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This study aimed to investigate the association between red blood cell distribution width (RDW) and the risk of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). A total of 1355 patients who met the diagnostic criteria for KD were reviewed between January 2018 and December 2019, including 636 patients with CALs and 719 patients without CALs. Blood samples for RDW were obtained at admission (before intravenous immunoglobulin treatment). A logistic regression analysis was performed, and a receiver operating characteristic curve was constructed to determine the prognostic value of RDW standard deviation (RDW-SD) and RDW coefficient of variation (RDW-CV). The study was registered at www.chictr.org.cn, No.: ChiCTR 2000040980. The results showed that RDW-SD increased in patients with complete KD and CALs compared with patients with complete KD without CALs (39 fL vs. 38 fL, respectively; p = 0.000). RDW-CV in patients with complete KD and CALs was significantly higher compared with patients with completed KD without CALs (p = 0.000). Further multivariate logistic regression analysis revealed that RDW-SD was an independent marker of CALs in patients with complete KD (p = 0.001), but no association was found between RDW-CV and CALs. The area under the curve of RDW-SD for predicting CALs in patients with complete KD was 0.606 (95% confidence interval 0.572–0.640; p = 0.000) with a sensitivity and specificity of 61% and 55%, respectively, when the optimal cut-off value of RDW-SD was 38.5 fL. RDW-CV increased in patients with incomplete KD and CALs compared with patients without CALs (13.55% vs 13.3%, respectively; p = 0.004), and multivariate logistic regression analysis revealed that RDW-CV was an independent marker of CALs in patients with incomplete KD (p = 0.021). The area under the curve of RDW-CV for predicting CALs in patients with incomplete KD was 0.597 (95% confidence interval 0.532–0.661; p = 0.004) with a sensitivity and specificity of 40% and 77%, respectively, when the optimal cut-off value of RDW-SD was 13.85%. Conclusion: RDW can be used as an independent predictive marker of CALs in patients with KD, but the type of KD should be considered. RDW-SD was an independent marker of CALs in patients with complete KD, while RDW-CV was a predictor of incomplete KD.

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N–Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90N–Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90N, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔT m = 8.83 ± 0.90°C) and isothermal titration calorimetry (K d = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90N and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90N, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC50 values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.

Purpose To explore the expression and related mechanism of miR-144-3p and PTEN in thyroid cancer (TC). Patients and Methods From February 2018 to November 2019, 62 patients with TC who received treatment in Chengwu Hospital Affiliated to Shandong First Medical University were collected. TC cells and human normal thyroid HTori-3 cells were purchased. The miR-144-3p-inhibitor, miR-144-3p-mimics, empty vector plasmid (miRNA-NC), si-PTEN and sh-PTEN were transfected into B-CPAP and HTh-7 cells. The expressions of miR-144-3p and PTEN in the specimens were tested by qRT-PCR (qP). WB was used to detect the expression of Bcl-2, APR3, N-cadherin, Slug and Bax proteins in the cells. The cell proliferation was detected by MTT, and the cell invasion was tested by Transwell. The apoptosis was detected by flow cytometry (FC). Results miR-144-3p was highly expressed and PTEN was weakly expressed in the patients' tissues. The AUC of miR-144-3p and PTEN was >0.8. miR-144-3p and PTEN were related to TNM stage, lymph node metastasis and differentiation degree of TC patients. The B-CPAP and HTh-7 with the greatest expression differences were selected for transfection. The expression of miR-144-3p in miR-144-3p-inhibitor group was significantly lower than that in NC group (P

Incorporation of highly selective and stable adsorbent with facile extraction technology is desired in practical analysis. Here we show the rational preparation of a urea-linked covalent organic framework functionalized polytetrafluoroethylene film (COF-117-PTFE) with ordered porous structure, rich functional groups, and large surface area-to-volume ratio as the effective adsorbent for convenient, selective and rapid thin film microextraction (TFME) of rhodamine B (RB). The COF-117-PTFE based TFME coupled with high performance liquid chromatography-fluorescence detector (HPLC-FLD) successfully realized the determination of RB with the limit of detection of 0.007 μg L

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.

Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.

Introduction: Vascular calcification (VC) is a complex, regulated process involved in many disease entities. So far, there are no treatments to reverse it. Exploring novel strategies to prevent VC is important and necessary for VC-related disease intervention. Objective: In this study, we evaluated whether MOTS-c, a novel mitochondria-related 16-aa peptide, can reduce vitamin D3 and nicotine-induced VC in rats. Methods: Vitamin D3 plus nicotine-treated rats were injected with MOTS-c at a dose of 5 mg/kg once a day for 4 weeks. Blood pressure, heart rate, and body weight were measured, and echocardiography was performed. The expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors was determined by Western blot analysis. Results: Our results showed that MOTS-c treatment significantly attenuated VC. Furthermore, we found that the level of phosphorylated AMPK was increased and the expression levels of the AT-1 and ET-B receptors were decreased after MOTS-c treatment. Conclusions: Our findings provide evidence that MOTS-c may act as an inhibitor of VC by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors.

Objective: To investigate the protective effect of methylprednisolone combined with ulinastatin pretreatment on inflammatory lung injury induced by single-lung ventilation. Methods: A total of 120 patients with radical resection of cancer surgery admitted to our hospital from January 2016 to December 2017 were randomly divided into control group, methylprednisolone group, ulinastatin group, and methylprednisolone combined with ulinastatin pretreatment group. Before single lung ventilation (T0), 30 min after ventilation (T1), and 60 min (T2) after the end of ventilation, enzyme-linked immunosorbent kit method was used to detect the levels of inflammatory factors TNF-α, IL-8 and IL-10. The mean airway pressure (Pmean) at each monitoring point and the oxygenation indexes (PaO 2 /FiO 2 ) before and after surgery were detected. And also, the extraction time, drainage volume and sputum volume of the drainage tube after surgery were measured. Results: Compared with the control group, the other three groups can reduce the levels of TNF-α and IL-8 in the blood of patients with esophageal cancer, improve IL-10 and increase the oxygenation index (P

Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K

Background: There are few studies on inflammatory storms in bronchoalveolar lavage fluid (BALF) of children with pneumonia. Therefore, we will retrospectively investigate characteristics of inflammatory storms in BALF of children with pneumonia in our hospital.Methods: 161 children with pneumonia were retrospectively divided into two groups: mild and severe pneumonia, according to the clinic diagnosis. Flow cytometry was performed to detect the levels of cytokines, including IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ. We performed receiver operator characteristic curve (ROC) and spearman correlation to evaluate the role of BALF inflammatory cytokines and cells in pneumonia.Results: 1) The levels of IL-6, IL-10, IL-17A, and TNF-α, and ratios of IL-6 to IL-10 and TNF-α to IL-10 in BALF of severe pneumonia group were higher than those of mild pneumonia group. 2) The number of inflammatory cells and the percentage of neutrophils in BALF of severe pneumonia group increased, and the percentage of macrophages decreased, compared with the mild pneumonia group. 3) ROC analysis showed that both the increase of the levels of IL-6, IL-10 and TNF-α, and ratios of IL-6 to IL-10 and TNF-α to IL-10, number of inflammatory cells and neutrophils, percentage of neutrophils, and the decrease of the percentage of macrophages exceeding the cut-off value could be used to distinguish children with severe pneumonia from mild pneumonia. Conclusion: In severe pediatric pneumonia, BALF inflammatory cytokines and inflammatory cell infiltration are more intense. And these inflammatory signals are important biomarkers for reflecting the severity of pediatric pneumonia.Trial registration: This study approved by the Medical Research Ethics Committee of Children’s Hospital of Chongqing Medical University, registered in http://www.chictr.org.cn/, No. ChiCTR2000034048(registration date, June 22, 2020).

Background Klebislla pneumoniae is an important bacterium and responsible for both infections acquired in hospital and community because of its multidrug resistance and the virulence. The aim of this research was to investigate clonal lineages, antibiotic resistance profiles and virulence factors of the hospital isolated Carbapenem Resistant strains. Methods Whole-genome sequencing of one strain was performed using the Illumina Hiseq and PacBio RS systems. Genomic information was comprehensively analyzed by various bioinformatics approaches. Molecular typing was based on multi locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) analysis. Antimicrobial susceptibility testing, drug resistance and virulence genes were determined. Results K. pneumoniae KPX comprised one circular chromosome and four circular plasmids. This strain harbors a variety of antimicrobial resistance and virulence determinants. The closest relative of K. pneumoniae KPX was another ST11 clinical isolate recovered Sichuan. Fifty isolates were phenotypically confirmed extended-spectrum beta-lactamases ESBLs producers. MLST analysis revealed 97% sequence type 11. Fifty Carbapenem Resistant isolates mainly belong to three clones according to the PFGE DNA patterns. PFGE patterns has more variety than ST profiles. In addition, KPC-2 (98.0%), SHV-11 (98.0%), TEM-1 (76.0%), CTX-M (76.0%), Oqxb1(66%), qnrS (70%), Int1 (42.0%), sul1 (82.0%), sul2 (96.0%), iutA (88%), iucABCD(10%), and rmpA2 (100%) genes were presented in multiple drug resistant strains. Conclusion The dataset presented in this study provided the genomic and epidemiological analysis of Carbapenem Resistant K. pneumoniae in hospital settings. Antimicrobial-resistance profiles suggested the presence of significant selective antibiotic pressure. Appropriate surveillance is essential to development of effective control strategies in the prevention of nosocomial infection.

Background: It is difficult to collect bronchoalveolar lavage fluid (BALF) from children. There are few studies on inflammatory storms in BALF of children with pneumonia. Therefore, we will retrospectively investigate characteristics of inflammatory storms in BALF of children with pneumonia in our hospital.Methods: This retrospective study included 161 children with pneumonia. Pediatric pneumonia was divided into two groups: mild and severe pneumonia, according to the clinic diagnosis. All clinic information and data came from our hospital’s database. Blood and BALF samples were collected and measured by Clinical laboratory and Clinical Molecular Medical Center. Flow cytometry was performed to detect the levels of cytokines, including IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ. We performed receiver operator characteristic curve (ROC) and spearman correlation to evaluate the role of BALF inflammatory cytokines and cells in pneumonia.Results: 1) The levels of IL-6, IL-10, IL-17A, and TNF-α, and ratios of IL-6 to IL-10 and TNF-α to IL-10 in BALF of severe pneumonia group were higher than those of mild pneumonia group. 2) The number of inflammatory cells and the percentage of neutrophils in BALF of severe pneumonia group increased, and the percentage of macrophages decreased, compared with the mild pneumonia group. 3) ROC analysis showed that the levels of IL-6, IL-10 and TNF-α, and ratios of IL-6 to IL-10 and TNF-α to IL-10, the number of inflammatory cells and neutrophils, as well as the percentage of neutrophils exceeded the cut-off value (60.37pg/mL, 2.54pg/mL, 13.07pg/mL, 29.30, 1.57, 3140.00*109/L, 768.00*109/L, 43.00%, respectively) could be used to distinguish children with severe pneumonia from children with mild pneumonia. While the percentage of macrophages in BALF decreased to below the cut-off value (36.00%) also had the discrimination ability. 4) The BALF levels of IL-6, IL-10, TNF-α and IFN-γ were correlated, positively with the inflammatory cell count and the percentage of neutrophils, and negatively with the percentage of macrophages.Conclusion: In severe pediatric pneumonia, BALF inflammatory cytokines and inflammatory cell infiltration are more intense, especially above the cut-off value. This study demonstrates that these inflammatory signals are potential biomarkers for predicting the severity of pediatric pneumonia.Trial registration: This study approved by the Medical Research Ethics Committee of Children’s Hospital of Chongqing Medical University, registered in http://www.chictr.org.cn/, No. ChiCTR2000034048(registration date, June 22, 2020).

This study aimed to investigate the association between red blood cell distribution width (RDW) and the risk of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). A total of 1355 patients who met the diagnostic criteria for KD were reviewed between January 2018 and December 2019, including 636 patients with CALs and 719 patients without CALs. Blood samples for RDW were obtained at admission (before intravenous immunoglobulin treatment). A logistic regression analysis was performed, and a receiver operating characteristic curve was constructed to determine the prognostic value of RDW standard deviation (RDW-SD) and RDW coefficient of variation (RDW-CV). The study was registered at www.chictr.org.cn , No.: ChiCTR 2000040980. The results showed that RDW-SD increased in patients with complete KD and CALs compared with patients with complete KD without CALs (39 fL vs. 38 fL, respectively; p = 0.000). RDW-CV in patients with complete KD and CALs was significantly higher compared with patients with completed KD without CALs (p = 0.000). Further multivariate logistic regression analysis revealed that RDW-SD was an independent marker of CALs in patients with complete KD (p = 0.001), but no association was found between RDW-CV and CALs. The area under the curve of RDW-SD for predicting CALs in patients with complete KD was 0.606 (95% confidence interval 0.572-0.640; p = 0.000) with a sensitivity and specificity of 61% and 55%, respectively, when the optimal cut-off value of RDW-SD was 38.5 fL. RDW-CV increased in patients with incomplete KD and CALs compared with patients without CALs (13.55% vs 13.3%, respectively; p = 0.004), and multivariate logistic regression analysis revealed that RDW-CV was an independent marker of CALs in patients with incomplete KD (p = 0.021). The area under the curve of RDW-CV for predicting CALs in patients with incomplete KD was 0.597 (95% confidence interval 0.532-0.661; p = 0.004) with a sensitivity and specificity of 40% and 77%, respectively, when the optimal cut-off value of RDW-SD was 13.85%. Conclusion: RDW can be used as an independent predictive marker of CALs in patients with KD, but the type of KD should be considered. RDW-SD was an independent marker of CALs in patients with complete KD, while RDW-CV was a predictor of incomplete KD.

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90

Nϵ-carboxymethyl-lysine (CML), an advanced glycation end product, is involved in vascular calcification (VC) in diabetic atherosclerosis. This study aimed to investigate the effects of CML on VC in diabetic atherosclerosis induced by vascular smooth muscle cell (VSMC)-derived foam cells. Human studies, animal studies and cell studies were performed. The human study results from 100 patients revealed a poor blood glucose and lipid status and more severe coronary lesions and stenosis in patients with coronary artery disease and diabetes mellitus. Intraperitoneal injection of streptozotocin combined with a high-fat diet was used to build a diabetic atherosclerosis model in ApoE-/- mice. The animal study results indicated that CML accelerated VC progression in diabetic atherosclerosis by accelerating the accumulation of VSMC-derived foam cells in ApoE-/- mice. The cell study results illustrated that CML induced VSMC-derived foam cells apoptosis and aggravated foam cells calcification. Consistent with this finding, calcium content and the expression levels of alkaline phosphatase, bone morphogenetic protein 2 and runt-related transcription factor 2 were significantly elevated in A7r5 cells treated with oxidation-low-density lipoprotein and CML. Thus, we concluded that CML promoted VSMC-derived foam cells calcification to aggravate VC in diabetic atherosclerosis, providing evidence for the contribution of foam cells to diabetic VC.

The elucidation of protein structures by X-ray crystallography remains the most effectual method to provide accurate structural details at atomic resolution for rational drug design and other biotechnological research studies. Also, emerging applications of protein crystals as ordered nanostructure scaffolds for catalysis, imaging, and drug delivery are attracting much attention. However, the first step of these applications is obtaining high-quality crystals, which is still an obstacle. Successful crystallization requires two steps: nucleation and crystal growth, while the nucleation is a precondition for harvesting the crystal of interest. So controlling protein nucleation may be an alternative breakthrough for this bottleneck. It is well known that nucleants can induce protein crystallization and improve crystal quality, so investigation on the nucleants that can be universally used for any protein crystallization is ongoing. This manuscript reviews the advances that have been achieved using nucleants in protein crystallization and it is a suitable reference for practical crystallization.

Recombinant human serum albumin (rHSA) is potential alternatives for human serum albumin (HSA) which may ease severe shortage of HSA worldwide. In theory, rHSA and HSA are the same. Structure decides function. Therefore, the 3D structural consistency analysis of rHSA and HSA is outmost importance, which is the base of their function consistency. In this paper, the crystal structures of rHSA at resolution limit of 2.22 A and HSA at 2.30 A were determined by X-ray diffraction (XRD), which were deposited in the Protein Data Bank (PDB) with accession codes 4G03 (rHSA) and 4G04 (HSA). The differences between rHSA and HSA were systematically analyzed from the crystallization behavior, diffraction data and three-dimensional (3D) structure. The superimposed contrasted analysis indicated that rHSA and HSA achieved a structural similarity of 99% with an r.m.s. deviation of 0.397 A for the corresponding overall Cα atoms. In addition, the number of α-helices in the rHSA or HSA molecule was verified to be 30. As a result, rHSA can potentially replace HSA. The study provides a theoretical and experimental basis for the clinical and additional applications of rHSA. Meanwhile, it is also a good example for applications of genetic engineering.

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 A; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, Kd, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 μM for A549; 14.29 μM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

The similarity of spatial structure between radicicol and matrine urged us to perform conformation modification of matrine, followed by L-shaped matrine derivatives, 6, 12, 21a-h and 22a-h were originally designed, synthesized and evaluated for Hsp90N inhibitors as anticancer agents. TSA (Thermal Shift Assay) results indicated that 21e, 22a-c and 22e-g exhibited strong binding force against Hsp90N with∣ΔTm∣ > 3, meanwhile, MTT assay also revealed these compounds displayed potent anticancer activity with IC50 values below 25 μM against HepG2, HeLa and MDA-MB-231 cells lines. Then, compound 22g with a high ΔTm = 10.92 was chosen as a representative to perform further mechanism study. It can induce cell apoptosis, arrest the cell cycle at the S phase and decrease the expression level of Hsp90 in Hela cell. These results originally provided targeted modification strategy for matrine derivatives to serve as Hsp90 inhibitors for cancer therapy.

One well-known prerequisite for successful crystallization from solution is a supersaturated solution. To achieve supersaturation, many methods are known, among which solvent evaporation is a common approach. For protein crystallization, the most widely used method is vapor diffusion, in which solvent evaporation from the crystallization solution is the major reason for achieving supersaturation. The solvent evaporation rate may affect the actual concentration distribution in the crystallization solution, thereby influencing the crystallization process. To explore the effect of evaporation rate on protein crystallization, we used lysozyme as a model protein and studied the crystallization success rate at different evaporation conditions. Successful crystallization occurred only when both supersaturation and evaporation rates were in suitable ranges. This study demonstrates that both supersaturation level and the rate of reaching supersaturation (or solvent evaporation rate) are important for lysozyme crystallization. To increase the chance of obtaining crystals, manipulation of solvent evaporation rate is one choice. According to this assumption, we performed crystallization screening trials at different evaporation rates using three model proteins. The trials demonstrate that control of the evaporation rate during crystallization may provide more opportunities to obtain crystals.

We present a new method for the realization of high-throughput protein crystallization screening using an array of 96 capillaries aligned in a circle. In this method, each capillary represents a single crystallization condition, and all capillaries experience identical magnetic field conditions. After crystallization, the crystals in the capillary can be directly diffracted without harvesting. This method proved easy to perform and is applicable for use in magnetic fields and may be further extended for use in other circumstances, for example, under space microgravity conditions.

Cross-linked protein crystal technology, as either a protein stabilisation or enzyme immobilisation method, has garnered more attention recently. This method not only can retain the original activity of the protein molecule but can also significantly enhance the crystals' mechanical and chemical stability. This review presents the preparation and mechanism of cross-linked protein crystals using glutaraldehyde. The mechanical, chemical and thermal properties of the cross-linked protein crystals are also reviewed in detail. In addition, this paper summarises the applications of cross-linked protein crystals in the fields of materials science, biosensors, chromatographic analysis, oral delivery and protein crystal quality improvement. Finally, the limitations and perspectives on cross-linked protein crystals are presented.

Heat shock protein 90 (Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90N–RJ19 was determined by X-ray diffraction (resolution limit, 2.0 A, PDB code 4L90). The crystal structure of Hsp90N–RJ19 was analyzed in detail and compared with that of native Hsp90N, Hsp90N-ATP, and Hsp90N-GDM, respectively. It was indicated that RJ19 interacted with Hsp90N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90N–RJ19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90N provide a rational basis for the design and optimization of novel anticancer drugs.

To investigate the effect and the mechanism of compound injection of Shenqi (Codonopsis and Astragalus) on Docetaxel resistance of human lung adenocarcinoma cell A549/ DTX. The cytotoxicities of Shenqi Injection were assayed with the MTT method, the effects of Shenqi Injection on apoptosis induced by Docetaxel in A549/ DTX was examined by flow cytometry (FCM). The expression levels of apoptosis regulator Bc1-2 and Bax were detected by Western blot. After treatment with Shenqi Injection for 24 hours, results showed that 15 μL / mL Shenqi Injection significantly increased toxicity of Docetaxel on A549/DTX. Shenqi Injection could reverse the Docetaxel resistance in A549/ DTX in vitro. The drug resistance reversal index (RI) was equal to 2.71 analyzed with MTT method. Shenqi Injection could enhance the apoptosis effect of Docetaxel on A549/DTX. We conclude that Shenqi Injection can reverse the drug resistance on A549/DTX, and its mechanism is to promote apoptosis may be related with the up-regulation of Bc1-2 expression and down-regulation of Bax expression.

This report describes the modification of crystallization plates by simply oxidizing the surface of the protein wells. The oxidized crystallization plates were tested in standard protein crystallization screening and reproducibility studies. The results showed that the protein wells of the treated plates were smoother and more optically transparent than those of the untreated plates, and more importantly, protein crystallization was significantly promoted after the oxidation treatment. Because there is no change to the routine screening protocol, this method is simple and easy to apply in protein crystallization.

PurposeIn China the maturity of the industrial development has the demonstration and reference implications for how to achieve enterprises competitiveness among the developing industries in a country. With the development of globalization, how to improve the enterprises competitiveness has became a serious problem to be solved for Chinese enterprises. The management innovation is reasonable and appropriate to solve this problem. Compared with the independent innovation, adoptive management innovation has become the main way for enterprises to fulfill the management innovation and change the management styles under the open economy condition. The research strives to reveal the “black box” in the management innovation adoptive process and give an answer to a series of questions, such as “what is the role of entrepreneurs in management innovation adoptive process?”Design/methodology/approachExploratory case study approach is taken to find the entrepreneurs' role in management innovation adoptive process of Chinese traditional industry.FindingsThis paper constructs the adoptive management innovation model from three dimensions, using exploratory case technique, which explores the key factors and mechanism of realizing management innovation adoption. Through the exploratory case analysis to verify the viewpoint which is proposed by the model: entrepreneurs played a leading role in the adoptive management innovation of non‐procedural process, and the role is the result of the mixed function of the external and internal environment. Entrepreneurs analyze and explore the new problems and opportunities, and their own experience and ability determine the cognition and explore degree towards these problems directly; entrepreneurs' integration ability of resources can be approved and accepted after the new practice has been proposed and become mature. Entrepreneur long‐term shaping on organizational resources determines whether the management innovations introduction would be really integrated into enterprise management system. The entrepreneur's typical behavior on “integration, learning and shaping” is the foundation and guarantee of adoptive management innovation, which have connective effect on adjacent stages.Originality/valueThe article describes Haier BPR process of adoptive management innovation and the adoptive management innovation mode, and analyzes the effect of entrepreneurs' role on adoptive management innovation of China's color TV industry. The Chinese color TV industry as the maturity industry has the demonstration and reference implications for how to achieve enterprises competitiveness in Chinese developing industries.

Objective To investigate the effect of endoplasmic reticulum stress (ER stress) in cisplatin-induced apoptosis of human cervical cancer HeLa cells. Methods HeLa cells were used as the study object which were divided into four groups: TUNI (5mg/L) group, cisplatin (6mg/L) group, TUNI(5mg/L)+cisplatin(6mg/L) group, and negative control group (no drug treatment). MTT assay was employed to examine the growth status of the cells. Hoechst staining was used to observe the morphological change in the nucleus. Immunoblotting was used to detect the activation of apoptotic proteins, caspase-3 and caspase-4. Indirect immunofluorescence was used to assess the expression of the protein disulfide isomerase (PDI) and phosphorylated histone H2AX (γ-H2AX). Results MTT assay showed that the growth inhibition rates were 2.65%±2.71%, 19.60%±4.34%, 44.69%±7.07% and 0% in TUNI group, cisplatin group, TUNI+cisplatin group and control group, respectively (P

PurposeThe color TV industry in China has become a mature industry. Its development demonstrates and provides reference implications for how developing industries within a country can achieve a technological leap. This paper aims to address this issue.Design/methodology/approachAn exploratory case study approach is taken to find the key factors in the technological catch‐up of China's traditional industry.FindingsIn the study it is found that China's color TV industry, as a mature traditional industry, has four‐dimensional key factors affecting the catch‐up of technology in the flat‐panel stage: market; merger and acquisition; international cooperation innovation for patent; and the roles of internal reform. “Market” is the window of opportunity and challenge; “merger and acquisition” is the key factor for making the patent convert from external mode to internal mode by deviant‐track. The “international cooperation innovation for patent” is also a key factor to ensure achievement of technology catch‐up and sustainable technological innovation. The role of internal reform promoter is the key factor in the technological catch‐up process in which taking entrepreneur as the core.Originality/valueThe article describes Changhong's flat‐panel TV technology catch‐up mode, analyzes four‐dimensional key factors affecting the technology catch‐up of China's color TV industry; the Chinese color TV industry as mature industry; and discusses which developments have demonstrated how to achieve a technological leap in developing industries.

This paper introduces a novel platform designed to be used in a strong static magnetic field (in a superconducting magnet). The platform is a sample holder that rotates in the strong magnetic field. Any samples placed in the platform will rotate due to the rotation of the sample holder. With this platform, a number of experiments such as material processing, culture of biological systems, chemical reactions, or other processes can be carried out. In this report, we present some preliminary experiments (protein crystallization, cell culture, and seed germination) conducted using this platform. The experimental results showed that the platform can affect the processes, indicating that it provides a novel environment that has not been investigated before and that the effects of such an environment on many different physical, chemical, or biological processes can be potentially useful for applications in many fields.

The effect of magnetic fields on water is still a highly controversial topic despite the vast amount of research devoted to this topic in past decades. Enhanced water evaporation in a magnetic field, however, is less disputed. The underlying mechanism for this phenomenon has been investigated in previous studies. In this paper, we present an investigation of the evaporation of water in a large gradient magnetic field. The evaporation of pure water at simulated gravity positions (0 gravity level (ab. g), 1 g, 1.56 g and 1.96 g) in a superconducting magnet was compared with that in the absence of the magnetic field. The results showed that the evaporation of water was indeed faster in the magnetic field than in the absence of the magnetic field. Furthermore, the amount of water evaporation differed depending on the position of the sample within the magnetic field. In particular, the evaporation at 0 g was clearly faster than that at other positions. The results are discussed from the point of view of the evaporation surface area of the water/air interface and the convection induced by the magnetization force due to the difference in the magnetic susceptibility of water vapor and the surrounding air.

The scope of civil aviation transportation ranges from ground to upper air, which the impact of emission varies at the vertical geographical altitude. The aircraft emissions near the airport have very bad effects on the low-altitude environment. The LTO emission calculating methods based on ICAO、EPA and FAA have been analyzed, then the emission results have been calculated and done the comparative study in this paper. The sameness and difference have been remarked on the EI, TIM of the calculation methods. At last the paper refers to the some concerns at the time of developing emission evaluation scheme.

Objective To investigate the effect of Huntingtin-interacting protein1 (HIP1) gene silencing on the proliferation of PC-3 cells in a human androgen-independent prostate tumor. Methods pSlience-shHIP1, a shRNA expression vector targeting HIP1, was constructed and transfected into PC-3 cells by liposome. RT-PCR was adopted to detect the silencing effect of HIP1 gene. Western bloting was then used to confirm the effective target point. Moreover, the scratch assay and growth curve assay were performed to analyze the effect of HIP1 on the proliferation of PC-3 cells. Results The efficiency of HIP1 gene silencing was increased to 83% (PConclusions The pSilence-HIP1 expression vector can specifically suppress the expression of the HIP1 gene. In addition, HIP1 gene silencing can inhibit the proliferation and migration of PC-3 cells.