RESUMEN
Terrorism refers to the claims and acts that create social panic, endanger public security, infringe upon persons and property, or threaten state organs and organizations to achieve political and ideological goals through violence, sabotage, intimidation and other means. According to the survey, 92 % of the world's countries have been subjected to terrorist attacks to varying degrees, involving South America, the Middle East and North Africa. Since 1970, there have been about 200,000 terrorist incidents worldwide. Global terrorist attacks have a wide range of targets, involving nearly 20 groups, resulting in up to 280,000 deaths and 360,000 injuries. Based on the GTD database, this paper selects the relevant data from 1998 to 2017, and uses the factor analysis model to establish the evaluation index system of terrorist attack harm from the perspective of terrorist attack harm. At the same time, GIS is used for quantitative analysis of the data, and time series model is used for correlation prediction. The results show that the comprehensive evaluation model of terrorist attacks has objectively and accurately evaluated the terrorist attacks in the past 20 years, among which 9/11 incident has the highest degree of harm, followed by the Salam Embassy bombing. The ranking of the harmfulness of the incident is basically consistent with the reports of mainstream media at home and abroad. From the perspective of the global spatial scope of terrorist attacks, terrorist attacks are shifting from North Africa and the Arabian Peninsula to the eastern front, and the Middle East has continued to gather, and the situation of terrorist attacks in the Middle East is not optimistic. At present and for some time to come, international terrorism will remain at a high level, and terrorist attacks will remain concentrated in the Middle East and the Arabian Peninsula.
RESUMEN
The peptidoglycan (PG) layer is a critical component of the bacterial cell wall and serves as an important target for antibiotics in both gram-negative and gram-positive bacteria. The hydrolysis of septal PG (sPG) is a crucial step of bacterial cell division, facilitated by FtsEX through an amidase activation system. In this study, we present the cryo-EM structures of Escherichia coli FtsEX and FtsEX-EnvC in the ATP-bound state at resolutions of 3.05 Å and 3.11 Å, respectively. Our PG degradation assays in E. coli reveal that the ATP-bound conformation of FtsEX activates sPG hydrolysis of EnvC-AmiB, whereas EnvC-AmiB alone exhibits autoinhibition. Structural analyses indicate that ATP binding induces conformational changes in FtsEX-EnvC, leading to significant differences from the apo state. Furthermore, PG degradation assays of AmiB mutants confirm that the regulation of AmiB by FtsEX-EnvC is achieved through the interaction between EnvC-AmiB. These findings not only provide structural insight into the mechanism of sPG hydrolysis and bacterial cell division, but also have implications for the development of novel therapeutics targeting drug-resistant bacteria.
Asunto(s)
Adenosina Trifosfato , División Celular , Proteínas de Escherichia coli , Escherichia coli , Peptidoglicano , Peptidoglicano/metabolismo , Hidrólisis , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/química , Escherichia coli/metabolismo , Escherichia coli/genética , Adenosina Trifosfato/metabolismo , Microscopía por Crioelectrón , Pared Celular/metabolismo , Conformación Proteica , Modelos Moleculares , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , N-Acetil Muramoil-L-Alanina Amidasa/genética , Proteínas de la Membrana Bacteriana Externa , Transportadoras de Casetes de Unión a ATP , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Lipoproteínas , Proteínas de Ciclo CelularRESUMEN
Lipopolysaccharide (LPS) is essential for most gram-negative bacteria and plays an important role in serum resistance, pathogenesis, drug resistance, and protection from harsh environments. The outer core oligosaccharide of LPS is involved in bacterial recognition and invasion of host cells. The D-galactosyltransferase WaaB is responsible for the addition of D-galactose to the outer core oligosaccharide of LPS, which is essential for Salmonella typhimurium invasion. Here we report the first crystal structures of WaaB and WaaB in complex with UDP to resolutions of 1.8 and 1.9 Å, respectively. Mutagenesis and enzyme activity assays confirmed that residues V186, K195, I216, W243, E276, and E269 of WaaB are essential for the binding and hydrolysis of UDP-galactose. The elucidation of the catalytic mechanism of WaaB is of great importance and could potentially be used for the design of novel therapeutic reagents.
RESUMEN
Objective: To investigate the effect of a novel EZH2 inhibitor GSK126 on cell growth, apoptosis and migration of prostate cancer cells. Methods: Prostate cancer PC-3 and DU145 cells were treated with GSK126 at different doses. Cell growth was detected by sulforhodamine assay. Cell apoptosis was assayed by Annexin V-/PI kit. Transwell chamber and wound healing assays were conducted to detect cell migration. The mRNA level was detected by quantitative PCR, and protein expression was detected by Western blot analysis. Results: GSK126 showed significant effect on cell growth and apoptosis when the dose was higher than 50 µmol/L. Wound healing assay revealed that scratch space in PC-3 cells was significantly increased in a dose-dependent manner in GSK126-treated groups[(247.2±24.4),(347.2±19.2) and (410.5±18.1) µm in low, medium and high dose (5.0, 20.0, 50.0 µmol/L), respectively] as compared with the control group[(171.3±17.8) µm](all P<0.05). Transwell assay showed that migrated PC-3 cells in control group was 322.0±17.9,while those in GSK126-treated groups were 198.3±15.4 (low),82.7±6.2 (medium) and 30.2±4.1 (high), and the differences between the control group and GSK126-treated groups were significant(all P<0.05). In addition, GSK126 up-regulated E-cadherin mRNA expression and down-regulated N-cadherin and Vimentin mRNA expression, whereas had no significant effect on Snail, Fibronectin and VEGF-A mRNA expression. The protein expression of E-cadherin was elevated but VEGF-A protein did not change in GSK126-treated groups. Similar results were exhibited in DU145 cell. Conclusion: GSK126 can significantly inhibit cell migration and invasion in prostate cancer PC-3 and DU145 cells, which may be resulted from its effect on epithelial-mesenchymal transition. GSK126 may be used as a potential anti-prostate cancer dug in clinic.
Asunto(s)
Indoles/farmacología , Neoplasias de la Próstata/fisiopatología , Piridonas/farmacología , Antígenos CD , Apoptosis/efectos de los fármacos , Cadherinas/análisis , Cadherinas/efectos de los fármacos , Cadherinas/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Proteína Potenciadora del Homólogo Zeste 2/análisis , Proteína Potenciadora del Homólogo Zeste 2/efectos de los fármacos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Fibronectinas/análisis , Fibronectinas/efectos de los fármacos , Fibronectinas/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/química , Neoplasias de la Próstata/genética , ARN Mensajero , Regulación hacia Arriba/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Vimentina/análisis , Vimentina/efectos de los fármacos , Vimentina/metabolismoRESUMEN
PURPOSE: To explore the effects and mechanisms of GSK126, a novel inhibitor of histone methyltransferase enhancer of zeste homologue 2, on cancer cell migration. METHODS: Gastric cancer cell line MGC803 and human lung adenocarcinoma cell line A549 were treated with GSK126 at three doses. Transwell and wound healing assays were conducted to detect cell migration. Human umbilical vein endothelial cells tube formation assay and chick embryo chorioallantoic membrane assay were performed to assess the effects of GSK126 on angiogenesis in vitro and in vivo, respectively. The mRNA level of VEGF-A was detected by quantitative PCR, and the protein levels of VEGF-A were detected both by western blot analysis and immunohistochemistry. Epi-fluorescent intensity was obtained by in vivo imaging. RESULTS: GSK126 inhibited cell migration in both MGC803 and A549 in a dose-dependent manner, as revealed by transwell and wound healing assays. The effects of GSK 126 were similar to those of gefitinib at the same doses. Moreover, GSK126 at doses of 20 and 50 µM inhibited angiogenesis both in vitro and in vivo. GSK126 reduced both the mRNA and protein expression of VEGF-A in a dose-dependent manner. Finally, in vivo imaging assay revealed that GSK126 at 200 mg/kg significantly inhibited cancer cell migration. CONCLUSIONS: GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Indoles/farmacología , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Piridonas/farmacología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Embrión de Pollo , Proteína Potenciadora del Homólogo Zeste 2 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/prevención & controlRESUMEN
OBJECTIVE: To compare seizure induced by different epileptic drugs in ICR mice. METHODS: Male adult ICR mice were injected with pilocarpine (Pilo), kainic acid (KA) and pentylenetetrazole (PTZ) to induce status epilepticus (SE). After 2 h of SE, seizures were terminated by injection of diazepam. Mice were sacrificed and sectioned for assessment of neuronal cell death by Fluro-Jade B staining after 7 d and mossy fiber sprouting by Timm staining after 28 d, respectively. Spontaneous seizures were detected by video for 28 d. RESULTS: Pilo and KA induced typical SE in ICR mice, which was identical to those observed in rats and C57/BL6 mice. Timm staining showed evident mossy fiber sprouting in both Pilo and KA treated mice. The incidences of spontaneous seizure were 57.1% and 35.7% in Pilo and KA treated mice, respectively. Mice treated with PTZ represented kindling model. No mossy fiber sprouting and spontaneous seizures were observed. No cell death was detected in all three groups. CONCLUSION: Similar seizure pattern is observed in ICR mice as in rats and C57/BL6 mice. Both Pilo and KA model are the ideal models for chronic temporal lobe epilepsy. ICR mice can be widely used as a cheaper substitute in epilepsy research.