Cyclooxygenase-2 (COX-2), considered to have tumor-promoting potential, is highly expressed in a variety of tumors, including breast cancer. Since the functions and action mechanisms of COX-2 in breast cancer have not been fully elucidated, in the present study, the effects of target inhibiting COX-2 with recombinant adenovirus Ad-COX-2-shRNA on malignant biological behavior were investigated in representative cell lines.
Multimodal therapeutic agents based on nanomaterials for cancer combination therapy have attracted increasing attention. In this report, a novel photo- and chemo-active nanohybrid was fabricated by assembling photosensitizer Zn(II)-phthalocyanine (ZnPc) and anticancer drug doxorubicin (DOX) on the biocompatible poly-L-lysine (PLL)-grafted graphene (G-PLL). This nanocomplex of G-PLL/DOX/ZnPc showed excellent physiochemical properties, including high solubility and stability in biological solutions, high drug loading efficiency, pH-triggered drug release, and ability to generalize 1O2 under light excitation. Compared to free drug molecules, cells treated with G-PLL/DOX/ZnPc showed a higher cellular uptake. Particularly, G-PLL/DOX/ZnPc elicited a remarkable synergistic anticancer activity owing to combined photodynamic and chemotherapeutic effects. The combination dose reduction indexes revealed that combining DOX with ZnPc provided strong synergistic effects (combination index< 0.1) against three cancer cell lines tested (HeLa, MCF-7, and B16). Thus, this study demonstrates programmable dual-modality therapy exemplified by G-PLL/DOX/ZnPc to synergistically treat cancers.
This paper describes the synthesis, formation mechanism, and mechanical property of multilayered ultrathin Pd nanosheets. An anisotropic, Hanoi Tower-like assembly of Pd nanosheets was identified by transmission electron microscopy and atomic force microscopy (AFM). These nanosheets may contain ultrathin Pd layers, down to single unit cell thickness. Selected area electron diffraction and scanning transmission electron microscopy data show the interconnected atomically thick layers stacking vertically with rotational mismatches, resulting in unique diffractions and Moiré patterns. Density functional theory (DFT) calculation with van der Waals correction (DFT+vdW) shows the adsorption of Pd4(CO)4(OAc)4 on Pd(110) surface (Ead = -5.68 eV) is much stronger than that on Pd(100) (Ead = -4.72 eV) or on Pd(111) (Ead = -3.80 eV). The adsorption strength of this Pd complex is significantly stronger than that of CO on the same Pd surfaces. The DFT+vdW calculation results suggest a new mechanism for the observed anisotropic growth of nanosheets with unusually high aspect ratio, in which the competitive adsorptions between Pd4(CO)4(OAc)4 complex and CO on various surfaces result in a favored growth along the ?110? directions and inhibition along ?111? directions. The mechanical property of these multilayered Pd nanosheets was studied using AFM and nanoindentation techniques, which indicate multilayered nanosheets show more plastic deformation than the bulk in response to an applied force.
Phenylethanolamine A (PA) is a new kind of ?-agonist, which was illegally used as a feed additive for growth promotion in China. In this study, a novel immunochromatographic assay (ICA) based on surface-enhanced Raman scattering (SERS) for the ultrasensitive and quantitative detection of phenylethanolamine A is presented. The principle of this new ICA is similar to that based on colloidal gold particles, but using Au(MBA)@Ag-Ab [e.g., polyclonal antibody of PA labeled Au@Ag core-shell nanoparticles (NPs) sandwiched with a Raman reporter (4-mercaptobenzoic acid, MBA)] as a probe. After ICA procedures, the specific Raman scattering intensity of MBA on the test line was measured for quantitative detection of PA. This assay was completed within 15 min. The IC50 and limit of detection (LOD) values of the ICA for PA detection were 0.06 ng mL(-1) and 0.32 pg mL(-1), respectively, which were 1-3 orders of magnitude lower than those obtained by other immunoassays, indicating the ultrasensitivity of this ICA. There was no cross-reactivity (CR) of the assay with another three ?-agonists (ractopamine, clenbuterol, and salbutamol), suggesting high specificity of the SERS-based ICA. A spiking experiment revealed that the recoveries of PA from pig urine samples were in range of 99.9- 101.2% with relative standard deviations (RSDs) of 3.6-5.8%. The results demonstrated that this SERS-based ICA was able to quantitatively detect PA in urine samples with high sensitivity, specificity, precision, and accuracy and might be a powerful method for the analysis of other target analytes in the food area.
Objective To investigate the effect of ulinastatin,a urinary trypsin inhibitor,on the postoperative liver function in patients who have received bilateral total knee arthroplasty(TKA)under pneumatic tourniquet. Methods Totally 40 patients who were scheduled to receive bilateral TKA under thigh tourniquet were randomly assigned into trial group(U group,receiving intravenous ulinastatin)and control group(C group,receiving natural saline). All patients received the same general anesthesia and postoperative analgesia. The plasma concentrations of alanine transaminase(ALT),total bilirubin(TBil),and direct bilirubin(DBil)were recorded and compared preoperatively and 4,24,48,and 72 hours after the surgery. Results The demographic data were not significantly different between these two groups(P>0.05). The ALT was not significantly changed after the surgery in the C group(P>0.05)but was significantly decreased 48 hours(P=0.002)and 72 hours(P=0.001)after the surgery in the U group. TBil and DBil were significantly increased 48 hours(P=0.012,P=0.000)and 72 hours(P=0.000,P=0.000)after the surgery in C group,while only that at 48 hours(P=0.010,P=0.038)was significantly increased in the U group. ALT 4 hours(P=0.026),48 hours(P=0.013),72 hours(P=0.004)after the surgery were significantly lower in the U group than those in C group. TBil at the 72 hours postoperatively in U group was significantly lower than that in C group(P=0.036). DBil was not significantly different between C group and U group at all time points(all P>0.05). Conclusion The application of ulinastatin in bilateral TKA can protect postoperative liver function.
The prognosis and management of hepatic fibrosis are closely related to the stage of the disease. The limitations of liver biopsy, which is the gold standard for treatment, include its invasiveness and sampling error. Ultrasound elasticity might be the most promising imaging technology for the noninvasive and accurate assessment of hepatic fibrosis. Real-time tissue elastography (RTE) measures the relative stiffness of the tissue in the region of interest caused by the heartbeat. Many studies have verified that RTE is useful for the diagnosis of hepatic fibrosis in patients with chronic hepatitis C (CHC).
Abstract Context: Cisplatin is a highly effective chemotherapeutic agent against many tumors; however, it has potent adverse effects. Zengmian Yiliu granule (ZMYL), a traditional Chinese medicine (TCM) compound, has been clinically used against platinum (Pt)-induced toxicity and to enhance the efficacy of cisplatin. Objective: The study was conducted to investigate the likelihood of potential pharmacokinetics drug-herbs interaction (DHI) between cisplatin and ZMYL. Materials and methods: An improved ICP-MS method combined with ultrafiltration and microwave-assisted digestion was performed to determine the total and free Pt concentrations in rat plasma after intraperitoneal administration of cisplatin (9?mg/kg) or a combined administration with ZMYL (1?g/kg) by gavage. Results: ZMYL produced a potential DHI on the pharmacokinetic parameters of cisplatin, calculated from the total Pt concentration. The clearance rate decreased from 110.52 to 66.12?mLh(-1?)kg(-1), the mean residence time extended from 63.1 to 164.54?h, the area under the plasma concentration-time curve increased from 86.58 to 152.93?µg?h?mL(-1), the elimination half-life extended from 48.38 to 126.4?h, and the elimination rate constant decreased from 0.017 to 0.006?h, in the ZMYL combination group (p?0.05). In terms of free Pt concentration, the apparent volume of distribution and clearance rate was statistically different (p?0.05). The Pt plasma protein binding ratios in the early dose stages were significantly boosted by the co-administration of ZMYL (p?0.01). Discussion and conclusion: ZMYL is a potential complementary and alternative medicine for cisplatin chemotherapy. The therapeutic benefits of ZMYL-cisplatin chemotherapy derived from pharmacokinetic interaction needs further investigation.
Angiopoietin2( ANGPT2 ) plays an important role in tumor angiopoiesis. ANGPT2 antagonises ANGPT1 resulting in an effect on the stability of blood vessels, which promotes tumor growth, invasion, proliferation as well as relating to tumor vascular density. A lot of researches published papers about anti-ANGPT2 for the treatment of tumor, and have made some progresses. In this review, the role of ANGPT2 in the pathogenesis of acute myelogenous leukemia (AML), including its effects on proliferation of leukemia cells, bone marrow angiopoiesis, tumor invasion and metastasis are briefly summarised in order to provide the basis for targeted ANGPT2 in treatment of AML.
Short-term outcomes of the Wallis system in the treatment of lumbar degenerative disease (LDD) have been shown to be effective, whereas there is a paucity of studies on the mid-long-term effects of the treatment of the Wallis system. This study was to evaluate the mid-long-term effects of the Wallis dynamic stabilization system in the treatment of LDD.
This paper presents the use of Ca2Mn2O5 as an oxygen-deficient perovskite electrocatalyst for oxygen evolution reaction (OER) in alkaline media. Phase-pure Ca2Mn2O5 was made under mild reaction temperatures through a reductive annealing method. This oxygen deficient perovskite can catalyze the generation of oxygen at ?1.50 V versus (vs) reversible hydrogen electrode (RHE) electrochemically, and reach an OER mass activity of 30.1 A/g at 1.70 V (vs RHE). In comparison to the perovskite CaMnO3, Ca2Mn2O5 shows higher OER activities. The molecular level oxygen vacancies and high spin electron configuration on manganese in the crystal structures are likely the contributing factors for the enhanced performance. This work demonstrates that oxygen-deficient perovskite, A2B2O5, is a new class of high performance electrocatalyst for those reactions that involve active oxygen intermediates, such as reduction of oxygen and OER in water splitting.
Strain TS-56T was isolated from the gut of a wood-feeding termite, Reticulitermes chinensis Snyder. Phylogenetic analyses based on 16S rRNA gene sequences revealed that the strain belonged to the genus Gryllotalpicola of the family Microbacteriaceae, with sequence similarities ranging from 96.6% to 97.8%. The isolate was Gram-stain- positive, non-motile, light yellow, irregular short rod-shaped (0.4-0.6 ?m in diameter, 0.6-1.0 ?m in length). Growth of strain TS-56T occurred at 20-35? (optimum, 30?), and at pH 4.0-8.0 (optimum, pH 5.0). The peptidoglycan of strain TS-56T contained ornithine, glutamic acid, alanine, homoserine and glycine. The acyl type was acetyl. The most abundant cellular fatty acids of strain TS-56T was cyclohexyl-C17:0 (88.79%). The respiratory menaquinone was MK-11. The polar lipid profile contained disphosphatidyl glycerol, phosphatidyl glycerol, phosphatidyl choline, phosphatidyl inositol, and two unknown glycolipids. DNA of the type strain had a G+C content of 67.4 mol%. Based on the phylogenetic properties and phenotypic distinctiveness, strain TS-56T represents a novel species of the genus Gryllotalpicola, for which the name Gryllotalpicola reticulitermitis sp. nov. is proposed. The type strain is TS-56T (=CGMCC 1.10363T =NBRC 109838T).
Atrazine is a member of the triazine herbicide family intensively used to control weeds for crop production. In this study, atrazine residues and its degraded products in alfalfa (Medicago sativa) were characterized using UPLC-TOF-MS/MS. Most of atrazine absorbed in plants was found as chemically modified derivatives like deisopropylated atrazine (DIA), dehydrogenated atrazine (DHA), or methylated atrazine (MEA), and some atrazine derivatives were conjugated through different functional groups such as sugar, glutathione, and amino acids. Interestingly, the specific conjugates DHA+hGSH (homoglutathione) and MEA-HCl+hGSH in alfalfa were detected. These results suggest that atrazine in alfalfa can be degraded through different pathways. The increased activities of glycosyltransferase and glutathione S-transferase were determined to support the atrazine degradation models. The outcome of the work uncovered the detailed mechanism for the residual atrazine accumulation and degradation in alfalfa and will help to evaluate whether the crop is suitable to be cultivated in the atrazine-polluted soil.
Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models.
Two-dimensional (2D) materials often show a range of intriguing electronic, catalytic, and optical properties that differ greatly from conventional nanoparticles. While planar configuration is often desirable, a range of applications such as catalysis and sensing benefit greatly from the accessibility to large surface areas. The 2D materials generally tend to form stacks in order to reduce the overall surface energy. Such densely packed structures however are detrimental when access to high surface area is required. Herewith we demonstrate a chemical strategy to generate Pd three-dimensional (3D) structures from its flexible 2D nanosheets. Solvent polarity is shown to play an important role to control the final morphology of these nanosheets. Our data indicate when these Pd 3D materials were integrated into hydrogen sensing devices, response time was found to be an order of magnitude faster than their 2D-constrained counterparts. The easy accessibility to the surfaces by hydrogen gas is considered to be an important factor for the observed fast response time based on the sensing model.
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
C-reactive protein (CRP) is an established marker of inflammation and has been proposed to play a proinflammatory role in pathologies of several diseases. CRP is primarily produced by the liver and released into circulation as a pentameric molecule composed of five identical subunits. It has been suggested that the activation of the proinflammatory actions of CRP requires sequential conformational changes triggered by local inflammatory conditions. These include the dissociation into the subunit form (monomeric CRP, mCRP) and further reduction of the intra-subunit disulfide bond of mCRP. This model predicts that mCRP is the primary isoform present in inflamed but not healthy tissues, however the supporting evidence is lacking. Herein, we stained tissue samples across multiple anatomical locations from several types of human diseases with highly selective monoclonal antibodies that can differentiate CRP and mCRP. The results indicated that mCRP is the predominant form existing in the lesions. Further immunoblotting of the patient tissue samples revealed the potential presence of reduced mCRP. Together, we conclude that mCRP but not CRP is the major isoform present in local inflammatory lesions, supporting the so-called cascading model of CRP function and regulation.
Photothermal therapy has attracted significant attention as a minimally invasive therapy methodology. In this work, we report PEGylated nickel carbide nanocrystals (Ni3C NCs) as an efficient photothermal agent for the first time. The nanoparticles exhibit a broad absorption from the visible to the near-infrared regions and a rapid rise in temperature when irradiated by an 808 nm laser even at a concentration of 100 ?g mL(-1). In vitro and in vivo cytotoxicity assays demonstrate they have good biocompatibility, which lays an important foundation for their biological application. In vitro studies reveal the efficient damage of cancer cells by the exposure of 808 nm laser with a power density of 0.50 W cm(-2). Furthermore, hematoxylin and eosin (H & E) and terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling (TUNEL) staining of tumor slices confirmed the obvious destruction of cancer cells in vivo by an 808 nm laser (0.50 W cm(-2)) after only a 5 min application. Our work may open up a new application domain for transition metal carbides for biomedicine.
Transposon mutagenesis, in combination with parallel sequencing, is becoming a powerful tool for en-masse mutant analysis. A probability generating function was used to explain observed miniHimar transposon insertion patterns, and gene essentiality calls were made by transposon insertion frequency analysis (TIFA). TIFA incorporated the observed genome and sequence motif bias of the miniHimar transposon. The gene essentiality calls were compared to: 1) previous genome-wide direct gene-essentiality assignments; and, 2) flux balance analysis (FBA) predictions from an existing genome-scale metabolic model of Shewanella oneidensis MR-1. A three-way comparison between FBA, TIFA, and the direct essentiality calls was made to validate the TIFA approach. The refinement in the interpretation of observed transposon insertions demonstrated that genes without insertions are not necessarily essential, and that genes that contain insertions are not always nonessential. The TIFA calls were in reasonable agreement with direct essentiality calls for S. oneidensis, but agreed more closely with E. coli essentiality calls for orthologs. The TIFA gene essentiality calls were in good agreement with the MR-1 FBA essentiality predictions, and the agreement between TIFA and FBA predictions was substantially better than between the FBA and the direct gene essentiality predictions.
Mining activities result in extensive soil degradation by removing the top soil, disturbing soil structure and altering microbial communities. Rehabilitation of spent mine sites through revegetation thus requires proper soil amendments. In this study, a pot trial was conducted to investigate the effects of a jarrah biochar on the growth and nutrient status of a native legume, Acacia tetragonophylla, grown in a mixture of topsoil and mine rejects. Two biochar application rates (37 and 74 t ha(-1)) and two types of biochar, namely nutrient-enriched and non-enriched, were tested. We measured the soil pH and electrical conductivity, the carbon (C) and nitrogen (N) contents and C and N isotope composition (?(13)C and ?(15)N) of soil and plants, the foliar phosphorus content and the growth and leaf biomass of the plants. Whilst no significant effect of biochar was observed on plant growth, biochar amendment affected soil properties and plant nutritional status. The highest rate of biochar application increased soil pH, C content and C/N ratio, and decreased soil ?(13)C. Biochar application also enhanced photosynthetic N use efficiency, as showed by the increase in foliar C/N ratio, and biological N fixation rates, as indicated by foliar ?(15)N. These positive effects were not observed when biochar was nutrient-enriched due to the associated increase in soil N. Revegetation of mine sites with acacia in combination with biochar amendment constitutes a plausible alternative to the wide use of N fertiliser through the supply of additional N to the system, even though other nutrients may be required in order to enhance plant early growth.
Podophyllum hexandrum and, to a much lesser extent P. peltatum, are sources of podophyllotoxin, extensively used as a chemical scaffold for various anti-cancer drugs. In this study, integrated omics technologies (including advanced mass spectrometry/metabolomics, transcriptome sequencing/gene assemblies, and bioinformatics) gave unequivocal evidence that both plant species possess a hitherto unknown aporphine alkaloid metabolic pathway. Specifically, RNA-seq transcriptome sequencing and bioinformatics guided gene assemblies/analyses in silico suggested presence of transcripts homologous to genes encoding all known steps in aporphine alkaloid biosynthesis. A comprehensive metabolomics analysis, including UPLC-TOF-MS and MALDI-MS imaging in situ, then enabled detection, identification, localization and quantification of the aporphine alkaloids, magnoflorine, corytuberine and muricinine, in the underground and aerial tissues. Interestingly, the purported presence of alkaloids in Podophyllum species has been enigmatic since the 19th century, remaining unresolved until now. The evolutionary and phylogenetic ramifications of this discovery are discussed.
With process optimization and technical innovation, laparoscopic gastrointestinal surgery has evolved dramatically over the last two decades and provided important improvement in the contemporary surgical practice and patients' recovery. With the emergence of many new minimally invasive technologies, including total laparoscopic surgery, single-incision laparoscopic surgery, and natural orifice specimen extraction, patents with gastrointestinal carcinomas may experience less pain and have lower perioperative complications, but the exact efficacy remains to be proven. Large-scale international multi-centre randomized controlled trial data have revealed that laparoscopic colorectal surgery is safe both in terms of short-term perioperative outcomes and long-term oncological efficacy. However, the question whether there is an equivalent oncological outcome compared to the open approach in gastric cancer is still unanswered by now and needs to be proven by future studies.
Two anaerobic bacterial strains, MB9-7(T) and MB9-9, were isolated from decomposing algal scum and were characterized using a polyphasic approach. Phylogenetic analysis of 16S rRNA gene sequences showed that strains MB9-7(T) and MB9-9 are closely related to each other (99.7?% similarity) and they are also closely related to Clostridium tyrobutyricum (96.5?%). The two strains were Gram-stain positive and rod-shaped. Growth occurred at 20-45 °C, at pH 4.0-8.0 and at NaCl concentrations of up to 2?% (w/v). Acid was produced from glucose, xylose and mannose. Products of fermentation in PYG medium were mainly butyrate, acetate, carbon dioxide and hydrogen. The predominant cellular fatty acids were C14?:?0 and C16?:?0. The cellular polar lipids comprised phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, two glycolipids, one phospholipid, one aminophospholipid and two aminolipids. The DNA G+C contents of strain MB9-7(T) and MB9-9 were 27.9 and 28.7 mol%, respectively. These results support the assignment of the new isolates to the genus Clostridium and also distinguish them from other species of the genus Clostridium. Hence, it is proposed that strains MB9-7(T) and MB9-9 represent a novel species of the genus Clostridium, with the suggested name Clostridium algifaecis sp. nov. The type strain is MB9-7(T) (?=?CGMCC 1.5188(T)?=?DSM 28783(T)).
Based on first-principles calculations in the framework of van der Waals density functional theory, we find that giant, Rashba-like spin splittings can be induced in both the surface states and quantum well states of thin Bi2Se3 films by application of an external electric field. The charge is redistributed so that the Dirac cones of the upper and lower surfaces become nondegenerate and completely gapless. Interestingly, a momentum-dependent spin texture is developed on the two surfaces of the films. Some of the quantum well states, which reside in the middle of the Bi2Se3 film under zero field, are driven to the surface by the electric field. The Rashba splitting energy has a highly non-linear dependence on the momentum and the electric field due to the large contribution of the high-order Rashba terms, which suggests complex spin dynamics in the thin films of Bi2Se3 under an electric field.
Inhibition of growth of the intestinal epithelium, a rapidly self-renewing tissue, is commonly found in various critical disorders. The RNA-binding protein HuR is highly expressed in the gut mucosa and modulates the stability and translation of target mRNAs, but its exact biological function in the intestinal epithelium remains unclear. Here, we investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells caused significant mucosal atrophy in the small intestine, as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. In addition, the HuR-deficient intestinal epithelium also displayed decreased regenerative potential of crypt progenitors after exposure to irradiation. HuR deficiency decreased expression of the Wnt coreceptor LDL receptor-related protein 6 (LRP6) in the mucosal tissues. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3'-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for normal mucosal growth in the small intestine by altering Wnt signals through up-regulation of LRP6 expression and highlight a novel role of HuR deficiency in the pathogenesis of intestinal mucosal atrophy under pathological conditions.
A new motif for infinite metal atom wires with tunable compositions and properties is developed based on the connection between metal paddlewheel and square planar complex moieties. Two infinite Pd chain compounds, [Pd4 (CO)4 (OAc)4 Pd(acac)2 ] 1 and [Pd4 (CO)4 (TFA)4 Pd(acac)2 ] 2, and an infinite Pd?Pt heterometallic chain compound, [Pd4 (CO)4 (OAc)4 Pt(acac)2 ] 3, are identified by single-crystal X-ray diffraction analysis. In these new structures, the paddlewheel moiety is a Pd four-membered ring coordinated by bridging carboxylic ligands and ?2 carbonyl ligands. The planar moiety is either Pd(acac)2 or Pt(acac)2 (acac=acetylacetonate). These moieties are connected by metallophilic interactions. The results showed that these one-dimensional metal wire compounds have photoluminescent properties that are tunable by changing ligands and metal ions. 3 can also serve as a single source precursor for making Pd4 Pt bimetallic nanostructures with precise control of metal composition.
ABSTRACT Objective: Work zone safety is one of the top priorities for transportation agencies. In recent years, a considerable volume of research has sought to determine work zone crash characteristics and causal factors. Unlike other non-work zone related safety studies (on both crash frequency and severity), there has not yet been a comprehensive review and assessment of methodological approaches for work zone safety. To address this deficit, this paper aims to provide a comprehensive review of the existing extensive research efforts focused on work zone crash-related analysis and modeling, in the hopes of providing researchers and practitioners a complete overview. Methods: Relevant literature published in the last five decades was retrieved from the National Work Zone Crash Information Clearinghouse and the Transport Research International Documentation (TRID) database, and other public digital libraries and search engines. Both peer-reviewed publications and research reports were obtained. Each study was carefully reviewed, and those that focused on either work zone crash data analysis or work zone safety modeling were identified. The most relevant studies are specifically examined and discussed in the paper. Results: The identified studies were carefully synthesized to understand the state-of-knowledge on work zone safety. Agreement and inconsistency regarding the characteristics of the work zone crashes discussed in the descriptive studies were summarized. Progress and issues about the current practices on work zone crash frequency and severity modeling are also explored and discussed. The challenges facing work zone safety research are then presented. Conclusions: The synthesis of the literature suggests that the presence of a work zone is likely to increase the crash rate. Crashes are not uniformly distributed within work zones and rear-end crashes are the most prevalent type of crashes in work zones. There was no across the board agreement among numerous papers reviewed on the relationship between work zone crashes and other factors such as time, weather, victim severity, traffic control devices, and facility types. Moreover, both work zone crash frequency and severity models still rely on relatively simple modeling techniques and approaches. Also, work zone data limitations have caused a number of challenges in analyzing and modeling work zone safety. Additional efforts on data collection, developing a systematic data analysis framework and using more advanced modeling approaches are suggested as future research tasks.
In gene therapy, how genetic therapeutics can be efficiently and safely delivered into target tissues/cells remains a major obstacle to overcome. To address this issue, nanoparticles consisting of non-covalently coupled polyethyleneimine (PEI) and folic acid (FA) to the magnetic and fluorescent core/shell of Fe3O4@SiO2(FITC) was tested for their ability to deliver Notch-1 shRNA. Our results showed that Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanoparticles are 64?nm in diameter with well dispersed and superparamagnetic. These nanoparticles with on significant cytotoxicity are capable of delivering Notch-1 shRNA into human breast cancer MDA-MB-231 cells with high efficiency while effectively protected shRNA from degradation by exogenous DNaseI and nucleases. Magnetic resonance (MR) imaging and fluorescence microscopy showed significant preferential uptake of Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanocomplex by MDA-MB-231 cells. Transfected MDA-MB-231 cells exhibited significantly decreased expression of Notch-1, inhibited cell proliferation, and increased cell apoptosis, leading to the killing of MDA-MB-231 cells. In light of the magnetic targeting capabilities of Fe3O4@SiO2(FITC)/PEI-FA, our results show that by complexing with a second molecular targeting therapeutic, such as Notch-1 shRNA in this report, Fe3O4@SiO2(FITC)/PEI-FA can be exploited as a novel, non-viral, and concurrent targeting delivery system for targeted gene therapy as well as for MR imaging in cancer diagnosis.
Little information is available on the prevalence of drug-resistance mutations in patients harboring the human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF)07_BC variant in Sichuan, China. This study examined 375 plasma samples from patients with HIV-1 who were infected with the CRF07_BC strain, including 104 drug-naive participants and 271 in whom antiretroviral therapy (ART) had failed. Only one participant in the drug-naive group had a drug-resistance mutation (M46L), compared with 31.73% of those in whom ART had failed. Further analysis showed that 19.56% of strains contained mutations conferring resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) alone, 0.74% were resistant to nucleoside reverse transcriptase inhibitors (NRTIs) alone, and 11.44% were dual-resistant to both NRTIs and NNRTIs. The most common mutation in the ART-failure group was M184V (35.88%), K103N (45.01%), Y181C (17.33%), and G190S/A (15.88%). The percentages of HIV-1 strains resistant to lamivudine, emtricitabine, efavirenz, etravirine, and nevirapine were 10.70%, 10.70%, 28.04%, 7.75%, and 26.20%, respectively. To explore site variants possibly related to drug resistance, variations in the ancestor/consensus CRF07_BC sequences from the therapy-naive and ART-failure groups were compared, and seven mutations at six positions were identified as being significantly differently distributed between the two groups (p<0.05). Detailed sequence data will provide information on CRF07_BC genetic characterizations, and improve our understanding of antiretroviral susceptibility and the evolution of drug-resistance mutations. This will be valuable in developing and implementing local public-health approaches for HIV drug-resistance prevention and treatment.
Hypoxia-inducible factor-1 (HIF-1) regulates the expression of the vascular endothelial growth factor (VEGF), a process requiring copper (Cu) participation. HIF-1 is also involved in the expression of more than a hundred of genes, but it is unknown how HIF-1 differentially controls the expression of these genes timely and spatially. The present study was undertaken to test the hypothesis that Cu is not required for the expression of all HIF-1-regulated genes, thus exploring mechanistic insights into the differential control of multiple gene expression by one transcription factor. Human umbilical vein endothelial cells (HUVECs) were treated with siRNA targeting HIF-1? to define the essential role of HIF-1 in the regulation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and insulin-like growth factor 2 (IGF-2) expression. A Cu chelator, tetraethylenepentamine (TEPA), was used to reduce intracellular availability of Cu. In comparison, a zinc chelator, N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), was used to reduce intracellular zinc concentration. The expression of both BNIP3 and IGF-2 was completely suppressed in the HIF-1? deficient cells. The removal of Cu suppressed the expression of BNIP3, but did not affect that of IGF-2. The reduction of intracellular zinc did not cause the same effect. Further screening identified a group of genes whose expression required Cu and the others did not need Cu. The present study thus demonstrates Cu-dependent and -independent HIF-1 regulation of gene expression, indicating a mechanism for differential control of multiple gene expression by one transcription factor.
Round haploid spermatids are formed at the completion of meiosis. These spermatids then undergo morphological and cytological changes during spermiogenesis. Although sperm proteomes have been extensively studied, relatively few studies have specifically investigated the proteome of round spermatids. We developed a label-free quantitative method in combination with 2D-nano-LC-ESI-MS/MS to investigate the proteome of round spermatids in mice. Analysis of the proteomic data identified 2,331 proteins in the round spermatids. Functional classification of the proteins based on Gene Ontology terms and enrichment analysis further revealed the following: 504 of the identified proteins are predicted to be involved in the generation of precursor metabolites and energy; 343 proteins in translation and protein targeting; 298 proteins in nucleotide and nucleic acid metabolism; 275 and 289 proteins in transport and cellular component organization, respectively. A number of the identified proteins were associated with cytoskeleton organization (183), protein degradation (116) and response to stimulus (115). KEGG pathway analysis identified 68 proteins that are annotated as components of the ribosomal pathway and 17 proteins were related to aminoacyl-tRNA biosynthesis. The round spermatids also contained 28 proteins involved in the proteasome pathway and 40 proteins in the lysosome pathway. A total of 60 proteins were annotated as parts of the spliceosome pathway, in which heterogeneous nuclear RNA is converted to mRNA. Approximately 94 proteins were identified as actin?binding proteins, involved in the regulation of the actin cytoskeleton. In conclusion, using a label-free shotgun proteomic approach, we identified numerous proteins associated with spermiogenesis in round spermatids.
Chronic low back pain is one of the major causes of disability and thus has a major socioeconomic impact. Intervertebral disc degeneration is the main cause of chronic low back pain. Treatment for chronic discogenic low back pain has traditionally been limited to either conservative management or surgical fusion. If conservative treatment fails, then surgical fusion is commonly considered. Current treatments are limited to treat the symptoms and not the underlying biologic alterations of the disc.
The aim of this research is to evaluate the effect of tetramethylpyrazine (TMP) and connective tissue growth factor (CTGF) miRNA plasmids on the expressive levels of CTGF, transforming growth factor-beta (TGFbeta) and type I collagen of rat hepatic stellate cells (HSC) which are stimulated by high glucose. The rat HSCs which were successfully transfected rat CTGF miRNA plasmids and the rat HSCs which were successfully transfected negative plasmids were cultured in vitro. After stimulus of the TMP and the high glucose, the protein levels and gene expressive levels of CTGF, TGF-beta and type I collagen were tested. The results indicated that high glucose increased the expression of CTGF mRNA, CTGF protein, TGF-beta mRNA,TGF-beta protein and type I collagen (P < 0.05). The expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in TMP group were lower than those in high glucose group and showed statistically significant differences (P < 0.05). Compared with high glucose group, the expressive levels of CTGF mRNA, CTGF protein, TGF-beta mRNA, TGF-beta and type I collagen in rat CTGF miRNA plasmid interference group were significantly lower (P < 0.05). However, no statistically significant difference was found in CTGF mRNA and CTGF protein levels between TMP group and CTGF miRNA group (P > 0.05), while type I collagen levels showed statistically significant differences (P < 0.05). It is concluded that high glucose could promote the expressions of CTGF, TGF-beta and type I collagen, and TMP and rat CTGF miRNA plasmids could reduce the expressions of CTGF, TGF-beta, type I collagen.
Alcohol is a well-established cause of esophageal carcinoma, but its effect on survival is little known and contradictory. To clarify whether drinking is an independent predictor of survival in esophageal carcinoma, 2151 Chinese patients, receiving surgical resection from January 1997 to December 2008, were followed until March 2014. Cox proportional hazards analysis was applied to evaluate the prognostic effect of alcohol consumption. The median follow-up was 64 months. The median overall survival (OS; 42 months) and disease-free survival (DFS; 33 months) for never-drinkers were significantly higher than ever-drinkers (27 and 22 months, respectively). In the multivariate Cox model that was adjusted for age, weight loss, stage according to criteria set by the American Joint Committee on Cancer, radicality of surgery, adjuvant treatment, smoking status, and gender, the hazard ratios of ever-drinking were 1.22 (1.06-1.41, P = 0.005) on OS, and 1.16 (1.01-1.34, P = 0.037) on DFS. The hazardous effect on OS and DFS of drinking grew statistically significantly in a dose-dependent manner with increasing amount of alcohol consumption per day (both P-value for trend < 0.05). The predictive effect of drinking on OS (P = 0.596) or DFS (P = 0.207) was not significant in the subgroup with esophageal adenocarcinoma (n = 195). The current study revealed that the survival is shortened, of those patients who consume alcohol before diagnosis of esophageal squamous cell carcinoma, which are not attributable to differences in stage, smoking status, and gender. Alcohol control should be emphasized to reduce mortality of esophageal carcinoma, and further outcome studies should include alcohol as a potential prognosticator.
Water-soluble phosphorescent polymeric nanoparticles with an average diameter of approximately 100?nm were synthesized by a coordination cross-linking reaction. The pyridine blocks in poly(4-vinyl pyridine-b-ethylene oxide) (P4VP-b-PEO) were cross-linked by the iridium chloride-bridged dimer in DMF solution. Owing to the presence of an iridium complex with different ligands in the core of the polymeric nanoparticles, NP-1, NP-2, and NP-3 showed bright green, yellow, and red phosphorescence, respectively. PEG chains in the shell gave the polymeric nanoparticles solubility and biocompatibility, which was confirmed by an MTT assay using HeLa cells as a model cancer cell line. The flow cytometry and laser confocal fluorescence microscopy results revealed NP-2, as an example, could be effectively uptaken by HeLa cells. Therefore, these polymeric nanoparticles can be used as luminescent probes for living cells. In addition, (1) O2 could be effectively generated in the presence of NP-2 upon irradiation with visible light (?>400?nm, 300?mW?cm(-2) ), which was confirmed by a clear decrease in the fluorescence intensity of 9,10-dimethylanthracene (DMA). After incubation with NP-2 at a concentration of 200??g?mL(-1) for 6?h, approximately 90?% of HeLa cells were effectively ablated upon irradiation with visible light for only 10?min, indicating the potential for photodynamic therapy with polymeric nanoparticles.
Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood. Although it causes severe diarrhea and gastroenteritis in humans, C. jejuni typically dwells as a commensal microbe within the intestines of most animals, including birds, where its colonization is asymptomatic. Pretreatment of C57BL/6 mice with the antibiotic vancomycin facilitated intestinal C. jejuni colonization, albeit with minimal pathology. In contrast, vancomycin pretreatment of mice deficient in SIGIRR (Sigirr(-/-)), a negative regulator of MyD88-dependent signaling led to heavy and widespread C. jejuni colonization, accompanied by severe gastroenteritis involving strongly elevated transcription of Th1/Th17 cytokines. C. jejuni heavily colonized the cecal and colonic crypts of Sigirr(-/-) mice, adhering to, as well as invading intestinal epithelial cells. This infectivity was dependent on established C. jejuni pathogenicity factors, capsular polysaccharides (kpsM) and motility/flagella (flaA). We also explored the basis for the inflammatory response elicited by C. jejuni in Sigirr(-/-) mice, focusing on the roles played by Toll-like receptors (TLR) 2 and 4, as these innate receptors were strongly stimulated by C. jejuni. Despite heavy colonization, Tlr4(-/-)/Sigirr(-/-) mice were largely unresponsive to infection by C. jejuni, whereas Tlr2(-/-)/Sigirr(-/-) mice developed exaggerated inflammation and pathology. This indicates that TLR4 signaling underlies the majority of the enteritis seen in this model, whereas TLR2 signaling had a protective role, acting to promote mucosal integrity. Furthermore, we found that loss of the C. jejuni capsule led to increased TLR4 activation and exaggerated inflammation and gastroenteritis. Together, these results validate the use of Sigirr(-/-) mice as an exciting and relevant animal model for studying the pathogenesis and innate immune responses to C. jejuni.
We propose and realize a simple technique to measure the tiny spin Hall effect of light from the ratio of the minimum and the maximum intensities along two cross-polarization directions, without the requirement of a position-sensitive detector in the conventional weak measurement. Furthermore, the weak intensity ratio is dramatically amplified by purposely choosing the intensity along the direction close to that of the minimum instead of the maximum along the perpendicular polarization direction, which is verified by the experimental results. In principle, this method also can be modified for measurement of the high extinction ratio of a polarizer.
FoxM1 is a specific transcription factor that has an important function in aggressive human carcinomas, including cervical cancer. However, the specific function and internal molecular mechanism in cervical cancer remain unclear. In this study, RNAi-mediated FoxM1 knockdown inhibited cell growth. This process also decreased the migration and invasion activities of HeLa cells in vitro. Downregulation of FoxM1 inhibited tumor growth and angiogenesis in vivo. In addition, the expressions of uPA, matrix metalloproteinase (MMP)-2, MMP-9 and VEGF were significantly decreased in vitro and in vivo. These results suggested that the inactivation of FoxM1 could be a novel therapeutic target for cervical cancer treatment.
The objective of this study was to evaluate the effects of charge-carrying amino acids (lysine (Lys), arginine (Arg), aspartic acid (Asp) and glutamic acid (Glu)) on the gelatinization and retrogradation properties of potato starch. Acidic amino acids (Asp and Glu) showed a decreasing trend in swelling power and granule size of potato starch, but increased amylose leaching and gelatinization temperature. Alkaline amino acid (Arg) showed an increasing trend in swelling power and granule size of potato starch, but decreasing amylose leaching and gelatinization temperature. Lys had no effect on the swelling power of potato starch, except at a high content (0.2 mol/kg). Like other two acidic amino acids, Lys also increased gelatinization temperature. Moreover, the addition of alkaline amino acids (Arg) decreased syneresis value of potato starch but acidic amino acids (Asp and Glu) increased it. Compared to Arg, the syneresis of potato starch with Lys was similar to that of its native starch.
We investigated whether thyroid autoantibody status influences pregnancy outcomes in euthyroid women, by comparing abnormal pregnancy outcome rates between those who tested positive for thyroid autoantibodies (Ab(+)) and those who tested autoantibody-negative (Ab(-)). Euthyroid pregnant women (n = 7,641) underwent tests for serum thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). The subjects were divided into 4 groups according to thyroid antibody status: TPOAb(-)/TgAb(-) (92.9 %); TPOAb(+)/TgAb(-) (3.2 %); TPOAb(-)/TgAb(+) (2.0 %); and TPOAb(+)/TgAb(+) (1.9 %). The incidence rates of the following abnormal pregnancy outcomes were compared among the 4 groups and analyzed by Fisher's exact test: gestational diabetes, gestational hypertension, placenta previa, placental abruption, premature rupture of fetal membrane (PROM), intrauterine growth restriction, fetal distress, fetal anomalies, stillbirth, preterm birth, and low birth weight. Among the 4 groups, there were no significant differences in age, gestational age, or in the incidence rates of abnormal pregnancy outcomes, except for PROM and low birth weight. The highest incidence rates for PROM and low birth weight were in the TPOAb(-)/TgAb(+) and TPOAb(+)/TgAb(+) subjects, respectively. TgAb positivity and TPOAb positivity were associated with PROM and low birth weight, respectively. Underlying factors that govern the association between thyroid autoantibodies and PROM and low birth weight require further investigation.
A freshwater algicidal bacterial strain, Lzh-5, isolated from Lake Taihu, with strong algicidal activity against Microcystis aeruginosa, was identified as Bacillus sp. based on its phenotypic characteristics and 16S ribosomal RNA (rRNA) gene sequence. The algicidal mode of Bacillus sp. Lzh-5 was indirect, attacking M. aeruginosa cells by releasing algicidal compounds. Two algicidal compounds (S-5A and S-5B) produced by Bacillus sp. Lzh-5 were purified with ethyl acetate extraction, column chromatography, and high-performance liquid chromatography and identified as hexahydropyrrolo[1,2-a]pyrazine-1,4-dione and 3-isopropyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione based on liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, and nuclear magnetic resonance analyses. The active algicidal compounds S-5A (hexahydropyrrolo[1,2-a]pyrazine-1,4-dione) and S-5B (3-isopropyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione) displayed high levels of algicidal activity against M. aeruginosa 9110, with LD50 values of 5.7 and 19.4 ?g/ml, respectively. This is the first report of 3-isopropyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as an algicidal compound. Compounds S-5A and S-5B also induced obvious morphological changes in M. aeruginosa 9110. In cocultures of M. aeruginosa 9110 and Bacillus sp. Lzh-5, the cell density of Bacillus sp. Lzh-5 and the concentrations of S-5A and S-5B correlated positively with the algicidal activity. Our results indicate that strain Lzh-5 and its two algicidal compounds are potentially useful for controlling cyanobacterial blooms in Lake Taihu.
Qinghai-Tibetan Plateau of China is known to be the plague endemic region where marmot (Marmota himalayana) is the primary host. Human plague cases are relatively low incidence but high mortality, which presents unique surveillance and public health challenges, because early detection through surveillance may not always be feasible and infrequent clinical cases may be misdiagnosed.
Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3 × 10? cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed.
The objective of this study was to evaluate effects of different amino acid additives (phenylalanine (Phe), methionine (Met), lysine (Lys), arginine (Arg), aspartic acid (Asp) and glutamic acid (Glu)) on the physicochemical properties of potato starch gels. Charge-carrying amino acids (Lys, Arg, Asp and Glu) significantly decreased the swelling power, solubility, light transmittance, L(?) value and gel strength of potato starch, but increased syneresis during freeze-thaw treatment, while neutral amino acids (Phe and Met) did not cause modifications in starch gels. During heating, potato starch with fortified charge-carrying amino acids showed a lower peak G' (storage modulus), when compared with Phe and Met. Results showed that charge-carrying amino acids could modify physicochemical properties and improve the nutritional values of starch-based products.
Insulin sensitizing drugs such as pioglitazone are not uniformly treatment effective among individual type 2 diabetic patients. Here, the relationship of pioglitazone efficacy to single nucleotide polymorphisms (SNP) of the adiponectin gene, a critical gene directly regulated by the drug, was examined in a cohort of Chinese Han type 2 diabetic patients.
Adverse maternal outcomes and perinatal complications are closely associated with overt maternal hypothyroidism, but whether these complications occur in women with subclinical hypothyroidism (SCH) during pregnancy remains controversial. The aim of this study was to evaluate the effects of SCH on maternal and perinatal outcomes during pregnancy.
Hand, foot, and mouth disease (HFMD) affects more than one million children, is responsible for several hundred child deaths every year in China and is the cause of widespread concerns in society. Only a small fraction of HFMD cases will develop further into severe HFMD with neurologic complications. A timely and accurate diagnosis of severe HFMD is essential for assessing the risk of progression and planning the appropriate treatment. Human serum can reflect the physiological or pathological states, which is expected to be an excellent source of disease-specific biomarkers. In the present study, a comparative serological proteome analysis between severe HFMD patients and healthy controls was performed via a two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy. Fifteen proteins were identified as differentially expressed in the sera of the severe HFMD patients compared with the controls. The identified proteins were classified into different groups according to their molecular functions, biological processes, protein classes and physiological pathways by bioinformatics analysis. The up-regulations of two identified proteins, serum amyloid A (SAA) and clusterin (CLU), were confirmed in the sera of the HFMD patients by ELISA assay. This study not only increases our background knowledge about and scientific insight into the mechanisms of HFMD, but also reveals novel potential biomarkers for the clinical diagnosis of severe HFMD.
Although inflammatory bowel diseases (IBD) are emerging and increasing in China, epidemiologic data are rarely available. This study was to investigate the epidemiological and clinical characteristics of IBD in Northern China.
Previously, we found that the naturally occurring stilbene compound resveratrol (RES) could potentiate cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity. Because some wild-type CFTR activators also potentiate its mutant forms, we investigated effect of RES on the two most common forms of CF-related mutation (deltaF508 and G551D-CFTR). Cell-based fluorescence studies indicated that RES dose-dependently potentiated both deltaF508 and G551D mutant CFTR Cl- channel activities. Transepithelial Cl- currents were stimulated by RES in deltaF508 and G551D mutant CFTR-expressing FRT cells. Further excised inside-out patch-clamp measurements revealed that RES significantly induced the chloride current of deltaF508 and G551D mutant CFTRs by increasing the open time of the channels. In ex vivo studies, RES stimulated fluid secretion in mouse trachea by optical measurement of single gland secretion. These data suggested that RES is a potent deltaF508 and G551D mutant CFTR potentiator, and RES may present a novel class of therapeutic lead compounds in treating cystic fibrosis.
Here we present the results from an intercomparison of multiple global gridded crop models (GGCMs) within the framework of the Agricultural Model Intercomparison and Improvement Project and the Inter-Sectoral Impacts Model Intercomparison Project. Results indicate strong negative effects of climate change, especially at higher levels of warming and at low latitudes; models that include explicit nitrogen stress project more severe impacts. Across seven GGCMs, five global climate models, and four representative concentration pathways, model agreement on direction of yield changes is found in many major agricultural regions at both low and high latitudes; however, reducing uncertainty in sign of response in mid-latitude regions remains a challenge. Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies.
Human enterovirus 68 (HEV-68) is an enterovirus associated with respiratory illness. In China, no information about HEV-68 is available for children yet. This study aimed to investigate the presence of HEV-68 in mainland China during 2009 through 2012 and to explore the migration events of HEV-68 across the world. Among 1565 children samples tested, 41 (2.6%) were positive for HEV and 223 (14.3%) for human rhinovirus (HRV). Seven (17.1%) of 41 HEV were HEV-68. Two HEV-68 and five HRV positive samples were detected in 585 adults samples. HEV-68 is the predominant type of enteroviruses in children with ARTI (acute respiratory tract infectious), followed by HEV-71 and coxsackievirus A6. Three HEV-68 infected children presented with severe pneumonia and one presented with severe asthma attack. The viruses were attributed to two new distinct sub-lineages of HEV-68 based on phylogenetic analysis of partial VP1 gene sequences. Migration events analysis showed USA and Netherlands acted as possible geographic source of HEV-68, where three strains immigrate to China. In conclusion, HEV-68 could play a predominant role in the enteroviruses associated ARTI in children. Additional surveillance is needed to clarify the reason that HEV-68 causes such a wide spectrum of disease, from asymptomatic to severe respiratory disease and even death.
Soil pollution with herbicides is a global problem. Before phytoremediation technology is developed for the plant-based clean-up of polluted soils, investigation of potential plants that can be used to accumulate and degrade herbicides is a critical step. In this study, three selected genotypes of ryegrass were comprehensively analyzed with regard to the atrazine accumulation, degradation and toxicological response. Under the conditions of soil with 0.8 mg kg(-1) atrazine, the maximum value for atrazine accumulation was 2.70 mg kg(-1) in shoots and 0.58 mg kg(-1) in roots. The residue of atrazine in soil with ryegrass cultivation was much lower than that in soil without ryegrass cultivation. Also, the content of atrazine residues in the rhizosphere was significantly lower than that in the non-rhizosphere soil. Activities of several enzymes (urease, invertase, polyphenol oxidase, acid phosphatase and alkaline phosphatase) in soil were assayed. These enzymes were depressed by atrazine but activated by ryegrass cultivation, even in the presence of atrazine. Finally, comparative studies have been conducted on the ryegrass genotypes in response to atrazine. They showed different capacities of degradation and bioaccumulation of atrazine. One of the grass cultivars Changjiang II (CJ) had better growth and higher levels of chlorophyll, but displayed less oxidative injury than two others, Abode (AB) and Jiewei (JW), under atrazine exposure.
O-Desmethylvenlafaxine (desvenlafaxine, ODV) is a recently approved antidepressant which in some clinical studies failed to meet a satisfactory end-point. The aim of this study was to prepare a series of phenolic esters of ODV and evaluate their potential as ODV prodrugs with improved brain uptake. Fifteen phenolic esters (compounds 1a-o) were synthesized and their pharmacokinetic profiles evaluated in rat. The four compounds producing the highest relative bioavailability of ODV in rat (compounds 1c, 1e, 1n, 1o) were then studied to evaluate their brain uptake. Of these four compounds, compound 1n (the piperonylic acid ester of ODV) demonstrated the highest Cmax of ODV both in the rat hypothalamus and total brain. Finally the pharmacokinetics of 1n were evaluated in beagle dog where the increase in relative bioavailability of ODV was found to be as great as in rat. This high relative bioavailability of ODV coupled with its good brain penetration make 1n the most promising candidate for development as an ODV prodrug.
Abstract Background: CYP4A11 is a member of the cytochrome P450 enzymes and is responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in the regulation of blood pressure. This study aimed to evaluate whether or not the CYP4A11 gene polymorphism T8590C (rs1126742) is involved in essential hypertension in the western Chinese Han population. Methods: In a case-control study, the participants included 864 (523 males and 341 females) patients with essential hypertension and 661 (422 males and 239 females) healthy subjects. The T8590C polymorphism of the CYP4A11 gene was analyzed by using the TaqMan® SNP Genotyping Assay. Results: For men, the frequencies of the CC genotype and the C allele were higher in essential hypertension than in the control group (p?=?0.022 and p?=?0.016, respectively). After adjustment of confounding factor such as diabetes, smoking, BMI, TG and TC, the significant difference was observed in CC genotype (OR?=?1.897, 95% confidence interval [CI] 1.026-3.508; p?=?0.041). No difference was found in all participants and females. Conclusions: The CC genotype and C allele were associated with essential hypertension in the male western Chinese Han population.
The naturally occurring polyphenol compound resveratrol (RES) has been receiving wide attention because of its variety of health benefits and favourable biological activities. Previous studies have shown that RES could induce intestinal chloride secretion in mouse jejunum and stimulate cAMP-dependent Cl- secretion in T84, primary cultured murine nasal septal and human sinonasal epithelial cells, but the precise molecular target is not clear. We therefore tested the hypothesis that RES may stimulate the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Using cell-based fluorescent assays, transepithelial short-circuit current measurements and excised inside-out patch-clamp analysis; we found that RES dose-dependently potentiate CFTR Cl- channel activities, which was reversed by CFTR inhibitors CFTR(inh)-172 and GlyH101. Transepithelial Cl- secretion by CFTR-expressing FRT cells was stimulated by RES with half maximal concentration -80 microM. Intracellular cAMP content was not elevated by RES in FRT cells. Excised inside-out patch-clamp analysis indicated that RES significantly increased the chloride currents of CFTR. In ex vivo studies, RES stimulated the transmucosal chloride current of rat colon by short-circuit current assay. These data suggested that CFTR is a molecular target of RES. Our findings add a new molecular target to RES, and RES may represent a novel class of therapeutic lead compounds in treating CFTR-related diseases including CF and habitual constipation.
Magnolol, a small-molecule hydroxylated biphenol, isolated from the root and stem bark of Magnolia officinalis, has been shown to possess antiproliferative effect on various cancer cell lines. In the current study, we found that magnolol potently inhibited proliferation and induced apoptosis in MCF-7 human breast cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with cell cycle arrest at G2/M phase, increased generation of reactive oxygen species (ROS), reduced mitochondrial membrane potential (MMP), release of cytochrome c (Cyto c) and apoptosis inducing factor (AIF) from mitochondria to cytosol, upregulation of Bax, p21 and p53, and down-regulation of Bcl-2, cyclin B1 and cyclin-dependent kinase 1 (CDK1). Our findings indicated that magnolol induced apoptosis in MCF-7 cells via the intrinsic pathway with release of AIF from mitochondrial and G2/M phase arrest pathway. Therefore, magnolol might be a potential lead compound in the therapy of breast cancer.
Phenylethanolamine A (PA) is a new emerged ?-adrenergic agonist that has been illegally used as an animal feed additive for growth promotion in China. In this study, an immunoaffinity chromatography (IAC) column for selective extraction of PA from swine feed, meat and liver samples was developed. The IAC column was constructed by covalently coupling specific polyclonal antibody (Ab) against PA to CNBr-activated Sepharose 4B and packed into a common solid phase extraction (SPE) cartridge. The extraction conditions including loading, washing and eluting solutions were carefully optimized. Under optimal conditions, the IAC column was characterized in terms of maximum capacity, selectivity, extraction recovery and stability. The maximum capacity of the ICA for PA extraction was found to be 239.4ng. For selectivity testing, 100ng of other three ?-adrenergic agonists (clenbuterol, ractopamine and salbutamol) was separately loaded onto the column, and it was observed that the tested compounds could not be captured on the column, e.g. the column could only selectively recognize PA. The recovery of the IAC for PA extraction was found within 96.47-101.98% when 10, 50 and 100ng PA were separately loaded onto IAC column. The IAC column was also applied to real sample extraction. Swine feed, meat and liver samples were collected and spiked with PA in range of 1.0-20ngg(-1). The spiked and unspiked samples were extracted by IAC column and measured by high performance liquid chromatography (HPLC). It was found that there was no detectable PA in the blank samples, and the extraction recoveries of the IAC for PA from the spiked samples were within 89.48-104.89%. The stability of the column was also tested. It was showed that after 35 times repeated usage, 60% of the maximum capacity was still remained. The proposed IAC was proven to be a feasible extraction method for PA from different matrices with the properties of high maximum capacity, selectivity, extraction efficiency and stability.
Molecularly imprinted polymers (MIPs) are prepared on the surface of modified silica gel using prometryne as a template, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as a crosslinker, and 2,2-azobisisobutyronitrile as an initiator. The structure of the MIPs was characterized using SEM and FTIR spectroscopy. The selectivity of the MIPs for the template molecule prometryne was proven by adsorption experiments. Highly selective SPE cartridges of MIP particles were developed and an optimized prometryne procedure was developed for the enrichment and clean-up of prometryne residues in water, soil, and wheat samples. The concentrations of prometryne in the samples were analyzed by HPLC. The average recoveries of prometryne spiked for water at 0.05?0.8 mg/L were 101.47-106.65% and the RSD was 2.63-4.71%. The average recoveries of prometryne spiked for soil at 0.05?0.8 mg/L were 87.34-94.91% with the RSD being 2.77-8.41%. The average recoveries of prometryne spiked for wheat plant at 0.2?2.0 mg/kg were 91.04-97.76% with the RSD being 6.53-10.69%. The method developed here can be regenerated and repeatedly used more than two dozen times.
Individuals carrying mutations at both ataxia telangiectasia mutated (ATM) gene alleles reportedly have increased plasma cholesterol and triglyceride levels. Previous studies have demonstrated that defective ATM function promotes atherosclerosis. We previously demonstrated that ATM facilitates the clearance of plasma apolipoprotein (Apo)E-deficient, ApoB48-containing (E-/B48) lipoproteins in ApoE-deficient mice (ApoE-/- mice). However, to date there is no exact explanation available as to the mechanism(s) through which ATM is involved in the removal of E-/B48 lipoprotein in ApoE-/- mice. In this study, to our knowledge, we demonstrate for the first time that heterozygous ATM mutation reduces the hepatocyte uptake of E-/B48 lipoproteins in ApoE-/- mice; however, heterozygous ATM mutation did not affect hepatocyte binding to E-/B48 lipoproteins. Moreover, our results revealed that ATM proteins were localized in the nucleus, early endosomes and late endosomes, but not in the plasma membrane in the hepatocytes of ApoE-/- mice. In addition, following treatment with the ATM activator, chloroquine, and E-/B48 lipoproteins, ATM interacted with class III phosphatidylinositol-3-kinases (PI3Ks) and the activated ATM protein enhanced class III PI3K activity. Furthermore, treatment with a class III PI3K inhibitor (LY290042 and 3-MA) attenuated the intracellular total cholesterol accumulation induced by ATM activation. These results provide insight into the mechanisms behind the involvment of ATM in the process of endocytosis of E-/B48 lipoprotein in ApoE-/- mice, demonstrating the role of class III PI3K protein.
Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). In order to explore the molecular mechanism of ATO in leukemia cells with time series, we adopted bioinformatics strategy to analyze expression changing patterns and changes in transcription regulation modules of time series genes filtered from Gene Expression Omnibus database (GSE24946). We totally screened out 1847 time series genes for subsequent analysis. The KEGG (Kyoto encyclopedia of genes and genomes) pathways enrichment analysis of these genes showed that oxidative phosphorylation and ribosome were the top 2 significantly enriched pathways. STEM software was employed to compare changing patterns of gene expression with assigned 50 expression patterns. We screened out 7 significantly enriched patterns and 4 tendency charts of time series genes. The result of Gene Ontology showed that functions of times series genes mainly distributed in profiles 41, 40, 39 and 38. Seven genes with positive regulation of cell adhesion function were enriched in profile 40, and presented the same first increased model then decreased model as profile 40. The transcription module analysis showed that they mainly involved in oxidative phosphorylation pathway and ribosome pathway. Overall, our data summarized the gene expression changes in ATO treated K562-r cell lines with time and suggested that time series genes mainly regulated cell adhesive. Furthermore, our result may provide theoretical basis of molecular biology in treating acute promyelocytic leukemia.
A new method has been developed to determine heptachlor and its metabolites heptachlor-exo-epoxide and heptachlor-endo-epoxide in pork. The pork samples were extracted with acetone-n-hexane (2:8, V:V) and cleaned up by gel permeation chromatography and florisil solid-phase extraction cartridge. The extract was then determined by gas chromatography equipped with electron capture detector (GC-ECD), followed by validation using gas chromatography-mass spectrometry (GC-MS) with negative chemical ionization. Linearity of calibration curves ranged from 0.01 to 0.5 mg L(-1), with correlation coefficients of more than 0.9980 for GC-ECD and GC-MS, respectively. At spiked concentrations of 0.01, 0.05, and 0.1 mg kg(-1), the average recovery and relative standard deviation values were 87.1-102.2 and 4.0-11.3 %, respectively. The limit of quantification for each analyte was 0.01 mg kg(-1), which satisfied the current maximum residue limit permitted in pork. Our results showed that the method developed was successfully used to determine heptachlor and heptachlor epoxide residues in real pork samples.
Cytotoxic T lymphocyte?associated antigen 4 (CTLA?4) regulates T?cell activation and Th1/Th2 cytokine production and is involved in the immune response against Hepatitis B virus (HBV) infection. To detect the association of the CTLA?4 gene polymorphisms with susceptibility to HBV infection a hospital?based case?control study was conducted. A total of 1,119 unrelated individuals were recruited. The CTLA?4 variants rs5742909, rs231775 and rs3087243 were genotyped via the TaqMan method in this cohort. A comparison with a chronic active hepatitis B group revealed that the SNP rs231775 exhibited signi?cant susceptibility to HBV progression, with the highest odds ratio (OR) reaching 1.659 and P=0.009?0.049. Although an HBV clearance group was used as a control, results of the present study demonstrated an association of rs5742909 with viral persistence [OR=1.694, 95% confidence intervals (CI)=1.124?2.553 and P=0.012]. Subsequent analyses revealed risk haplotypes (C?A?A and T?A?G, for which the highest OR reached 1.865) compared with the protective haplotype C?G?G. Therefore, SNPs in the CTLA?4 gene may be associated with HBV progression and viral persistence which is consistent with its emerging role in the T regulatory cells in the pathogenesis of disease.
Dufulin is a newly developed antiviral agent (or pesticide) that activates systemic acquired resistance of plants. This pesticide is widely used in China to prevent abroad viral diseases in rice, tobacco and vegetables. In this study, the potential impacts such as soil type, moisture, temperature, and other factors on Dufulin degradation in soil were investigated. Degradation of Dufulin followed the first-order kinetics. The half-life values varied from 2.27 to 150.68 days. The dissipation of Dufulin was greatly affected by soil types, with DT50 (Degradation half time) varying between 17.59, 31.36, and 43.32 days for Eutric Gleysols, Cumulic Anthrosols, and Dystric Regosols, respectively. The elevated moisture accelerated the decay of Dufulin in soil. Degradation of Dufulin increased with temperature and its half-life values ranged from 16.66 to 42.79 days. Sterilization of soils and treatment with H2O2 resulted in a 6- and 8-fold decrease in degradation rates compared to the control, suggesting that Dufulin degradation was largely governed by microbial processes. Under different light spectra, the most effective degradation occurred with 100-W UV light (DT50?=?2.27 days), followed by 15-W UV light (DT50?=?8.32 days) and xenon light (DT50?=?14.26 days). Analysis by liquid chromatography-mass spectroscopy (LC-MS) revealed that 2-amino-4-methylbenzothiazole was one of the major decayed products of Dufulin in soils, suggesting that elimination of diethyl phosphate and 2-fluorobenzaldehyde was most like the degradation pathway of Dufulin in Eutric Gleysols.
Adhesion of cancer cell to endothelial cells and the subsequent trans-endothelial migration are key steps in hematogenous metastasis. However, the molecular mechanisms of cancer cell/endothelial cell interaction under hemodynamic shear flow and how shear flow-induced cancer cell mechanotransduction are yet to be fully defined. In this study, we identified that the integrins of both platelet glycoprotein IIb/IIIa (GP IIb/IIIa) and ?v?3 were crucial for hematogenous metastasis of human breast carcinoma MDA-MB-231cells. The cell migration and invasion were studied by using Millicell cell culture insert system. The numbers of invaded MDA-MB-231 cells significantly increased by thrombin-activated platelets and reduced by eptifibatide, a platelet inhibitor. Meanwhile, RGDWE peptides, a specific inhibitor of ?v?3 integrin, also inhibited MDA-MB-231 cell invasion. We further used a parallel-plate flow chamber to investigate MDA-MB-231 cell adhesion under flow conditions. Alike in static condition, the adhesion capability of MDA-MB-231 cells to endothelial monolayer was also significantly affected by GP IIb/IIIa and ?v?3 integrins. The expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and ?v?3 integrin in MDA-MB-231 cells were up-regulated after low shear stress exposure (1.84dynes/cm(2), 2h). Moreover, we also demonstrated that low shear stress induced a sustained activation of p85 (a regulatory subunit of PI3K) and Akt. Pre-treating MDA-MB-231 cells with the specific PI3K inhibitor of LY294002 abolished the shear stress induced-Akt activation, and the expression of MMP-2, MMP-9, vascular endothelial growth factor (VEGF) and ?v?3 integrin were also down-regulated. Immunofluorescence assay showed that low shear stress also induced ?v?3 integrin clustering and nuclear factor-?B (NF-?B) activation. Interestingly, shear stress-induced activation of Akt and NF-?B was attenuated by LM609, a specific antibody of ?v?3 integrin. It suggests that ?v?3 integrin might be as a mechanosensor to trigger both PI3K/Akt and NF-?B signaling pathways. Taken together, these results establish that GP IIb/IIIa and ?v?3 integrins are essential mediators, and provide insight into how shear stress-induced ?v?3 integrin activation and the downstream pathways for contribution to MDA-MB-231 cell adhesion, migration and invasion.
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