Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer

Background: Gastric cancer is one of the cancers with wide incidence, difficult treatment and high mortality in the world, especially in Asia and Africa. In our previous work, a novel o-aminobenzamide analogue F8 was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC50 of 0.26 μM for HGC-27). However, the poor water solubility of compound F8 prevents its further progress in preclinical studies.Aim: To improve the water solubility and drug-likeness of F8 via salt formation.Method: Different acids and F8 were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation in vitro and in vivo were used to obtain the optimal salt form with the best druggability.Results: our continuous efforts have finally confirmed F8·2HCl as the optimal salt form with maintained in vitro antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the F8·2HCl displayed superior in vivo antitumor efficacy (TGI of 70.1% in 75 mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that F8·2HCl exerts an antitumor effect through the regulation of cell cycle-related protein (CDK2 and p21), apoptosis-related protein Cleaved Caspase-3, proliferation marker Ki67, and cell adhesion molecule E-cadherin. In addition, F8·2HCl showed acceptable safety in the in vivo acute toxicity assay.Conclusion: Salting is an effective means to improve the drug-like properties of compound F8, and F8·2HCl can serve as a promising therapeutic agent against undifferentiated gastric cancer

A study of effects of different impact loads on the dynamic and elastoplastic behavior in reservoir rocks at the beginning of hydraulic fracturing

Successful hydraulic fracturing is very important in the development of hydrocarbon-bearing formations. The loading introduced by hydraulic fracturing causes deformation and failure, which are related to the damage accumulation and hydraulic fracture initiation process. This study employs a numerical model that considers the dynamic and elastoplastic behaviors in rocks under the influence of impact loads. The acceleration and wave propagation behaviors are quantified using the model. A time integration algorithm is used to ensure numerical accuracy and stability. The effects of loading rate, loading location, and heterogeneity are quantified. Results show that the elastoplastic and dynamic can effectively capture the wavy mechanical responses in the domain. Strain rate, acceleration, and plasticity can all exhibit oscillatory distribution patterns. Increasing the loading rate can magnify acceleration, strain rate, and the maximum plastic strain, while it reduces the range experiencing these induced changes. Changing the loading types and introducing the heterogeneity consideration both largely alter the mechanical response in the domain, and the waveforms of the mechanical parameters are significantly changed. Failure can occur earlier in layers with more elastic mechanical properties. Exerting 50 MPa loading in 0.01 ms can effectively introduce deformation and failures in the reservoir rock. Doubling the loading rate can effectively improve the ability of creating rock failures, which facilitates the following fracture initiation and propagation processes. This study can be a reference for the understanding of near-well and instantaneous rock mechanical behaviors at the beginning of fracturing

Diversity and antibacterial potential of the Actinobacteria associated with Apis mellifera ligustica

Insect-associated Actinobacteria are a potentially rich source of novel natural products with antibacterial activity. Here, the community composition of Actinobacteria associated with Apis mellifera ligustica was investigated by integrated culture-dependent and independent methods. A total of 61 strains of Streptomyces genera were isolated from the honeycomb, larva, and different anatomical parts of the honeybee’s body using the culture-dependent method. Amplicon sequencing analyses revealed that the actinobacterial communities were dominated by the family of Bifidobacteriaceae and Microbacteriaceae in the honeybee gut, and Nocardiaceae and Pseudonocardiaceae in the honeycomb, whereas only Streptomyces genera were isolated by the culture-dependent method. Culture-independent analyses showed more diverse actinobacterial communities than those of culture-dependent methods. The antibacterial bioassay showed that most crude extracts of representative isolates exhibited antibacterial activities. Among them, the crude extract of Streptomyces sp. FCF01 showed the best antibacterial activities against Staphylococcus aureus, Micrococcus tetragenus, and Pseudomonas syringae pv. actinidiae (Psa) with the disc diameter of inhibition zone diameter (IZD) of 23.00, 15.00, and 13.33 mm, respectively. Chemical analysis of Streptomyces sp. FCF01 led to the isolation of three secondary metabolites, including mayamycin (1), mayamycin B (2), and N-(2-Hydroxyphenyl) acetamide (3). Among them, compound 1 displayed strong antibacterial activity against S. aureus, M. tetragenus, and Psa with minimum inhibitory concentrations (MIC) values of 6.25, 12.5, and 6.25 μg/ml, respectively. In addition, two novel derivative compounds 1a and 1b were synthesized by acetylation of compound 1. Both compounds 1a and 1b displayed similar antibacterial activities with those of metabolite 1. These results indicated that Streptomyces species associated with honeybees had great potential in finding antibiotics

Heavy Metals in Soil and Crops of an Intensively Farmed Area: A Case Study in Yucheng City, Shandong Province, China

Yucheng City is located in northwestern Shandong Province, China, and is situated on the Huang-Huai-Hai Plain, the largest alluvial plain in China. In this study, 86 surface soil samples were collected in Yucheng City and analyzed for cation exchange capacity (CEC), soil organic matter (SOM), pH, available phosphorus (avail. P), phosphorus (P), aluminum (Al), and iron (Fe). These soils were also analyzed for ‘total’ chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb), together with 92 wheat samples and 37 corn samples. There was no obvious heavy metal contamination in the soil and irrigation water. But the long-term accumulation of heavy metals in soil has lead to an increase of Ni, As, Hg and Pb concentrations in some of wheat and corn samples and Cd in wheat samples. Because of the numerous sources of soil heavy metals and the lower level of heavy metal in irrigation water, there is no significant relation between soil heavy metal concentrations and irrigation water concentrations. Cr, Ni were mainly from the indigenous clay minerals according to multivariate analysis. Little contribution to soil heavy metal contents from agricultural fertilizer use was found and the local anomalies of As, Cd, Hg, Pb in wheat and corn grain are attributed to the interactive effects of irrigation and fertilizer used. Aerial Hg, however may also be the source of Hg for soil, wheat and corn

A Novel Cold-Regulated Cold Shock Domain Containing Protein from Scallop Chlamys farreri with Nucleic Acid-Binding Activity

Background: The cold shock domain (CSD) containing proteins (CSDPs) are one group of the evolutionarily conserved nucleic acid-binding proteins widely distributed in bacteria, plants, animals, and involved in various cellular processes, including adaptation to low temperature, cellular growth, nutrient stress and stationary phase. Methodology: The cDNA of a novel CSDP was cloned from Zhikong scallop Chlamys farreri (designated as CfCSP) by expressed sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE) approach. The full length cDNA of CfCSP was of 1735 bp containing a 927 bp open reading frame which encoded an N-terminal CSD with conserved nucleic acids binding motif and a C-terminal domain with four Arg-Gly-Gly (RGG) repeats. The CSD of CfCSP shared high homology with the CSDs from other CSDPs in vertebrate, invertebrate and bacteria. The mRNA transcripts of CfCSP were mainly detected in the tissue of adductor and also marginally detectable in gill, hepatopancreas, hemocytes, kidney, mantle and gonad of healthy scallop. The relative expression level of CfCSP was up-regulated significantly in adductor and hemocytes at 1 h and 24 h respectively after low temperature treatment (P,0.05). The recombinant CfCSP protein (rCfCSP) could bind ssDNA and in vitro transcribed mRNA, but it could not bind dsDNA. BX04, a cold sensitive Escherichia coli CSP quadruple-deletion mutant, was used to examine the cold adaptation ability of CfCSP. After incubation at 17uC for 120 h, the strain of BX04 containing the vector pINIII showed growth defect and failed to form colonies, while strain containing pINIII-CSPA or pINIII

Finite Element Analysis of Grouting Compactness Monitoring in a Post-Tensioning Tendon Duct Using Piezoceramic Transducers

With the development of the post-tensioning technique, prestressed concrete structures have been widely used in civil engineering. To ensure the long-term effectiveness of the prestressed tendon, the grouting quality of the tendon duct is one of the important factors. However, it is still a challenge to monitor the grouting quality of post-tensioning tendon ducts, due to the invisibility of the grouting. The authors’ previous work proposed a real-time method that employed a stress wave-based active sensing approach with piezoceramic transducers to monitor the grouting compactness of a Post-Tensioning Tendon Duct (PTTD). To further understand the piezoceramic induced stress wave propagation in the PTTD with different grouting levels, this paper develops a two-dimensional finite element model for monitoring the grouting compactness of the tendon duct with a piezoceramic transducer. A smart aggregate (SA) developed to utilize one Lead Zirconate Titanate (PZT) transducer with marble protection is installed in the center location of the tendon duct as an actuator. Two PZT patches are bonded on the bottom and top surface of the tendon duct as the sensors. The analysis results show that the finite element analysis results are in good agreement with the experimental results, which demonstrates that the finite element analysis is feasible and reliable. For the top half of the specimen, not much stress wave could be detected before the full grouting level, except for negligible signals that may propagate through the walls of the tendon duct. When the tendon duct grouting is at 100%, the stress wave propagates to the top of the specimen, and the displacements are symmetric in both left-right and top-bottom directions before the stress waves reach the boundary. The proposed two-dimensional finite element model has the potential to be implemented to simulate the stress wave propagation principle for monitoring grouting compaction of the post-tensioning tendon duct

Feasibility Study of Steel Bar Corrosion Monitoring Using a Piezoceramic Transducer Enabled Time Reversal Method

Steel bars, which are commonly used as reinforcements in concrete structures, are slender rods and are good conduits for stress wave propagation. In this paper, a lead zirconate titanate (PZT)-based steel bar corrosion monitoring approach was proposed. Two PZT transducers are surface-bonded on the two ends of a steel rod, respectively. One works as actuator to generate stress waves, and the other functions as a sensor to detect the propagated stress waves. Time reverse technology was applied in this research to monitor the corrosion of the steel bars with a high signal to noise ratio (SNR). Accelerated corrosion experiments of steel bars were conducted. The anti-corrosion performance of the protected piezoceramic transducers was tested first, and then they were used to monitor the corrosion of the steel bar using the time reversal method. The degree of corrosion in the steel bar was determined by the ratio of mass loss during the experiment. The experimental results show that the peak values of the signal that were obtained by time reversal operation are linearly related to the degree of corrosion of the steel bar, which demonstrates the feasibility of the proposed approach for monitoring the corrosion of steel bars using the time reversal method enabled by piezoceramic transducers

Monitoring of Grouting Compactness in a Post-Tensioning Tendon Duct Using Piezoceramic Transducers

A post-tensioning tendon duct filled with grout can effectively prevent corrosion of the reinforcement, maintain bonding behavior between the reinforcement and concrete, and enhance the load bearing capacity of concrete structures. In practice, grouting of the post-tensioning tendon ducts always causes quality problems, which may reduce structural integrity and service life, and even cause accidents. However, monitoring of the grouting compactness is still a challenge due to the invisibility of the grout in the duct during the grouting process. This paper presents a stress wave-based active sensing approach using piezoceramic transducers to monitor the grouting compactness in real time. A segment of a commercial tendon duct was used as research object in this study. One lead zirconate titanate (PZT) piezoceramic transducer with marble protection, called a smart aggregate (SA), was bonded on the tendon and installed in the tendon duct. Two PZT patch sensors were mounted on the top outside surface of the duct, and one PZT patch sensor was bonded on the bottom outside surface of the tendon duct. In the active sensing approach, the SA was used as an actuator to generate a stress wave and the PZT sensors were utilized to detect the wave response. Cement or grout in the duct functions as a wave conduit, which can propagate the stress wave. If the cement or grout is not fully filled in the tendon duct, the top PZT sensors cannot receive much stress wave energy. The experimental procedures simulated four stages during the grout pouring process, which includes empty status, half grouting, 90% grouting, and full grouting of the duct. Experimental results show that the bottom PZT sensor can detect the signal when the grout level increases towards 50%, when a conduit between the SA and PZT sensor is formed. The top PZT sensors cannot receive any signal until the grout process is completely finished. The wavelet packet-based energy analysis was adopted in this research to compute the total signal energy received by PZT sensors. Experimental results show that the energy levels of the PZT sensors can reflect the degree of grouting compactness in the duct. The proposed method has the potential to be implemented to monitor the tendon duct grouting compactness of the reinforced concrete structures with post tensioning

The clone of wheat dehydrin-like gene wzy2 and its functional analysis in Pichia pastoris

Dehydrin is one of the responsive proteins under water-deficit stress. The aim of this study was to explore function of dehydrins in cells and the relationship with drought tolerance under water-deficit stress. We used winter wheat (Triticum aestivum) Zhengyin No.1 as the material, the complete cDNA sequence of dehydrin wzy2 was cloned and the code sequence of wzy2 was transformed into yeast (Pichia pastoris) for eukaryotic expression. We also analyzed the relationship between wheat dehydrin wzy2 gene and drought resistance. Our results indicate that the whole cDNA sequence of dehydrin wzy2 gene was 819-bp long, containing an open reading frame of 459 bp. The deduced wzy2 protein had 152 amino acid residues, which formed a 15.5 ku polypeptide with a predicted isoelectric point (pI) of 7.17. It was YnSK2 type of dehydrin superfamily. Methanol was used to induce the expression of wzy2 gene in transformed P. pastoris GS115. Sodium dodecyl sulfate- polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting further confirmed that the wzy2 was successfully transformed into P. pastoris and expressed specifically and effectively in yeast. With drought tolerance and cold tolerance treatment to recombinant P. pastoris, wzy2 gene can significantly improve the growth of the transgenic yeast under salt and drought stress compared with the control of pPIC9K yeast cell. However, in low temperature stress conditions, survival rate of the transferred wzy2 yeast cell had no significant improvement compared with the control of pPIC9K yeast cell. These results further indicate that YnSK2 type dehydrin could be induced by salt and osmotic stress rather than low temperature.Key words: Triticum aestivum L., eukaryotic expression, dehydrin-like, Pichia pastoris, drought tolerance

Sema4C Is Required for Vascular and Primary Motor Neuronal Patterning in Zebrafish

Endothelial cells (ECs) and neurons share a number of common signaling pathways and molecular mediators to orchestrate directional migration and guide the pattern of the vascular network and nervous system. So far, research concerning the functional coupling between vascular and neuronal pathfinding remains insufficient. Semaphorin4C (sema4C), a member of class 4 semaphorins, is initially described in the nervous system, whose role has been demonstrated in diverse biological developments. The present study focused on the role of sema4C in the vascular and neural development process in zebrafish embryos. It confirmed that sema4C is expressed in both the nervous system and intersegmental vessels (ISVs) in zebrafish embryos by diverse expression analysis. It also showed that the knockdown of sema4C caused a serious pathfinding anomaly both in the ISVs and primary motor neurons (PMNs) of zebrafish embryos. In addition, overexpressing exogenous sema4C mRNA in sema4C morphants remarkably neutralized the defective pattern of the vascular and neural system. Collectively, this report suggests that sema4C acts as a dual guiding factor regulating vascular and neuronal development. These findings elucidate a new molecular mechanism underlying blood vessel and nerve development and might serve as groundwork for future research on functional coupling between both systems