Discovery of a Novel Analogue of FR901533 and the Corresponding Biosynthetic Gene Cluster From Streptosporangium Roseum No. 79089

FR901533 (1, also known as WS79089B), WS79089A (2), and WS79089C (3) are polycyclic aromatic natural products with promising inhibitory activity to endothelin-converting enzymes. In this work, we isolated five tridecaketide products from Streptosporangium roseum No. 79089, including 1-3, benaphthamycin (4) and a novel FR901533 analogue (5). The structure of 5 was characterized based on spectroscopic data. Compared to the major product 2, the new compound 5 has an additional hydroxyl group at C-12 and an extra methyl group at the 13-OH. The configuration of C-19 of these compounds was determined to be R using Mosher\u27s method. A putative biosynthetic gene cluster for compounds 1-5 was discovered by analyzing the genome of S. roseum No. 79089. This 38.6-kb gene cluster contains 38 open reading frames, including a minimal polyketide synthase (wsaA-C), an aromatase (wsaD), three cyclases (wsaE, F and W) and a series of tailoring enzymes such as monooxygenases (wsaO1-O7) and methyltransferases (wsaM1 and M2). Disruption of the ketosynthase gene (wsaA) in this gene cluster abolished the production of 1-5, confirming that this gene cluster is indeed responsible for the biosynthesis of 1-5. A type II polyketide biosynthetic pathway was proposed for this group of natural endothelin-converting enzyme inhibitors

Nitrogen-doped graphene-ionic liquid-glassy carbon microsphere paste electrode for ultra-sensitive determination of quercetin

The analysis of quercetin (Qu) is of great significance owing to its multiple biomedical effects. In this work, a nitrogendoped graphene-ionic liquid-glassy carbon microsphere paste electrode (N-GE/GCILE) was constructed for the determination of Qu. Cyclic voltammetry (CV) and square wave voltammetry (SWV) were employed to investigate the electrochemical behavior of Qu. In comparison with unmodified glassy carbon microsphere paste electrode, the modified electrode exhibited better electrocatalytic activity towards Qu. The influencing conditions on sensitivity such as the amount of modifier, accumulation potential and time, and electrolyte pH value were respectively discussed. Under the optimized conditions, two linear ranges of 0.002- 0.1 μM and 0.1-10 μM were obtained, with a detection limit of 1 nM (S/N=3). The method was applied in Qu determination in blueberry juice with the recoveries of 102.5-105.0 %

Optimal Control of a Delay-Varying Computer Virus Propagation Model

By incorporating the objective of keeping a low number of infected nodes and a high number of recovered nodes at a lower cost into a known computer virus model (the delay-varying SIRC model) extended by introducing quarantine, a novel model is described by means of the optimal control strategy and theoretically analyzed. Through the comparison of simulation results, it is shown that the propagation of computer virus with varying latency period can be suppressed effectively by the optimal control strategy

A proteomic view of Caenorhabditis elegans caused by short-term hypoxic stress

<p>Abstract</p> <p>Background</p> <p>The nematode <it>Caenorhabditis elegans </it>is both sensitive and tolerant to hypoxic stress, particularly when the evolutionarily conserved hypoxia response pathway HIF-1/EGL-9/VHL is involved. Hypoxia-induced changes in the expression of a number of genes have been analyzed using whole genome microarrays in <it>C. elegans</it>, but the changes at the protein level in response to hypoxic stress still remain unclear.</p> <p>Results</p> <p>Here, we utilized a quantitative proteomic approach to evaluate changes in the expression patterns of proteins during the early response to hypoxia in <it>C. elegans</it>. Two-dimensional difference gel electrophoresis (2D-DIGE) was used to compare the proteomic maps of wild type <it>C. elegans </it>strain N2 under a 4-h hypoxia treatment (0.2% oxygen) and under normoxia (control). A subsequent analysis by MALDI-TOF-TOF-MS revealed nineteen protein spots that were differentially expressed. Nine of the protein spots were significantly upregulated, and ten were downregulated upon hypoxic stress. Three of the upregulated proteins were involved in cytoskeletal function (LEV-11, MLC-1, ACT-4), while another three upregulated (ATP-2, ATP-5, VHA-8) were ATP synthases functionally related to energy metabolism. Four ribosomal proteins (RPL-7, RPL-8, RPL-21, RPS-8) were downregulated, indicating a decrease in the level of protein translation upon hypoxic stress. The overexpression of tropomyosin (LEV-11) was further validated by Western blot. In addition, the mutant strain of <it>lev-11(x12</it>) also showed a hypoxia-sensitive phenotype in subsequent analyses, confirming the proteomic findings.</p> <p>Conclusions</p> <p>Taken together, our data suggest that altered protein expression, structural protein remodeling, and the reduction of translation might play important roles in the early response to oxygen deprivation in <it>C. elegans</it>, and this information will help broaden our knowledge on the mechanism of hypoxia response.</p

Geochronology, geochemistry, and tectonic significance of the Shirenshan gneiss in the southern margin of the North China Block

The Shirenshan Block is a complex geological body located in the southern margin of the North China Block (NCB). From south to north, it can be divided into the Taihua Group migmatite, and the Shirenshan gneiss and magmatic rocks. The petrographic features, tectonic setting, provenance, and geological age of the Shirenshan gneiss using comprehensive field investigations, microstructural analysis, zircon U-Pb radioactive dating, and geochemical analyses were investigated for this study. The petrology, geochemistry, and geochronology of the Shirenshan gneiss suggests that it is mainly a felsic rock and its protolith was a high-K calc-alkaline series A-type granite. The protolith is high in SiO2, Al2O3, K2O, Na2O, and low in CaO and MgO. Overall, the Sr-Nd isotope composition of the samples showed no significant difference, indicating that the Taihua Group migmatite and the Shirenshan gneiss have the same source material. The Shirenshan block may be partially melted from the Taihua group and formed during activity of the Luo-Luan Fault. By the method of zircon dating analysis, the protolith age of the Shirenshan block was determined as 1559±16Ma (Early Proterozoic). Then, the crystallization age of the syntectonic migmatite is 439.2±7.6Ma, which was formed by subduction of the Taihua Group. During the early Cretaceous (119.5±1.3Ma), the Shirenshan gneiss may have experienced regional migmatization and formed the zircon rims age of the Yanshanian period. Litho-geochemical features of the Shirenshan block are similar to A1-type granites indicating that they are post-orogenic. Therefore, the metamorphic deformation of the Shirenshan gneiss reflects the tectonics in the southern margin of the NCB.</p

Autonomous detection of damage to multiple steel surfaces from 360° panoramas using deep neural networks

Structural health assessments are essential for infrastructure. By using an autonomous panorama vision‐based inspection system, the limitations of the human cost and safety factors of previously time‐consuming tasks have been overcome. The main damage detection challenges to panorama images are (1) the lack of annotated panorama defect image data, (2) detection in high‐resolution images, and (3) the inherent distortion disturbance for panorama images. In this paper, a new PAnoramic surface damage DEtection Network (PADENet) is presented to solve the challenges by (a) using an unmanned aerial vehicle to capture panoramic images and a distorted panoramic augmentation method to expand the panoramic dataset, (b) employing the proposed multiple projection methods to process high‐resolution images, and (c) modifying the faster region‐based convolutional neural network and training via transfer learning on VGG‐16, which improves the precision for detecting multiple types of damage in distortion. The results show that the proposed method is optimal for surface damage detection

A CpG Methylation Signature as a Potential Marker for Early Diagnosis of Hepatocellular Carcinoma From HBV-Related Liver Disease Using Multiplex Bisulfite Sequencing.

BACKGROUND: Aberrant methylation of CpG sites served as an epigenetic marker for building diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC). METHODS: Using Illumina 450K and EPIC Beadchip, we identified 34 CpG sites in peripheral blood mononuclear cell (PBMC) DNA that were differentially methylated in early HCC versus HBV-related liver diseases (HBVLD). We employed multiplex bisulfite sequencing (MBS) based on next-generation sequencing (NGS) to measure methylation of 34 CpG sites in PBMC DNA from 654 patients that were divided into a training set (n = 442) and a test set (n = 212). Using the training set, we selected and built a six-CpG-scorer (namely, cg14171514, cg07721852, cg05166871, cg18087306, cg05213896, and cg18772205), applying least absolute shrinkage and selection operator (LASSO) regression. We performed multivariable analyses of four candidate risk predictors (namely, six-CpG-scorer, age, sex, and AFP level), using 20 times imputation of missing data, non-linearly transformed, and backwards feature selection with logistic regression. The final model's regression coefficients were calculated according to "Rubin's Rules". The diagnostic accuracy of the model was internally validated with a 10,000 bootstrap validation dataset and then applied to the test set for validation. RESULTS: The area under the receiver operating characteristic curve (AUROC) of the model was 0.81 (95% CI, 0.77-0.85) and it showed good calibration and decision curve analysis. Using enhanced bootstrap validation, adjusted C-statistics and adjusted Brier score were 0.809 and 0.199, respectively. The model also showed an AUROC value of 0.84 (95% CI 0.79-0.88) of diagnosis for early HCC in the test set. CONCLUSIONS: Our model based on the six-CpG-scorer was a reliable diagnosis tool for early HCC from HBVLD. The usage of the MBS method can realize large-scale detection of CpG sites in clinical diagnosis of early HCC and benefit the majority of patients

Non-destructive 3D Microtomography of Cerebral Angioarchitecture Changes Following Ischemic Stroke in Rats Using Synchrotron Radiation

A better understanding of functional changes in the cerebral microvasculature following ischemic injury is essential to elucidate the pathogenesis of stroke. Up to now, the simultaneous depiction and stereological analysis of 3D micro-architectural changes of brain vasculature with network disorders remains a technical challenge. We aimed to explore the three dimensional (3D) microstructural changes of microvasculature in the rat brain on 4, 6 hours, 3 and 18 days post-ischemia using synchrotron radiation micro-computed tomography (SRμCT) with a per pixel size of 5.2 μm. The plasticity of angioarchitecture was distinctly visualized. Quantitative assessments of time-related trends after focal ischemia, including number of branches, number of nodes, and frequency distribution of vessel diameter, reached a peak at 6 h and significantly decreased at 3 days and initiated to form cavities. The detected pathological changes were also proven by histological tests. We depicted a novel methodology for the 3D analysis of vascular repair in ischemic injury, both qualitatively and quantitatively. Cerebral angioarchitecture sustained 3D remodeling and modification during the healing process. The results might provide a deeper insight into the compensatory mechanisms of microvasculature after injury, suggesting that SRμCT is able to provide a potential new platform for deepening imaging pathological changes in complicated angioarchitecture and evaluating potential therapeutic targets for stroke