Synthesis and evaluation of non-dimeric HCV NS5A inhibitors

Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).     

Molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein

The MUC1 oncoprotein is known to be linked with different types of cancer. Therefore, it is of interest to document the molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein. We report the structure based molecular binding features compounds such as amrinone, ethambutol, pyrazinamide and vasicoline the MUC1 oncoprotein for further consideration in drug discovery.     

Meta-analysis identified the TNFA -308G > A promoter polymorphism as a risk factor for disease severity in patients with rheumatoid arthritis

Introduction

The goal of this study is to investigate whether the -308G > A promoter polymorphism in the tumor necrosis factor alpha (TNFA) gene is associated with disease severity and radiologic joint damage in a large cohort of patients with rheumatoid arthritis (RA).

Methods

A long-term observational early RA inception cohort (n = 208) with detailed information about disease activity and radiologic damage after 3, 6 and 9 years of disease was genotyped for the TNFA -308G > A promoter polymorphism (rs1800629). A longitudinal regression analysis was performed to assess the effect of genotype on RA disease severity and joint damage. Subsequently, a meta-analysis, including all publically available data, was performed to further test the association between joint erosions and the TNFA polymorphism. To learn more about the mechanism behind the effect of the polymorphism, RNA isolated from peripheral blood from RA patients (n = 66) was used for TNFA gene expression analysis by quantitative PCR.

Results

Longitudinal regression analysis with correction for gender and disease activity showed a significant difference in total joint damage between GG and GA+AA genotype groups (P = 0.002), which was stable over time. The meta-analysis, which included 2,053 patients, confirmed an association of the genetic variant with the development of erosions (odds ratio 0.78, 95% CI 0.62, 0.98). No significant differences in TNFA gene expression were observed for the different genotypes, confirming earlier findings in healthy individuals.

Conclusions

Our data confirm that the TNFA -308G > A promoter polymorphism is associated with joint damage in patients with RA. This is not mediated by differences in TNFA gene expression between genotypes.     

Simulation of stent deployment in a realistic human coronary artery

Background  

The process of restenosis after a stenting procedure is related to local biomechanical environment. Arterial wall stresses caused by the interaction of the stent with the vascular wall and possibly stress induced stent strut fracture are two important parameters. The knowledge of these parameters after stent deployment in a patient derived 3D reconstruction of a diseased coronary artery might give insights in the understanding of the process of restenosis.     

Switchgrass growth and pine–switchgrass interactions in established intercropping systems

Intercropping switchgrass (Panicum virgatum L.) with loblolly pine (Pinus taeda L.) has been proposed for producing bioenergy feedstock in the southeastern United States. This study investigated switchgrass growth and pine–switchgrass interactions at two established experimental fields (7‐year‐old Lenoir site and 5‐year‐old Carteret site) located on the coastal plain of eastern United States. Position effects (edge and center of switchgrass alley in intercropping plots) and treatment effects (intercropping vs. grass‐only) on aboveground switchgrass growth were evaluated. Interspecific interactions with respect to capturing resources (light, soil water, and nitrogen) were investigated by measuring photosynthetically active radiation (PAR) above grass canopy, soil moisture, and soil mineral nitrogen contents. Switchgrass growth was significantly (P = 0.001) affected by treatments in Lenoir and by position (P < 0.0001) in both study sites. Relative to the center, PAR above grass canopy at edge in both sites was about 48% less during the growing season. Soil water content during the growing season at the edge of grass alley was significantly (P = 0.0001) lower by 23% than at the center in Lenoir, while no significant (P = 0.42) difference was observed in Carteret, in spite of more grass growth at center at both sites. Soil mineral nitrogen content at the center of intercropping plots in Lenoir (no fertilization during 2015) was significantly (P < 0.07) lower than at the edge during the peak of growing season (June, July, and August), but not during early and late parts of growing season (May, September, and November). Position effects on soil water and mineral nitrogen were less evident under conditions with higher external inputs (rainfall and fertilization) and lower plant uptake during nongrowing seasons. Results from this study contributed to a better understanding of above‐ and belowground pine–switchgrass interactions which is necessary to properly manage this new cultivation system for bioenergy production in the southeastern United States.     

Influence of host developmental state on host suitability and reproductive biology of the parasitoid Eucelatoria bryani

Eucelatoria bryani Sabrosky (Diptera: Tachinidae) successfully parasitized 2nd through 5th instars and prepupal Heliothis zea (Boddie) (Lepidoptera: Noctuidae) in the laboratory. Percent successful parasitism (that which resulted in the production of adult parasitoid progeny) increased with host developmental state, reaching 95% in 5th instars, but fell to 63% in prepupae. While 25% of the exposed prepupae metamorphosed to pupae, none developed into adults. E. bryani maggots emerged from only 5% of H. zea pupae. The mean number of fly puparia and adults produced per successfully parasitized larva increased with host stadium, reaching 14.5±1.33 (SEM) and 10.6±1.02, respectively, in prepupae. The sex ratio of adult parasitoid progeny per host larval stadium was variable, and did not appear to follow a pattern. A formula for calculating a host favorability index is presented. This index allows a direct comparison of the overall impact and reproductive potential of E. bryani attacking hosts of varying developmental states.

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Résumé Les influences de l'état de développement de l'hôte sur le taux de parasitisme, la production de descendants, l'émergence des adultes et le taux sexuel de la techinaire E. bryani Sabrosky ont été examinés au laboratoire. Un parasitisme réussi,-qui entraîne la formation d'un parasitoïde adulte-, s'effectue dans les chenilles de stades 2 à 5 et dans les prénymphes d'Heliothis zea Boddie. II s'agit d'un élargissement considérable de la gamme connue des tailles convenables d'hôtes. Bien que le parasitisme n'ait jamais réussi avec les chenilles de premier stade, une très forte mortalité, 93% a été observée quand ces petites chenilles ont été exposées à la tachinaire. Pour permettre l'introduction par le larvipositeur des asticots dans la chenille, la mouche perfore la cuticule de l'hôte avec un sclérite modifié; ainsi, une grande partie de la mortalité est provoquée vraisemblablement par le traumatisme dû au parasitoïde. Le succès du parasitisme a augmenté en fonction du développement de l'hôte du second stade (30%) au cinquième stade (95%), pour tomber à 63% dans les prénymphes. Cependant, aucune des prénymphes exposées aux mouches n'a été capable de donner des papillons.Les production moyennes de pupes et de mouches par chenille effectivement parasitée ont augmenté avec le stade de développement de l'hôte pouratteindre dans les prénymphes respectivement 14,5±1,33 et 10,6±1,02. Le taux sexuel des mouches obtenues a été très variable pour les différents stades de développement des chenilles, sans qu'aucune corrélation ait pu être mise en évidence. Une formule permettant de calculer un indice d'adéquation de l'hôte est proposé. Cet indice permet une comparaison directe des impacts globaux et des potentiels reproducteurs des femelles de E. bryani attaquant des hôtes à différents stades.

     

Trehalose Increases Freeze-Thaw Damage in Liposomes Containing Chloroplast Glycolipids

Chloroplast thylakoids contain three classes of glycolipids, monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and sulfoquinovosyldiacylglycerol (SQDG). We have investigated the stability of large unilamellar vesicles made from egg phosphatidylcholine (EPC) and different chloroplast glycolipids during freezing to -18 degreesC, as a function of the presence of three sugars: glucose, sucrose, or trehalose. Contrary to the situation in thylakoids, where cryoprotection increases from glucose < sucrose < trehalose, liposomes containing 50% DGDG showed the opposite behavior. In fact, carboxyfluorescein leakage increased over the control values (freezing in the absence of sugar) in the presence of trehalose. This effect was not seen in vesicles made from pure EPC, or a mixture of EPC and MGDG, or EPC and SQDG. Liposomes made from mixtures of all three glycolipids, however, showed even more leakage in the presence of trehalose than liposomes containing only DGDG and EPC. Copyright 1998 Academic Press.     

Organophosphate toxicity in wild turkeys

An accidental poisoning of wild turkeys (Meleagris gallopavo silvestris) by O,O-Diethyl O-[p-(methylsulfinyl) phenyl] phosphorothioate is reported. Diagnosis was achieved by history, clinical observations, postmortem lesions, diagnostic therapy and pesticide analysis.     

Effect of artificial diet media, glucose, protein hydrolyzates, and other factors on oviposition in wax eggs by Trichogramma pretiosum

Artificial diet media were clearly inferior to dilute KCl-MgSO₄ solutions as ovipositional stimulants for Trichogramma pretiosum. Depending on their concentrations, glucose, protein hydrolyzates, and free amino acids either had no effect on or were inhibitors of oviposition when they were mixed with KCl-MgSO₄ solutions. Oviposition into artificial eggs containing salt solutions formulated to correspond to the concentration of potassium, magnesium, and sodium in insect components revealed that the hemolymph mimic and the mimic of Sitotroga cerealella eggs were poor, and that the mimic of whole Heliothis spp. larvae, which was similar to the concentration of these cations in Heliothis virescens eggs, was the most active in eliciting oviposition.

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Effet du substrat alimentaire artificiel du glucose, des hydrolysats de protéine et autres facteurs sur la ponte de Trichogramma pretiosum dans des oeufs en paraffine

Résumé La ponte de T. pretiosum Riley dans des milieux de culture contenant des concentrations de K⁺-Mg²⁺ correspondant à celle de l'hémolymphe d'insecte ou à celle des oeufs d'Heliothis virescens Fabricius était nettement inférieure à celle obtenue dans des solutions diluées de KCl, MgSO₄.La ponte dans des solutions de KCl-MgSO₄ était fortement inhibée par le glucose ou par l'hydrolisat de caséine à 2,5%. Le glucose et les hydrolysats de protéine et de levure à 1,3% ou à des concentrations inférieures n'ont pas stimulé la ponte. Des solutions aqueuses (sans KCl-MgSO₄) soit de glucose et d'hydrolysat de caséine, soit d'acides aminés libres ont été des stimulants de ponte extrêmement faibles. Quand des solutions de KCl, MgSO₄ et NaCl sont dosées en fonction des résultats d'analyses élémentaires des constituants de l'insecte, la ponte était très faible dans des oeufs artificiels contenant des solutions correspondant aux concentrations en K, Mg et Na, soit de l'hémolymphe d'Heliothis zea, soit des oeufs de Sitotroga cerealella. La ponte était beaucoup plus élevée dans des solutions correspondant aux analyses du dernier stade larvaire d'Heliothis spp. Par suite de l'activité de ponte plus élevée, du coût beaucoup plus faible et du niveau inférieur en éléments nutritifs disponibles pour entretenir la croissance microbienne, les solutions diluées de KCl-MgSO₄ peuvent être supérieures aux régimes artificiels et à l'hémolymphe pour la récolte d'oeufs de Trichogrammes à utiliser dans des régimes artificiels.