Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood-brain barrier.

The human blood-brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae, group B Streptococcus, and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.

A SARS-CoV-2 Mpro fluorescent sensor for exploring pharmacodynamic substances from traditional Chinese medicine.

The main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) plays a critical role in the replication and life cycle of the virus. Currently, how to screen SARS-CoV-2 Mpro inhibitors from complex traditional Chinese medicine (TCM) is the bottleneck for exploring the pharmacodynamic substances of TCM against SARS-CoV-2. In this study, a simple, cost-effective, rapid, and selective fluorescent sensor (TPE-S-TLG sensor) was designed with an AIE (aggregation-induced emission) probe (TPE-Ph-In) and the SARS-CoV-2 Mpro substrate (S-TLG). The TPE-S-TLG sensor was characterized using UV-Vis absorption spectroscopy, fluorescence spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential, and Fourier transform infrared (FTIR) spectroscopy techniques. The limit of detection of this method to detect SARS-CoV-2 Mpro was measured to be 5 ng mL-1. Furthermore, the TPE-S-TLG sensor was also successfully applied to screen Mpro inhibitors from Xuebijing injection using the separation and collection of the HPLC-fully automatic partial fraction collector (HPLC-FC). Six active compounds, including protocatechualdehyde, chlorogenic acid, hydroxysafflower yellow A, caffeic acid, isoquercetin, and pentagalloylglucose, were identified using UHPLC-Q-TOF/MS that could achieve 90% of the Mpro inhibition rate for the Xuebijing injection. Accordingly, the strategy can be broadly applied in the detection of disease-related proteases as well as screening active substances from TCM.

Highly efficient activation of periodate by a manganese-modified biochar to rapidly degrade methylene blue.

In this study, the manganese oxide/biochar composites (Mn@BC) were synthesized from Phytolacca acinosa Roxb. The Mn@BC was analyzed via techniques of Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction analysis (XRD). The results show that MnOx is successfully loaded on the surface of BC, and the load of MnOx can increase the number of surface functional groups of BC. X-ray photoelectron spectroscopy (XPS) shows that MnOx loaded on BC mainly exists in three valence forms: Mn(Ⅱ), Mn(Ⅲ), and Mn(Ⅳ). The ability of Mn@BC to activate periodate (PI) was studied by simulating the degradation of methylene blue (MB) dye. The degradation experiment results showed that the MB removal rate by the Mn@BC/PI system reached 97.4% within 30 min. The quenching experiment and electron paramagnetic resonance (EPR) analysis confirmed that Mn@BC can activate PI to produce iodate (IO3•), singlet oxygen (1O2), and hydroxyl radical (•OH), which can degrade MB during the reaction. Response surface methodology (RSM) based on Box-Behnken Design (BBD) was used to determine the interaction between pH, Mn@BC and PI concentration in the Mn@BC/PI system, and the optimum technological parameters were determined. When pH = 5.4, Mn@BC concentration 0.56 mg/L, PI concentration 1.1 mmol/L, MB removal rate can reach 98.05%. The cyclic experiments show that Mn@BC can be reused. After four consecutive runs, the removal rate of MB by the Mn@BC/PI system is still 82%, and the Mn@BC/PI system also shows high performance in treating MB in actual water bodies and degrading other pollutants. This study provides a practical method for degrading dyes in natural sewage.

Ehrlichia chaffeensis Etf-3 Induces Host RAB15 Upregulation for Bacterial Intracellular Growth.

Ehrlichia chaffeensis infects human monocytes or macrophages and causes human monocytic ehrlichiosis (HME), an emerging life-threatening zoonosis. After internalization, E. chaffeensis resides in membrane-bound inclusions, E. chaffeensis-containing vesicles (ECVs), which have early endosome-like characteristics and fuse with early autophagosomes but not lysosomes, to evade host innate immune microbicidal mechanisms and obtain nutrients for bacterial intracellular growth. The mechanisms exploited by E. chaffeensis to modulate intracellular vesicle trafficking in host cells have not been comprehensively studied. Here, we demonstrate that E. chaffeensis type IV secretion system (T4SS) effector Etf-3 induces RAB15 upregulation in host cells and that RAB15, which is localized on ECVs, inhibits ECV fusion with lysosomes and induces autophagy. We found that E. chaffeensis infection upregulated RAB15 expression using qRT-PCR, and RAB15 was colocalized with E. chaffeensis using confocal microscopy. Silence of RAB15 using siRNA enhanced ECV maturation to late endosomes and fusion with lysosomes, as well as inhibited host cell autophagy. Overexpression of Etf-3 in host cells specifically induced RAB15 upregulation and autophagy. Our findings deepen the understanding of E. chaffeensis pathogenesis and adaptation in hosts as well as the function of RAB15 and facilitate the development of new therapeutics for HME.

A Rapid and Accurate UHPLC Method for Determination of Monosaccharides in Polysaccharides of Different Sources of Radix Astragali and Its Immune Activity Analysis.

With the escalating demand for Astragalus polysaccharides products developed from Radix Astragali (RA), the necessity for quality control of polysaccharides in RA has become increasingly urgent. In this study, a specific method for the simultaneous determination of seven monosaccharides in polysaccharides extracted from Radix Astragali (RA) has been developed and validated using ultra-performance liquid chromatography equipped with an ultraviolet detector (UHPLC-UV) for the first time. The 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatizations were separated on a C18 column (Waters ACQUITYTM, Milfor, MA, USA, 1.8 µm, 2.1 × 100 mm) using gradient elution with a binary system of 5 mm ammonium formate (0.1% formic acid)-acetonitrile for 24 min. Additionally, seven monosaccharides showed good linear relationships (R2, 0.9971-0.9995), adequate precision (RSD < 4.21%), and high recoveries (RSD < 4.70%). The established method was used to analyze 109 batches of RA. Results showed that the Astragalus polysaccharides (APSs) mainly consist of mannose (Man), rhamnose (Rha), glucose (Glu), galactose (Gal), arabinose (Ara), xylose (Xyl); and fucose (Fuc); however, their composition was different among RA samples from different growth patterns, species, growth years, and origins, and the growth mode of RA and the age of wild-simulated RA can be accurately distinguished by principal component analysis (PCA). In addition, the immunological activity of APSs were also evaluated jointly by measurement of the NO release with RAW264.7, with the results showing that APSs have a promoting effect on the release of NO and exhibit a significant correlation with Man, Glu, Xyl, and Fuc contents. Accordingly, the new established monosaccharides analytical method and APS-immune activity determination in this study can provide a reference for quality evaluation and the establishment of quality standards for RA.

[A new cucurbitane glycoside from Picrorhiza scrophulariiflora].

Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.

Identification of an individualized therapy prognostic signature for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are the most common cancers in the head and neck. Therapeutic response-related genes (TRRGs) are closely associated with carcinogenesis and prognosis in HNSCC. However, the clinical value and prognostic significance of TRRGs are still unclear. We aimed to construct a prognostic risk model to predict therapy response and prognosis in TRRGs-defined subgroups of HNSCC. METHODS: The multiomics data and clinical information of HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA). The profile data GSE65858 and GSE67614 chip was downloaded from public functional genomics data Gene Expression Omnibus (GEO). Based on TCGA-HNSC database, patients were divided into a remission group and a non-remission group according to therapy response, and differentially expressed TRRGs between those two groups were screened. Using Cox regression analysis and Least absolute shrinkage and selection operator (LASSO) analysis, candidate TRRGs that can predict the prognosis of HNSCC were identified and used to construct a TRRGs-based signature and a prognostic nomogram. RESULT: A total of 1896 differentially expressed TRRGs were screened, including 1530 upregulated genes and 366 downregulated genes. Then, 206 differently expressed TRRGs that was significantly associated with the survival were chosen using univariate Cox regression analysis. Finally, a total of 20 candidate TRRGs genes were identified by LASSO analysis to establish a signature for risk prediction, and the risk score of each patient was calculated. Patients were divided into a high-risk group (Risk-H) and a low-risk group (Risk-L) based on the risk score. Results showed that the Risk-L patients had better overall survival (OS) than Risk-H patients. Receiver operating characteristic (ROC) curve analysis revealed great predictive performance for 1-, 3-, and 5-year OS in TCGA-HNSC and GEO databases. Moreover, for patients treated with post-operative radiotherapy, Risk-L patients had longer OS and lower recurrence than Risk-H patients. The nomogram involves risk score and other clinical factors had good performance in predicting survival probability. CONCLUSIONS: The proposed risk prognostic signature and Nomogram based on TRRGs are novel promising tools for predicting therapy response and overall survival in HNSCC patients.

High-normal unconjugated bilirubin is associated with decreased risk of chronic kidney disease in type 2 diabetes: A real-world study.

OBJECTIVE: To investigate the association between serum unconjugated bilirubin (UCB) within normal limits and chronic kidney disease (CKD) in T2DM patients. METHOD: This cross-sectional, real-world study was performed in 8661 hospitalised T2DM patients. The subjects were stratified into quintiles based on serum UCB levels. The clinical characteristics and CKD prevalence were compared among the UCB quantile groups. The associations of serum UCB levels and quintiles with CKD were also analysed by binary logistic regression. RESULTS: After controlling for age, sex, and diabetes duration (DD), the CKD prevalence (20.4%, 12.2%, 10.6%, 8.3%, and 6.4% for the first, second, third, fourth, and fifth quintiles, respectively, p < 0.001 for trend) was significantly decreased across the serum UCB quintiles. The fully adjusted regression model showed negative associations of serum UCB levels (OR: 0.660, 95% CI: 0.585-0.744; p < 0.001 for trend) and quintiles (p < 0.001) with the presence of CKD. Compared with the subjects in the lowest UCB quintile, the risk of CKD decreased by 36.2%, 54.3%, 53.8%, and 62.1%, respectively, in those from the second to the highest UCB quintile. Additionally, C-reactive protein (CRP) levels were significantly higher in the subjects with CKD than in those without CKD (p < 0.001), and significantly decreased across the UCB quintiles (p < 0.001 for trend). CONCLUSIONS: Serum UCB levels within the normal range were significantly and negatively linked to CKD in T2DM patients. High-normal UCB may be an independent protective factor for CKD by its antioxidant and the following anti-inflammatory activities through its signalling activity, which was indicated by clearly decreased CRP levels across the UCB quintiles.

Deep learning-driven multi-view multi-task image quality assessment method for chest CT image.

BACKGROUND: Chest computed tomography (CT) image quality impacts radiologists' diagnoses. Pre-diagnostic image quality assessment is essential but labor-intensive and may have human limitations (fatigue, perceptual biases, and cognitive biases). This study aims to develop and validate a deep learning (DL)-driven multi-view multi-task image quality assessment (M[Formula: see text]IQA) method for assessing the quality of chest CT images in patients, to determine if they are suitable for assessing the patient's physical condition. METHODS: This retrospective study utilizes and analyzes chest CT images from 327 patients. Among them, 1613 images from 286 patients are used for model training and validation, while the remaining 41 patients are reserved as an additional test set for conducting ablation studies, comparative studies, and observer studies. The M[Formula: see text]IQA method is driven by DL technology and employs a multi-view fusion strategy, which incorporates three scanning planes (coronal, axial, and sagittal). It assesses image quality for multiple tasks, including inspiration evaluation, position evaluation, radiation protection evaluation, and artifact evaluation. Four algorithms (pixel threshold, neural statistics, region measurement, and distance measurement) have been proposed, each tailored for specific evaluation tasks, with the aim of optimizing the evaluation performance of the M[Formula: see text]IQA method. RESULTS: In the additional test set, the M[Formula: see text]IQA method achieved 87% precision, 93% sensitivity, 69% specificity, and a 0.90 F1-score. Extensive ablation and comparative studies have demonstrated the effectiveness of the proposed algorithms and the generalization performance of the proposed method across various assessment tasks. CONCLUSION: This study develops and validates a DL-driven M[Formula: see text]IQA method, complemented by four proposed algorithms. It holds great promise in automating the assessment of chest CT image quality. The performance of this method, as well as the effectiveness of the four algorithms, is demonstrated on an additional test set.

Associations of maternal pre-pregnancy BMI and gestational weight gain with the risks of adverse pregnancy outcomes in Chinese women with gestational diabetes mellitus.

BACKGROUND: Give the high background risk of adverse pregnancy outcomes (APOs), it is important to understand the associations of maternal pre-pregnancy body mass index (ppBMI), gestational weight gain (GWG) with APOs in women with gestational diabetes mellitus (GDM). We addressed the independent and joint associations of maternal ppBMI and GWG with APOs in Chinese women with GDM. METHODS: 764 GDM women with singleton delivery were studied and they were stratified into three weight groups by ppBMI (underweight, normal weight and overweight/obesity) following classification standards for Chinese adults and three GWG groups (inadequate, adequate, excessive GWG) by the 2009 Institute of Medicine guidelines, respectively. Univariate and multivariate logistic regression analyses were performed to estimate the odds ratios of APOs. RESULTS: Maternal overweight/obesity was associated with increased odds of pregnancy-induced hypertension [PIH, adjusted odds ratio (aOR): 2.828, 95% confidence interval (CI) 1.382-5.787], cesarean delivery (CS) (aOR 2.466, 95%CI 1.694-3.590), preterm delivery (aOR 2.466, 95%CI 1.233-4.854), LGA (aOR 1.664, 95%CI 1.120-2.472), macrosomia (aOR 2.682, 95%CI 1.511-4.760) and any pregnancy complication (aOR 2.766, 95%CI 1.840-4.158) compared with healthy weight. Inadequate GWG was less likely to develop PIH (aOR 0.215, 95%CI 0.055-0.835), CS (aOR 0.612, 95%CI 0.421-0.889) and any pregnancy complication (aOR 0.628, 95%CI 0.435-0.907), but had higher risk of preterm birth (aOR 2.261, 95%CI 1.089-4.692), while excessive GWG was more vulnerable to LGA (aOR 1.929, 95%CI 1.272-2.923), macrosomia (aOR 2.753, 95%CI 1.519-4.989) and any pregnancy complication (aOR 1.548, 95%CI 1.006-2.382) as compared to adequate GWG. Furthermore, compared to normal weight mothers with adequate GWG, obese mothers with excessive GWG had the highest risk of any pregnancy complication (aOR 3.064, 95%CI 1.636-5.739). CONCLUSIONS: Maternal overweight/obesity and GWG were associated with APOs in the already high-risk settings of GDM. Obese mothers with excessive GWG may confer the greatest risk of adverse outcomes. It was very helpful to reduce the burden of APOs and benefit GDM women by promoting a healthy pre-pregnancy BMI and GWG.

Altered m6A modification is involved YAP-mediated apoptosis response in 4-vinylcyclohexene diepoxide induced ovotoxicity.

4-Vinylcyclohexene diepoxide (VCD), an industrial occupational health hazard chemical associated with premature ovarian insufficiency (POI) and reproductive failure. Recently, investigators have paid an increasing attention on VCD model of menopause recapitulates the natural, physiological transition through perimenopause to menopause. The current study sought to examining the mechanisms of follicular loss and exploring the effect of the model on systems outside of the ovaries. In this study, 28 days female SD rats were injected with VCD (160 mg/kg) vehicle for 15 consecutive days, euthanized in the diestrus phase approximately 100 days after the onset of treatment. Reproductive system injury, Neuroendocrine, sex hormone levels and receptor were observed, the levels of N6-methyladenosine (m6A) RNA modification and the expression of modulator genes were first measured. The VCD treated rats showing irregular estrous cycles, significantly reduced in the number of primordial follicles, the preantral and antral follicles also decreased significantly, accompanied by the plasma level of FSH increased and anti-Mullerian hormone (AMH) were decreased. The total m6A level was significantly decreased after exposure to VCD. Moreover, ALKBH5-mediated YAP m6A modification changed in VCD - induced premature ovarian insufficiency. These present work provides a new perspective on m6A modification in the VCD-induced POI rat model, which could provide valuable insights into the mechanisms underlying follicle development and finding new therapeutic targets for follicle prematurely exhausted. Also provide novel methodological guidance and endocrine basis to guide research and extend the applications in premature ovarian insufficiency model.

A Multichannel Fluorescent Array Sensor for Discrimination of Different Types of Drug-Induced Kidney Injury.

The differences in urinary proteins could provide a novel opportunity to distinguish the different types of drug-induced kidney injury (DIKI). In this research, Au nanoparticles-polyethyleneimine (AuNPs-PEI) and the three fluorophore-labeled proteins (FLPs) have been constructed as a multichannel fluorescent array sensor via electrostatic interaction, which was used to detect the subtle changes in urine collected from the pathological state of DIKI. Once the urine from different types of DIKI was introduced, the binding equilibrium between AuNPs-PEI and FLPs would be broken due to the competitive binding of urinary protein, and the corresponding fluorescence response pattern would be generated. Depending on the different fluorescence response patterns, the different types of DIKI were successfully identified by principal component analysis (PCA) and linear discriminant analysis (LDA). Accordingly, the strategy was expected to be a powerful technique for evaluating the potential unclear mechanisms of nephrotoxic drugs, which would provide a promising method for screening potential renal-protective drugs.

Discrimination of Radix Astragali from Different Growth Patterns, Origins, Species, and Growth Years by an H1-NMR Spectrogram of Polysaccharide Analysis Combined with Chemical Pattern Recognition and Determination of Its Polysaccharide Content and Immunological Activity.

The fraud phenomenon is currently widespread in the traditional Chinese medicine Radix Astragali (RA) market, especially where high-quality RA is substituted with low-quality RA. In this case, focused on polysaccharides from RA, the classification models were established for discrimination of RA from different growth patterns, origins, species, and growth years. 1H Nuclear Magnetic Resonance (H1-NMR) was used to establish the spectroscopy of polysaccharides from RA, which were used to distinguish RA via chemical pattern recognition methods. Specifically, orthogonal partial least squares discriminant analysis (OPLS-DA) and linear discriminant analysis (LDA) were used to successfully establish the classification models for RA from different growth patterns, origins, species, and growth years. The satisfactory parameters and high accuracy of internal and external verification of each model exhibited the reliable and good prediction ability of the developed models. In addition, the polysaccharide content and immunological activity were also tested, which was evaluated by the phagocytic activity of RAW 264.7. And the result showed that growth patterns and origins significantly affected the quality of RA. However, there was no significant difference in the aspects of origins and growth years. Accordingly, the developed strategy combined with chemical information, biological activity, and multivariate statistical method can provide new insight for the quality evaluation of traditional Chinese medicine.

Classification and Authentication of Lonicerae Japonicae Flos and Lonicerae Flos by Using 1H-NMR Spectroscopy and Chemical Pattern Recognition Analysis.

Lonicerae japonicae flos and Lonicerae flos are increasingly widely used in food and traditional medicine products around the world. Due to their high demand and similar appearance, they are often used in a confused or adulterated way; therefore, a rapid and comprehensive analytical method is highly required. In this case, the comparative analysis of a total of 100 samples with different species, growth modes, and processing methods was carried out by nuclear magnetic resonance (1H-NMR) spectroscopy and chemical pattern recognition analysis. The obtained 1H-NMR spectrums were employed by principal component analysis (PCA), partial least-squares discriminant analysis (PLS-DA), orthogonal partial least-squares discriminant analysis (OPLS-DA), and linear discriminant analysis (LDA). Specifically, after the dimensionality reduction of data, linear discriminant analysis (LDA) exhibited good classification abilities for the species, growth modes, and processing methods. It is worth noting that the sample prediction accuracy from the testing set and the cross-validation predictions of the LDA models were higher than 95.65% and 98.1%, respectively. In addition, the results showed that macranthoidin A, macranthoidin B, and dipsacoside B could be considered as the main differential components of Lonicerae japonicae flos and Lonicerae Flos, while secoxyloganin, secologanoside, and sweroside could be responsible for distinguishing cultivated and wild Lonicerae japonicae Flos. Accordingly, 1H-NMR spectroscopy combined with chemical pattern recognition gives a comprehensive overview and provides new insight into the quality control and evaluation of Lonicerae japonicae flos.

pSuc-EDBAM: Predicting lysine succinylation sites in proteins based on ensemble dense blocks and an attention module.

BACKGROUND: Lysine succinylation is a newly discovered protein post-translational modifications. Predicting succinylation sites helps investigate the metabolic disease treatments. However, the biological experimental approaches are costly and inefficient, it is necessary to develop efficient computational approaches. RESULTS: In this paper, we proposed a novel predictor based on ensemble dense blocks and an attention module, called as pSuc-EDBAM, which adopted one hot encoding to derive the feature maps of protein sequences, and generated the low-level feature maps through 1-D CNN. Afterward, the ensemble dense blocks were used to capture feature information at different levels in the process of feature learning. We also introduced an attention module to evaluate the importance degrees of different features. The experimental results show that Acc reaches 74.25%, and MCC reaches 0.2927 on the testing dataset, which suggest that the pSuc-EDBAM outperforms the existing predictors. CONCLUSIONS: The experimental results of ten-fold cross-validation on the training dataset and independent test on the testing dataset showed that pSuc-EDBAM outperforms the existing succinylation site predictors and can predict potential succinylation sites effectively. The pSuc-EDBAM is feasible and obtains the credible predictive results, which may also provide valuable references for other related research. To make the convenience of the experimental scientists, a user-friendly web server has been established ( http://bioinfo.wugenqiang.top/pSuc-EDBAM/ ), by which the desired results can be easily obtained.

RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma.

BACKGROUND: Accumulated evidence suggests that RING finger proteins (RNFs) are involved in the carcinogenesis of cancers. However, RNF38, a member of the RNF protein family, has not been studied in nasopharyngeal carcinoma (NPC). METHODS: RNF38 expression was analyzed by RT-PCR, Western blotting and Immunohistochemistry. Biological functions of RNF38 were evaluated by cell growth, colony formation, apoptosis, migration and invasion assays in vitro. Xenograft growth and lung metastasis models were conducted to investigate the effect of RNF38 in vivo. Liquid chromatography coupled with tandem mass spectrometry, co-immunoprecipitation, and CHX assay were implemented to detect the interaction among RNF38 and ACTN4. RESULTS: RNF38 was significantly downregulated in NPC cells and tissues. Immunohistochemistry implied that loss of RNF38 was an independent prognostic factor for poor outcomes of NPC patients. Gain- and loss-of-function experiments showed that RNF38 inhibited proliferation and metastasis in NPC in vitro and in vivo. Upregulation of RNF38 promoted apoptosis of NPC cells to etoposide but not cisplatin. ACTN4 was upregulated in NPC and negatively correlated with RNF38. Mechanistic investigations suggested that RNF38 inactivates the NF-𝛋B and ERK1/2 signaling pathways by inducing ubiquitination and degradation of ACTN4. RNF38 suppress the development of NPC by interacting with ACTN4. CONCLUSIONS: RNF38 plays a potential cancer suppressor gene role in NPC tumorigenesis and is a prognostic biomarker in NPC.

Spatiotemporally comparative analysis of three common infectious diseases in China during 2013-2015.

BACKGROUND: Dengue fever (DF), influenza, and hand, foot, and mouth disease (HFMD) have had several various degrees of outbreaks in China since the 1900s, posing a serious threat to public health. Previous studies have found that these infectious diseases were often prevalent in the same areas and during the same periods in China. METHODS: This study combined traditional descriptive statistics and spatial scan statistic methods to analyze the spatiotemporal features of the epidemics of DF, influenza, and HFMD during 2013-2015 in mainland China at the provincial level. RESULTS: DF got an intensive outbreak in 2014, while influenza and HFMD were stable from 2013 to 2015. DF mostly occurred during August-November, influenza appeared during November-next March, and HFMD happened during April-November. The peaks of these diseases form a year-round sequence; Spatially, HFMD generally has a much higher incidence than influenza and DF and covers larger high-risk areas. The hotspots of influenza tend to move from North China to the southeast coast. The southeastern coastal regions are the high-incidence areas and the most significant hotspots of all three diseases. CONCLUSIONS: This study suggested that the three diseases can form a year-round sequence in southern China, and the southeast coast of China is a particularly high-risk area for these diseases. These findings may have important implications for the local public health agency to allocate the prevention and control resources.

The Incidence of Amyotrophic Lateral Sclerosis in Ohio 2016-2018: The Ohio Population-Based ALS Registry.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal, neuromuscular disease with no cure. ALS incidence rates have not been assessed specifically in Ohio, yet the state contains both metropolitan and rural areas with a variety of environmental factors that could contribute to disease etiology. We report the incidence of ALS in Ohio residents diagnosed from October 2016 through September 2018. METHODS: We engaged practitioners from 9 Ohio sites to identify newly diagnosed ALS patients and to complete case report forms with demographic and clinical information. ALS was diagnosed according to the Awaji criteria and classified as either definite, probable, or possible. We developed a method to estimate missing cases using a Poisson regression model to impute cases in counties with evidence of undercounting. RESULTS: We identified 333 newly diagnosed ALS patients residing in Ohio during the 2-year index period and found incidence rates varied in the 88 state counties. After incorporating the estimated 27% of missing cases, the corrected crude annual incidence was 1.96/100,000 person-years, and the age- and gender-standardized incidence was 1.71/100,000 person-years (standardized to the 2010 US census). DISCUSSION/CONCLUSION: The estimated Ohio incidence of ALS is overall similar to that reported in other states in the USA. This study reveals a geospatial variation in incidence within the state, and areas with higher rates warrant future investigation.

Adsorption of 17ß-estradiol from aqueous solution by raw and direct/pre/post-KOH treated lotus seedpod biochar.

Five biochars derived from lotus seedpod (LSP) were applied to examine and compare the adsorption capacity of 17ß-estradiol (E2) from aqueous solution. The effect of KOH activation and the order of activation steps on material properties were discussed. The effect of contact time, initial concentration, pH, ionic strength and humic acid on E2 adsorption were investigated in a batch adsorption process. Experimental results demonstrated that the pseudo second-order model fitted the experimental data best and that adsorption equilibrium was reached within 20 hr. The efficiency of E2 removal increased with increasing E2 concentration and decreased with the increase of ionic strength. E2 adsorption on LSP-derived biochar (BCs) was influenced little by humic acid, and slightly affected by the solution pH when its value ranged from 4.0 to 9.0, but considerably affected at pH 10.0. Low environmental temperature is favorable for E2 adsorption. Chemisorption, π-π interactions, monolayer adsorption and electrostatic interaction are the possible adsorption mechanisms. Comparative studies indicated that KOH activation and the order of activation steps had significant impacts on the material. Post-treated biochar exhibited better adsorption capacity for E2 than direct treated, pre-treated, and raw LSP biochar. Pyrolyzed biochar at higher temperature improved E2 removal. The excellent performance of BCs in removing E2 suggested that BCs have potential in E2 treatment and that the biochar directly treated by KOH would be a good choice for the treatment of E2 in aqueous solution, with its advantages of good efficiency and simple technology.

Effect of trichostatin A on Burkitt's lymphoma cells: Inhibition of EPS8 activity through Phospho-Erk1/2 pathway.

Histone deacetylase inhibitors (HDACi) manifest great potential for treatment of Burkitt's lymphoma (BL), an aggressive B-cell lymphoma. Epidermal growth factor receptor pathway substrate 8 (EPS8) is confirmed overexpressed and associated with poor prognosis in solid tumors and leukemia. However, EPS8 expression and the relationship between EPS8 and HDACi on BL remains obscure. Here, we hypothesized that trichostatin A (TSA), a pan-HDACi, could inhibit BL cells by downregulating EPS8. We demonstrated that TSA reduced cell viability, induced apoptosis and cell arrest at G0/G1. Mechanismly, TSA attenuated EPS8 and downstream Phospho-Erk1/2 pathway. Knockdown of EPS8 resulted in a significant reduction in cellular proliferation and suppressed Phospho-Erk1/2 pathway activity, particularly when combined with TSA. Conversely, overexpression of EPS8 rescued this phenomenon. Then we showed that the combination of TSA and Epirubicin had a more significant effect when compared with TSA or Epirubicin alone. Finally, knockdown of EPS8 and TSA had a synergistic suppression effect on BALB/c nude mice. In conclusion, this study reveals that TSA affects BL cells by suppressing Phospho-Erk1/2 pathway through downregulating EPS8.