Genome-wide mapping of spontaneous genetic alterations in diploid yeast cells.

Genomic alterations including single-base mutations, deletions and duplications, translocations, mitotic recombination events, and chromosome aneuploidy generate genetic diversity. We examined the rates of all of these genetic changes in a diploid strain of Saccharomyces cerevisiae by whole-genome sequencing of many independent isolates (n = 93) subcloned about 100 times in unstressed growth conditions. The most common alterations were point mutations and small (<100 bp) insertion/deletions (n = 1,337) and mitotic recombination events (n = 1,215). The diploid cells of most eukaryotes are heterozygous for many single-nucleotide polymorphisms (SNPs). During mitotic cell divisions, recombination can produce derivatives of these cells that have become homozygous for the polymorphisms, termed loss-of-heterozygosity (LOH) events. LOH events can change the phenotype of the cells and contribute to tumor formation in humans. We observed two types of LOH events: interstitial events (conversions) resulting in a short LOH tract (usually less than 15 kb) and terminal events (mostly cross-overs) in which the LOH tract extends to the end of the chromosome. These two types of LOH events had different distributions, suggesting that they may have initiated by different mechanisms. Based on our results, we present a method of calculating the probability of an LOH event for individual SNPs located throughout the genome. We also identified several hotspots for chromosomal rearrangements (large deletions and duplications). Our results provide insights into the relative importance of different types of genetic alterations produced during vegetative growth.

Alpiniamides E-G from the Saline Lake-Derived Streptomyces sp. QHA48 and Their Lipid Accumulation Inhibitory Activity.

Alpiniamides E-G, three previously unreported linear polyketide derivatives, along with two known compounds, were isolated from Streptomyces sp. QHA48, which was isolated from the saline lakes of Qinghai-Tibet Plateau. The structures of these compounds were determined through analysis of their spectroscopic data, as well as density functional theory prediction of NMR chemical shifts, application of the DP4+ algorithm and electronic circular dichroism (ECD) calculations. In a cell-based lipid-lowering assay, all five alpiniamides exhibited significant inhibition of lipid accumulation in HepG2 cells without inducing cytotoxic effects at a concentration of 27 µM.

Structurally Diverse Metabolites from the Marine-Derived Streptomyces sp. DS-27 Based on Two Different Culture Conditions.

Nine new compounds, including streptothiomycin A-E (1-5), two cyclopentenones (6, 7), one α-pyrone (8), wailupemycin Q (20), along with sixteen known compounds were identified from a rhizosphere strain Streptomyces sp. DS-27 derived from the marine cordgrass Spartina alterniflora under two different culture conditions. All of the structures were elucidated by extensive analysis of 1D/2D NMR and HR-ESI-MS data. The absolute configurations were determined by NOESY analysis, ECD, specific rotation and GIAO NMR calculations, and DP4+ probability analysis. Bioactivity investigation showed that compounds 5 and 7 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner, which indicates their anti-inflammatory potential.

Strepolyketide D, a new SEK15-derived polyketide compound from salt-lake-derived Streptomyces sp. DBC5.

A new SEK15-derived polyketide compound, strepolyketide D (1), was isolated from salt-lake-derived Streptomyces sp. DBC5, together with two known analogues (2-3). Their structures were elucidated based on spectroscopic analysis of IR, MS, 1 D and 2 D NMR. Compound 2 elicited moderate antioxidation with IC50 value of 39.26 µg/ml. The results of the study revealed that salt-lake actinomycetes of Lake Dabancheng appear to have immense potential as a source of polyketide compounds.

Identification of Novel Sphydrofuran-Derived Derivatives with Lipid-Lowering Activity from the Active Crude Extracts of Nocardiopsis sp. ZHD001.

Lipid-lowering is one of the most effective methods of prevention and treatment for cardiovascular diseases. However, most clinical lipid-lowering drugs have adverse effects and cannot achieve the desired efficacy in some complex hyperlipidemia patients, so it is of great significance to develop safe and effective novel lipid-lowering drugs. In the course of our project aimed at discovering the chemical novelty and bioactive natural products of marine-derived actinomycetes, we found that the organic crude extracts (OCEs) of Nocardiopsis sp. ZHD001 exhibited strong in vivo efficacies in reducing weight gain, lowering LDL-C, TC, and TG levels, and improving HDL-C levels in high-fat-diet-fed mice models. Chemical investigations of the active OCEs led to identifying two new sphydrofuran-derived compounds (1-2) and one known 2-methyl-4-(1-glycerol)-furan (3). Their structures were elucidated by the analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and ECD calculations. Among these compounds, compound 1 represents a novel rearranged sphydrofuran-derived derivative. Bioactivity evaluations of these pure compounds showed that all the compounds exhibited significant lipid-lowering activity with lower cytotoxicity in vitro compared to simvastatin. Our results demonstrate that sphydrofuran-derived derivatives might be promising candidates for lipid-lowering drugs.

Suncheonosides E-M and Benzothioate Derivatives from the Marine-Derived Streptomyces sp. ZSN77.

Thirteen new compounds, including suncheonosides E-M (1-9), four benzothioate derivatives (10-13), and one known compound (14), were identified from the marine-derived Streptomyces sp. ZSN77. Suncheonosides E-M incorporate ß-d-glucose, while the reported suncheonosides (A-D) incorporate only l-rhamnose. All of the structures were determined by extensive analysis of NMR spectroscopic and HRESIMS data. Bioactivity evaluation of these compounds showed that 6 had significant activity against PC3 cells with an IC50 value of 4.1 ± 0.1 µM, while compounds 12 and 14 exhibited cytotoxicity against HCT116 cells with IC50 values of 7.3 ± 0.4 and 3.9 ± 0.3 µM, respectively. In addition, compounds 1, 2, 6, 10, and 14 displayed potent in vivo anti-inflammatory efficacy with inhibition of NO production in a dose-dependent manner.

Microfluidic Microwave Sensor Loaded with Star-Slotted Patch for Edible Oil Quality Inspection.

In this paper, we present a new microfluidic microwave sensor loaded with a star-slotted patch for detecting the quality of edible oil. The relative dielectric permittivity and the quality of edible oil will change after being heated at a high temperature. Therefore, the quality of edible oil can be detected by measuring the relative dielectric permittivity of edible oil. The sensor is used to determine the edible oil with different dielectric permittivity by measuring the resonance frequency offset of the input reflection coefficient, which operates at 2.68 GHz. This sensor is designed based on a resonant approach to provide the best sensing accuracy and is implemented using a substrate integrated waveguide structure combined with a pentagonal slot antenna operating at 2.3~2.9 GHz. It can detect greasy liquids with the real part of the complex permittivity ranging from two to three.

Role of long non-coding RNA H19 in therapy resistance of digestive system cancers.

Digestive system cancers are associated with high morbidity and mortality. Chemotherapy and radiotherapy are the main treatment modalities for these cancers. However, the development of therapy resistance leads to high rates of tumor recurrence and metastasis, resulting in dismal prognosis. Long non-coding RNA (LncRNA) H19, one of the most intriguing non-coding RNAs, has been shown to play a key role in the development and therapy resistance of various digestive system cancers (including hepatocellular carcinoma, colorectal cancer, pancreatic ductal adenocarcinoma, esophageal carcinoma, gastric cancer, and biliary system cancer) by regulating the abnormal expression of genes. In this review, we discuss the potential mechanisms of LncRNA H19 related therapy resistance in the context of digestive system cancers. LncRNA H19 is a potential novel therapeutic target for amelioration of cancer therapy resistance.

Safety and efficacy of spleen aminopeptide oral lyophilized powder for improving quality of life and immune response in patients with advanced breast cancer: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Health-related quality of life (HRQoL) is an important consideration in managing patients. Spleen aminopeptide oral lyophilized powder (SAOLP) has been used to enhance cellular immunity in a patient. This multicenter, randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL in patients with breast cancer. Patients diagnosed with advanced breast cancer were included, and were administered SAOLP or placebo 4 mg qd for two cycles. The primary endpoint was improvement in HRQoL on day 42 measured by the EORTC QLQ-C30 and EORTC QLQ-BR23. Secondary endpoints included immunologic function, improvement in HRQoL on day 21 and 84, objective response rate, disease control rate, BMI and adverse events. On day 42, on the EORTC QLQ-C30 or EORTC QLQ-BR23, scores on the functional scales and QoL scale were significantly higher and scores on symptom scales were significantly lower in patients who received SAOLP compared to placebo (P < 0.05). On day 84, the number of CD3, CD4 and CD8 cells were significantly higher in patients who received SAOLP. There were no significant differences in objective response rate, disease control rate or BMI. SAOLP may improve HRQoL and the immune response in patients with advanced breast cancer, represents a convenient and safe adjuvant therapy.

Physapubescin B enhances the sensitivity of gastric cancer cells to trametinib by inhibiting the STAT3 signaling pathway.

Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.

Pyrimidine Nucleosides from Streptomyces sp. SSA28.

Eleven new pyrimidine nucleosides (1-11) and 12 known analogues (12-23) were isolated from the marine-derived Streptomyces sp. SSA28. All of the new structures were elucidated by extensive NMR spectroscopic analysis and HRESIMS data. The absolute configurations of compound 1 were determined by X-ray diffraction. The configurations of 2-16 were investigated by ECD calculations. Compounds 11-16 showed cytotoxicity against HCT-116 human colon cancer cell lines with IC50 values from 0.39 ± 0.03 to 6.63 ± 0.47 µM.

Bioactive staurosporine derivatives from the Streptomyces sp. NB-A13.

Six new (1-6) and nine known (7-15) staurosporine derivatives were isolated from the rice solid fermentation of the marine-derived Streptomyces sp. NB-A13. The structures of the new staurosporine derivatives were established by extensive spectroscopic data interpretation. The absolute configurations of 1 and 2 were assigned by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. All of these compounds were screened for their cytotoxic activities against PC-3 and SW-620 cell lines. Compound 7 exhibited stronger inhibitory activity against SW-620 cell lines than the positive control staurosporine (25.10 nM), with IC50 values of 9.99 nM. Moreover, compounds 1-5, 8-13 and 15 also showed significant cytotoxicities with IC50 values ranging from 0.02 to 16.60 µM, while 6 exhibited no cytotoxic potency. Additionally, compounds 1-7 were also tested for enzyme inhibition activities of Protein kinase C theta (PKC-θ), and showed activity with IC50 values ranging from 0.06 to 9.43 µM except for compound 6, which has no inhibition activity.

A new medermycin analog from the marine-derived actinomycetes Streptomyces sp. ZS-A45.

A new medermycin analog (1) was isolated from the marine-derived actinomycetes Streptomyces sp. ZS-A45. The structure elucidation of compound 1 was determined by the HRESIMS and extensive NMR analysis. And compound 1 exhibited significant cytotoxicity against PC3 cell lines with IC50 values of 0.81 ± 0.42 µm.

The Influence of Different Knowledge-Driven Methods on Landslide Susceptibility Mapping: A Case Study in the Changbai Mountain Area, Northeast China.

Landslides are one of the most frequent geomorphic hazards, and they often result in the loss of property and human life in the Changbai Mountain area (CMA), Northeast China. The objective of this study was to produce and compare landslide susceptibility maps for the CMA using an information content model (ICM) with three knowledge-driven methods (the artificial hierarchy process with the ICM (AHP-ICM), the entropy weight method with the ICM (EWM-ICM), and the rough set with the ICM (RS-ICM)) and to explore the influence of different knowledge-driven methods for a series of parameters on the accuracy of landslide susceptibility mapping (LSM). In this research, the landslide inventory data (145 landslides) were randomly divided into a training dataset: 70% (81 landslides) were used for training the models and 30% (35 landslides) were used for validation. In addition, 13 layers of landslide conditioning factors, namely, altitude, slope gradient, slope aspect, lithology, distance to faults, distance to roads, distance to rivers, annual precipitation, land type, normalized difference vegetation index (NDVI), topographic wetness index (TWI), plan curvature, and profile curvature, were taken as independent, causal predictors. Landslide susceptibility maps were developed using the ICM, RS-ICM, AHP-ICM, and EWM-ICM, in which weights were assigned to every conditioning factor. The resultant susceptibility was validated using the area under the ROC curve (AUC) method. The success accuracies of the landslide susceptibility maps produced by the ICM, RS-ICM, AHP-ICM, and EWM-ICM methods were 0.931, 0.939, 0.912, and 0.883, respectively, with prediction accuracy rates of 0.926, 0.927, 0.917, and 0.878 for the ICM, RS-ICM, AHP-ICM, and EWM-ICM, respectively. Hence, it can be concluded that the four models used in this study gave close results, with the RS-ICM exhibiting the best performance in landslide susceptibility mapping.

A Method for Improving Controlling Factors Based on Information Fusion for Debris Flow Susceptibility Mapping: A Case Study in Jilin Province, China.

Debris flow is one of the most frequently occurring geological disasters in Jilin province, China, and such disasters often result in the loss of human life and property. The objective of this study is to propose and verify an information fusion (IF) method in order to improve the factors controlling debris flow as well as the accuracy of the debris flow susceptibility map. Nine layers of factors controlling debris flow (i.e., topography, elevation, annual precipitation, distance to water system, slope angle, slope aspect, population density, lithology and vegetation coverage) were taken as the predictors. The controlling factors were improved by using the IF method. Based on the original controlling factors and the improved controlling factors, debris flow susceptibility maps were developed while using the statistical index (SI) model, the analytic hierarchy process (AHP) model, the random forest (RF) model, and their four integrated models. The results were compared using receiver operating characteristic (ROC) curve, and the spatial consistency of the debris flow susceptibility maps was analyzed while using Spearman's rank correlation coefficients. The results show that the IF method that was used to improve the controlling factors can effectively enhance the performance of the debris flow susceptibility maps, with the IF-SI-RF model exhibiting the best performance in terms of debris flow susceptibility mapping.

Cyclizidine-Type Alkaloids from Streptomyces sp. HNA39.

Eight new cyclizidine-type alkaloids (1-8) and one known alkaloid (9) were identified from the chemical investigations of a marine-derived actinomycete, Streptomyces sp. HNA39. Among these alkaloids, compounds 3, 7, and 8 contain a chlorine atom, and the known alkaloid, (+)-ent-cyclizidine (9), is now first reported as a natural product. Their structures were elucidated by extensive NMR-spectroscopic analysis and HRESIMS data. The absolute configurations of all of the compounds were established by ECD calculations. Cytotoxicity evaluations of all of the compounds showed that compound 2 exhibited significant activity against the PC3 and HCT116 human-cancer-cell lines with IC50 values of 0.52 ± 0.03 and 8.3 ± 0.1 µM, respectively. Interestingly, compounds 2, 5, 7, and 8 exhibited moderate inhibition against the ROCK2 protein kinase with IC50 values from 7.0 ± 0.8 to 42 ± 3 µM.

Bioactive Indolocarbazoles from the Marine-Derived Streptomyces sp. DT-A61.

Nine new indolocarbazoles (1-9) were isolated from the marine-derived Streptomyces sp. DT-A61. Among them compounds 1-8 featured a hydroxy group at the C-3 or C-9 position. All purified compounds were identified by 1D and 2D NMR and HRESIMS data. The absolute configurations of 4-6, 8, and 9 were determined by electronic circular dichroism spectroscopic data. Compound 7 exhibited significant activity against human prostate PC-3 cancer cells with an IC50 value of 0.16 µM. Compounds 1, 5, 6, and 9 showed moderate inhibition against the same cell line with IC50 values of 8.0, 3.6, 3.1, and 5.6 µM. Compound 2 displayed a notable inhibitory effect against Rho-associated protein kinase (ROCK2) with an IC50 value of 5.7 nM, which was similar to the positive control staurosporine (IC50 7.8 nM).

Medermycin-Type Naphthoquinones from the Marine-Derived Streptomyces sp. XMA39.

Four new medermycin-type naphthoquinones, strepoxepinmycins A-D (1-4), and one known compound, medermycin (5), were identified from Streptomyces sp. XMA39. Their structures were elucidated by analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and ECD calculations. Among these compounds, strepoxepinmycin A (1) represents a rare 5,10-oxepindione ring system typically formed by a Baeyer-Villiger oxidation, and strepoxepinmycin B (2) is an isolation artifact derived from 1. Bioactivity evaluations of these compounds showed that compounds 3 and 4 exhibited cytotoxicity against HCT-116 and PC-3 cancer cell lines and 4 exhibited moderate inhibition of ROCK 2 protein kinase. In addition, all of the new compounds showed antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus and antifungal activity against Candida albicans.

Combined System of Magnetic Resonance Sounding and Time-Domain Electromagnetic Method for Water-Induced Disaster Detection in Tunnels.

Underground construction projects such as tunnel construction are at high risk of water-induced disasters. Because this type of disaster poses a serious threat to worker safety and productivity, instruments and methods that can accurately detect the water source are critical. In this study, a water detection instrument that combines Magnetic Resonance Sounding (MRS) and Time-domain Electromagnetic Method (TEM) techniques to yield a joint MRS-TEM interpretation method was developed for narrow underground spaces such as tunnels. Joint modules including a transmitter and receiver were developed based on a dual-purpose and modular design concept to minimize the size and weight of the instrument and consequently facilitate transportation and measurement. Additionally, wireless control and communication technology was implemented to enable inter-module cooperation and simplify instrument wiring, and wireless synchronization was accomplished by implementing a Global Positioning System (GPS)-based timing scheme. The effectiveness and reliability of the instrument were verified via indoor laboratory tests and field measurement signal tests. Furthermore, the practicability of the combined instrument and its interpretation method was verified via a field case performed in a tunnel in Hubei, China.

Mass Spectrometric Characteristics of Prenylated Indole Derivatives from Marine-Derived Penicillium sp. NH-SL.

Two prenylated indole alkaloids were isolated from the ethyl acetate extracts of a marine-derived fungus Penicillium sp. NH-SL and one of them exhibited potent cytotoxic activity against mouse hepa 1c1c7 cells. In order to detect other bioactive analogs, we used liquid chromatogram tandem mass spectrometry (LC-MS/MS) to analyze the mass spectrometric characteristics of the isolated compounds as well as the crude extracts. As a result, three other analogs were detected, and their structures were deduced according to the similar fragmentation patterns. This is the first systematic report on the mass spectrometric characteristics of prenylated indole derivatives.