em que vivemos. O rápido avanço das tecnologias digitais e as transformações industriais em direção à Indústria 4.0 também tem afetado a indústria florestal, principalmente os processos relacionados às compras florestais. A silvicultura 4.0 tem sido alvo de iniciativas de pesquisa nos últimos anos. No entanto, as publicações concentraram-se amplamente nas tecnologias digitais. Este artigo tem como objetivo apresentar um framework para fornecer uma visão holística da Silvicultura 4.0 a partir de uma perspectiva da cadeia de suprimentos florestal. O framework consiste em quatro componentes principais, incluindo as tecnologias digitais pertinentes a cada uma das atividades de negócios da cadeia de suprimentos; a infraestrutura da rede; a inteligência do sistema de próxima geração; e o ecossistema digital da cadeia de suprimentos florestais colaborativa. Esses componentes são essenciais para que a transformação da indústria florestal, na direção de uma verdadeira interconexão entre todos os atores da cadeia de suprimentos. Alguns benefícios econômicos, ambientais e sociais esperados do Silvicultura 4.0 são discutidos, bem como os impactos e desafios potenciais.

Abstract: Forest industry plays an important role in global economy and has significant influences in our lives and the environment that we live in. With the rapid advancement of digital technologies and industrial transformations towards Industry 4.0, similar trend has been found in the forest industry and especially on its forest procurement side. Forestry 4.0 has been proposed as research initiatives in recent years. However, publications have largely focused on the digital technologies. This article is aimed at presenting a framework to provide a holistic view of Forestry 4.0 from a forest supply chain perspective. The framework consists of four major components including the digital technologies pertinent to each of the supply chain business activities; the network infrastructure; the next generation system intelligence; and the collaborative forest supply chain digital ecosystem. These components are essential for the forest industry transformation to become truly interconnected among its supply chain actors. Some economic, environmental, and social expected benefits of Forestry 4.0 are discussed as well as potential impacts and challenges.

Abstract Bone infection or osteomyelitis is usually a complication of inflammation-related traumatic bone injury. Selenium has been shown to have potential cytoprotective effects and the ability to reduce oxidative stress and apoptotic events in osteomyelitis, but the exact mechanism remains unclear. Here, we used LPS-induced apoptotic MC3T3-E1 cells and aimed to confirm selenium's protective effect on cell apoptosis as well as to investigate the underlying mechanisms of this role. Our investigation confirmed selenium-mediated inhibition of LPS-induced cell apoptosis and ROS accumulation in MC3T3-E1 cells. Upon selenium treatment, the bcl-2 levels were upregulated, while the levels of Bax and cyto-C were down-regulated. Furthermore, these effects were accompanied by the suppression of miR-155 and the phosphorylation of protein kinase B (Akt). A more in-depth study demonstrated that LY294002 (a specific inhibitor of PI3K), abolished the selenium-mediated cytoprotective effect of MC3T3-E1 cells against LPS-induced injury and down-regulation of miR-155. In general, these results demonstrated that selenium exerts a cytoprotective effect by attenuating cell apoptosis and oxidative damage via a PI3K/Akt/miR-155-dependent mechanism.

Not much is known about the roles of long non-coding RNAs (lncRNAs) for chronic kidney disease (CKD). In this study, we included CKD patient cohorts and normal controls as a discovery cohort to identify putative lncRNA biomarkers associated with CKD. We first compared the lncRNA expression profiles of CKD patients with normal controls, and identified differentially expressed lncRNAs and mRNAs. Co-expression network based on the enriched differentially expressed mRNAs and lncRNAs was constructed using WGCNA to identify important modules related to CKD. A lncRNA-miRNA-mRNA pathway network based on the hub lncRNAs and mRNAs, related miRNAs, and overlapping pathways was further constructed to reveal putative biomarkers. A total of 821 significantly differentially expressed mRNAs and lncRNAs were screened between CKD and control samples, which were enriched in nine modules using weighted correlation network analysis (WGCNA), especially brown and yellow modules. Co-expression network based on the enriched differentially expressed mRNAs and lncRNAs in brown and yellow modules uncovered 7 hub lncRNAs and 53 hub mRNAs. A lncRNA-miRNA-mRNA pathway network further revealed that lncRNAs of HCP5 and NOP14-AS1 and genes of CCND2, COL3A1, COL4A1, and RAC2 were significantly correlated with CKD. The lncRNAs of NOP14-AS1 and HCP5 were potential prognostic biomarkers for predicting the risk of CKD.

Abstract Background: Acute myeloid leukemia (AML) is an aggressive and mostly incurable hematological malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve AML clinical outcomes. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show biological anti-tumor characteristics in our previous studies. However, its potential effect on leukemia remains unknown. The present research aims to investigate the underlying mechanism of treating leukemia with ATPR in vitro. Methods: In this study, the AML cell lines NB4 and THP-1 were treated with ATPR. Cell proliferation was analyzed by the CCK-8 assay. Flow cytometry was used to measure the cell cycle distribution and cell differentiation. The expression levels of cell cycle and differentiation-related proteins were detected by western blotting and immunofluorescence staining. The NBT reduction assay was used to detect cell differentiation. Results: ATPR inhibited cell proliferation, induced cell differentiation and arrested the cell cycle at the G0/G1 phase. Moreover, ATPR treatment induced a time-dependent release of reactive oxygen species (ROS). Additionally, the PTEN/PI3K/Akt pathway was downregulated 24 h after ATPR treatment, which might account for the anti-AML effects of ATPR that result from the ROS-mediated regulation of the PTEN/PI3K/AKT signaling pathway. Conclusions: Our observations could help to develop new drugs targeting the ROS/PTEN/PI3K/Akt pathway for the treatment of AML.

Abstract Background: Conjunctival filtering bleb scar formation is the main reason for the failure of glaucoma filtration surgery. Cytoglobin (Cygb) has been reported to play an important role in extracellular matrix (ECM) remodeling, fibrosis and tissue damage repairing. This study aimed to investigate the role of Cygb in anti-scarring during excessive conjunctival wound healing after glaucoma filtration surgery. Methods: Cygb was overexpressed in human tenon fibroblasts (hTFs) by transfecting hTFs with lentiviral particles encoding pLenti6.2-FLAG-Cygb. Changes in the mRNA and protein levels of fibronectin, collagen I, collagen III, TGF-β1, and HIF1α were determined by RT-PCR and western blotting respectively. Results: After Cygb overexpression, hTFs displayed no significant changes in visual appearance and cell counts compared to controls. Whereas, Cygb overexpression significantly decreased the mRNA and protein expression levels of collagen I, collagen III and fibronectin compared with control (p < 0.01). There was also a statistically significant decrease in the mRNA and protein levels of TGF-β1 and HIF-1α in hTFs with overexpressed Cygb compared with control group (p < 0.05). Conclusion: Our study provided evidence that overexpression of Cygb decreased the expression levels of fibronectin, collagen I, collagen III, TGF-β1 and HIF-1α in hTFs. Therefore, therapies targeting Cygb expression in hTFs may pave a new way for clinicians to solve the problem of post-glaucoma surgery scarring.

Abstract A new 3-node triangular hybrid displacement function Mindlin-Reissner plate element is developed. Firstly, the modified variational functional of complementary energy for Mindlin-Reissner plate, which is eventually expressed by a so-called displacement function F, is proposed. Secondly, the locking-free formulae of Timoshenko’s beam theory are chosen as the deflection, rotation, and shear strain along each element boundary. Thirdly, seven fundamental analytical solutions of the displacement function F are selected as the trial functions for the assumed resultant fields, so that the assumed resultant fields satisfy all governing equations in advance. Finally, the element stiffness matrix of the new element, denoted by HDF-P3-7β, is derived from the modified principle of complementary energy. Together with the diagonal inertia matrix of the 3-node triangular isoparametric element, the proposed element is also successfully generalized to the free vibration problems. Numerical results show that the proposed element exhibits overall remarkable performance in all benchmark problems, especially in the free vibration analyses.