Transcriptional Responses in Adult Zebrafish (Danio rerio) Exposed to Propranolol and Metoprolol.

ß-adrenergic receptor blockers (ß-blockers) are widely detected in the aquatic environment; however, the effects of these pharmaceuticals on aquatic organisms remain uncertain. In this study, adult zebrafish were exposed to two different ß-blockers, propranolol and metoprolol, for 96 h. After exposure, the transcriptional responses of genes encoding the ß-adrenergic receptor (i.e., adrb1, adrb2a, adrb2b, adrb3a and adrb3b), genes involved in detoxification and the stress response (i.e., hsp70, tap, mt1 and mt2), and genes related to the antioxidant system (i.e., cu/zn-sod, mn-sod, cat and gpx) were examined in the brain, liver and gonad. Our results show that both propranolol and metoprolol exposure changes the mRNA level of ß-adrenergic receptors, indicating clear pharmacological target engagement of the ß-blockers. The transcription of genes related to antioxidant responses and detoxification process were induced, suggesting that ß-blocker exposure can activate the detoxification process and result in oxidative stress in fish. Moreover, the transcriptional responses displayed substantial tissue- and gender-specific effects. Considering the environmental concentrations of propranolol and metoprolol, these results suggest that these pharmaceuticals are unlikely to pose a risk to fish. However, the impacts in prolonged exposure, along with other possible side effects due to ß-adrenergic receptor blockade, should be further assessed.

Preparative resolution of gatifloxacin enantiomers with pre-column esterification strategy and comparing their enantioselectivity to bacteria and antibody.

Gatifloxacin (GFX) is a kind of chiral fluoroquinolones compound due to the methyl group at the C-3 position of the piperazine ring[1]. Although the enantiomers of GFX show similar levels of antimicrobial activity and pharmacokinetics[2], the other biological activities (i.e., toxicity or enantioselective recognition to various receptors in vivo) of GFX enantiomers have not yet been studied. With this in mind, we developed a rapid and cost-effective high performance liquid chromatographic (HPLC) separation procedure for GFX enantiomers with a pre-column esterification strategy. With significant enhancement of drug solubility and optimization for chromatographic conditions, the proposed method was scaled up to preparative HPLC to obtain optical active S-(-)- and R-(+)-GFX. The antibacterial activities of GFX enantiomers after preparative separation were further verified by measuring the Minimum Inhibitory Concentration (MIC) values against Escherichia coli ATCC 25922. In addition, the binding selectivity of GFX enantiomers to protein receptor were evaluated by antibody using enzyme-linked immunosorbent assay (ELISA) for the first time.

Transformer fault diagnosis method based on SMOTE and NGO-GBDT.

In order to improve the accuracy of transformer fault diagnosis and improve the influence of unbalanced samples on the low accuracy of model identification caused by insufficient model training, this paper proposes a transformer fault diagnosis method based on SMOTE and NGO-GBDT. Firstly, the Synthetic Minority Over-sampling Technique (SMOTE) was used to expand the minority samples. Secondly, the non-coding ratio method was used to construct multi-dimensional feature parameters, and the Light Gradient Boosting Machine (LightGBM) feature optimization strategy was introduced to screen the optimal feature subset. Finally, Northern Goshawk Optimization (NGO) algorithm was used to optimize the parameters of Gradient Boosting Decision Tree (GBDT), and then the transformer fault diagnosis was realized. The results show that the proposed method can reduce the misjudgment of minority samples. Compared with other integrated models, the proposed method has high fault identification accuracy, low misjudgment rate and stable performance.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

Improved effect of fresh ginseng paste (radix ginseng-ziziphus jujube) on hyperuricemia based on network pharmacology and molecular docking.

Background: Hyperuricemia (HUA) is a metabolic disease caused by reduced excretion or increased production of uric acid. This research aims to study the practical components, active targets, and potential mechanism of the "Radix ginseng (RG)-Ziziphus jujube (ZJ)" herb pair through molecular docking, network pharmacology, and animal experiments. Methods: The potential targets of "Radix ginseng (RG)-Ziziphus jujube (ZJ)" herb pair were obtained from the TCMSP database. The therapeutic targets of HUA were acquired from the GendCards, OMIM, PharmGkb, and TTD databases. Protein-protein interaction network (PPI) was constructed in the STRING 11.0 database. The David database was used for enrichment analysis. Molecular Docking was finished by the AutoDock Vina. And we employed Radix ginseng and Ziziphus jujube as raw materials, which would develop a new functional food fresh ginseng paste (FGP) after boiling. In addition, benzbromarone (Ben) (7.8 mg/kg) and allopurinol (All) (5 mg/kg) were used as positive drugs to evaluate the hyperuricemia induced by FGP (400 and 800 mg/kg) potassium oxazine (PO) (100 mg/kg) and hypoxanthine (HX) (500 mg/kg) on mice. Results: The results showed that 25 targets in the "RG-ZJ" herb pair interacted with hyperuricemia. Then protein-protein interaction (PPI) analysis showed that TNF, IL-1ß, and VEGFA were core genes. KEGG enrichment analysis showed that the Toll-like receptor signaling pathway and IL-17 signaling pathway were mainly involved. Meantime, animal experiments showed that FGP could improve the HUA status of mice by reducing serum UA BUN, XO, and liver XO levels (p < 0.05, p < 0.01). Furthermore, we analyzed the main ingredients of FGP by HPLC. We found that the main ingredients of FGP had solid binding activity to the core target of HUA by molecular docking. Conclusion: This study explored the active ingredients and targets of the "RG-ZJ" herb pair on HUA through network pharmacology, molecular docking, and animal experiments. It revealed the improvement of FGP in mice with HUA.

Effects of swimming on the development of atherosclerosis in mice.

OBJECTIVE: To investigate the effects of swimming on the formation of atherosclerotic lesions and the corresponding mechanism. METHODS: 20 ApoE-deficient young male mice of SFP grade were assigned equally into two groups: atherosclerosis group and swimming group. Atherosclerosis models were established by feeding with high cholesterol diet. Swimming exercise was performed at a frequency of 90 min per day, 6 days per weeks for 10 weeks. The weight index, histologic changes of aorta area, blood lipid levels, expression levels of eNOS, tNOS and iNOS, expression levels of MMP-9 and MMP-14, inflammatory factor levels, and oxidative stress status were compared between the two groups. RESULTS: Compared to the atherosclerosis group, the plaque area, plaque rupture rates, and vulnerable index in the aorta of the swimming group were significantly less and the fibrous cap thickness was greater. The weight of mice and serum lipid levels in the swimming group were superior. In addition, in contrast to atherosclerosis group, mRNA expression levels of eNOS, tNOS, iNOS, and SOD in the swimming group were signifiantly elevated, while the levels of MMP-9, MMP-14 and MDA, and serum levels of IL-6, Lp-PLA2, and TNF-α were significantly decreased. CONCLUSION: Swimming exercise significantly decreases the development of atherosclerotic plaque in ApoE-deficient mice, possibly due to a reduction in the expression of blood lipid, MMP-9, MMP-14, MDA, IL-6, Lp-PLA2, and TNF-α and elevation in the expression of eNOS, tNOS, iNOS, and SOD.

Landscape and progress of global COVID-19 vaccine development.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected billions of lives globally, and the world hopes to end this epidemic by effective vaccination. In this review, we depict the latest panorama of global COVID-19 vaccine research and development based on different technology platforms, and summarize key characteristics and available evidence on vaccines authorized for emergency use, in order to provide insights into improve coordination in the COVID-19 outbreak response for related stakeholders.

4-Bromo-2-[1-(4-eth-oxy-phen-yl)-1-methyl-eth-yl]-1-methyl-benzene.

In title compound, C(18)H(21)BrO, the dihedral angle between two rings is 85.72°. No classical hydrogen bonds are found and only van der Waals forces stabilize the crystal packing.

Machine learning based early warning system enables accurate mortality risk prediction for COVID-19.

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.

Efficient dehydrogenation of a formic acid-ammonium formate mixture over Au3Pd1 catalyst.

A series of AuPd/C catalysts were prepared and tested for the first time for active and stable dehydrogenation of a formic acid-ammonium formate (FA-AF) mixture. The catalysts with different Au-to-Pd molar ratios were prepared using a facile simultaneous reduction method and characterized using transmission electron microscopy (TEM), high-resolution TEM, energy dispersive X-ray spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. It was found that the catalytic activity and stability of the Au3Pd1/C catalyst was the best. The initial turnover frequency for the dehydrogenation of the FA-AF mixture over the Au3Pd1/C catalyst can reach 407.5 h-1 at 365 K. The reaction order with respect to FA and AF is 0.25 and 0.55, respectively. The apparent activation energy of dehydrogenation is 23.3 ± 1.3 kJ mol-1. The catalytic activity of the Au3Pd1/C catalyst remains ca. 88.0% after 4 runs, which is much better than the single Pd/C catalyst. The mechanism for the dehydrogenation is also discussed.

Rare-Earth Y(OTf)3 Catalyzed Coupling Reaction of Ethers with Azaarenes.

Rare-earth catalysis has become a hot topic in the field of catalytic organic reaction. Chain ethers mostly have lower reactivity and lower boiling points which limited their reaction scope. Herein, we found a rare-earth Y(OTf)3 can catalyze the coupling reaction of ethers especially chain ethers and thioethers with azaarenes. This protocol features simple operations, a broad substrate scope (31 examples), moderate to good yields (up to 85%), and atom economy.

[Adaptive network-based fuzzy inference system for the forecast of spectra].

Because of the function of independent adaptation and study of NN and the best nonlinear speculating ability of fuzzy system, the adaptive network-based fuzzy inference system (ANFIS) which is composed of them absorbs their virtue. When applying it to the data analysis and model construction, the authors got the good nonlinear forecast by learning data, such as fluorescence spectrum. Fluorescence spectrometry is an important means of researching inside structure of molecule, which works easy, and features rapidness and high precision. So its forecast is more important. In the present paper, the authors utilize the spectra of the N2 to calculate, and prove that the means can forecast important spectrum information, the error is very small, less than 1. 66 percent, which is conformed to meet the demand of the experiment. In short, the approach is workable.

[Physico-chemical Characteristics of Individual Aerosol Particles in Marine Atmosphere on South Hemisphere].

During the 29th Chinese National Antarctic Research Expedition (CHIANRE), individual particle samples were collected from South China to Antarctic during November 2012 to April 2013. A transmission electron microscopy with energy-dispersive X-ray spectrometry (TEM-EDS) was employed to analyze the morphology, mixing state, composition, and relative abundances of individual aerosol particles. Atmospheric particles were classified into four types:sea salt, mineral, S-rich and C-rich. Sea salt aerosols (SSA) were dominant in the marine particles from South China to Antarctic, and they were further divided into three sub-types:fresh SSA, partially aged SSA, and fully aged SSA. Partially and fully aged SSA accounted for 86% of total SSA number. Interestingly, surface of partially aged SSA and fully aged SSA contained abundant rod-like Na2SO4. Mineral dust particles increased in the coastal areas which were influenced by continental air. In addition, we found that S-rich particles were abundant at two sampling sites (the middle eastern of Indian Ocean and Antarctic inland). The back trajectories of air masses indicated that these S-rich particles were mainly formed via the oxidation of dimethyl sulfide (DMS) emitted from the marine phytoplanktons. Our study suggests that the SSA aging process in the South Hemisphere atmosphere was controlled by the DMS which is different from the SSA aging under the influence of anthropogenic pollutants in the North Hemisphere.

[Preparation and characterization of monoclonal antibodies against S100A9].

OBJECTIVE: To prepare monoclonal antibodies (mAbs) against S100A9, and characterize these antibodies' properties for functional studies. METHODS: We amplified cDNA fragment of S100A9 from adult human liver sample, then constructed the vectors pGEX-4T-1-S100A9 and pET-32a-S100A9 for protein expression. The S100A9 protein fused respectively with the His-tag and GST-tag were expressed in E.coli and purified for immunizing mice as antigen and hybridoma screening, respectively. After hybriodma screening, the titer of mAbs was determined by ELISA and the specificity was identified by Western blotting and indirect immunofluorescence technique. RESULTS: Both GST-tagged and His-tagged S100A9 fusion proteins were successfully constructed and expressed in E.coli. Eighteen hybridoma cell strains secreting S100A9 mAbs were obtained, of which 15 showed strong positive reaction but 3 showed weak positive reaction to the recombinant protein in Western blotting. Two hybridoma cell strains were capable of binding to S100A9 native protein in tumor tissue interstitial fluid. CONCLUSION: We successfully prepared the mAbs against S100A9 protein, which provide the useful tool for further study on biological function and clinical detection of S100A9.

[Fire severity of burnt area in Huzhong forest region of Great Xing' an Mountains, Northeast China based on normalized burn ratio analysis].

Based on the TM images and 3S technology, and by using normalized burn ratio (NBR) , this paper quantitatively evaluated the fire severity of burnt area in Huzhong forest region of the Great Xing' an Mountains from 1986 to 2010, and analyzed the relationships of the fire severity with environmental factors such as vegetation type, elevation, slope, and aspect. In Huzhong forest region, the fire occurrence frequency and total burnt area had an obvious inter-annual change. High incidence of forest fire was from June to August, and heavily burnt area occupied 84. 2% of the total burnt area. In the burnt area, larch forest accounted for 89. 9%. 68. 8% of burnt area located at the elevations from 1000 m to 1500 m, and 62. 5% located in eastern, southern, western, and northern slopes. There was no obvious difference in the burnt area between sunny and shady slopes. The burnt area at the slope degrees 15 degree-25 degrees occupied 38.4% of the total. High severity burnt area was the largest (70% of the total), followed by moderate severity burnt area (about 10%), and low severity burnt area and un-burnt area (<5% ). The majority of the forest fires in Huzhong forest region were of high severity fire, which caused great damages to the forest resources. It was suggested that in the forest fire management in Great Xing' an Mountains forest region, it would be urgent to implement forest fuel treatments to reduce fire severity to guarantee the forest ecosystem security.

Intermittent Cyclic Mechanical Tension-Induced Calcification and downregulation of ankh gene expression of end plate chondrocytes.

STUDY DESIGN: Intermittent Cyclic Mechanical Tension (ICMT) was applied to end plate chondrocytes by using an FX-4000T Flexercell Tension Plus unit (Flexcell International Corporation, Hillsborough, NC). Changes of end plate chondrocytes were observed after ICMT stimulation. OBJECTIVE: To investigate the relationship between mechanical stimulation and calcification of end plate chondrocytes. SUMMARY OF BACKGROUND DATA: Previous study showed that end plate calcification was related to mechanical stress, but there was no clear evidence to indicate whether or not mechanical stimulation could induce calcification of end plate chondrocytes in vitro. METHODS: Rat end plate chondrocytes were cultured and ICMT (strain at 0.5 Hz sinusoidal curve at 10% elongation) was applied for 25 days, 4 hours a day and continued to culture for 5 days. End plate chondrocytes were incubated for 12 hours in the presence or absence of 10 ng/mL of transforming growth factor-ß1 (TGF-ß1) (prepared from a stock solution at 10 µg/mL in 2 mM citric acid containing 2 mg/mL bovine serum albumin) in MEM/F-12 containing a final concentration of 1% FCS. End plate chondrocytes calcification was stained by alizarin red S (AR-S). End plate chondrocytes viability was examined by LIVE/DEAD viability/cytotoxicity kit (Invitrogen, Carlsbad, CA). Related gene expression was examined by reverse transcription-polymerase chain reaction and Western blot. RESULTS: LIVE/DEAD assay verified that the nonloading (NC) group and the ICMT group end plate chondrocytes remained adherent, with no change in viability after the application of ICMT. Alizarin red staining showed that ICMT induced the calcification of end plate chondrocytes. Real-time reverse transcription-polymerase chain reaction showed that mRNA expression of endogenous TGF-ß1 decreased and mRNA expression of type I, type X, osteocalcin and osteopontin increased after ICMT. The ankh gene expression of both mRNA and protein levels decreased in the ICMT stimulation. The ankh gene expression of both mRNA and protein levels increased in TGF-ß1 stimulation. Compared with NC group, the alkaline phosphatase activities significantly increased in ICMT group. CONCLUSION: Our results directly showed that ICMT induced the calcification and downregulation of ankh gene expression of end plate chondrocytes, which may be caused by the endogenous TGF-ß1.

Transcriptional responses in the brain, liver and gonad of Japanese ricefish (Oryzias latipes) exposed to two anti-estrogens.

The study of endocrine disruption is being increasingly conducted at the mRNA level of genes, as this approach might yield insight into the modes of action and mechanisms of toxicity. In this study, the transcriptional responses of a set of functionally relevant genes associated with the pathways of the hypothalamic-pituitary-gonadal (HPG; or HPG[L]-liver) axis of Japanese ricefish were examined after treatment with two model anti-estrogens, letrozole (LET) and tamoxifen (TAM), at three concentrations (30, 100 and 300µg/L) for 72h. The results showed that LET and TAM produced distinct expression profiles in a complex tissue- and gender-specific manner, confirming that they exert their anti-estrogenic effects via different molecular mechanisms. For example, the transcriptional levels of hepatic vitellogenin were significantly downregulated in females exposed to either LET or TAM, while they were significantly upregulated in TAM-exposed males and did not exhibit any change in LET-treated males. The expression of genes involved in steroidogenesis was also modulated by these two anti-estrogens in a way that corresponded with their anticipated mode of action. Overall, the data not only provide mechanistic information of anti-estrogenic chemicals but also demonstrate the potential of investigation of gene expression in the HPG(L) axis of model fish for diagnostic and predictive assessments of the risks associated with chemical exposure.

Transcriptional responses in Japanese medaka (Oryzias latipes) exposed to binary mixtures of an estrogen and anti-estrogens.

Determining ecotoxicological risks of exposure to mixtures of endocrine disrupting chemicals (EDCs) remains a daunting challenge in environmental toxicology. Recently, some studies have illustrated that transcriptional profiling of genes offers the potential to identify the chemical causation of effects that are induced by exposure to complex mixtures. In the present study, the transcriptional responses of a set of genes involved in the hypothalamic-pituitary-gonadal (HPG, or HPG[L]-liver) axis of Japanese medaka (Oryzias latipes) were systematically examined after treatment with a combination of an estrogen (17α-ethinylestradiol [EE2], 20 ng/L) and two model anti-estrogens, the aromatase inhibitor (AI) letrozole (LET) and the selective estrogen-receptor modulator (SERM) tamoxifen (TAM), at three concentrations (30, 100 and 300 µg/L) for 72 h. The data presented demonstrate that although gene transcription analyses increase our mechanistic understanding of the modes of action (MOAs) of EDCs, the characteristic of most genes altered by a certain single chemical exposure may not be useful for diagnostic chemical causation in a mixture exposure situation. For example, the induction of one vitellogenin gene (VTG1) transcription caused by EE2 in male fish was effectively blocked after exposure to a combination of EE2 and LET but not EE2 and TAM. Moreover, the responses in gene transcription to coexposure were elicited partially in a nonmonotonic concentration-dependent manner. Therefore, the application of transcriptional profiling of genes for screening complex environmental samples should be further evaluated until biomarker gene responses are robust and sensitive enough to properly assess the complex interactions.

Phenolic composition and antioxidant activity in seed coats of 60 Chinese black soybean (Glycine max L. Merr.) varieties.

Phenolics in black soybean seed coat (BSSC) are considered to be responsible for the health benefits of black soybean. BSSCs of 60 Chinese varieties were examined for phenolic contents, anthocyanin profiles, and antioxidant activity. Total phenolic and condensed tannin contents ranged from 512.2 to 6057.9 mg gallic acid equivalents/100 g and from 137.2 to 1741.1 mg (+)-catechin equivalents/100 g, respectively. Six anthocyanins (delphinidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-glucoside, petunidin-3-glucoside, peonidin-3-glucoside, and malvidin-3-glucoside) were detected by HPLC. Total anthocyanin contents (TAC) were from 98.8 to 2132.5 mg/100 g, and cyanidin-3-glucoside was the most abundant anthocyanin in all varieties, with a distribution of 48.8-94.1% of TAC. Antioxidant properties detected by DPPH, FRAP, and ORAC methods all showed wide variations ranging from 4.8 to 65.3 µg/100 mL (expressed as EC(50)), from 17.5 to 105.8 units/g, and from 42.5 to 1834.6 µmol Trolox equivalent/g, respectively. Sixty varieties were classified into four groups by hierarchical clustering analysis, and group 4 consisting of nine varieties had the highest phytochemicals content and antioxidant activity.