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The ISAT (Inventory Spatial Allocation Tool) v2.0 is an integrated tool that has been developed to configure nested domains, downscale regional emission inventories, allocate local emission inventories, and generate model-ready emission inventories for the Weather Research and Forecasting (WRF)–Air Quality Numerical Model (AQM). The tool consists of four modules, namely “Prepgrid”, “Downscale”, “Mapinv”, and “Prepmodel”, which are designed to perform specific tasks. The Prepgrid module utilizes a nested-domain configuration algorithm based on WRF-AQM nested rules and the target domain shapefile. The Downscale module establishes a “sub-grid nearest” method to downscale the regional emission inventory based on spatial surrogate, thereby improving the accuracy and computational efficiency of the process. The Mapinv module allocates a user-defined regional- and/or city-level emission inventory to grid level based on the target domain shapefile and the spatial surrogate. Finally, the Prepmodel module generates the model-ready inventories by introducing unique user-friendly emission sector IDs using abbreviations and speciation profiles based on species in the emission inventory and chemical mechanisms, which is available for both the CMAQ and CAMx models. The ISAT v2.0 tool provides a user-friendly solution for model users to configure and run WRF-AQM. And it provides a framework and related algorithms for researchers to develop similar tools for WRF-AQM.

The emission of condensable particulate matter (CPM) and its environmental impacts are arousing concern in China with the effective control of filter particulate matter (FPM). This study established an up-to-date and unit-based CPM emission inventory for industrial sectors and systematically evaluated the effects of CPM on primary and secondary PM

Nasal epithelium provides a physical barrier to potentially harmful stimuli. Cilia, which is on the apical side of the human nasal epithelial cells (HNEpCs), plays a critical role in removing inhaled harmful matter. Ciliary beat frequency (CBF) and ciliary beat pattern (CBP) are the two important indicators for ciliary beat function. However, impacts of the fine particulate matter (PM2.5) on CBF and CBP are still unknown. We aimed to evaluate the impact of PM2.5 on the ciliary beat function of the HNEpCs and its potential mechanisms. After exposed to PM2.5 for 12 h, cilia of HNEpCs were in disordered arrangement. The ciliary coverage rate was decreased after PM2.5 exposure of a series of concentration, while the proportion of basal cells was continuously increased and could be observed on the apical side of the HNEpCs which is hardly be observed without PM2.5 exposure. PM2.5 increased the CBF after 12 h exposure, while 24 h exposure increased the CBF at the relative lower dosage groups and then made a decrease at relative higher dosage groups. CBF were classified into two different types, which had different changes following PM2.5 exposure. CBP showed significant changes characterized as the increased dyskinesia index. Total levels of cellular ATP and the mitochondrial membrane potential were decreased following 12 h exposure of PM2.5, while no change was found in O2 consumption. In conclusion, PM2.5 impact the ciliary beat function of HNEpCs, and the mitochondrial dysfunction might play an important role in it.

Studies have indicated that ambient pollutant exposure correlates with nasal disease, in which nasal mucosa microbiota play a crucial role. However, the association between exposure to real-ambient air pollutants and the composition of nasal mucosa microbiota has not been well studied. This study aimed to explore the composition of nasal mucosa microbiota after exposure to real-ambient air pollutants with a special system. We monitored PM2.5, O3, etc. in the system and confirmed PM2.5 and O3 were the main pollutants. SD rats were exposed to the system for 16 weeks in summer or 22 weeks in autumn-winter. The concentrations of PM2.5 were 24.00 μg/m3 in the Summer stage and 22.21 μg/m3 in the autumn-winter stage. The O3 concentrations were 25.46 and 13.55 μg/m3, respectively. Exposure altered bacterial beta diversity in the summer stage. There were 4 and 3 different bacteria at the king, order, family and genus levels between the two groups at the two stages, respectively. The abundance of opportunistic pathogens changed, Pseudomonas decreased in summer stage, and Bifidobacterium increased in the autumn-winter stage. The influence of the season on the nasal mucosa microbiota was analyzed. The alpha diversity of the autumn-winter stage was higher than that of the summer stage. LEfSe analysis revealed 34 differential bacterial taxa at the king, order, family and genus level in the two control groups and 31 of the two exposure groups, which were not the same as the bacteria between the control groups and exposure groups. We found that PM2.5 combined with O3 exposure was associated with the composition of the nasal mucosa microbiota and the abundance of opportunistic pathogens, in which season likely impacted the microbiota.

This study presents the mass concentrations of PM2.5, O3, SO2 and NOx at one urban, one suburban and two rural locations in the Changchun region from September 25 to October 27 2013. Major chemical components of PM2.5 at the four sites were daily sampled and analyzed. Most of daily concentrations of SO2 (7–82 μg/m3), O3 (27–171 μg/m3) and NOx (14–213 μg/m3) were below the limits of the National Ambient Air Quality Standard (NAAQS) in China. However, PM2.5 concentrations (143–168 μg/m3) were 2-fold higher than NAAQS. Higher PM2.5 concentrations (~ 150 μg/m3) were measured during the pre-harvest and harvest at the urban site, while PM2.5 concentrations significantly increased from 250 to 400 μg m− 3 at suburban and rural sites with widespread biomass burning. At all sites, PM2.5 components were dominated by organic carbon (OC) and followed by soluble component sulfate (SO42 −), ammonium (NH4+) and nitrate (NO3−). Compared with rural sites, urban site had a higher mineral contribution and lower potassium (K+ and K) contribution to PM2.5. Severe atmospheric haze events that occurred from October 21 to 23 were attributed to strong source emissions (e.g., biomass burning) and unfavorable air diffusion conditions. Furthermore, coal burning originating from winter heating supply beginning on October 18 increased the atmospheric pollutant emissions. For entire crop harvest period, the Positive Matrix Factorization (PMF) analysis indicated five important emission contributors in the Changchun region, as follows: secondary aerosol (39%), biomass burning (20%), supply heating (18%), soil/road dust (14%) and traffic (9%).

This study presents the observations of PM10 and PM2.5 concentrations at an agricultural site from April to October 2012 in Dehui city, China. Ambient air was sampled by filter-based samplers and online PM monitors. The filter samples were analyzed to determine the abundance of ionic/inorganic elements, organic carbon (OC) and elemental carbon (EC). The daily PM10 concentrations varied significantly over the monitoring period, with an average of 168±63 (in the range of 52-277)μg/m(3) during the land preparation/planting period (26 April-15 June), 85±65 (36-228)μg/m(3) during the growing season (16 June-25 September), and 207±88 (103-310)μg/m(3) during the harvest period (26 September-31 October). PM2.5 accounted for 44%, 56% and 66% of atmospheric PM10 during these periods, respectively. The PM10 diurnal variation showed a distinct peak from 16:00 to 21:00 (LST) during the growing and harvesting seasons, while a gradual increase throughout the daytime until 17:00 was observed during tilling season. Mineral dust elements (Al, Ca, Fe, and Mg) dominated the PM10 chemical composition during the tilling season; OC, NO3(-), SO4(2-) and NH4(+) during the growing season; and carbonaceous species (i.e., OC and EC) during the harvesting season. Our results indicate that the soil particles emitted by farm tillage and organic matter released from straw burning are the two most significant sources of PM10 emissions contributing to the recurring high pollution events in this region. Therefore, development of agricultural PM inventories from soil tillage and straw burning is prioritized to support air quality modeling.

This study reports a case of an advanced pancreatic cancer patient with liver metastasis who was treated with a combination of chemotherapy, targeted drugs, and high-intensity focused ultrasound (HIFU). The abdominal pain was successfully relieved after the HIFU therapy. The patient had an 18-month survival with satisfactory quality of life. Large-scale randomized clinical trials are necessary to evaluate the long-term efficacy of HIFU treatment with or without chemotherapy and/or targeted drug therapy for pancreatic carcinoma.

Introduction Saponins are bioactive compounds employed in the prevention and treatment of cardiovascular and cerebrovascular diseases. The adventitious roots of Panax notoginseng may offer an alternative source of saponins. Identification and determination of saponins in the crude extract is challenging owing to their similar structures and the lack of standards. Objective To develop a rapid, sensitive and accurate method based on solid-phase extraction followed by ultra-performance liquid chromatography–electrospray ionisation mass spectrometry (UPLC-ESI-MS) for the identification and quantification of saponins in P. notoginseng. Methodology Following extraction using Waters OasisTM HLB cartridges, the analytes were subjected to a UPLC system with a Waters Acquity BEH C18 chromatographic column and a binary mobile phase system consisting of 0.05% formic acid in water and acetonitrile under gradient elution conditions, with final detection by ESI-MS in the positive ion mode. Results The UPLC-ESI-MS method gave limits of detection and quantification within the range 0.015–0.382 and 0.052–1.124 µg/mL, respectively, for 15 studied saponins. The instrumentation/injection precision (RSD) was 4.5% for a low concentration and 3.2% for an intermediate concentration sample. The intra- and inter-day repeatability was less than 2.65% (RSD). The method described was validated using spiked samples with different amounts of saponin standards. Conclusion This UPLC-ESI-MS assay provides a suitable quality control method for the tentative identification and determination of major biological active constituents in adventitious and native roots of P. notoginseng. Copyright © 2008 John Wiley & Sons, Ltd.

The flower buds of Panax notoginseng have been commonly used for the treatment of hypertension, vertigo, tinnitus and acute faucitis in China. The amount of total saponins in the flower buds is higher than in any other parts of P. notoginseng. However, the compositions of flower buds have not been quantified clearly until now. A sensitive and efficient high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed for the first time to simultaneously quantify eight active saponins in the flower buds of P. notoginseng, including notoginsenoside R(1) and ginsenosides Rg(1), Re, Rb(1), Rb(2), Rb(3), Rd and F(2). The analysis was performed on a reversed-phase C(18) column with gradient elution of acetonitrile and 0.01% aqueous formic acid. The proposed method provided good linearity, reproducibility and sensitivity for the simultaneous quantification of the investigated saponins with overall intra- and inter-day precision and accuracy of better than 4.1% (RSD) and higher than 95% (accuracy), respectively. The recoveries for all the saponins determined were in the range 94.7-104.8% with RSD better than 3.1%. Using the optimized method, we were able to analyze samples from different villages of Wenshan Prefecture, China, which is helpful for quality control of flower buds of P. notoginseng.

AIM: To develop a prognostic model to predict survival of patients with colorectal cancer (CRC). METHODS: Survival data of 837 CRC patients undergoing surgery between 1996 and 2006 were collected and analyzed by univariate analysis and Cox proportional hazard regression model to reveal the prognostic factors for CRC. All data were recorded using a standard data form and analyzed using SPSS version 18.0 (SPSS, Chicago, IL, United States). Survival curves were calculated by the Kaplan-Meier method. The log rank test was used to assess differences in survival. Univariate hazard ratios and significant and independent predictors of disease-specific survival and were identified by Cox proportional hazard analysis. The stepwise procedure was set to a threshold of 0.05. Statistical significance was defined as P < 0.05. RESULTS: The survival rate was 74% at 3 years and 68% at 5 years. The results of univariate analysis suggested age, preoperative obstruction, serum carcinoembryonic antigen level at diagnosis, status of resection, tumor size, histological grade, pathological type, lymphovascular invasion, invasion of adjacent organs, and tumor node metastasis (TNM) staging were positive prognostic factors (P < 0.05). Lymph node ratio (LNR) was also a strong prognostic factor in stage III CRC (P < 0.0001). We divided 341 stage III patients into three groups according to LNR values (LNR1, LNR ≤ 0.33, n = 211; LNR2, LNR 0.34-0.66, n = 76; and LNR3, LNR ≥ 0.67, n = 54). Univariate analysis showed a significant statistical difference in 3-year survival among these groups: LNR1, 73%; LNR2, 55%; and LNR3, 42% (P < 0.0001). The multivariate analysis results showed that histological grade, depth of bowel wall invasion, and number of metastatic lymph nodes were the most important prognostic factors for CRC if we did not consider the interaction of the TNM staging system (P < 0.05). When the TNM staging was taken into account, histological grade lost its statistical significance, while the specific TNM staging system showed a statistically significant difference (P < 0.0001). CONCLUSION: The overall survival of CRC patients has improved between 1996 and 2006. LNR is a powerful factor for estimating the survival of stage III CRC patients.

AIM: To identify and assess mutations in the K-ras and BRAF genes in a cohort of Chinese patients with colorectal cancer (CRC) for their association with various clinicopathological parameters and prognosis. METHODS: Genomic DNA was isolated from frozen tissues. Pyrosequencing analysis was conducted to detect mutations in the K-ras (codons 12, 13, and 61) and BRAF genes (codon 600). Statistical analysis was carried out using SPSS-15.0 software. RESULTS: Among the 118 colorectal cancer patients, we detected 41 (34.7%) mutations in the K-ras gene. Mutation frequencies at codon 12 and codon 13 were 23.7% (28/118) and 10.2% (12/118), respectively. Only one patient harbored a point mutation at codon 61 (0.8%, 1/118). Gender was the only factor that showed an obvious relationship with K-ras gene mutation (female 44.7% vs male 28.2%, P = 0.037). Other clinicopathological features, such as age, location of the tumor, tumor differentiation, Tumor, Node and Metastases classification, and the Union for International Cancer Control staging, showed no positive relationship with K-ras gene mutations. No significant correlation was observed between the presence of K-ras mutations (codons 12, 13, and 61) and the survival of the patients. BRAF mutations were rare, and only two patients (1.7%) harbored a detectable mutation at codon 600. CONCLUSION: K-ras gene mutation is a common event in our 118 Chinese CRC patients, with an obvious relationship with gender. However, it seems not to be an independent prognostic factor in CRC patients. The BRAF gene is rarely mutated in Chinese CRC patients.

Liming Xu,1,2,* Mo Dan,1,* Anliang Shao,1 Xiang Cheng,1,3 Cuiping Zhang,4 Robert A Yokel,5 Taro Takemura,6 Nobutaka Hanagata,6 Masami Niwa,7,8 Daisuke Watanabe7,81National Institutes for Food and Drug Control, No 2, Temple of Heaven, Beijing, 2School of Information and Engineering, Wenzhou Medical University, Wenzhou, 3School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 4Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 5College of Pharmacy, University of Kentucky, Lexington, KY, USA; 6Nanotechnology Innovation Station for Nanoscale Science and Technology, National Institute for Materials Science, Tsukuba, Ibaraki, 7Department of Pharmacology, Nagasaki University, 8BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, Japan*These authors contributed equally to this workBackground: Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood.Method: To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray.Results: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200Ω·cm2. After Ag-NPS exposure for 24hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes.Conclusion: These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes.Keywords: Ag nanoparticles, astrocytes, BBB model, global gene expression analysis, antioxidant defense

Mo Dan,1,2 Michael T Tseng,3 Peng Wu,4 Jason M Unrine,5 Eric A Grulke,4 Robert A Yokel1,21Department of Pharmaceutical Sciences, College of Pharmacy, 2Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA; 3Departments of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, USA; 4Chemical and Materials Engineering Department, 5Department of Plant and Soil Science, University of Kentucky, Lexington, KY, USAPurpose: Ceria engineered nanomaterials (ENMs) have current commercial applications and both neuroprotective and toxic effects. Our hypothesis is that ceria ENMs can associate with brain capillary cells and/or cross the blood–brain barrier.Methods: An aqueous dispersion of ~5 nm ceria ENM was synthesized and characterized in house. Its uptake space in the Sprague Dawley rat brain was determined using the in situ brain perfusion technique at 15 and 20 mL/minute flow rates; 30, 100, and 500 µg/mL ceria perfused for 120 seconds at 20 mL/minute; and 30 µg/mL perfused for 20, 60, and 120 seconds at 20 mL/minute. The capillary depletion method and light and electron microscopy were used to determine its capillary cell and brain parenchymal association and localization.Results: The vascular space was not significantly affected by brain perfusion flow rate or ENM, demonstrating that this ceria ENM did not influence blood–brain barrier integrity. Cerium concentrations, determined by inductively coupled plasma mass spectrometry, were significantly higher in the choroid plexus than in eight brain regions in the 100 and 500 µg/mL ceria perfusion groups. Ceria uptake into the eight brain regions was similar after 120-second perfusion of 30, 100, and 500 µg ceria/mL. Ceria uptake space significantly increased in the eight brain regions and choroid plexus after 60 versus 20 seconds, and it was similar after 60 and 120 seconds. The capillary depletion method showed 99.4% ± 1.1% of the ceria ENM associated with the capillary fraction. Electron microscopy showed the ceria ENM located on the endothelial cell luminal surface.Conclusion: Ceria ENM association with brain capillary endothelial cells saturated between 20 and 60 seconds and ceria ENM brain uptake was not diffusion-mediated. During the 120-second ceria ENM perfusion, ceria ENM predominately associated with the surface of the brain capillary cells, providing the opportunity for its cell uptake or redistribution back into circulating blood.Keywords: ceria engineered nanomaterial, brain microvascular endothelial cell association, in situ brain perfusion, capillary depletion