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β-glucans are linear polysaccharides of d-glucose monomers linked through β-glycosidic bonds and are widely present in nature. Different sources lead to their structural differences. β-glucan has long been acknowledged to be a safe and functional component. Its biological activities include lipid-lowering, hypoglycemic, antitumor and immune regulation etc. A large number of studies have shown that soluble β-glucan can bind to their receptors on the surface of immune cells, activates the pro-inflammatory response of innate immune cells, and enhances the host's antitumor defense. A variety of soluble β-glucans have been widely used in clinical antitumor studies as an immunostimulant to treat the cancer patient. In this paper, we reviewed the molecular structure, antitumor immune activities, structure-activity relationship and clinical trials of soluble β-glucans in order to provide the overall scene of β-glucans as immunostimulant to fight the cancer.

Hypertension is the most prevalent chronic disease and a risk factor for various diseases. Although its mechanisms and therapies are constantly being updated and developed, they are still not fully clarified. In recent years, novel gut microbiota and its metabolites have attracted widespread attention. It is strongly linked with physiological and pathological systems, especially TMA and TMAO. TMA is formed by intestinal microbial metabolism of choline and L-carnitine and converted into TMAO by FMO3. This paper collected and collated the latest researches and mainly discussed the following four parts. It introduced gut microbiota; provided a focus on TMA, TMA-producing bacteria, and TMAO; summarized the alternations in hypertensive patients and animals; discussed the mechanisms of TMAO with two respects; and summarized the regulatory factors may be as new interventions and therapies of hypertension. And, more relevant studies are still prospected to be accomplished between hypertension and TMA/TMAO for further clinical services.

Background Periodontal disease is a chronic inflammatory disease that includes primarily gingivitis and periodontitis, caused by bacterial infection of the supporting structures of the teeth. For years, much attention has been diverted to periodontal disease among the elderly, not enough attention is paid to adolescents. The purpose of this meta-analysis is to evaluate the epidemic trend of periodontal disease in adolescents in mainland China. Methods We conducted a comprehensive literature search through PubMed, Embase, CNKI, Chongqing VIP database, Chinese Wan Fang Database, and CBM. A series of subgroup analyses were done to explore the epidemiological characteristics of periodontal disease (gender, location, age, survey year, and geographical distribution) with the help of related software. Results Thirty studies were included in this study. The data extraction and analysis were from three indexes, including bleeding on probing (BOP), pocket depth (PD), and dental calculus (DC). The detection rates of BOP(+), PD ≥4 mm and DC(+) were 48.8% (95% CI: 36.2-61.4%), 1.0% (0.0-2.0%), and 49.8% (41.0-58.6%), respectively. There were significant differences for the prevalence of gingivitis both in gender and area: the prevalence was higher in males than that in females, and risk ratio was 1.04 (95% CI, 1.01-1.06); a lower prevalence in urban areas compared with rural areas, and the risk ratio was 0.90 (95% CI, 0.85-0.96). Conclusions This study shows a high prevalence of gingivitis among adolescents in China. Higher-quality epidemiological surveys with standard examination criteria are needed.

Background The correct staging of distant metastasis is crucial in deciding an adequate course of therapy for cancer patients. This meta-analysis was carried out to produce an evaluation and comparison of the performances of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18FDG PET-CT) and contrastenhanced magnetic resonance imaging (MRI) in detecting distant metastasis in patients suffering malignant tumors. Systematic literature searches of the MEDLINE and Embase databases were conducted to identify relevant studies in the period from December 31, 1950 to August 1, 2019. We used the following search terms: MRI, magnetic resonance imaging, PET, positron emission tomography, staging, distant metastasis, and distant recurrence. The searches were carried out by two independent reviewers. We only included relevant studies that evaluated both 18FDG PET-CT and contrast-enhanced MRI in relation to distant metastasis detection in the same patients with malignant tumors. The two reviewers independently extracted relevant data from the eligible studies, and the quality of each study was determined with "Quality Assessment of Diagnostic Accuracy Studies-2". Using the bivariate model, we obtained pooled estimates for sensitivity and specificity. The area under the curve (AUC) of summary receiver operating characteristic (SROC) curves for 18FDG PET-CT and contrast-enhanced MRI was used to extra and synthesize, respectively. Methods Pooled sensitivities and specificities, and the AUC of SROC curves for 18FDG PET-CT and contrast-enhanced MRI were used to measure the main outcomes, respectively. Results Across all 13 studies (1,465 patients), 18FDG PET-CT had similar sensitivity (0.84 vs. 0.85) and specificity (0.96 vs. 0.98) to contrast-enhanced MRI. In the 5 studies related to head and neck cancer (511 patients), 18FDG PET-CT had similar sensitivity (0.82 vs. 0.81) and specificity (0.97 vs. 0.98) to contrastenhanced MRI. In the 6 lung cancer-related studies (779 patients), sensitivity (0.72 vs. 0.85) and specificity (0.95 vs. 1.00) tended to be lower in 18FDG PET-CT than in contrast-enhanced MRI. Conclusions :18FDG PET-CT and contrast-enhanced MRI both performed well as detectors of distant metastasis in the diagnosis of cancer patients. The subgroup analysis suggests that 18FDG PET-CT and contrast-enhanced MRI may possess different advantageous qualities for distant metastasis staging of patients with various types of tumor.

Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 104 pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4–5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.

Hepatitis B virus (HBV) infection is a global public health problem that plagues approximately 240 million people. Chronic hepatitis B (CHB) often leads to liver inflammation and aberrant repair which results in diseases ranging from liver fibrosis, cirrhosis, to hepatocellular carcinoma. Despite its narrow species tropism, researchers have established various in vivo models for HBV or its related viruses which have provided a wealth of knowledge on viral lifecycle, pathogenesis, and immunity. Here we briefly revisit over five decades of endeavor in animal model development for HBV and summarize their advantages and limitations. We also suggest directions for further improvements that are crucial for elucidation of the viral immune-evasion strategies and for development of novel therapeutics for a functional cure.

With improvement in living standards and average life expectancy, atherosclerotic cardiovascular disease incidences and mortality have been increasing annually. Paeonia suffruticosa, a natural herb, has been used for the treatment of atherosclerotic cardiovascular disease for thousands of years in Eastern countries. Paeonol is an active ingredient extracted from Paeonia suffruticosa. Previous studies have extensively explored the clinical benefits of paeonol. However, comprehensive reviews on the cardiovascular protective effects of paeonol have not been conducted. The current review summarizes studies reporting on the protective effects of paeonol on the cardiovascular system. This study includes studies published in the last 10 years. The biological characteristics of Paeonia suffruticosa, pharmacological mechanisms of paeonol, and its toxicological and pharmacokinetic characteristics were explored. The findings of this study show that paeonol confers protection against atherosclerotic cardiovascular disease through various mechanisms, including inflammation, platelet aggregation, lipid metabolism, mitochondria damage, endoplasmic reticulum stress, autophagy, and non-coding RNA. Further studies should be conducted to elucidate the cardiovascular benefits of paeonol.

Previous studies have linked self-management with social support and family function. However, little is known about the mechanisms underlying these relationships. This study aimed to explore the underlying relationships between social support (family function) and self-management and to examine whether well-being mediated these relationships in elderly patients with hypertension. A cross-sectional design was used to study 517 elderly patients with hypertension. Demographics, self-management behaviors, social support, family function and well-being were collected by questionnaires. Results showed that social support, family function and well-being were separately associated with self-management behaviors. When social support, family function and well-being were included in the regression model simultaneously, social support and family function were no longer the significant predictors of self-management, demonstrating mediation. Using bootstrapping approach, 89.9% of the relationship between social support and self-management was explained by well-being, and 66.3% of the relationship between family function and self-management was explained by well-being. Improving self-management in patients with hypertension should be a comprehensive approach which should take social support, family function and well-being into account. Health providers should realize the importance of focusing on the promotion of well-being, especially among elderly hypertensive patients with low social support and low family function.

Terminally differentiated cells can be generated by lineage reprogramming, which is, however, hindered by incomplete conversion with residual initial cell identity and partial functionality. Here, we demonstrate a new reprogramming strategy by mimicking the natural regeneration route, which permits generating expandable hepatic progenitor cells and functionally competent human hepatocytes. Fibroblasts were first induced into human hepatic progenitor-like cells (hHPLCs), which could robustly expand in vitro and efficiently engraft in vivo. Moreover, hHPLCs could be efficiently induced into mature human hepatocytes (hiHeps) in vitro, whose molecular identity highly resembles primary human hepatocytes (PHHs). Most importantly, hiHeps could be generated in large quantity and were functionally competent to replace PHHs for drug-metabolism estimation, toxicity prediction and hepatitis B virus infection modeling. Our results highlight the advantages of the progenitor stage for successful lineage reprogramming. This strategy is promising for generating other mature human cell types by lineage reprogramming.

Auranofin is a gold (1)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examined in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. Funding Agencies|Swedish Cancer Society; Radiumhemmets Forskningsfonder; Vetenskapsradet; Barncancerfonden; Knut and Alice Wallenbergs Foundation

Ultrasound treatment and high-pressure homogenization were used to prepare soybean protein (SP)-phosphatidylcholine (PC) nanoemulsions in this study. Nanoemulsions prepared by high-pressure homogenization were more stable. The structural changes of SP and PC under ultrasound treatment and high-pressure homogenization treatment were investigated by Raman spectroscopy. It could be concluded that ultrasound and high-pressure homogenization treatments increased both the content of α-helix and unordered structure but decreased that of β-structures of SP, while the interaction between SP and PC decreased α-helix content and also reduced unordered structure and β-sheet structure. Ultrasound treatment and high-pressure homogenization exposed more tryptophan and tyrosine residues to promote hydrophobic interaction between SP and PC, which was beneficial for stabilizing the nanoemulsion. The SP-PC interaction exerted a more significant effect on side chain structure than those observed under ultrasound treatment and high-pressure homogenization. The dominant g-g-t vibrational mode of the disulfide bond of soybean protein was not appreciably changed by the two preparations. High-pressure homogenization increased the disorder of lipid chains of PC, promoting SP-PC interaction and thereby increasing the stability of the nanoemulsion. The structural change provided a theoretical basis for preparation of two nanoemulsions.

Keep hepatocytes fresh Freshly isolated primary human hepatocytes (PHHs) quickly lose their identity and function in vitro, limiting their application in modeling infectious liver diseases and screening drugs. Xiang et al. describe a simple and effective five-chemical culture condition that can maintain the mature function of cultured PHHs for an extended period of time. PHHs cultured in this way can support the entire viral life cycle and recapitulate long-term infection of the hepatitis B virus. This system created a useful drug-screening platform for developing new antiviral strategies. Science , this issue p. 399

Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation. b-AP15 was found to affect organelle transport in treated cells, raising the possibility that microtubule-transport of toxic protein aggregates is inhibited, leading to enhanced cytotoxicity. In contrast to the antiproliferative effects of the clinically used proteasome inhibitor bortezomib, the effects of b-AP15 are not further enhanced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Our results suggest an inhibitory effect of b-AP15 on the transport of misfolded proteins, resulting in a lack of aggresome formation, and a strong proteotoxic stress response.

Background We examined changes in hepatitis B core-related antigen (HBcrAg) during the four sequential phases of chronic hepatitis B virus (HBV) infection: hepatitis B e antigen (HBeAg)-positive chronic infection (EPCI) and hepatitis (EPCH), followed by HBeAg-negative chronic infection (ENCI) and hepatitis (ENCH). We compared the performance of serum HBcrAg, hepatitis B surface antigen (HBsAg), and HBV DNA in predicting EPCH and ENCH. Methods We enrolled 492 consecutive patients: 49 with EPCI, 243 with EPCH, 101 with ENCI, and 99 with ENCH. HBcrAg was detected by chemiluminescent enzyme immunoassays. HBsAg and HBeAg were detected by chemiluminescent microparticle immunoassays. HBV DNA was detected by real-time PCR. Predictive performance of HBcrAg, HBsAg, and HBV DNA was evaluated using ROC curves. Results Areas under ROC curves (AUCs) of HBcrAg, HBsAg, and HBV DNA for predicting EPCH were 0.738, 0.812, and 0.717, respectively; optimal cutoffs were ≤1.43×10⁵ kU/mL, ≤1.89×10⁴ IU/mL, and ≤3.97×10⁷ IU/mL, with sensitivities and specificities of 66.3% and 77.6%, 65.0% and 93.9%, and 60.5% and 79.6%, respectively. AUCs of HBcrAg, HBsAg, and HBV DNA for predicting ENCH were 0.887, 0.581, and 0.978, respectively; optimal cutoffs were >26.8 kU/mL, >2.29×10² IU/mL, and >8.75×10³ IU/mL, with sensitivities and specificities of 72.7% and 95.1%, 86.9% and 39.6%, and 89.9% and 92.1%, respectively. Conclusions HBsAg and HBV DNA were the best predictors of EPCH and ENCH, respectively. HBcrAg is an important surrogate marker for predicting EPCH and ENCH.

The effect of high pressure homogenization (HPH) treatment (40 to 200MPa) on the structure, interfacial properties and oxidative stability of soy protein isolate emulsions were investigated. After HPH process, emulsifying activity (EAI) and emulsion stability (ESI) could be improved by 114% and 125%, percentage of protein adsorbed to oil-in-water emulsions significantly improved when the pressure was not more than 160 MPa. SDS-PAGE showed that the HPH caused more low molecular mass subunits as the samples were treated below 160 MPa. FTIR traced the changes of four conformations in the secondary structure. Within a suitable pressure range, the apparent viscosity increased with the increasing of pressure, which reflected shear thinning; rheological measurement of emulsions showed G'>G'', G' and G'' both increased significantly with frequency increasing; emulsions treated by HPH had better oxidative stability. This paper suggested the HPH was a useful method for preparation the highly viscous and stable emulsions.

Implant-tooth-supported fixed dentures are designed clinically due to the limitation of the local anatomy in specific implant sites or following an implant failure. However, it is difficult to precisely simulate the post-surgical biomechanical behavior on alveolar bone tissue with daily mastication. This paper presents and validates a reliable system to predict alveolar bone material properties and to identify the best fit treatment. We randomly chose 23 patients who had been followed for at least three years after Implant-tooth-supported fixed dentures. A poroelastic finite element model (FEM) is designed to characterize the biomechanical stresses of the aortic tissue for each patient. The Kernel least mean square is used to model the relationship between the alveolar bone material properties and biomechanical stress features generated by the daily occlusal force. Therefore, the alveolar bone material properties and the optimal treatment can be predicted by this integrated model prior to the operation for a new patient. The prediction accuracy of our model is 91.5%, more accurate than linear finite element model-LFEM (72.8%), mass-spring model-MSM (78.5%), and mass tensor model-MTM (80.2%). That demonstrates the high value of this model as a decision-making assistant for surgical planning of the patients who are scheduled to undergo dentures. The results of this paper demonstrate that this integrated model can predict alveolar bone material properties postoperatively with high accuracy. It combines bio-mechanical and machine learning approach to create a surgical planning tool which may support the clinical decision in the future.

Metagenomic next-generation sequencing (mNGS) holds promise as a diagnostic tool for unbiased pathogen identification and precision medicine. However, its medical utility depends largely on assay simplicity and reproducibility. In the current study, we aimed to develop a streamlined Illumina and Oxford Nanopore-based DNA/RNA library preparation protocol and rapid data analysis pipeline. The Illumina sequencing-based mNGS method was first developed and evaluated using a set of samples with known aetiology. Its sensitivity for RNA viruses (influenza A, H1N1) was 2 EID50/mL, and a good correlation between viral loads and mapped reads was observed. Then, the rapid turnaround time of Nanopore sequencing was tested by sequencing influenza A virus and adenoviruses. Furthermore, 11 respiratory swabs or sputum samples pre-tested for a panel of pathogens were analysed, and the pathogens identified by Illumina sequencing showed 81.8% concordance with qPCR results. Additional sequencing of cerebrospinal fluid (CSF) samples from HIV-1-positive patients with meningitis/encephalitis detected HIV-1 RNA and Toxoplasma gondii sequences. In conclusion, we have developed a simplified protocol that realizes efficient metagenomic sequencing of a variety of clinical samples and pathogen identification in a clinically meaningful time frame.

Background and aims Interferon (IFN)-α, composed of numerous subtypes, plays a crucial role in immune defense. As the most studied subtype, IFN-α2 has been used for treating chronic hepatitis B virus (HBV) infection, with advantages of finite treatment duration and sustained virologic response, but its efficacy remains relatively low. This study aimed to screen for IFN-α subtypes with the highest anti-HBV potency and to characterize mechanisms of IFN-α-mediated HBV restriction. Approach and results Using cell culture-based HBV infection systems and a human-liver chimeric mouse model, IFN-α subtype-mediated antiviral response and signaling activation were comprehensively analyzed. IFN-α14 was identified as the most effective subtype in suppression of HBV covalently closed circular DNA transcription and HBV e antigen/HBV surface antigen production, with median inhibitory concentration values approximately 100-fold lower than those of the conventional IFN-α2. IFN-α14 alone elicited IFN-α and IFN-γ signaling crosstalk in a manner similar to the combined use of IFN-α2 and IFN-γ, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. Guanylate binding protein 5, one of the most differentially expressed genes between IFN-α14-treated and IFN-α2-treated liver cells, was identified as an HBV restriction factor. A strong IFN-α-IFN-α receptor subunit 1 interaction determines the anti-HBV activity of IFN-α. The in vivo anti-HBV activity of IFN-α14 and treatment-related transcriptional patterns were further confirmed, and few adverse effects were observed. Conclusions A concerted IFN-α and IFN-γ response in liver, which could be efficiently elicited by IFN-α subtype 14, is associated with potent HBV suppression. These data deepen the understanding of the divergent activities of IFN-α subtypes and the mechanism underlying the synergism between IFN-α and IFN-γ signaling, with implications for improved IFN therapy and HBV curative strategies.

Background: Shenmai Injection (SMI) has been widely used in the treatment of cardiovascular diseases and can reduce side effects when combined with chemotherapy drugs. However, the potential protective mechanism of SMI on the cardiotoxicity caused by anthracyclines has not been clear. Methods: We used network pharmacology methods to collect the compound components in SMI and myocardial injury targets, constructed a ‘drug-disease’ target interaction network relationship diagram, and screened the core targets to predict the potential mechanism of SMI in treating cardiotoxicity of anthracyclines. In addition, the rat model of doxorubicin cardiotoxicity was induced by injecting doxorubicin through the tail vein. The rats were randomized in the model group, miR-30a agomir group, SMI low-dose group, SMI high-dose group，and the control group. The cardiac ultrasound was used to evaluate the structure and function of the rat heart. HE staining was used to observe the pathological changes of the rat myocardium. Transmission electron microscopy was used to observe myocardial autophagosomes. The expression of miR-30a and Beclin 1 mRNA in the rat myocardium was detected by RT-qPCR. Western Blot detected the expression of LC3-II/LC3-I and p62 protein. Results: The network pharmacological analysis found that SMI could act synergistically through multiple targets and multiple pathways, which might exert a myocardial protective effect through PI3K-Akt signaling pathways and cancer microRNAs. In vivo, compared with the control group, the treatment group could improve the cardiac structure and function, and reduce myocardial pathological damage and the number of autophagosomes. The expression of miR-30a in the myocardium of rats in miR-30a agomir group and SMI group increased (P

Background Periodontitis is a prevalent oral inflammatory disease, which can cause periodontal ligament to a local hypoxia environment. However, the mechanism of hypoxia associated long non‐coding RNAs (lncRNAs) involved in periodontitis is still largely unknown. Methods Microarray was performed to detect the expression patterns of lncRNAs in 3 pairs of gingival tissues from patients with periodontitis and healthy controls. The expression of lncRNA 01126 (LINC01126), miR‐518a‐5p and hypoxia‐inducible factor‐1α (HIF‐1α) in periodontal tissues and in human periodontal ligament cells (hPDLCs) under hypoxia was measured by quantitative real‐time polymerase chain reaction or western blot. Fluorescence in situ hybridization and cell fraction assay were performed to determine the subcellular localization of LINC01126 and miR‐518a‐5p. Overexpression or knockdown of LINC01126 or HIF‐1α was used to confirm their biological roles in hPDLCs. MTT assays were performed to evaluate hPDLCs proliferation ability. Flow cytometry was used to detect apoptosis. ELISA was used to measure the expression levels of interleukin (IL)‐1β, IL‐6, IL‐8 and TNF‐α. Dual‐luciferase reporter assays were performed to assess the binding of miR‐518a‐5p to LINC01126 and HIF‐1α. RNA immunoprecipitation assay was used to identify whether LINC01126 and miR‐518a‐5p were significantly enriched in AGO‐containing micro‐ribonucleoprotein complexes. Results We selected LINC01126, which was the most highly expressed lncRNA, to further verify its functions in periodontitis‐induced hypoxia. The expression of LINC01126 was increased in periodontal tissues. In vitro experiment demonstrated that LINC01126 suppressed proliferation, promoted apoptosis and inflammation of hPDLCs under hypoxia via sponging miR‐518a‐5p. Moreover, we identified HIF‐1α acted as a direct target of miR‐518a‐5p in hPDLCs and LINC01126 promoted periodontitis pathogenesis by regulating the miR‐518a‐5p/HIF‐1α/MAPK pathway. Conclusion LINC01126 promotes periodontitis pathogenesis of hPDLCs via miR‐518a‐5p/HIF‐1α/MAPK pathway, providing a possible clue for LINC01126‐based periodontal therapeutic approaches., LINC01126, which was the most highly expressed lncRNA, to further verify its functions in periodontitis‐induced hypoxia. The expression of LINC01126 were increased in periodontal tissues. In vitro experiment demonstrated that LINC01126 suppressed proliferation, promoted apoptosis and inflammation of hPDLCs under hypoxia via sponging miR‐518a‐5p. Moreover, we identified HIF‐1α acted as a direct target of miR‐518a‐5p in hPDCLs and LINC01126 promoted periodontitis pathogenesis by regulating the miR‐518a‐5p/HIF‐1α/MAPK pathway. In brief, LINC01126 promotes periodontitis pathogenesis of hPDLCs via miR‐518a‐5p/HIF‐1α/MAPK pathway, providing a possible clue for LINC01126‐based periodontal therapeutic approaches.

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.

Background Recent evidence has indicated that long non-coding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) to modulate mRNAs expression by sponging microRNAs (miRNAs). However, the specific mechanism and function of lncRNA-miRNA-mRNA regulatory network in non-small cell lung cancer (NSCLC) remains unclear. Materials and methods We constructed a lung cancer related lncRNA-mRNA network (LCLMN) by integrating differentially expressed genes (DEGs) with miRNA-target interactions. We further performed topological feature analysis and random walk with restart (RWR) analysis of LCLMN. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate the target DEGs in LCLMN. The expression levels of significant lncRNAs in NSCLC were validated by quantitative real-time PCR (RT-qPCR). The prognostic value of the potential lncRNA was evaluated by Kaplan-Meier analysis. Results A total of 33 lncRNA nodes, 580 mRNA nodes and 2105 edges were identified from LCLMN. Based on functional enrichment analysis and co-expression analysis, lncRNA EPB41L4A-AS1 was demonstrated to be correlated with the tumorigenesis of NSCLC. RT-qPCR results confirmed that the expression levels of lncRNA EPB41L4A-AS1 in NSCLC tissues were downregulated compared with adjacent non-cancerous tissues. Kaplan-Meier analysis showed that high expression of lncRNA EPB41L4A-AS1 was associated with better overall survival (OS) in NSCLC patients. Further investigation identified that high expression levels of COL4A3BP, CDS2, PURA, PDCD6IP, and TMEM245 were also correlated with better OS in NSCLC patients. Conclusion In this study, we constructed a lncRNA-miRNA-mRNA ceRNA network to investigate potential prognostic biomarkers for NSCLC. We found that lncRNA EPB41L4A-AS1 could function as a regulator in the pathogenesis of NSCLC.

Brain-derived neurotrophic factor (BDNF) is a biomarker of depression. Recent studies have found adenosine deaminase acting on RNA1 (ADAR1) is a novel target being sensitive to stress at epigenetic level. The epigenetic regulation mechanism of stress-related depression is still unclear so far. To explore the potential regulating mechanism of ADAR1 on BDNF, over and low expression of ADAR1 in PC12 and SH-SY5Y cell lines are prepared. In the meanwhile, chronic unpredictable stress (CUS) mice are treated with ADAR1 inducer (interferon-γ, IFN-γ). ADAR1 regulates BDNF expression, which is proven by that over and low expressions of ADAR1 increase and decrease BDNF mRNA and protein respectively in vitro. Additionally, ADAR1 inducer alleviates the depressive-like behavior of CUS mice by recovering the decreased BDNF protein in brain and serum. Moreover, over and low expressions of ADAR1 reduce and enhance microRNA-432 (miR-432) expression respectively in vitro. Furtherly, over and low miR-432 expressions lead to decreased and increased BDNF and ADAR1 mRNA, protein and immunoreactivity respectively in vitro. The above results demonstrate that ADAR1 is involved in antidepressant action by regulating BDNF via miR-432. Those novel findings can provide a new idea for the study of epigenetic regulation mechanism, early diagnosis, and effective treatment of stress-related depression.

Background The concept of perceived control reflects the belief that one has resources needed to cope with negative events and the ability to positively influence consequences of those negative events. In patients with heart failure, perceived control is associated with a variety of health outcomes. Perceived control is commonly measured using the Control Attitudes Scale-Revised (CASR). There is no Chinese version of the CAS-R (CCAS-R). Objective The purpose of this article was to perform linguistic validation and psychometric evaluation of the CCAS-R. Methods The CAS-R was translated into Chinese according to Brislin's model. Then, a multicenter observational study was performed. Floor and ceiling effects, internal consistency, structural validity, and hypothesis testing were all assessed for psychometric validation of the CCAS-R. Results A total of 227 patients with chronic heart failure were included. There were no ceiling or floor effects detected. Cronbach α was 0.94, indicating a high reliability. The results of the confirmatory factor analysis showed that the 1-factor structure as proposed by the original CAS-R fits the data well. The results of the principal component analysis suggested that the 1-factor structure was optimal as well, accounting for 71.6% of the total variance. The a priori hypothesis was supported by a statistically significant correlation between the CCAS-R and 3 theoretically related variables. Conclusion We developed a semantically equivalent version of the CAS-R in Chinese. The evaluation of the instruments' psychometric properties demonstrated that the CCAS-R has good reliability and validity for use in Chinese patients with chronic heart failure.

Background A virus community is the spectrum of viral strains populating an infected host, which plays a key role in pathogenesis and therapy response in viral infectious diseases. However automatic and dedicated pipeline for interpreting virus community sequencing data has not been developed yet. Results We developed Quasispecies Analysis Package (QAP), an integrated software platform to address the problems associated with making biological interpretations from massive viral population sequencing data. QAP provides quantitative insight into virus ecology by first introducing the definition “virus OTU” and supports a wide range of viral community analyses and results visualizations. Various forms of QAP were developed in consideration of broader users, including a command line, a graphical user interface and a web server. Utilities of QAP were thoroughly evaluated with high-throughput sequencing data from hepatitis B virus, hepatitis C virus, influenza virus and human immunodeficiency virus, and the results showed highly accurate viral quasispecies characteristics related to biological phenotypes. Conclusions QAP provides a complete solution for virus community high throughput sequencing data analysis, and it would facilitate the easy analysis of virus quasispecies in clinical applications.

Currently, there is no efficacious pharmacological treatment for traumatic brain injury (TBI). Previous studies revealed that L-lactate preconditioning has shown rich neuroprotective effects against cerebral ischemia, and therefore has the potential to improve neurological outcomes after TBI. L-lactate played a neuroprotective role by activating GPR81 in diseases of the central nervous system (CNS) such as TBI and cerebral ischemia. In this study we investigated the effects of L-lactate preconditioning on TBI and explored the underlying mechanisms. In this study, the mNSS test revealed that L-lactate preconditioning alleviates the neurological deficit caused by TBI in rats. L-lactate preconditioning significantly increased the expression of GPR81, PSD95, GAP43, BDNF, and MCT2 24 h after TBI in the cortex and hippocampus compared with the sham group. Taken together, these data suggested that L-lactate preconditioning is an effective method with which to recover neurological function after TBI. This reveals the mechanism of L-lactate preconditioning on TBI and provides a potential therapeutic method for TBI in humans.

Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin–proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.

Tissue adhesives have been widely used in surgical procedures. Compared to traditional surgical sutures, tissue adhesives provide fast bonding experiences and full closure of wounds. However, current tissue adhesives are mostly fossil-based synthetic products. Therefore, it is of great significance to explore the use of natural materials in tissue adhesives. Whey is a low-end byproduct of cheese manufacturing. Whey protein, a group of small globular proteins, can exhibit adhesive properties if their structures are modified by physical or chemical means. The objectives of this study were to investigate the functional and structural properties of whey protein-based tissue adhesive, along with the antibacterial effect of totarol, a natural antimicrobial agent. Whey protein isolate (WPI) solutions (25%&ndash, 33% protein) were mixed with different levels (0.1%&ndash, 0.3% w/w) of totarol. The mixtures were analyzed for total plate count and yeast and mold count. The lap-shear bonding strength was tested after the WPI-totarol solutions were mixed with a crosslinking agent, glutaraldehyde (GTA). The lap-shear bonding strength of the tissue adhesive was about 20 kPa, which is comparable to that of a commercial BioGlue&reg, The microstructures of the mixtures were analyzed by scanning electron microscopy (SEM).

In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China)1; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4+ and CD8+ T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease for which treatment focuses on suppressing an overactive immune system and maintaining the physiological balance of synovial fibroblasts (SFs). We found that miR-30-5p was highly expressed in rheumatoid arthritis synovial fibroblasts (RASFs). Subsequently, we predicted that phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2) might be a putative target of miR-30-5p. Recent studies have reported that PIK3R2 can maintain the physiological homeostasis of RASFs. Therefore, miR-30-5p inhibitor has the potential to be used in the treatment of RA, but low levels of miR-30-5p inhibitor internalization affect its application. Triptolide (TP) is an effective drug in the treatment of RA but induces severe toxicity and has a narrow therapeutic window. In this study, the cell internalization performance of miR-30-5p inhibitor was improved by loading it into cell membrane penetrating peptide (CADY)-modified mesoporous silica nanoparticles (MSNs), and the toxicity of TP was decreased by loading it into a controlled drug release system based on MSNs. The nanodrug carrier was constructed by filling a phase-change material (PCM) of 1-tetradecanol and drugs into MSNs that could be triggered by an NIR laser with thermo-chemo combination RA therapy. Our results show that the miR-30-5p inhibitor-loaded MSNs@CADY significantly inhibited RASF proliferation and increased apoptosis. In addition, MSNs@PCM@TP under 808 nm laser irradiation were effective in downregulating immune system activation in an RA rat model. Finally, the results of a pharmacodynamics study showed that the combination of MSNs@CADY@miR-30-5p inhibitor and MSNs@PCM@TP under 808 nm laser significantly increased the effectiveness of RA treatment. These findings provide a novel understanding of RA pathogenesis and a theoretical basis for RA treatment.

Changing ecological communities in response to anthropogenic activities and climate change has become a worldwide problem. The eutrophication of waterbodies in freshwater and seawater caused by the effects of human activities and nutrient inputs could result in harmful algae blooms (HABs), decreases water quality, reductions in biodiversity and threats to human health. Rapid and accurate monitoring and assessment of aquatic ecosystems are imperative. Environmental DNA (eDNA) analysis using high-throughput sequencing has been demonstrated to be an effective and sensitive assay for detecting and monitoring single or multiple species in different samples. In this study, we review the potential applications of eDNA approaches in controlling and mitigating eutrophication and HABs in freshwater and marine ecosystems. We use recent studies to highlight how eDNA methods have been shown to be a useful tool for providing comprehensive data in studies of eutrophic freshwater and marine environments. We also provide perspectives on using eDNA techniques to reveal molecular mechanisms in biological processes and mitigate eutrophication and HABs in aquatic ecosystems. Finally, we discuss the feasible applications of eDNA for monitoring biodiversity, surveying species communities and providing instructions for the conservation and management of the environment by integration with traditional methods and other advanced techniques.

Ginsenoside Rg3, a ginsenoside isolated from Panax ginseng, can regulate autophagy via AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. AMPK/mTOR signaling and autophagy have been reported to be involved in osteogenesis. Here, the effect of Rg3 on ovariectomy (OVX)-induced osteoporosis is explored. In vivo, rats were treated with 20 mg/kg Rg3 after OVX and the body weight (BW) was monitored. Bone mineral density (BMD), hematoxylin-eosin staining of femur tissues, osteogenesis, autophagy, and AMPK/mTOR signaling were analyzed. In vitro, MC3T3-E1 cells were treated with 0, 1, 5, 10, 20, and 100 μmol/L Rg3. 10 and 20 μmol/L Rg3, which had no significant effect on cell viability and significantly affected AMPK/mTOR signaling, were chosen for further analysis. Then osteogenic differentiation was induced with Rg3 or/and AMPK inhibitor (Compound C). AMPK/mTOR signaling, autophagy, osteogenic differentiation, and mineralization by Alizarin Red staining were analyzed. The expression or activity of AMPK/mTOR signaling-related proteins, autophagy markers, and osteogenesis markers was measured by western blotting or commercial kits, and cell viability by cell counting kit-8 assay kits. Rg3 significantly alleviated OVX-induced BW increases, BMD declines and histological changes of femur tissues, promoted osteogenesis, autophagy, and AMPK signaling, but inhibited mTOR signaling in vivo. Moreover, Rg3 significantly enhanced AMPK signaling, autophagy, osteogenic differentiation, and mineralization, but suppressed mTOR signaling in vitro. However, Compound C significantly reversed Rg3-induced alterations in vitro, indicating that Rg3 regulated autophagy, osteogenic differentiation, and mineralization via AMPK/mTOR signaling. Hence, it was speculated that Rg3 might attenuate OVX-induced osteoporosis via AMPK/mTOR signaling pathway.

Zebrafish is an excellent model organism for studying innate immune cell behavior due to its transparent nature and reliance solely on its innate immune system during early development. The Zebrafish Mycobacterium marinum (M. marinum) infection model has been well-established in studying host immune response against mycobacterial infection. It has been suggested that different macrophage cell death types will lead to the diverse outcomes of mycobacterial infection. Here we describe a protocol using intravital microscopy to observe macrophage cell death in zebrafish embryos following M. marinum infection. Zebrafish transgenic lines that specifically label macrophages and neutrophils are infected via intramuscular microinjection of fluorescently labeled M. marinum in either the midbrain or the trunk. Infected zebrafish embryos are subsequently mounted on low melting agarose and observed by confocal microscopy in X-Y-Z-T dimensions. Because long-term live imaging requires using low laser power to avoid photobleaching and phototoxicity, a strongly expressing transgenic is highly recommended. This protocol facilitates the visualization of the dynamic processes in vivo, including immune cell migration, host pathogen interaction, and cell death.

In invertebrates, UNC-45 regulates myosin stability and functions. Vertebrates have two distinct isoforms of the protein: UNC-45B, expressed in muscle cells only and UNC-45A, expressed in all cells and implicated in regulating both Non-Muscle Myosin II (NMII)- and microtubule (MT)-associated functions. Here we show that both, in vitro and in cells, UNC-45A binds to the MT lattice leading to MT bending, breakage and depolymerization. Furthermore, we show that UNC-45A destabilizes MTs independent of its NMII C-terminal binding domain and even in presence of the NMII inhibitor blebbistatin. These findings identified UNC-45A as a novel type of MT-severing protein with a not mutually exclusive but rather dual role in regulating NMII activity and MT stability. Because many human diseases, from cancer to neurodegenerative diseases, are caused by or associated with deregulation of MT stability our findings have profound implications in both, the biology of MTs as well as the biology of human diseases and possible therapeutic implications for their treatment.

Ammonium (NH4+) is an important nitrogen source and is widely used as a fertilizer in agricultural systems. However, excess NH4+ inhibits root growth, and, subsequently, vegetative shoot growth and yield. This study examines whether auxin is involved in differential NH4+ tolerance in rice (Oryza sativa L.), and how auxin is regulated under high-NH4+ conditions in rice. An NH4+-sensitive (Kasalath, Kas) and an NH4+-insensitive (Koshihikari, Kos) rive cultivar were cultured hydroponically with or without exogenous indole-3-acetic acid (IAA) and auxin biosynthesis inhibitors. Root growth, root area, tissue IAA content, and transcription of genes involved in auxin biosynthesis, conjugation and degradation were determined. pDR5::GUS staining and auxin measurement show that high NH4+ can decrease free IAA content in roots. In addition, quantitative RT-PCR, pharmacology, and genetics analysis suggest that Kos possesses a higher capacity for auxin biosynthesis and a weaker capacity for auxin metabolism compared to Kas under high-NH4+ stress. We conclude that the NH4+-tolerant cultivar possesses a higher capacity to maintain auxin homeostasis under high-NH4+ stress, and that this advantage is incurred by promotion of auxin biosynthesis and a suppression of auxin metabolism.

This research paper addresses the hypothesis that RagD is a key signalling factor that regulates amino acid (AA) mediated-casein synthesis and cell proliferation in cow mammary epithelial cells (CMECs). The expression of RagD was analysed at different times during pregnancy and lactation in bovine mammary tissue from dairy cows. We showed that expression of RagD at lactation period was higher (P < 0·05) than that at pregnancy period. When CMECs were treated with methionine (Met) or lysine (Lys), expression of RagD, β-casein (CSN2), mTOR and p-mTOR, and cell proliferation were increased. Further, when CMECs were treated to overexpress RagD, expression of CSN2, mTOR and p-mTOR, and cell proliferation were up-regulated. Furthermore, the increase in expression of CSN2, mTOR and p-mTOR, and cell proliferation in response to Met or Lys supply was inhibited by inhibiting RagD, and those effects were reversed in the overexpression model. When CMECs were treated with RagD overexpression together with mTOR inhibition or conversely with RagD inhibition together with mTOR overexpression, results showed that the increase in expression of CSN2 and cell proliferation in response to RagD overexpression was prevented by inhibiting mTOR, and those effects were reversed by overexpressing mTOR. The interaction of RagD with subunit proteins of mTORC1 was analysed, and the result showed that RagD interacted with Raptor. CMECs were treated with Raptor inhibition, and the result showed that the increase in expression of mTOR and p-mTOR in response to RagD overexpression was inhibited by inhibiting Raptor.In conclusion, our study showed that RagD is an important activation factor of mTORC1 in CMECs, activating AA-mediated casein synthesis and cell proliferation, potentially acting via Raptor.

Objectives: Trifluoperazine (TFP) has potential anticancer activity that was demonstrated in different types of cancer cells. However, little is known about its effects in the T-cell ALK+ anaplastic large cell lymphoma (ALCL). In this study, we investigated the effects of TFP in this aggressive type of cancer.Methods: The cytotoxicities of TFP on DEL and SUP-M2 cells were measured by trypan blue staining. The effects of TFP on cell cycle and apoptosis in DEL and SUP-M2 cells were determined by flow cytometry. The underlying anticancer mechanism of TFP was investigated by real-time PCR, Western Blotting, and nucleophosmin-ALK (NPM-ALK) tyrosine kinase assay in DEL cells.Results: Our results show that TFP did not significantly affect cell viability of human normal lymphocytes, whereas it reduced the cell viability of the ALK+ T-cell lymphoma cells, DEL and SUP-M2, in concentration- and time-dependent manners. TFP also induced cell cycle arrest at G0/G1 phase, and caused cell apoptosis in these cells...

Modulatory neurons project widely throughout the brain, dynamically altering network processing based on an animal's physiological state. The connectivity of individual modulatory neurons can be complex, as they often receive input from a variety of sources and are diverse in their physiology, structure, and gene expression profiles. To establish basic principles about the connectivity of individual modulatory neurons, we examined a pair of identified neurons, the "contralaterally projecting, serotonin-immunoreactive deutocerebral neurons" (CSDns), within the olfactory system of Drosophila Specifically, we determined the neuronal classes providing synaptic input to the CSDns within the antennal lobe (AL), an olfactory network targeted by the CSDns, and the degree to which CSDn active zones are uniformly distributed across the AL. Using anatomical techniques, we found that the CSDns received glomerulus-specific input from olfactory receptor neurons (ORNs) and projection neurons (PNs), and networkwide input from local interneurons (LNs). Furthermore, we quantified the number of CSDn active zones in each glomerulus and found that CSDn output is not uniform, but rather heterogeneous, across glomeruli and stereotyped from animal to animal. Finally, we demonstrate that the CSDns synapse broadly onto LNs and PNs throughout the AL but do not synapse upon ORNs. Our results demonstrate that modulatory neurons do not necessarily provide purely top-down input but rather receive neuron class-specific input from the networks that they target, and that even a two cell modulatory network has highly heterogeneous, yet stereotyped, pattern of connectivity.SIGNIFICANCE STATEMENT Modulatory neurons often project broadly throughout the brain to alter processing based on physiological state. However, the connectivity of individual modulatory neurons to their target networks is not well understood, as modulatory neuron populations are heterogeneous in their physiology, morphology, and gene expression. In this study, we use a pair of identified serotonergic neurons within the Drosophila olfactory system as a model to establish a framework for modulatory neuron connectivity. We demonstrate that individual modulatory neurons can integrate neuron class-specific input from their target network, which is often nonreciprocal. Additionally, modulatory neuron output can be stereotyped, yet nonuniform, across network regions. Our results provide new insight into the synaptic relationships that underlie network function of modulatory neurons.

Background Liver biopsy is the gold standard to assess pathological features (eg inflammation grades) for hepatitis B virus-infected patients although it is invasive and traumatic; meanwhile, several gene profiles of chronic hepatitis B (CHB) have been separately described in relatively small hepatitis B virus (HBV)-infected samples. We aimed to analyse correlations among inflammation grades, gene expressions and clinical parameters (serum alanine amino transaminase, aspartate amino transaminase and HBV-DNA) in large-scale CHB samples and to predict inflammation grades by using clinical parameters and/or gene expressions. Methods We analysed gene expressions with three clinical parameters in 122 CHB samples by an improved regression model. Principal component analysis and machine-learning methods including Random Forest, K-nearest neighbour and support vector machine were used for analysis and further diagnosis models. Six normal samples were conducted to validate the predictive model. Results Significant genes related to clinical parameters were found enriching in the immune system, interferon-stimulated, regulation of cytokine production, anti-apoptosis, and etc. A panel of these genes with clinical parameters can effectively predict binary classifications of inflammation grade (area under the ROC curve [AUC]: 0.88, 95% confidence interval [CI]: 0.77-0.93), validated by normal samples. A panel with only clinical parameters was also valuable (AUC: 0.78, 95% CI: 0.65-0.86), indicating that liquid biopsy method for detecting the pathology of CHB is possible. Conclusions This is the first study to systematically elucidate the relationships among gene expressions, clinical parameters and pathological inflammation grades in CHB, and to build models predicting inflammation grades by gene expressions and/or clinical parameters as well.

While chronic hepatitis B remains a global public health problem, the detailed spatiotemporal dynamics of the key molecular events leading to the multiplication and egress of hepatitis B virus (HBV) are still largely unclear. Previously, we developed a chromogenic in situ hybridization assay for detection of HBV RNA, DNA and covalently closed circular DNA in clinical liver biopsies. Here, we report the establishment of a fluorescent in situ hybridization method for the visualization of HBV RNA, HBV core particle DNA and intranuclear DNA in a tetracycline-inducible HBV replication system (HepAD38) and a de novo infection system (HepG2-NTCP). Using 3D-STORM (three-dimensional stochastic optical reconstruction microscopy), we were able to obtain images of HBV RNA and DNA with improved spatial resolution allowing in-depth analyses of key virological events within complex subcellular compartments. Taken together, these techniques should facilitate a deeper understanding of the molecular events of the HBV life cycle and shed new light on the intricate mechanisms of virus-host interactions.

To optimize the performance of the hepatobiliary scintigraphy (HS) for suspected biliary atresia (BA) using a timesaving and semiquantitative method without a loss in diagnostic accuracy.A retrospective analysis of 185 patients with persistent jaundice who underwent surgery were included. According to the surgical evaluation and pathological diagnosis, patients were divided into a BA group (99 cases) and an infant hepatitis syndrome (IHS) group (86 cases). 99mTc-labeled diethylacetanilide-iminodiacetic acid (99mTc-EHIDA) HS was performed before surgery. The average intestinal radioactivity uptake value minus the background average of radioactivity uptake value at 6 h after label injection (abbreviated as 6-h I-B) was calculated and the difference in 6-h I-B between the two groups was evaluated. The difference in diagnostic efficacy between 6-h I-B and the conventional 24-h HS in BA was also evaluated.A significant difference in 6-h I-B between the two groups was found (t=-5.975, P0.001) and a high level of efficacy of 6-h I-B in the diagnosis of BA was detected. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of 6-h I-B in the diagnosis of BA were 87.88%, 47.67%, 69.19%, 65.91%, and 77.36% respectively, while the corresponding parameters of the 24-h hepatobiliary imaging were 90.91%, 36.05%, 65.41%, 62.07%, and 77.50% respectively, with no significant difference between these values in the diagnosis of BA.HS plays an important role in the diagnosis of infantile jaundice due to conjugated hyperbilirubinemia. The timesaving and semiquantitative method of the 6-h hepatobiliary static imaging showed the same high sensitivity and NPV of the conventional 24-h HS in preventing unnecessary surgery. In the setting of suspected BA, imaging resource utilization could be improved via reducing the acquisition time and simplifying the examination process. The 24-h delay in imaging was considered unnecessary because it was not significantly superior.

The PTPN22 gene encoding the Lyp/Pep protein tyrosine phosphatase is a negative regulator of T-cell receptor (TCR) signaling. Recent studies have shown that phosphorylation of end-binding protein 1 (EB1) is associated with the TCR activation. In this study, using 2-hybrid and mass spectrometry analyses, we identified EB1 as a protein associated with PTPN22. Furthermore, we discovered that EB1 specifically bound to the P1 domain of PTPN22 by competing with CSK, and the variant PTPN22-R620W does not affect the association with EB1, which is instrumental with respect to the regulation of TCR signaling. In addition, PTPN22 dephosphorylates EB1 at tyrosine-247 (Y247), which decreases the expression of the T-cell activation markers CD25 and CD69 and the phosphorylation levels of the TCR molecules ZAP-70, LAT, and Erk, leading to the eventual downregulation of the transcription factor NFAT and reduced the levels of secreted IL-2. The findings of this study provide new insights into the TCR signaling and the T-cell immune response, which are important for clarifying the mechanism of PTPN22-related autoimmune diseases.

Regeneration of cardiomyocytes, endothelial cells and vascular smooth muscle cells (three major lineages of cardiac tissues) following myocardial infarction is the critical step to recover the function of the damaged heart. Myeloid ecotropic viral integration site 1 (Meis1) was first discovered in leukemic mice in 1995 and its biological function has been extensively studied in leukemia, hematopoiesis, the embryonic pattering of body axis, eye development and various genetic diseases, such as restless leg syndrome. It was found that Meis1 is highly associated with Hox genes and their cofactors to exert its regulatory effects on multiple intracellular signaling pathways. Recently with the advent of bioinformatics, biochemical methods and advanced genetic engineering tools, new function of Meis1 has been found to be involved in the cell cycle regulation of cardiomyocytes and endothelial cells. For example, inhibition of Meis1 expression increases the proliferative capacity of neonatal mouse cardiomyocytes, whereas overexpression of Meis1 results in the reduction in the length of cardiomyocyte proliferative window. Interestingly, downregulation of one of the circular RNAs, which acts downstream of Meis1 in the cardiomyocytes, promotes angiogenesis and restores the myocardial blood supply, thus reinforcing better regeneration of the damaged heart. It appears that Meis1 may play double roles in modulating proliferation and regeneration of cardiomyocytes and endothelial cells post-myocardial infarction. In this review, we propose to summarize the major findings of Meis1 in modulating fetal development and adult abnormalities, especially focusing on the recent discoveries of Meis1 in controlling the fate of cardiomyocytes and endothelial cells.

In recent years, although the concept and means of modern treatment of chronic heart failure(CHF) are continually improving, the readmission rate and mortality rate are still high. At present, there is evidence that there is a link between gut microbiota and heart failure, so the intervention of gut microbiota and its metabolites is expected to become a potential new therapeutic target in heart failure. Traditional Chinese medicine(TCM) has apparent advantages in stabilizing the disease, improving heart function, and improving the quality of life. It can exert its effect by operating in the gut microbiota and is an ideal intestinal micro-ecological regulator. Therefore, this article will mainly discuss the advantages of traditional Chinese medicine in treating CHF, the relationship between traditional Chinese medicine and gut microbiota, the relationship between CHF and gut microbiota, and the ways of regulating gut microbiota by traditional Chinese medicine to prevent and treat CHF. It will specify the target and mechanism of traditional Chinese medicine treating heart failure by acting gut microbiota and provide ideas for the treatment of heart failure.

UNC-45A is a ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system. However, emerging studies from both our and other laboratories support a role of UNC-45A outside of actomyosin regulation. This includes studies showing that UNC-45A: regulates gene transcription, co-localizes and biochemically co-fractionates with gamma tubulin and regulates centrosomal positioning, is found in the same subcellular fractions where MT-associated proteins are, and is a mitotic spindle-associated protein with MT destabilizing activity in absence of the actomyosin system.Here, we extended our previous findings and show that UNC45A is variably expressed across a spectrum of cell lines with the highest level being found in HeLa cells and in ovarian cancer cells inherently paclitaxel-resistant. Furthermore, we show that UNC-45A is preferentially expressed in epithelial cells, localizes to mitotic spindles in clinical tumor specimens of cancer and co-localizes and co-fractionates with MTs in interphase cells independent of actin or myosin.In sum, we report alteration of UNC45A localization in the setting of chemotherapeutic treatment of cells with paclitaxel, and localization of UNC45A to MTs both in vitro and in vivo. These findings will be important to ongoing and future studies in the field that further identify the important role of UNC45A in cancer and other cellular processes.

Serotonin plays different roles across networks within the same sensory modality. Previously, we used whole-cell electrophysiology in Drosophila to show that serotonergic neurons innervating the first olfactory relay are inhibited by odorants (Zhang and Gaudry, 2016). Here we show that network-spanning serotonergic neurons segregate information about stimulus features, odor intensity and identity, by using opposing coding schemes in different olfactory neuropil. A pair of serotonergic neurons (the CSDns) innervate the antennal lobe and lateral horn, which are first and second order neuropils. CSDn processes in the antennal lobe are inhibited by odors in an identity independent manner. In the lateral horn, CSDn processes are excited in an odor identity dependent manner. Using functional imaging, modeling, and EM reconstruction, we demonstrate that antennal lobe derived inhibition arises from local GABAergic inputs and acts as a means of gain control on branch-specific inputs that the CSDns receive within the lateral horn.

Tumors and heart disease are two of the leading causes of human death. With the development of anti-cancer therapy, the survival rate of cancer patients has been significantly improved. But at the same time, the incidence of cardiovascular adverse events caused by cancer treatment has also been considerably increased, such as arrhythmia, left ventricular (LV) systolic and diastolic dysfunction, and even heart failure (HF), etc., which seriously affects the quality of life of cancer patients. More importantly, the occurrence of adverse events may lead to the adjustment or the cessation of anti-cancer treatment, which affects the survival rate of patients. Understanding the mechanism of cardiotoxicity (CTX) induced by antineoplastic drugs is the basis of adequate protection of the heart without impairing the efficacy of antineoplastic therapy. Based on current research, a large amount of evidence has shown that oxidative stress (OS) plays an essential role in CTX induced by antineoplastic drugs and participates in its toxic reaction directly and indirectly. Here, we will review the mechanism of action of OS in cardiac toxicity of antineoplastic drugs, to provide new ideas for researchers, and provide further guidance for clinical prevention and treatment of cardiac toxicity of anti-tumor drugs in the future.

Ventricular remodeling (VR) is a complex pathological process of cardiomyocyte apoptosis, cardiac hypertrophy, and myocardial fibrosis, which is often caused by various cardiovascular diseases (CVDs) such as hypertension, acute myocardial infarction, heart failure (HF), etc. It is also an independent risk factor for a variety of CVDs, which will eventually to damage the heart function, promote cardiovascular events, and lead to an increase in mortality. MicroRNAs (miRNAs) can participate in a variety of CVDs through post-transcriptional regulation of target gene proteins. Among them, microRNA-30 (miR-30) is one of the most abundant miRNAs in the heart. In recent years, the study found that the miR-30 family can participate in VR through a variety of mechanisms, including autophagy, apoptosis, oxidative stress, and inflammation. VR is commonly found in ischemic heart disease (IHD), hypertensive heart disease (HHD), diabetic cardiomyopathy (DCM), antineoplastic drug cardiotoxicity (CTX), and other CVDs. Therefore, we will review the relevant mechanisms of the miR-30 in VR induced by various diseases.

Although the mechanism of the occurrence and development of heart failure has been continuously explored in the past ten years, the mortality and readmission rate of heart failure is still very high. Modern studies have shown that gut microbiota is associated with a variety of cardiovascular diseases, among which the study of gut microbiota and heart failure attracts particular attention. Therefore, understanding the role of gut microbiota in the occurrence and development of heart failure will help us further understand the pathogenesis of heart failure and provide new ideas for its treatment. This paper introduced intestinal flora and its metabolites, summarized the changes of intestinal flora in patients with heart failure, clarified that intestinal barrier damage and bacterial translocation induced inflammation and immune response aggravated heart failure, and altered intestinal microflora affected various metabolic pathways including trimethylamine/TMAO, SCFA, and Bile acid pathway leads to heart failure. At the same time, regulating intestinal microflora through diet, probiotics, antibiotics, fecal transplantation and microbial enzyme inhibitors has grown up to be a potential treatment for many metabolic disorders.