Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a–3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R₁ are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R₁, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.     

Synthesis,antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

Novel 1-(1-aryl-4,5dihydro-1H-imidazoline)-3-chlorosulfonylourea derivatives 3a–3f were synthesized in the reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with chlorosulfonyl isocyanate. The second series of compounds 4a–4f was prepared from the respective 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorsulfonylureas 3a–3f and 1,1′-carbonyldiimidazole (CDI). The selected compounds were tested for their activity against Herpes simplex virus and coxsackievirus B3 (CVB3). It was determined that three derivatives, i.e 3d, 4a and 4d are active against Herpes simplex virus (HSV-1). Compounds 3d and 4c are active against CVB3. Their favorable activity can be primarily attributed to their low lipophilicity values. Moreover, the lack of substituent in the phenyl moiety or 4-methoxy substitution can be considered as the most beneficial for the antiviral activity.     

“Reversed” intraguild predation: red fox cubs killed by pine marten

Camera traps deployed at a badger Meles meles set in mixed pine forest in north-eastern Poland recorded interspecific killing of red fox Vulpes vulpes cubs by pine marten Martes martes. The vixen and her cubs settled in the set at the beginning of May 2013, and it was abandoned by the badgers shortly afterwards. Five fox cubs were recorded playing in front of the den each night. Ten days after the first recording of the foxes, a pine marten was filmed at the set; it arrived in the morning, made a reconnaissance and returned at night when the vixen was away from the set. The pine marten entered the den several times and killed at least two fox cubs. It was active at the set for about 2 h. This observation proves that red foxes are not completely safe from predation by smaller carnivores, even those considered to be subordinate species in interspecific competition.     

Glucocorticoids Recruit Tgfbr3 and Smad1 to Shift Transforming Growth Factor-β Signaling from the Tgfbr1/Smad2/3 Axis to the Acvrl1/Smad1 Axis in Lung Fibroblasts

Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.     

Fragmentation pathways of acylated flavonoid diglucuronides from leaves of Medicago truncatula

Introduction – Flavonoids are important plant compounds occurring in tissues mostly in the form of glycoconjugates. Most frequently the sugar moiety is comprised of mono‐ or oligosaccharides consisting of common sugars like glucose, rhamnose or galactose. In some plant species the glycosidic moiety contains glucuronic acid and may be acylated by phenylpropenoic acids. Methodology – Flavonoid glyconjugates were extracted from leaves of Medicago truncatula ecotype R108 and submitted to analysis using high‐performance liquid chromatography combined with high‐resolution tandem (quadrupole‐time of flight, QToF) mass spectrometry. Results – The studied leaf extracts contained 26 different flavonoid glycosides among which 22 compounds were flavone (apigenin, luteolin, chrysoeriol and tricin) glucuronides and 13 were acylated with aromatic acids (p‐coumaric, ferulic or sinapic). The fragmentation pathways observed in positive and negative ion mass spectra differed substantially between each other and from these of flavonoid glycosides which did not contain acidic sugars. The application of high‐resolution MS techniques allowed unequivocal differentiation between ions with the same nominal m/z values containing different substituents (e.g. ferulic acid or glucuronic acid). Eleven of the identified flavonoids have not been reported previously in this species. Perspectives – The presented unique fragmentation pathways of flavonoid glucuronates enable detection of these compounds in tissue extracts from different plant species. Copyright © 2009 John Wiley & Sons, Ltd.     

Temporally stable genetic variability and dynamic kinship structure in a fluctuating population of the root vole Microtus oeconomus

Genetic variability, kin structure and demography of a population are mutually dependent. Population genetic theory predicts that under demographically stable conditions, neutral genetic variability reaches equilibrium between gene flow and drift. However, density fluctuations and non‐random mating, resulting e.g. from kin clustering, may lead to changes in genetic composition over time. Theoretical models also predict that changes in kin structure may affect aggression level and recruitment, leading to density fluctuations. These predictions have been rarely tested in natural populations. The aim of this study was to analyse changes in genetic variability and kin structure in a local population of the root vole (Microtus oeconomus) that underwent a fourfold change in mean density over a 6‐year period. Intensive live‐trapping resulted in sampling 88% of individuals present in the study area, as estimated from mark–recapture data. Based on 642 individual genotypes at 20 microsatellite loci, we compared genetic variability and kin structure of this population between consecutive years. We found that immigration was negatively correlated with density, while the number of kin groups was positively correlated with density. This is consistent with theoretical predictions that changes in kin structure play an important role in population fluctuations. Despite the changes in density and kin structure, there was no genetic differentiation between years. Population‐level genetic diversity measures did not significantly vary in time and remained relatively high (H_E range: 0.72–0.78). These results show that a population that undergoes significant demographic and social changes may maintain high genetic variability and stable genetic composition.     

Inbreeding depresses sperm competitiveness,but not fertilization or mating success in male Tribolium castaneum

As populations decline to levels where reproduction among close genetic relatives becomes more probable, subsequent increases in homozygous recessive deleterious expression and/or loss of heterozygote advantage can lead to inbreeding depression. Here, we measure how inbreeding across replicate lines of the flour beetle Tribolium castaneum impacts on male reproductive fitness in the absence or presence of male–male competition. Effects on male evolution from mating pattern were removed by enforcing monogamous mating throughout. After inbreeding across eight generations, we found that male fertility in the absence of competition was unaffected. However, we found significant inbreeding depression of sperm competitiveness: non-inbred males won 57 per cent of fertilizations in competition, while inbred equivalents only sired 42 per cent. We also found that the P₂ ‘offence’ role in sperm competition was significantly more depressed under inbreeding than sperm ‘defence’ (P₁). Mating behaviour did not explain these differences, and there was no difference in the viability of offspring sired by inbred or non-inbred males. Sperm length variation was significantly greater in the ejaculates of inbred males. Our results show that male ability to achieve normal fertilization success was not depressed under strong inbreeding, but that inbreeding depression in these traits occurred when conditions of sperm competition were generated.     

Biodegradation of diesel/biodiesel blends by a consortium of hydrocarbon degraders: effect of the type of blend and the addition of biosurfactants

Biodegradation experiments for diesel/biodiesel blends in liquid cultures by-petroleum degrading microbial consortium showed that for low amendments of biodiesel (10%) the overall biodegradation efficiency of the mixture after seven days was lower than for petroleum diesel fuel. Preferential usage of methyl esters in the broad biodiesel concentration range and diminished biodegradation of petroleum hydrocarbons for 10% biodiesel blend was confirmed. Rhamnolipids improved biodegradation efficiency only for blends with low content of biodiesel. Emulsion formation experiments showed that biodiesel amendments significantly affected dispersion of fuel mixtures in water. The presence of rhamnolipids biosurfactant affected stability of such emulsions and altered cell surface properties of tested consortium.     

Synthesis of new analogs of benzotriazole,benzimidazole and phthalimide—potential inhibitors of human protein kinase CK2

New derivatives of 4,5,6,7-tetrabromo-1H-1,2,3-benzotriazole (TBBt), 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi), and N-substituted tetrabromophthalimides were synthesized and their effect on the activity of human protein kinase CK2 was examined. The most active were derivatives with N-hydroxypropyl substituents (IC₅₀ in 0.32–0.54 μM range) whereas derivatives of phthalimide were almost ineffective.     

The new face of nucleolin in human melanoma

Nucleolin is multifunctional protein mainly present in nucleoli but also detected in cytoplasm and plasma membranes. Extranuclear nucleolin differs from the nuclear form by its glycosylation. Studies on expression of nucleolin in breast cancer suggest a possible association to the metastatic cascade. In the present study, Vicia villosa lectin (VVL) precipitation followed by subsequent polyacrylamide gel electrophoresis and mass spectrometry analysis demonstrates nucleolin as a VVL-positive glycoprotein expressed in melanoma. The presence of VVL-positive nucleolin in the melanoma cell membrane and cytoplasm was confirmed by confocal microscopy. Using bioinformatic peptide prediction programs, nucleolin was shown to contain multiple possible MHC class-I binding peptides in its sequence which makes nucleolin an interesting melanoma marker and target for immunodiagnostic and possibly therapeutic purposes. This paper is an original contribution from the meeting which took place on 28–and 29 May, 2008, in Nottingham, UK, celebrating the contribution of Professor I.A. “Tony” Dodi (+29.1.2008) to the EU project “Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumour immunology (ENACT)”.