Search

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 (5) and AZD5099 (6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 (6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure–activity relationships of the compounds were also studied.

The elemental sulfur corrosion resistance and corrosion mechanisms of nickel-based alloy 825 at high temperature and high pressure are still missing. This work investigates the elemental sulfur corrosion of nickel-based alloy 825 in CO2–H2S-containing environment at high temperature and high pressure using weight loss measurement, surface characterization and in-situ electrochemical techniques including electrochemical noise, electrochemical impedance spectroscopy as well as polarization curves. The results show that in the absence of elemental sulfur nickel-based alloy 825 hardly corrodes in the environment containing 0.5 MPa CO2 and 1.6 MPa H2S at 100 °C, since the passive film on the substrate could offer an enough protective performance. However, with the increasing elemental sulfur content, the corrosion of nickel-based alloy 825 becomes more and more obvious. Under the condition of full coverage of elemental sulfur, the uniform corrosion rate of the specimen can be as high as 0.327 mm/y. Moreover, under such a condition, serious localized corrosion could also be observed on the specimen surface. Based on results of electrochemical measurement and surface analysis, it is considered that underneath the elemental sulfur deposit the formation of a strong acidic environment generated from the hydrolysis of elemental sulfur largely destroys the passive film, leading to serious corrosion. Therefore, nickel-based alloy 825 used in high sulfur-containing environment should pay close attention to safety risk from elemental sulfur corrosion. The results of this work could provide a reference for the material selection in high sulfur natural gas field.

New Delhi metallo-β-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all β-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

A useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles was developed. By using potassium iodate as an oxidant in water at 60 °C, a wide range of 2-acylamino-1,3,4-oxadiazoles were afforded in moderate to excellent yields within two hours. This method could provide a facile shortcut to generate a series of 2-acylamino-1,3,4-oxadiazoles in medicinal chemistry. Interestingly, some highly potent antibiotic compounds were found through this synthetic method, and some of them displayed a significant improvement in activity compared with the corresponding 1,4-diacylthiosemicarbazides. Compound 2n was the most active against Staphylococcus aureus with MIC (minimum inhibitory concentration) of 1.56 mg/mL, and compounds 2m and 2q were the most active against Bacillus subtilis with MIC of 0.78 mg/mL. The preliminary cytotoxic activities of the most potent compounds 2m, 2n, and 2q against the androgen-independent (PC-3) prostate cancer cell line were more than 30 μM (IC50 > 30 μM).

Ethylene oxide (EO) is one of the most crucial materials in plastic industries. The traditional catalytic process requires high temperature and pressure to produce EO. A chlorine-assisted system has been reported to produce EO, but it required noble metal catalysts, which significantly increased the cost. In this work, a MOF-derived Co3O4/nitrogen-doped carbon composite (Co3O4/NC) prepared through a two-step calcination method exhibited remarkable chlorine evolution reaction (ClER) activity as compared with a commercial RuO2 catalyst, which can be attributed to the higher specific surface area and lower resistance of its porous structure and nitrogen-doped carbon. Furthermore, the Co3O4/NC maintained a stable potential and a high faradaic efficiency throughout the 10-hour electrolysis test. [ABSTRACT FROM AUTHOR]

We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the "Trojan horse" strategy. The conjugates could combine with Fe3+ ions as the deferasirox. However, both conjugates were inactive against tested bacteria, including S. aureus, E. coli, A. baumannii, and P. aeruginosa. The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic, or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm. Therefore, the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration. Keywords: Oxazolidinone; Deferasirox; Antibacterial; Siderophore; "Trojan horse" strategy [ABSTRACT FROM AUTHOR]

One of the main goals in biogeography and ecology is the study of patterns of species diversity and the driving factors in these patterns. However, such studies have not focused on Sternorrhyncha in China, although this region hosts massive species distribution data. Here, based on the 15,450 distribution records of Sternorrhyncha species in China, we analyzed patterns in species richness and endemism at 1° × 1° grid size and determined the effects of environmental variables on these patterns using correlations analysis and the model averaging approach. We found that species richness and endemism of Sternorrhyncha species are unevenly distributed, with high values in the eastern and southeastern coastal regions of mainland China, as well as Taiwan Island. Furthermore, the key factors driving species richness and endemism patterns are inconsistent. Species richness patterns were strongly affected by the normalized difference vegetation index, which is closely related to the feeding habits of Sternorrhyncha, whereas endemism patterns were strongly affected by the elevation range. Therefore, our results indicate that the range size of species should be considered to understand the determinants of species diversity patterns.

Copyright of Journal of Chinese Pharmaceutical Sciences is the property of Journal of Chinese Pharmaceutical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rye (Secale cereale) is a valuable gene donor for wheat improvement, especially for its resistance to diseases. Developing rye-derived resistance sources is important for wheat breeding. In the present study, two wheat-rye derivatives, designated JS016 and JS110, were produced by crossing common wheat cultivar Yangmai 23 with Pakistani rye accession W2A. Using sequential genomic in situ hybridization (GISH) and multicolor fluorescence in situ hybridization (mc-FISH), JS016 and JS110 were identified as a T6BS.6RL translocation line and a T6BS.6BL6RL translocation line, respectively. Ten newly 6RL chromosome arm-specific markers were developed and used to confirm the 6RL translocation. The wheat 55K single-nucleotide polymorphism (SNP) array further verified the molecular cytogenetic identification results above and clarified their breakpoints at 430.9 and 523.0 Mb of chromosome 6B in JS016 and JS110, respectively. Resistance spectrum and allelism test demonstrated that JS016 and JS110 possessed novel powdery mildew resistance gene(s) that was derived from the 6RL translocation but differed from Pm20. Moreover, JS016 and JS110 had better agronomic traits than the previously reported 6RL translocation line carrying Pm20. To efficiently transfer and detect the 6RL translocation from JS016 and JS110, one 6RL-specific Kompetitive allele specific PCR (KASP) marker was developed and validated in high throughput marker-assisted selection (MAS).

In this study, a progressive damage model was developed for the mechanical response and damage evolution of carbon fiber stitched composite laminates under low-velocity impact (LVI). The three-dimensional Hashin and Hou failure criteria were used to identify fiber and matrix damage. The cohesive zone model was adopted to simulate the delamination damage, combined with the linear degradation discounting of the equivalent displacement method to characterize the stiffness degradation of the material, and the corresponding user material subroutine VUMAT was coded. The finite element analysis of the LVI of stitched composite laminates under different energies was finished in Abaqus/Explicit. Furthermore, the simulation predictions matched well with the results of the experimental tests. Based on this, composite laminates’ mechanical response and damage forms with different thicknesses and stitch densities were analyzed. The findings show that the main damages of composite laminates were matrix tensile damage and delamination. The stitching process could improve the impact tolerance of composite laminates, inhibiting delamination and reducing the area of the delamination damage. The higher the density of the stitching, the more noticeable its inhibition would be. The thickness of the laminate also had a more significant effect on the damage to the laminate. Thin plates were more prone to matrix tensile damage due to their lower flexural rigidity, whereas thick plates were more susceptible to delamination because of their higher flexural rigidity.

Wheat powdery mildew is a devastating disease leading to severe yield loss. The powdery mildew resistance gene Pm21, encoding a nucleotide-binding leucine-rich repeat receptor (NLR) protein, confers broad-spectrum resistance to powdery mildew and has great potential for controlling this disease. In this study, a large-scale mutagenesis was conducted on wheat cultivar (cv.) Yangmai 18 carrying Pm21. As a result, a total of 113 independent mutant lines susceptible to powdery mildew were obtained, among which, only one lost the whole Pm21 locus and the other 112 harbored one- (107) or two-base (5) mutations in the encoding region of Pm21. From the 107 susceptible mutants containing one-base change, we found that 25 resulted in premature stop codons leading to truncated proteins and 82 led to amino acid changes involving in 59 functional sites. We determined the mutations per one hundred amino acids (MPHA) indexes of different domains, motifs, and non-domain and non-motif regions of PM21 protein and found that the loss-of-function mutations occurred in a tendentious means. We also observed a new mutation hotspot that was closely linked to RNBS-D motif of the NB-ARC domain and relatively conserved in different NLRs of wheat crops. In addition, we crossed all the susceptible mutants with Yangmai 18 carrying wild-type Pm21, subsequently phenotyped their F1 plants and revealed that the variant E44K in the coiled-coil (CC) domain could lead to dominant-negative effect. This study revealed key functional sites of PM21 and their distribution characteristics, which would contribute to understanding the relationship of resistance and structure of Pm21-encoded NLR.

Background Safflower (Carthamus tinctorius L.), well known for its flower, is widely used as a dye and traditional Chinese medicine. Flavonoids, especially flavonoid glycosides, are the main pigments and active components. However, their biosynthesis is largely unknown. Interestingly, the colour of flowers in safflower changed from yellow to red during flower development, while much of the gene and chemical bases during colour transition are unclear. Methods In this research, widely targeted metabolomics and transcriptomics were used to elucidate the changes in flavonoid biosynthesis from the gene and chemical points of view in flowers of safflower during colour transition. The screening of differential metabolites depended on fold change and variable importance in project (VIP) value. Differential expressed genes (DEGs) were screened by DESeq2 method. RT-PCR was used to analyse relative expressions of DEGs. Results A total of 212 flavonoid metabolites, including hydroxysafflor yellow A, carthamin and anthocyanins, were detected and showed a large difference. The candidate genes of glycosyltransferases and flavonoid hydroxylase that might participate in flavonoid glycoside biosynthesis were screened. Ten candidate genes were screened. Through integrated metabolomics and transcriptome analysis, a uridine diphosphate glucose glycosyltransferase gene, CtUGT9 showed a significant correlation with flavonoid glycosides in safflower. In addition, expression analysis showed that CtUGT9 was mainly expressed in the middle development of flowers and was significantly upregulated under MeJA treatment. Our results indicated that CtUGT9 might play an important role in flavonoid glycoside biosynthesis during colour-transition in safflower.

The repellent and contact effects of Plectranthus tomentosa extracts of leaf and stem tissue on different stages of Tetranychus kanzawai were tested using the leaf-dip and insect-dip methods, and the constituents of the Plectranthus tomentosa extract were also determined. It was found that the repellent effect on Tetranychus kanzawai female adults has reached up to 84.43% after 60 min, with significant mortality of Tetranychus kanzawai at all growth stages. Sixty-nine components of the extract were identified by gas chromatography-mass spectrometry, of which limonene, followed by terpinolene, were present at the highest concentration. This research demonstrated that Plectranthus tomentosa has strong repellent and contact effects against Tetranychus kanzawai, offering potential natural strategies for the environmentally protective control of Tetranychus kanzawai in tea gardens and providing the foundation for the biomimetic synthesis of pesticides.

The drought resistance mechanism of typical mosses in the karst area was studied, and the water and photosynthetic physiological adaptation of mosses to karst environmental change was analyzed in this paper, which provided the basis for the restoration and control of karst rocky desertification ecological environment. Three superior plants in the rocky desertification area of Guizhou province were selected; they are, respectively, Erythrodontium julaceum (Schwaegr.) Par., Barbula unguiculata Hedw., and Bryum argenteum Hedw. Results show that the three kinds of plant rock mosses of leaf water potential (Ψs), free water content (Va), total water content, and relative water content (RWC) decreased; bound water (Vs), water saturation deficit (WSD), and Vs/Va ratio increased; transpiration rate (Tr) fell slightly, under drought stress. The physiological indexes of water have different degrees of recovery after rehydration. The total chlorophyll content shows a trend of first increasing followed by falling and then rising. RWC was negatively related to qN and positively related to Fv/Fm, yield, ETR, and qP. After rewetting, the fluorescence parameters are returned to average level under mild-to-moderate stress. At the same time, it is hard to get back to the control level under severe pressure. The water use efficiency (WUE) decreased with stress and recovered to different degrees after rehydration.

Freesia hybrida is a group of cultivars in the genus Freesia with a strong floral scent composed of diverse volatile organic compounds (VOCs). In this study, the VOCs of 34 F. hybrida were extracted and analyzed by headspace solid phase microextraction and gas chromatography mass spectrometry (HS-SPME-GC-MS). A total of 164 VOCs whose relative contents were higher than 0.05% were detected. The numbers of VOCs in all germplasms differed between 11 to 38, and the relative contents ranged from 32.39% to 94.28%, in which most germplasms were higher than 80%. Terpenoids, especially monoterpenes, were the crucial type of VOCs in most germplasms, of which linalool and D-limonene were the most frequently occurring. Principal component analysis (PCA) clearly separated samples based on whether linalool was the main component, and hierarchical clustering analysis (HCA) clustered samples into 4 groups according to the preponderant compounds linalool and (E)-β-ocimene. Comparison of parental species and hybrids showed heterosis in three hybrids, and the inherited and novel substances suggested that monoterpene played an important role in F. hybrida floral scent. This study established a foundation for the evaluation of Freesia genetic resources, breeding for the floral aroma and promoting commercial application.

The stress field around the tip of an elliptically blunted crack induced by an edge dislocation has been obtained in closed form, from which the mode I and mode II stress intensity factors induced by the edge dislocation are obtained. The solutions apply to the edge dislocation either emitted from crack-tip surface or originated elsewhere, and for the dislocation located anywhere around the crack tip. The effects of the crack length, the crack-tip bluntness, the origination and position of the dislocation on the stress intensity factors are examined. [ABSTRACT FROM AUTHOR]

In order to explore the changes in fracture mechanical properties of pipeline steel welded joints in hydrogen environment, the notched tensile in-situ hydrogen charging method was used to study the hydrogen embrittlement susceptibility of X80 steel base metal, welds and heat-affected zones under a total pressure of 12 MPa and a hydrogen partial pressure of 0.36 MPa. A high-pressure slow strain rate tensile testing machine was employed to conduct notch tensile test, and a high-pressure fracture toughness testing machine and a high-pressure corrosion fatigue testing machine were used to carry out fracture toughness and fatigue crack growth rate tests on X80 steel, respectively. The crack propagation behavior of X80 steel was studied by combining fracture toughness tests and fatigue crack propagation rate tests. Results showed that under the same conditions, compared with the base metal and heat-affected zone, the reduction of area at the weld position was significantly reduced, showing a higher susceptibility to hydrogen embrittlement. Compared with the original data in air at normal temperature and pressure, the crack tip opening displacement(CTOD) value of the weld position in the hydrogen partial pressure environment of 0.36 MPa changed slightly, and no secondary cracks appeared on the fracture surface. Compared with the air environment, the fatigue crack growth rate of X80 steel welds in a hydrogen partial pressure environment of 0.36 MPa increased by 1 order of magnitude, signifying that hydrogen could increase the fatigue crack growth rate of the material. However, according to the actual pipeline pressure fluctuation, the hydrogen embrittlement sensitivity of X80 steel was smaller under 0.36 MPa hydrogen partial pressure.