The aryl hydrocarbon receptor (AhR) is commonly described as a transcription factor, which regulates xenobiotic-metabolizing enzymes. Recent studies have suggested that the binding of ligands to the ...AhR also activates the Src kinase. In this manuscript, we show that the AhR, through the activation of Src, activates focal adhesion kinase (FAK) and promotes integrin clustering. These effects contribute to cell migration. Further, we show that the activation of the AhR increases the interaction of FAK with the metastatic marker, HEF1/NEDD9/CAS-L, and the expression of several integrins. Xenobiotic exposure, thus, may contribute to novel cell-migratory programs.
Aryl hydrocarbon receptor (AhR), or dioxin receptor, is a transcription factor that induces adaptive metabolic pathways in response to environmental pollutants. Recently, other pathways were found to ...be altered by AhR and its ligands. Indeed, developmental defects elicited by AhR ligands suggest that additional cellular functions may be targeted by this receptor, including cell migration and plasticity. Here, we show that dioxin-mediated activation of Ahr induces Nedd9/Hef1/Cas-L, a member of the Cas protein family recently identified as a metastasis marker. The Hef1 gene induction is mediated by two xenobiotic responsive elements present in this gene promoter. Moreover, using RNA interference, we show that Nedd9/Hef1/Cas-L mediates the dioxin-elicited changes related to cell plasticity, including alterations of cellular adhesion and shape, cytoskeleton reorganization, and increased cell migration. Furthermore, we show that both E-cadherin repression and Jun N-terminal kinases activation by dioxin and AhR also depend on the expression of Nedd9/Hef1/Cas-L. Our study unveils, for the first time, a link between pollutants exposure and the induced expression of a metastasis marker and shows that cellular migration and plasticity markers are regulated by AhR and its toxic ligands.
UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of substrates, and they derivatize ...xenobiotics and metabolites for detoxification. However, most UGT homologs have not been well characterized, and their potential for biomedical and environmental applications is underexplored. In this work, we have used a fluorescent assay for screening substrates of a plant UGT homolog by monitoring the formation of UDP. We optimized the assay such that it could be used for high-throughput screening of substrates of the
UGT enzyme, UGT71G1, and our results show that 34 of the 159 screened compound samples are potential substrates. With an LC-MS/MS method, we confirmed that three of these candidates indeed were glycosylated by UGT71G1, which includes bisphenol A (BPA) and 7-Ethyl-10-hydroxycamptothecin (SN-38); derivatization of these toxic compounds can lead to new environmental and medical applications. This work suggests that UGT homologs may recognize a substrate profile that is much broader than previously anticipated. Additionally, it demonstrates that this screening method provides a new means to study UDP-glycosyltransferases, facilitating the use of these enzymes to tackle a wide range of problems.
► Residual rice husk ash (RHA) from South Vietnam as a pozzolanic material.
► The non-ground RHA can be applied as a pozzolanic material.
► Compressive strength of cylindrical concrete in the 47–66
...MPa range was obtained.
► Without adversely affecting the properties of concrete up to 20% of RHA replacement.
This work investigates the effects of adding residual rice husk ash (RHA) from South Vietnam, generated when burning rice husk pellets in the boiler, to cement. To improve pozzolanic reactivity, RHA was ground for 1
h. The non-ground RHA and ground RHA were used to test strength activity index according to ASTM C311. The properties of the concrete were investigated, including compressive strength, concrete electrical resistivity, and ultrasonic pulse velocity. Results show that the non-ground RHA can be applied as a pozzolanic material. Decreasing the non-ground RHA average particle size provides a positive effect on the compressive strength of mortar. Compressive strength of cylindrical concrete in the 47–66
MPa range was obtained in this study. The results also indicate that up to 20% of ground RHA could be advantageously blended with cement without adversely affecting the strength and durability properties of concrete.
Cystathionine beta synthase (
CBS
) is one of the 225 genes on chromosome 21 (HSA 21) that are triplicated in persons with trisomy 21 (Down syndrome). Although most triplicate HSA21 genes have their ...orthologous genes on murine chromosome 16, the murine ortholog of
hCBS
is on murine chromosome 17 and thus is not present in the well-studied Ts65Dn mouse model of trisomy 21. Persons with trisomy 21 (T21) present deficits in neurotransmission and exhibit early brain aging that can partially be explained by monoamine neurotransmitter alterations. We used transgenic mice for the
hCBS
gene, which overexpress the CBS protein in various brain regions, to study if CBS overexpression induces modifications in the monoamine neurotransmitters in the hypothalamus, thalamus, hippocampus, and striatum from transgenic and control female and male mice aged 3–4 months and 11–12 months. Sex, age, and brain area each influenced neurotransmitter levels. Briefly, the serotonin pathway was modified by CBS overexpression in various brain areas in female mice but not in male mice. The dopamine pathway was modified in brain regions according to sex and age. These results may allow us to better understand the role of the transsulfuration pathway and especially CBS overexpression in the metabolism of biogenic amines and the catecholamine catabolism in persons with trisomy 21.
Aim To compare the impact of covered stent-graft transjugular intrahepatic portosystemic shunt (TIPS) versus serial paracentesis on survival of patients with medically refractory ascites. Materials ...and methods In this retrospective study, cirrhotic patients who underwent covered stent-graft TIPS for refractory ascites from 2003–2013 were compared with similar patients who underwent serial paracentesis during 2009–2013. Demographic and liver disease data, Model for End-Stage Liver Disease (MELD) scores, and survival outcomes were obtained from hospital electronic medical records and the social security death index. After propensity score weighting to match study group characteristics, survival outcomes were compared using Kaplan–Meier statistics with log-rank analysis. Results Seventy TIPS (70% men, mean age 55.7 years, mean MELD 15.1) and 80 paracentesis (58% men, mean age 53.5 years, mean MELD 22.5) patients were compared. The TIPS haemodynamic success rate was 100% (mean portosystemic pressure gradient reduction 13 mmHg). Paracentesis patients underwent a mean of 7.9 procedures. After propensity score weighting to balance group features, TIPS patients showed a trend toward enhanced survival compared with paracentesis patients (median survival 1037 versus 262 days, p = 0.074). TIPS conferred a significant increase or trend toward improved survival compared with paracentesis at 1 (66% versus 44%, p = 0.018), 2 (56% versus 38%, p = 0.057), and 3 year (49% versus 32%, p = 0.077) time points. Thirty and 90 day mortality rates were not statistically increased by TIPS. Conclusion Covered stent-graft TIPS improves intermediate- to long-term survival without significantly increasing short-term mortality of ascites patients, and suggests a greater potential role for TIPS in properly selected ascitic patients when medical management fails.
To describe the use of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark, Sweden, and the United Kingdom (UK).
We identified new users of darifenacin, fesoterodine, oxybutynin, ...solifenacin, tolterodine, and trospium aged 18 years or older from the Danish National Registers (2004-2012), the Swedish National Registers (2006-2012), and UK Clinical Practice Research Datalink (2004-2012). Users were followed until disenrollment, cancer diagnosis, death, or study end. Treatment episodes, identified by linking consecutive prescriptions, were described with respect to duration, drug switch, and drug add-on.
Mean age of OAB drug users was 66 years in Denmark (n = 72,917) and Sweden (n = 130,944), and 62 years in the UK (n = 119,912); 60% of Danish and Swedish patients and 70% of UK patients were female. In Denmark, of 224,680 treatment episodes, 39% were with solifenacin, and 35% with tolterodine; 2% were with oxybutynin. In Sweden, of 240,141 therapy episodes, 37% were with tolterodine and 35% with solifenacin; 5% were with oxybutynin. In the UK, of 245,800 treatment episodes, 28% were with oxybutynin, 27% with solifenacin, and 26% with tolterodine. In the three countries, 49%-52% of treatment episodes comprised one prescription and over 80% of episodes ended because of no refill; less than 20% ended because of a switch to another antimuscarinic. During the study years, we observed a change in OAB treatment preference from tolterodine to solifenacin.
In these cohorts, persistence with antimuscarinic drugs was low. By 2012, the preferred drug was solifenacin; oxybutynin use was marginal in Nordic countries compared with the UK.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highly pathogenic avian influenza virus H5N1 is endemic in poultry in East and Southeast Asia with disease outbreaks recently spreading to parts of central Asia, Europe and Africa. Continued ...interspecies transmission to humans has been reported in Vietnam, Thailand, Cambodia, Indonesia and China, causing pandemic concern. Here, we genetically characterize 82 H5N1 viruses isolated from poultry throughout Indonesia and Vietnam and 11 human isolates from southern Vietnam together with sequence data available in public databases to address questions relevant to virus introduction, endemicity and evolution. Phylogenetic analysis shows that all viruses from Indonesia form a distinct sublineage of H5N1 genotype
Z viruses suggesting this outbreak likely originated from a single introduction that spread throughout the country during the past two years. Continued virus activities in Indonesia were attributed to transmission via poultry movement within the country rather than through repeated introductions by bird migration. Within Indonesia and Vietnam, H5N1 viruses have evolved over time into geographically distinct groups within each country. Molecular analysis of the H5N1 genotype
Z genome shows that only the M2 and PB1-F2 genes were under positive selection, suggesting that these genes might be involved in adaptation of this virus to new hosts following interspecies transmission. At the amino acid level 12 residues were under positive selection in those genotype
Z viruses, in the HA and PB1-F2 proteins. Some of these residues were more frequently observed in human isolates than in avian isolates and are related to viral antigenicity and receptor binding. Our study provides insight into the ongoing evolution of H5N1 influenza viruses that are transmitting in diverse avian species and at the interface between avian and human hosts.
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