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Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Qo and Qi sites of cytochrome bc1). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets., Graphical abstract A highly potent antimalarial compound, RYL-581, has a potential multi-targeting mechanism of action by simultaneously binding to three pockets (allosteric site of PfNDH2, Qo and Qi sites of Pfbc1).Image 1

Aminoacyl-tRNA synthetases (ARSs) are widely found in organisms, which can activate amino acids and make them bind to tRNA through ester bond to form the corresponding aminoyl-tRNA. The classic function of ARS is to provide raw materials for protein biosynthesis. Recently, emerging evidence demonstrates that ARSs play critical roles in controlling inflammation, immune responses, and tumorigenesis as well as other important physiological and pathological processes. With the recent development of genome and exon sequencing technology, as well as the discovery of new clinical cases, ARSs have been reported to be closely associated with a variety of cardiovascular diseases (CVDs), particularly angiogenesis and cardiomyopathy. Intriguingly, aminoacylation was newly identified and reported to modify substrate proteins, thereby regulating protein activity and functions. Sensing the availability of intracellular amino acids is closely related to the regulation of a variety of cell physiology. In this review, we summarize the research progress on the mechanism of CVDs caused by abnormal ARS function and introduce the clinical phenotypes and characteristics of CVDs related to ARS dysfunction. We also highlight the potential roles of aminoacylation in CVDs. Finally, we discuss some of the limitations and challenges of present research. The current findings suggest the significant roles of ARSs involved in the progress of CVDs, which present the potential clinical values as novel diagnostic and therapeutic targets in CVD treatment., Graphical abstract, Zou et al. reviewed the functional roles of aminoacyl-tRNA synthetases (ARSs) in cardiovascular diseases (CVDs) and discussed the involved molecular mechanisms. These reviews provide important insights into the potential value of ARS and provide potential diagnosis biomarker or therapeutic targets for CVDs, especially for angiogenesis and cardiomyopathy.

Background Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts. CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement. Case summary We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism (CH) diagnosed with CHF. The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine. He has developed normally without neurocognitive deficits. Abnormal liver function was observed in the patient at the age of 4 years and 11 mo, and elevated levels of liver function indices were persistent for 5 mo. Radiological imaging indicated hepatospleno-megaly without narrowing of the portal vein but dilated splenic vein. A liver biopsy confirmed the pathological features of CHF. Genetic testing revealed two novel homozygous mutations, namely, c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A (p.R974H) in DUOX2 related to CH. The patient was treated with compound glycyrrhizin tablet, ursodeoxycholic acid, and levothyroxine after diagnosis. The patient achieved a favorable clinical outcome during a follow-up period of over 2 years. Conclusion Herein, we report the first case of a Chinese boy with comorbidity of CHF and CH, carrying both PKHD1 gene and DUOX2 gene novel mutations. Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.

The thiol redox proteome refers to all proteins whose cysteine thiols are subjected to various redox-dependent posttranslational modifications (PTMs) including S-glutathionylation (SSG), S-nitrosylation (SNO), S-sulfenylation (SOH), and S-sulfhydration (SSH). These modifications can impact various aspects of protein function such as activity, binding, conformation, localization, and interactions with other molecules. To identify novel redox proteins in signaling and regulation, it is highly desirable to have robust redox proteomics methods that can provide global, site-specific, and stoichiometric quantification of redox PTMs. Mass spectrometry (MS)-based redox proteomics has emerged as the primary platform for broad characterization of thiol PTMs in cells and tissues. Herein, we review recent advances in MS-based redox proteomics approaches for quantitative profiling of redox PTMs at physiological or oxidative stress conditions and highlight some recent applications. Considering the relative maturity of available methods, emphasis will be on two types of modifications: 1) total oxidation (i.e., all reversible thiol modifications), the level of which represents the overall redox state, and 2) S-glutathionylation, a major form of reversible thiol oxidation. We also discuss the significance of stoichiometric measurements of thiol PTMs as well as future perspectives toward a better understanding of cellular redox regulatory networks in cells and tissues.

To investigate the contributions of atmospheric particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5) to heavy air pollution events in Fen-Wei Plain, China and identify their sources, a combination of wavelet analysis and low-atomic number (Z) particle electron probe X-ray microanalysis (EPMA) was utilized in a typical haze episode lasting 10 days (from Nov. 11 to 20, 2016) at Jinzhong, an inland city adjacent to Taiyuan, the capital of Shanxi Province. A 3-layer wavelet decomposition filtration was performed using the daubechies wavelet functions (db6) and the distribution of the real wavelet transformation coefficients and variance of wavelet series for various pollutants within 240 h was plotted. Five dominant periods of PM2.5 in mass concentration were observed, peaking at 101 h, 144 h, 50–51 h, 27–28 h, and 18 h in sequence from high to low in the wavelet variance chart. They were similar to those of PM10, SO2, and CO and partially overlapped with those of NO2, but different from those of O3, implying that PM2.5 have the same sources as PM10, SO2, and CO and have complicated relations with O3 and NO2. It was further found that the chemical compositions of PM2.5 in the dominant periods made great changes compared to the non-dominant periods. The relative number abundance of elemental carbon (EC) and droplets rich in CNOS (likely the mixture of carbonaceous matter with secondary aerosols such as NH4NO3 and (NH4)2SO4/NH4HSO4) in the first and second dominant period were significantly higher than that in other periods. It is concluded that coal and biomass combustion and secondary particles are still the main contributors to the wintertime heavy air pollution events in Fen-Wei Plain, suggesting that the wavelet analysis combined with low-Z particle EPMA is useful in examination of atmospheric particulate matter's origin, evolution, and roles played in haze events.

Background To investigate the diagnostic value of arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM) imaging in distinguishing nasopharyngeal carcinoma (NPC) in T1 stage from healthy controls (HC). Methods Forty-five newly diagnosed NPC patients in the T1 stage and thirty-one healthy volunteers who underwent MR examinations for both 3D pseudo-continuous ASL (pCASL) and IVIM were enrolled in this study. The Mann-Whitney test was used to compare the mean values of blood flow (BF) derived from pCASL and IVIM derived parameters, including apparent diffusion coefficient (ADC), pure molecular diffusion (D), pseudo-diffusion coefficient (D*) and perfusion fraction (f) between NPC tumor and benign nasopharyngeal mucosa of HC. Receiver Operating Characteristic (ROC) was performed to determine diagnostic cutoff and efficiency. The correlation coefficients among parameters were investigated using Spearman’s test. Results The NPC in the T1 stage showed higher mean BF, lower ADC, D, and f compared to benign nasopharyngeal mucosa (P < 0.001) with the area under curve of ROC of 0.742–0.996 (highest by BF). BF cutoff was set at > 36 mL/100 g/min; the corresponding sensitivity, specificity, and accuracy in differentiating NPC stage T1 from benign nasopharyngeal mucosa were 95.56% (43/45), 100% (31/31) and 97.37% (74/76), respectively. BF demonstrated moderate negative correlation with D* on HC (ρ [Spearman correlation coefficients] = − 0.426, P = 0.017). Conclusions ASL and IVIM could reflect the difference in perfusion and diffusion between tumor and benign nasopharyngeal mucosa, indicating a potential for accessing early diagnosis of NPC. Notably, BF, with a specificity of 100%, demonstrated better performance compared to IVIM in distinguishing malignant lesions from healthy tissue.

Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood with the overall 5 years' survival less than 40%. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and over expressed in multiple cancers, including neuroblastoma. We found that higher PLK1 expression related to poor outcome of NB patients. BI2536, a small molecule inhibitor against PLK1, significantly reduced cell viability in a panel of NB cell lines, with IC50 less than 100 nM. PLK1 inhibition by BI 2536 treatment induced cell cycle arrest at G2/M phase and cell apoptosis in NB cells. Realtime PCR array revealed the PLK1 inhibition related genes, such as BIRC7, TNFSF10, LGALS1 and DAD1 et al. Moreover, autophagy activity was investigated in the NB cells treated with BI 2536. BI 2536 treatment in NB cells increased LC3-II puncta formation and LC3-II expression. Formation of autophagosome induced by BI 2536 was observed by transmission electron microscopy. However, BI2536 abrogated the autophagic flux in NB cells by reducing SQSTM1/p62 expression and AMPKαT172 phosphorylation. These results provide new clues for the molecular mechanism of cell death induced by BI 2536 and suggest that BI 2536 may act as new candidate drug for neuroblastoma.

Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G(2)/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.

ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

Background: Pulmonary arterial hypertension (PAH) is a disease that the pulmonary artery is abnormally elevated. P2Y12 is an adenosine diphosphate (ADP) receptor and it act as the target of thienopyridine antiplatelet drugs by controlling vascular remodeling. Inhibition of P2Y12 receptor in the process of PAH was explored in this study.Methods: The PAH model was established in Sprague-Dawley rats by single subcutaneous injection of 60 mg/kg monocrotaline (MCT). The ticagrelor solution (a selective P2Y12R inhibitor) was intraperitoneally injected into rats at a dose of 14 mg/kg from the time of MCT injection to day 28.Results: In the lung tissues of PAH rats, the marked P2Y12R was detected. Treatment with ticagrelor greatly decreased P2Y12R level and efficiently abolished the upregulation of α-SMA as demonstrated by Western blot and RT-PCR. The wall thickness and occlusion score of the pulmonary arterioles showed that blockade of P2Y12R could relieve lung remodeling caused by PAH. The haemodynamic changes at 4 weeks determined that P2Y12R inhibition affected RV pressure and right heart hypertrophy.Conclusions: P2Y12R might be involved in the pathogenesis of PAH. Blockade of P2Y12R has potential in treating PAH.

BackgroundEEF1E1 has been reported to play a role in ovarian cancer, breast cancer, non-small cell lung cancer and other cancers, but its role and mechanism in hepatocellular carcinoma (HCC) are still unknown.MethodsEEF1E1 expression in human HCC was analyzed via the GTEx and TCGA database. Logistic regression analysis was used to analyze the clinicopathological correlation of EEF1E1 expression. The correlation between EEF1E1 expression and patients’ prognosis was analyzed in HCC, shown by forest plots, nomogram and Kaplan–Meier curves. Hazard ratio (HR) with 95% confidence intervals and log-rank p-value were calculated via multivariate/univariate survival analyses. Moreover, the correlation between EEF1E1 and tumor immune infiltration was analyzed using the gsva package with the ssgsea algorithm. Pearson correlation was used to investigate the correlation between EEF1E1 expression and p53 pathway genes expression. Two third-party databases were used to validate the content of EEF1E1 protein and mRNA expression patterns and prognosis analysis. The immunohistochemistry and multiplex immunohistochemistry was used to verify the bio-informatics results.ResultsEEF1E1 mRNA and protein expression in tumor was statistically higher than normal (EEF1E1 mRNA: p < 0.001; EEF1E1 protein: p < 0.01). Results from paired t-test (cancer and adjacent tissues) exhibited consistent trend (t = 7.572, p < 0.001). Immunohistochemistry showed that EEF1E1 is highly expressed in cancer. The expression of EEF1E1 was positively correlated with body weight, BMI, tumor status, vascular invasion, AFP, logistic grade, T stage and pathological stage. The univariate Cox model revealed that high EEF1E1 expression was strongly associated with worse OS (HR=2.581; 95% CI: 1.782-3.739; p < 0.001), as was T stage, pathologic stage, Histologic grade. High EEF1E1 expression was the only independent prognostic factor associated with OS (HR=2.57; 95% CI: 1.715-3.851; p < 0.001) in the multivariate analysis. EEF1E1 was significantly correlated with various immune cells, including cytotoxic cells, DC, macrophages, neutrophils, NK cd56bright, TFH, Tgd, Th17, Th2, Treg. Multiplex immunohistochemistry showed that the EEF1E1 protein level is positively correlated to the CD3, CD4, PD1 and is negatively correlated to the CD8. The expression level of EEF1E1 in HCC was significantly correlated with the key genes involved in the p53 pathway. The expression of EEF1E1, ATM, p53 and CASPASE3 in HCC tissues was significantly higher than that in adjacent tissues.ConclusionEEF1E1 is highly expressed in cancer tissues in HCC. EEF1E1’s high expression is significantly correlated with worse prognosis and immune cell infiltration of HCC. EEF1E1 may be participating in EEF1E1/ATM/p53 signaling pathway in HCC.

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. Hepatitis B virus (HBV) is one of the leading causes of HCC, but the precise mechanisms by which this infection promotes cancer development are not fully understood. Recently, miR-340-5p, a microRNA (miRNA) that has been identified as a cancer suppressor gene, was found to inhibit the migration and invasion of liver cancer cells. However, the effect of miR-340-5p on cell proliferation and apoptosis in HBV-associated HCC remains unknown. In our study, we show that miR-340-5p plays an important role during HBV infection and hepatocellular carcinoma development. Specifically, this miRNA directly binds to the mRNA encoding activating transcription factor 7 (ATF7), a protein that both promotes cell proliferation and suppresses apoptosis through its interaction with heat shock protein A member 1B (HSPA1B). We further found that miR-340-5p is downregulated by HBV, which enhances ATF7 expression, leading to enhanced cell proliferation and inhibition of apoptosis. Notably, ATF7 is upregulated in HCC tissue, suggesting that HBV may target miR-340-5p in vivo to promote ATF7/HSPA1B-mediated proliferation and apoptosis and regulate liver cancer progression. This work helps to elucidate the complex interactions between HBV and host miRNAs and further suggests that miR-340-5p may represent a promising candidate for the development of improved therapeutic strategies for HCC.

Objective Less than half of eligible Chinese rural women have been screened for breast and cervical cancer. The objective of this study was to describe individual-level reasons for attending or not attending ‘two cancers’ screening using Andersen's Behavioral Model of Health Services Use. Study design Cross-sectional study. Methods The study sample was from the Health Services Survey in 2013 in Jiangsu, China. A total of 6520 rural women aged 36–65 years answered the questions on ‘two cancers’ screening participation and were included in the final analysis, which consisted of univariate and multivariate logistic regression. Results In the results of multivariate logistic regression, factors significantly associated with having ‘two cancers’ screening included educational level (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.65–0.92), per capita household income (OR = 0.65, 95% CI = 0.58–0.73), availability of female medical faculty in township facilities (OR = 0.35, 95% CI = 0.28–0.42), quality of life (OR = 0.72, 95% CI = 0.58–0.90), being nulliparous (OR = 3.21, 95% CI = 1.96–5.26), and multiparous (OR = 1.91, 95% CI = 1.68–2.16). Conclusion To reduce inadequate screening service utilization of breast and cervical cancer in rural areas, efforts should be made not only to target the vulnerable rural women with lower income, lower educational level, and lower health conditions but also to further improve access to female primary-care providers. Strategies are also urgently needed to focus on nulliparous and multiparous women.

Streptococcus mutans, a facultatively aerobic and Gram-positive bacterium, is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. In this study, the aromatic-amino-acid aminotransferase fromStreptococcus mutans(SmAroAT) was recombinantly expressed inEscherichia coli. An effective purification protocol was established. The recombinant protein was crystallized using the hanging-drop vapor-diffusion method with PEG 3350 as the primary precipitant. The crystal structure ofSmAroAT was solved at 2.2 Å resolution by the molecular-replacement method. Structural analysis indicated that the proteins of the aromatic-amino-acid aminotransferase family have conserved structural elements that might play a role in substrate binding. These results may help in obtaining a better understanding of the catabolism and biosynthesis of aromatic amino acids.

Background The hypothalamic paraventricular nucleus (PVN) is the center of the regulation of autonomic nervous system functions and cardiovascular activity. Phosphoinositide-3 kinase (PI3K)-AKT pathway in PVN contributes to mediate sympathetic nerve activity and is activated in spontaneously hypertensive rats. Overactivation of the sympathetic output was considered as an important mechanism of the arrhythmias. In the present study, we aimed to explore whether targeted regulation of sympathetic activity in PVN could reduce the peripheral sympathoexcitatory and attenuate the ventricular arrhythmias (VAs) in myocardial infarction (MI) rats via PI3K-AKT pathway. Methods A stainless steel gauge guide cannula was stereotaxically implanted into the PVN, and 7 days later, rats were randomly divided into the following 4 groups: group A, control + dimethyl sulfoxide (DMSO); group B, control + LY294002; group C, MI surgery + DMSO; and group D, MI surgery + LY294002. Studies were conducted seven days post-MI. Myocardial function, infarct size, inducible VAs by programmed electrical stimulation, renal sympathetic nerve activity (RSNA), and protein level of PI3K and AKT were measured. Results MI increased the protein ratios of p-PI3K-to-total-PI3K and p-AKT-to-total-AKT in PVN but can be reduced by LY294002 treatment. Inhibition of sympathetic nerve activity in PVN led to a reversion in plasma norepinephrine, RSNA and inducible VAs in MI rats. Conclusions PI3K-AKT pathway in the PVN was a main mechanism in regulating sympathetic activity and arrhythmias in MI rats. Targeted inhibition of sympathetic activity in PVN may be a potential treatment for the VAs via PI3K-AKT pathway.

Background Population ageing in China has brought increasing attention to the health inequalities of the elderly. The purpose of this paper is to measure income-related health inequality among the elderly in China and decompose its causes. Methods The data are from the China Health and Retirement Longitudinal Study (CHARLS) survey in 2013, which contains 6176 individuals aged 60 years and above. A multiple linear regression model was used to analyze the influencing factors of self-rated health (SRH) among the elder people. Furthermore, the corrected concentration index were used to measure income-related health inequality. Wagstaff-type decomposition analysis was employed to explore the cause of inequality. The measurement and decomposition of health inequality was also performed separately in the male and female subgroups. Results Most elderly declared their health status as “fair” (51.33%) or “poor” (21.88%). Income, gender, residence, region, health insurance and other factors had significant association with SRH (P

Very early-onset inflammatory bowel disease (VEO-IBD) is defined as IBD diagnosed in children younger than 6 years of age. VEO-IBD is often associated with a monogenic etiology or primary immune deficiency. Here, we report the case of a 7-month-old Chinese girl diagnosed with VEO-IBD who had a variant in the interleukin-10 receptor A (IL-10-RA) gene. The patient presented with recurrent fevers, abdominal pain, diarrhea, perianal abscesses, and oral ulcers. Whole-exome sequencing (WES) identified a novel compound heterozygote mutation, c.395T>G (p.Leu132Arg)/ex.1del (p.?), in the IL-10RA gene of the patient. The missense mutation c.395T>G (p.Leu132Arg) was inherited from her mother, and ex.1del (p.?) was inherited from her father. Neither mutation has been reported previously. The IL-10RA function of the patient was defective, as demonstrated by a failure of signal transducer and activator of transcription 3 (STAT3) activation in peripheral blood mononuclear cells (PBMCs) stimulated with recombinant IL-10. The patient underwent matched unrelated peripheral blood hematopoietic stem cell transplantation (HSCT), and the clinical manifestations were dramatically improved. In summary, we identified a novel compound heterozygote mutation, c.395T>G (p.Leu132Arg)/ex.1del (p.?), in IL-10RA that caused VEO-IBD in a Chinese child, which further expands the mutational spectrum of IL-10RA.

Background Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with a high incidence of lethal arrhythmia. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), a diffusible axonal chemorepellent that can induce growth cone collapse and axon repulsion of several neuronal populations, is crucial in neurodevelopment during disease development and progression. However, whether EphrinB2 could inhibit cardiac sympathetic hyperinnervation after MI remains unclear. Methods and results A rat model of MI was developed by left anterior descending coronary artery ligation. EphrinB2 expression was markedly increased in the infarcted border at 3 days after MI. Downregulation of EphrinB2 by intramyocardial injection of lentivirus carrying EphrinB2-shRNA significantly increased sympathetic hyperinnervation along with downregulated RhoA expression. In contrast, injection of EphrinB2-overexpressing lentivirus markedly upregulated EphrinB2, concomitant with inhibition of sympathetic sprouting and upregulated RhoA expression, accompanied by decreased incidence of ventricular arrhythmias (VAs). However, co-administering EphrinB2-overexpressing lentivirus and Fasudil (Rho kinase inhibitor) nearly abolished the inhibition of nerve sprouting effect. Additionally, EphrinB2 expression did not affect nerve growth factor level in the infarcted heart. Conclusions Overexpression of EphrinB2 may ameliorate MI-induced sympathetic hyperinnervation and further reduce the incidence of VAs, at least in part by activating RhoA-mediated axonal retraction.

Vertebrate evolution was accompanied with two rounds of whole genome duplication followed by functional divergence in terms of regulatory circuits and gene expression patterns. As a basal and slow-evolving chordate species, amphioxus is an ideal paradigm for exploring the origin and evolution of vertebrates. Single cell sequencing has been widely employed to construct the developmental cell atlas of several key species of vertebrates (human, mouse, zebrafish and frog) and tunicate (sea squirts). Here, we performed single-nucleus RNA sequencing (snRNA-seq) and single-cell assay for transposase accessible chromatin sequencing (scATAC-seq) for different stages of amphioxus (covering embryogenesis and adult tissues). With the datasets generated we constructed the developmental tree for amphioxus cell fate commitment and lineage specification, and revealed the underlying key regulators and genetic regulatory networks. The generated data were integrated into an online platform, AmphioxusAtlas, for public access at http://120.79.46.200:81/AmphioxusAtlas.

Background: Lipid accumulation product (LAP) is considered to be a new convenient useful indicator to assess the visceral fat. However, the association between LAP and family history of diabetes remains an undetermined concept. Therefore, we aimed to evaluate the risk factors of impaired fasting glucose (IFG) and diabetes, and explore the possible interacting influences of LAP with other factors on the risk of IFG and diabetes among Chinese normotension adults.Methods: A multistage stratified cluster sampling method was conducted to select urban residents aged 45-86 years in Bengbu, China. For each eligible participant, data on questionnaire survey, anthropometric measurements and laboratory tests were obtained. LAP was calculated and divided into four categories according to quartile. The effects of body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR) and LAP for predicting IFG and diabetes were performed by multiple logistic regressions and receiver operating characteristic (ROC) analyses. The interaction effects were evaluated by relative excess risk of interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI). If the 95% CI of RERI and AP do not include 0, the 95% CI of SI do not include 1, the interactions are statistically significant. Results: 6467 normotension subjects (2695 men and 3772 women) were enrolled in our study, the prevalence of IFG and diabetes were 9.37% and 14.33%, respectively. It was revealed that the prevalence rates of IFG and diabetes were gradually increased according to increasing LAP quartiles (P for trend Conclusion: LAP significantly associates with IFG and diabetes risk in the study population, it has better performance than BMI, WC and WHtR. Apart from that, our results also demonstrated that there might be synergistic effect between LAP and family history of diabetes on the risk of IFG and diabetes.

Owing to its broad-spectrum antivirus activities, interferon (IFN) is an important alternative agent for use in the treatment of hepatitis B virus (HBV)-infected patients; however, the mechanism involved in the inhibition of HBV infection and replication by IFN remains unclear. We previously reported that the induction of TRIM5γ is important in the IFN treatment of HBV patients as it promotes the degradation of the HBx protein, while the manner in which TRIM5γ is induced by IFN and how TRIM5γ interacts with HBx remain unestablished until date. Our present findings confirmed the TRIM5γ-HBx-DDB1 interactions in the HBV-infected Primary human hepatocytes (PHH), and we further found that STAT3, and not STAT1, was responsible for the induction of TRIM5γ upon IFN stimulation and that the zinc binding site His123 on the BBOX domain was a decisive site in the interaction between TRIM5γ BBOX and HBx. In addition, based on the BBOX domain, we detected a 7-amino acid peptide with the potential of promoting HBx degradation and inhibiting HBV replication. On the other hand, we noted that the TRIM5γ expression was inhibited by HBV in chronically HBV infected patients. Thus, our study identified the crucial role of STAT3 in the induction of TRIM5γ, as well as proposed a 7-amino acid, small peptide as a potential candidate for the development of therapeutic agents targeting HBx.

Smoking is an independent risk factor for atherosclerosis. The smoke produced by tobacco burning contains more than 7000 chemicals, among which nicotine is closely related to the occurrence and development of atherosclerosis. Nicotine, a selective cholinergic agonist, accelerates the formation of atherosclerosis by stimulating nicotinic acetylcholine receptors (nAChRs) located in neuronal and non-neuronal tissues. This review introduces the pathogenesis of atherosclerosis and the mechanisms involving nicotine and its receptors. Herein, we focus on the various roles of nicotine in atherosclerosis, such as upregulation of growth factors, inflammation, and the dysfunction of endothelial cells, vascular smooth muscle cells (VSMC) as well as macrophages. In addition, nicotine can stimulate the generation of reactive oxygen species, cause abnormal lipid metabolism, and activate immune cells leading to the onset and progression of atherosclerosis. Exosomes, are currently a research hotspot, due to their important connections with macrophages and the VSMC, and may represent a novel application into future preventive treatment to promote the prevention of smoking-related atherosclerosis. In this review, we will elaborate on the regulatory mechanism of nicotine on atherosclerosis, as well as the effects of interference with nicotine receptors and the use of exosomes to prevent atherosclerosis development.

Acute liver failure (ALF) in childhood is a rapidly progressive, potentially life-threatening condition that occurs in previously healthy children of all ages. However, the etiology of ~50% of cases with pediatric ALF remains unknown. We herein report a 4-year-old Chinese girl with recurrent ALF (RALF) due to a mutation in the neuroblastoma amplified sequence (NBAS) gene. The patient had suffered from multiple episodes of fever-related ALF since early childhood. She had also suffered from acute kidney injury, hypertension, mild pulmonary hypertension, pleural effusion, and hypothyroidism. A novel compound heterozygote mutation, c.3596G> A (p.C1199Y)/ex.9del (p.216-248del), in the NBAS gene was identified by whole-exome sequencing (WES). The missense mutation c.3596G> A (p. C1199Y) was inherited from her father, and ex.9del (p.216-248del) was inherited from her mother. The patient was managed with intensive treatments, such as renal replacement therapy (CRRT), intravenous antibiotics, and glucose infusion, and was discharged after full recovery. We identified a novel compound heterozygote mutation in the NBAS gene that caused fever-related RALF in a Chinese child, which further expands the mutational spectrum of NBAS.

Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn’s disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Fecal samples were collected from 20 healthy children and 29 newly diagnosed pediatric CD patients. 16S rRNA/ITS2 gene sequencing and targeted metabolomics analysis were applied to profile the gut bacterial microbiome, mycobiome, and metabolome, respectively. Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including Faecalibacterium, Clostridium clusters IV and XIVb, Roseburia, and Ruminococcus, which were correlated with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were associated with reduced relative abundances of Bifidobacterium and Clostridium clusters IV and XIVb which contain bile salt hydrolases (BSH) genes. IFX treatment enriched the BSH-producing bacteria in CD subjects, which may explain a decreased level of conjugated BAs and an increase in unconjugated BAs as well as the unconjugated/conjugated BAs ratio. Furthermore, a sustained response (SR) of IFX therapy was associated with higher abundances of Methylobacterium, Sphingomonas, Staphylococcus, and Streptococcus, and higher fecal concentrations of amino acids, including L-aspartic acid, linoleic acid, and L-lactic acid at baseline. Our study suggests that the effects of IFX might be partially mediated by enriching bacteria taxa that producing SCFAs and BSH thereby inhibiting inflammation and restoring the BA metabolism. Some fecal bacteria and metabolites may be predictive of outcomes of IFX therapy for pediatric CD patients.

Rationale: Apatinib is a novel anti-angiogenic agent that targets vascular endothelial growth factor receptor-2, thereby inhibiting tumor angiogenesis, and is effective in the treatment of brain metastases (BM) and peritumoral brain edema (PTBE). There are no previous reports of combination therapy with apatinib and fractionated stereotactic radiotherapy (FSRT) for BM from primary lung mucoepidermoid carcinoma (MEC). Patient Concerns: A 63-year-old man underwent left lower lobectomy and mediastinal lymph node dissection in April 2018. Diagnoses: Postoperative pathology demonstrated high-grade MEC. The patient developed 3 BM with PTBE 3 months after undergoing surgery. Interventions: The patient received a combination of FSRT and apatinib (250–500 mg/d) as maintenance therapy. Outcomes: The 3 BM showed nearly complete responses, and the PTBE areas shrank visibly. A new BM lesion occurred 7 months after the first FSRT and was treated with a second dose of FSRT. The patient developed extensive metastasis and atelectasis 9 months later. He died of pulmonary infection in December 2019. The overall survival time was 20 months. Lessons: Limited BM from primary lung MEC may be treated effectively with combination therapy with apatinib and FSRT when chemotherapy alone is not effective or tolerated. Further studies are needed to investigate the clinical outcomes and toxicities associated with the treatment.

Background Acinetobacter baumannii (A. baumannii) is one of the pivotal pathogens responsible for nosocomial infections, especially in patients with low immune response, and infection with carbapenem-resistant A. baumannii has been increasing in recent years. Rapid and accurate detection of carbapenem-resistance genes in A. baumannii could be of immense help to clinical staff. Methods In this study, a 15-μL reaction system for recombinase polymerase amplification (RPA) was developed and tested. We collected 30 clinical isolates of A. baumannii from the Burn Institute of Southwest Hospital of Third Military Medical University (Army Medical University) for 6 months and tested antibiotic susceptibility using the VITEK 2 system. A. baumannii was detected based on the blaOXA-51 gene by PCR, qPCR and 15 μL-RPA, respectively. Sensitivity and specificity were evaluated. In addition, PCR and 15 μL-RPA data for detecting the carbapenem-resistance gene blaOXA-23 were comparatively assessed. Results The detection limit of the blaOXA-51 gene by 15 μL RPA was 2.86 CFU/ml, with sensitivity comparable to PCR and qPCR. No positive amplification signals were detected in non-Acinetobacter isolates, indicating high specificity. However, only 18 minutes were needed for the 15 μL RPA assay. Furthermore, an antibiotic susceptibility test showed that up to 90% of A. baumannii strains were resistant to meropenem and imipenem; 15 μL RPA data for detecting blaOXA-23 showed that only 10% (n = 3) of A. baumannii isolates did not show positive amplification signals, and the other 90% of (n = 27) isolates were positive, corroborating PCR results. Conclusion We demonstrated that the new 15 μL RPA assay for detecting blaOXA-23 in A. baumannii is faster and simpler than qPCR and PCR. It is a promising alternative molecular diagnostic tool for rapid and effective detection of A. baumannii and drug-resistance genes in the field and point-of-care testing.

BackgroundThe epidemic of 2019 novel coronavirus (COVID-19) struck China in late December, 2019, resulting in about 200000 deaths all over the world. Numerous observational studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte proportion and the platelet-to-lymphocyte ratio (PLR) are inflammatory markers. Our study aimed to detect the role of NLR, PLR in predicting the prognosis of COVID-19.MethodsFour hundred and fifteen consecutive patients were enrolled in Shanghai Public Health Clinical Center affiliated to Fudan University, between 20 January and 11 April 2020 with confirmed COVID-19. Epidemiology, symptoms, signs, and laboratory examinations during the hospital stay were collected and compared between non-severe and severe patients. Statistical analysis was performed by SPSS 25.0 software.ResultsFour hundred and fifteen laboratory-confirmed COVID-19 patients were included in our study, among which 386 (93%) patients were not severe, and 27 (7%) were severe. The proportion of males in severe cases is higher than in non-severe cases (75.86% vs. 50.52%, P=0.008). The age between the two groups is different (p=0.022). Compared with non-severe patients, severe patients exhibited more comorbidities, including hypertension (48.28% vs. 19.43%, pConclusionsNLR is an independent risk factor of severe COVID-19 patients. PLR, NLR were significantly different between severe and non-severe patients, so assessment of NLR, PLR may help identify high risk cases with COVID-19.

Background This study aimed to understand the association between socioeconomic status (SES) and Health Related Quality of Life (HRQoL) and the contribution of SES to health inequality among Tibetans of agricultural and pastoral areas (APA) in Tibet, China. Methods The data were from Health Survey of Tibetans in APA conducted in 2014. A total of 816 respondents were enrolled for the analysis Multiple linear regression was employed to examine the relationship between SES and HRQoL. Concentration index (CI) was used to measure the degree of health inequality and a Wagstaff-type CI decomposition method was applied to measure the contribution of SES to inequality. Results SES had significant association with HRQoL among the Tibetans in APA. The high SES group was more likely to have a higher Eq-5d index (0.77 vs. 0.67, P P Conclusion The results showed SES is positively associated with HRQoL among Tibetans in APA. There was a slight pro-rich inequality in the health of the participants and most health inequality was attributable to SES. This study is helpful in gaining an insight into the HRQoL, health inequality and the relationship between SES and health inequality among Tibetans of APA in China.

Background Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the clinical features and molecular defects of BWS patients in China. Methods Thirty-one patients with clinical suspicion of BWS were retrospectively recruited to the study from Shanghai Children’s Hospital between January 2014 and December 2017. Clinical data, including demographics, clinical features, and molecular testing results were extracted and systematically analyzed. Results Twenty-one patients with a BWS score ≥ 4 (6, IQR 4, 7) were clinically diagnosed with BWS, and 10 children with a BWS score ≥ 2 and Conclusions The current study presents the first cohort study of BWS patients in mainland China. The clinical and molecular features of the patients are similar to those of other reported BWS patients in the Chinese population.

Malignant ventricular arrhythmias (VAs) following myocardial infarction (MI) is a lethal complication resulting from sympathetic nerve hyperactivity. Numerous evidence have shown that inflammation within the paraventricular nucleus (PVN) participates in sympathetic hyperactivity. Our aim was to explore the role of Macrophage‐inducible C‐type lectin (Mincle) within the PVN in augmenting sympathetic activity following MI,and whether NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome/IL‐1β axis is involved in this activity. MI was induced by coronary artery ligation. Mincle expression localized in microglia within the PVN was markedly increased at 24 hours post‐MI together with sympathetic hyperactivity, as indicated by measurement of the renal sympathetic nerve activity (RSNA) and norepinephrine (NE) concentration. Mincle‐specific siRNA was administrated locally to the PVN, which consequently decreased microglial activation and sympathetic nerve activity. The MI rats exhibited a higher arrhythmia score after programmed electric stimulation than that treated with Mincle siRNA, suggesting that the inhibition of Mincle attenuated foetal ventricular arrhythmias post‐MI. The underlying mechanism of Mincle in sympathetic hyperactivity was investigated in lipopolysaccharide (LPS)‐primed naïve rats. Recombinant Sin3A‐associated protein 130kD (rSAP130), an endogenous ligand for Mincle, induced high levels of NLRP3 and mature IL‐1β protein. PVN‐targeted injection of NLRP3 siRNA or IL‐1β antagonist gevokizumab attenuated sympathetic hyperactivity. Together, the data indicated that the knockdown of Mincle in microglia within the PVN prevents VAs by attenuating sympathetic hyperactivity and ventricular susceptibility, in part by inhibiting its downstream NLRP3/IL‐1β axis following MI. Therapeutic interventions targeting Mincle signalling pathway could constitute a novel approach for preventing infarction injury.

Background This study aimed to explore the effects of (body mass index) BMI on health related quality of life (HRQoL) among the elderly in Jiangsu, China. Methods A total of 10,257 community dwelling elderly (≥60 years old) were enrolled in a cross-sectional study. HRQoL was measured via the Eq-5d-3 L. Chi-square tests and one-way ANOVA analyses were used to compare the frequencies and scores of Eq-5d responses among different BMI groups (defined as “underweight”, “normal weight”, “overweight” and “obese”). Logistic regression analyses were conducted to examine the associations between BMI and HRQoL. Results Among the subjects, the proportion of “normal weight”, “underweight”, “overweight” and “obese” were 66.0, 8.3, 23.1, and 2.6%, respectively. The score of the Eq-5d index among total participants was 0.8036 and the Visual Analog Scale (VAS) score was 75.47. For both the responses frequency and scores of Eq-5d-3 L, there were significant differences among BMI groups (P

Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ., The co-occurrence of gut microbiota dysbiosis and bile acid (BA) metabolism alteration has been reported in several human liver diseases. However, the gut microbiota dysbiosis in infantile cholestatic jaundice (CJ) and the linkage between gut bacterial changes and alterations of BA metabolism have not been determined. To address this question, we performed 16S rRNA gene sequencing to determine the alterations in the gut microbiota of infants with CJ, and assessed their association with the fecal levels of primary and secondary BAs. Our data reveal that CJ infants show marked declines in the fecal levels of primary BAs and most secondary BAs. A decreased ratio of cholic acid (CA)/chenodeoxycholic acid (CDCA) in infants with CJ indicated a shift in BA synthesis from the primary pathway to the alternative BA synthesis pathway. The bacterial taxa enriched in infants with CJ corresponded to the genera Clostridium, Gemella, Streptococcus, and Veillonella and the family Enterobacteriaceae and were negatively correlated with the fecal BA level and the CDCA/CA ratio but positively correlated with the serological indexes of impaired liver function. An increased ratio of deoxycholic acid (DCA)/CA was observed in a proportion of infants with CJ. The bacteria depleted in infants with CJ, including Bifidobacterium and Faecalibacterium prausnitzii, were positively and negatively correlated with the fecal levels of BAs and the serological markers of impaired liver function, respectively. In conclusion, the reduced concentration of BAs in the gut of infants with CJ is correlated with gut microbiota dysbiosis. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. IMPORTANCE Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ.