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101.
Zhongli Gao William J. Hurst Etienne Guillot Werngard Czechtizky Ulrike Lukasczyk Raisa Nagorny Marie-Pierre Pruniaux Lothar Schwink Juan Antonio Sanchez Siegfried Stengelin Lei Tang Irvin Winkler James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(11):3416-3420
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. 相似文献
102.
103.
Cécile Echalier Soultan Al-Halifa Aude Kreiter Christine Enjalbal Pierre Sanchez Luisa Ronga Karine Puget Pascal Verdié Muriel Amblard Jean Martinez Gilles Subra 《Amino acids》2013,45(6):1395-1403
Despite correct purity of crude peptides prepared on trityl resin by Fmoc/tBu microwave assisted solid phase peptide synthesis, surprisingly, lower yields than those expected were obtained while preparing C-terminal acid peptides. This could be explained by cyclization/cleavage through diketopiperazine formation during the second amino acid deprotection and third amino acid coupling. However, we provide here evidence that this is not the case and that this yield loss was due to high temperature promoted hydrolysis of the 2-chlorotrityl ester, yielding premature cleavage of the C-terminal acid peptides. 相似文献
104.
Manon Ruffin Mélanie Voland Solenne Marie Monique Bonora Elise Blanchard Sabine Blouquit-Laye Emmanuel Naline Philippe Puyo Philippe Le Rouzic Loic Guillot Harriet Corvol Annick Clement Olivier Tabary 《生物化学与生物物理学报:疾病的分子基础》2013,1832(12):2340-2351
Cystic fibrosis (CF) airway epithelium is constantly subjected to injury events due to chronic infection and inflammation. Moreover, abnormalities in CF airway epithelium repair have been described and contribute to the lung function decline seen in CF patients. In the last past years, it has been proposed that anoctamin 1 (ANO1), a Ca2 +-activated Cl? channel, might offset the CFTR deficiency but this protein has not been characterized in CF airways. Interestingly, recent evidence indicates a role for ANO1 in cell proliferation and tumor growth. Our aims were to study non-CF and CF bronchial epithelial repair and to determine whether ANO1 is involved in airway epithelial repair. Here, we showed, with human bronchial epithelial cell lines and primary cells, that both cell proliferation and migration during epithelial repair are delayed in CF compared to non-CF cells. We then demonstrated that ANO1 Cl? channel activity was significantly decreased in CF versus non-CF cells. To explain this decreased Cl? channel activity in CF context, we compared ANO1 expression in non-CF vs. CF bronchial epithelial cell lines and primary cells, in lung explants from wild-type vs. F508del mice and non-CF vs. CF patients. In all these models, ANO1 expression was markedly lower in CF compared to non-CF. Finally, we established that ANO1 inhibition or overexpression was associated respectively with decreases and increases in cell proliferation and migration. In summary, our study demonstrates involvement of ANO1 decreased activity and expression in abnormal CF airway epithelial repair and suggests that ANO1 correction may improve this process. 相似文献
105.
Omatoyo K Dalrymple Trina Halfhide Innocent Udom Benjamin Gilles John Wolan Qiong Zhang Sarina Ergas 《Aquatic biosystems》2013,9(1):1-11
Microalgae feedstock production can be integrated with wastewater and industrial sources of carbon dioxide. This study reviews the literature on algae grown on wastewater and includes a preliminary analysis of algal production based on anaerobic digestion sludge centrate from the Howard F. Curren Advanced Wastewater Treatment Plant (HFC AWTP) in Tampa, Florida and secondary effluent from the City of Lakeland wastewater treatment facilities in Lakeland, Florida. It was demonstrated that a mixed culture of wild algae species could successfully be grown on wastewater nutrients and potentially scaled to commercial production. Algae have demonstrated the ability to naturally colonize low-nutrient effluent water in a wetland treatment system utilized by the City of Lakeland. The results from these experiments show that the algae grown in high strength wastewater from the HFC AWTP are light-limited when cultivated indoor since more than 50% of the outdoor illumination is attenuated in the greenhouse. An analysis was performed to determine the mass of algae that can be supported by the wastewater nutrients (mainly nitrogen and phosphorous) available from the two Florida cities. The study was guided by the growth and productivity data obtained for algal growth in the photobioreactors in operation at the University of South Florida. In the analysis, nutrients and light are assumed to be limited, while CO2 is abundantly available. There is some limitation on land, especially since the HFC AWTP is located at the Port of Tampa. The temperature range in Tampa is assumed to be suitable for algal growth year round. Assuming that the numerous technical challenges to achieving commercial-scale algal production can be met, the results presented suggest that an excess of 71 metric tons per hectare per year of algal biomass can be produced. Two energy production options were considered; liquid biofuels from feedstock with high lipid content, and biogas generation from anaerobic digestion of algae biomass. The total potential oil volume was determined to be approximately 337,500 gallons per year, which may result in the annual production of 270,000 gallons of biodiesel when 80% conversion efficiency is assumed. This production level would be able to sustain approximately 450 cars per year on average. Potential biogas production was estimated to be above 415,000 kg/yr, the equivalent of powering close to 500 homes for a year. 相似文献
106.
107.
Nicolas Guillot Dmitrij Kollins Juan J. Badimon Detlef Schlondorff Randolph Hutter 《PloS one》2013,8(3)
Background
Intimal injury rapidly activates TGFβ and enhances vascular repair by the growth of endothelial (EC) and vascular smooth muscle cells (VSMC). The response to the TGFβ family of growth factors can be modified by BAMBI (BMP, Activin, Membrane Bound Inhibitor) acting as a non-signaling, competitive antagonist of TGFβ type I receptors such as ALK 1 and 5. In vivo the effect of BAMBI will depend on its cell-specific expression and of that of the ALK type receptors. We recently reported EC restricted BAMBI expression and genetic elimination of BAMBI resulting in an in vitro and in vivo phenotype characterized by endothelial activation and proliferation involving alternative pathway activation by TGFβ through ALK 1.Methodology/Principal Findings
To test the hypothesis that BAMBI modulates arterial response to injury via its effects on endothelial repair and arterial wall neovascularization we used a model of femoral arterial denudation injury in wild type (WT) and BAMBI−/− mice. Arterial response was evaluated at 2 and 4 weeks after luminal endothelial denudation of femoral arteries. The BAMBI−/− genotype mice showed accelerated luminal endothelial repair at 2 weeks and a highly unusual increase in arterial wall neovascularization compared to WT mice. The exuberant intimal and medial neovessel formation with BAMBI−/− genotype was also associated with significant red blood cell extravasation. The bleeding into the neointima at 2 weeks transiently increased it’s area in the BAMBI−/−genotype despite the faster luminal endothelial repair in this group. Vascular smooth muscle cells were decreased at 2 weeks in BAMBI−/− mice, but comparable to wild type at 4 weeks.Conclusions/Significance
The absence of BAMBI results in a highly unusual surge in arterial wall neovascularization that surprisingly mimiks features of intra-plaque hemorrhage of advanced atheroma in a mechanical injury model. This suggests important effects of BAMBI on arterial EC homeostasis that need to be further studied in a model of inflammatory atherosclerosis. 相似文献108.
Emmanuelle Génin Baptiste Coustet Yannick Allanore Ikue Ito Maria Teruel Arnaud Constantin Thierry Schaeverbeke Adeline Ruyssen-Witrand Shigeto Tohma Alain Cantagrel Olivier Vittecoq Thomas Barnetche Xavier Le Lo?t Patrice Fardellone Hiroshi Furukawa Olivier Meyer Benjamin Fernández-Gutiérrez Alejandro Balsa Miguel A. González-Gay Gilles Chiocchia Naoyuki Tsuchiya Javier Martin Philippe Dieudé 《PloS one》2013,8(4)
Background
BANK1 and BLK belong to the pleiotropic autoimmune genes; recently, epistasis between BANK1 and BLK was detected in systemic lupus erythematosus. Although BLK has been reproducibly identified as a risk factor in rheumatoid arthritis (RA), reports are conflicting about the contribution of BANK1 to RA susceptibility. To ascertain the real impact of BANK1 on RA genetic susceptibility, we performed a large meta-analysis including our original data and tested for an epistatic interaction between BANK1 and BLK in RA susceptibility.Patients and Methods
We investigated data for 1,915 RA patients and 1,915 ethnically matched healthy controls genotyped for BANK1 rs10516487 and rs3733197 and BLK rs13277113. The association of each SNP and RA was tested by logistic regression. Multivariate analysis was then used with an interaction term to test for an epistatic interaction between the SNPs in the 2 genes.Results
None of the SNPs tested individually was significantly associated with RA in the genotyped samples. However, we detected an epistatic interaction between BANK1 rs3733197 and BLK rs13277113 (Pinteraction = 0.037). In individuals carrying the BLK rs13277113 GG genotype, presence of the BANK1 rs3733197 G allele increased the risk of RA (odds ratio 1.21 [95% confidence interval 1.04–1.41], P = 0.015. Combining our results with those of all other studies in a large trans-ethnic meta-analysis revealed an association of the BANK1 rs3733197 G allele and RA (1.11 [1.02–1.21], P = 0.012).Conclusion
This study confirms BANK1 as an RA susceptibility gene and for the first time provides evidence for epistasis between BANK1 and BLK in RA. Our results illustrate the concept of pleiotropic epistatic interaction, suggesting that BANK1 and BLK might play a role in RA pathogenesis. 相似文献109.
Miguel Angel Luque-Fernandez Gilles Van Cutsem Eric Goemaere Katherine Hilderbrand Michael Schomaker Nompumelelo Mantangana Shaheed Mathee Vuyiseka Dubula Nathan Ford Miguel A. Hernán Andrew Boulle 《PloS one》2013,8(2)
Background
Innovative models of care are required to cope with the ever-increasing number of patients on antiretroviral therapy in the most affected countries. This study, in Khayelitsha, South Africa, evaluates the effectiveness of a group-based model of care run predominantly by non-clinical staff in retaining patients in care and maintaining adherence.Methods and Findings
Participation in “adherence clubs” was offered to adults who had been on ART for at least 18 months, had a current CD4 count >200 cells/ml and were virologically suppressed. Embedded in an ongoing cohort study, we compared loss to care and virologic rebound in patients receiving the intervention with patients attending routine nurse-led care from November 2007 to February 2011. We used inverse probability weighting to estimate the intention-to-treat effect of adherence club participation, adjusted for measured baseline and time-varying confounders. The principal outcome was the combination of death or loss to follow-up. The secondary outcome was virologic rebound in patients who were virologically suppressed at study entry. Of 2829 patients on ART for >18 months with a CD4 count above 200 cells/µl, 502 accepted club participation. At the end of the study, 97% of club patients remained in care compared with 85% of other patients. In adjusted analyses club participation reduced loss-to-care by 57% (hazard ratio [HR] 0.43, 95% CI = 0.21–0.91) and virologic rebound in patients who were initially suppressed by 67% (HR 0.33, 95% CI = 0.16–0.67).Discussion
Patient adherence groups were found to be an effective model for improving retention and documented virologic suppression for stable patients in long term ART care. Out-of-clinic group-based models facilitated by non-clinical staff are a promising approach to assist in the long-term management of people on ART in high burden low or middle-income settings. 相似文献110.
Two cyprinid species, Parachondrostoma toxostoma, an endemic threatened species, and Chondrostoma nasus, an invasive species, live in sympatry in southern France and form two sympatric zones where the presence of intergeneric hybrids is reported. To estimate the potential threat to endemic species linked to the introduction of invasive species, we focused on the DAB genes (functional MHC IIB genes) because of their adaptive significance and role in parasite resistance. More specifically, we investigated (1) the variability of MHC IIB genes, (2) the selection pattern shaping MHC polymorphism, and (3) the extent to which trans-species evolution and intergeneric hybridization affect MHC polymorphism.In sympatric areas, the native species has more diversified MHC IIB genes when compared to the invasive species, probably resulting from the different origins and dispersal of both species. A similar level of MHC polymorphism was found at population level in both species, suggesting similar mechanisms generating MHC diversity. In contrast, a higher number of DAB-like alleles per specimen were found in invasive species. Invasive species tended to express the alleles of two DAB lineages, whilst native species tended to express the alleles of only the DAB3 lineage. Hybrids have a pattern of MHC expression intermediate between both species. Whilst positive selection acting on peptide binding sites (PBS) was demonstrated in both species, a slightly higher number of positively selected sites were identified in C. nasus, which could result from parasite-mediated selection. Bayesian clustering analysis revealed a similar pattern of structuring for the genetic variation when using microsatellites or the MHC approach. We confirmed the importance of trans-species evolution for MHC polymorphism. In addition, we demonstrated bidirectional gene flow for MHC IIB genes in sympatric areas. The positive significant correlation between MHC and microsatellites suggests that demographic factors may contribute to MHC variation on a short time scale. 相似文献