Synthesis of N,N-dialkylaniline-2'-deoxyuridine conjugates for DNA-mediated electron transfer studies

Syntheses of two analogs of deoxyuridine with N,N-dialkylaniline chromophores are reported. 5-[3-(N-methylphenylamino)propanoyl]-2'-deoxyuridine (1) and 5-[2-(4-N,N-dimethylaminophenyl)ethyl)]-2'-deoxyuridine (2) are prepared by palladium-mediated coupling. Preparation of 2 was facilitated by in situ transient O4-trimethylsilyl protection during alkynylation which suppressed secondary cyclization of the coupling adduct.     

Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1

Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.     

Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant

The effectsof both surfactant distribution patterns and ventilation strategiesutilized after surfactant administration were assessed in lung-injuredadult rabbits. Animals received 50 mg/kg surfactant via intratrachealinstillation in volumes of either 4 or 2 ml/kg. A subset ofanimals from each treatment group was euthanized for evaluation of theexogenous surfactant distribution. The remaining animals wererandomized into one of three ventilatory groups: group1 [tidal volume(VT) of 10 ml/kg with 5 cmH₂O positive end-expiratorypressure (PEEP)]; group 2 (VT of 5 ml/kg with 5 cmH₂O PEEP); orgroup 3 (VT of 5 ml/kg with 9 cmH₂O PEEP). Animals wereventilated and monitored for 3 h. Distribution of the surfactant wasmore uniform when it was delivered in the 4 ml/kg volume. When thedistribution of surfactant was less uniform, arterial PO₂ values were greater ingroups 2 and3 compared with group1. Oxygenation differences among the differentventilation strategies were less marked in animals with the moreuniform distribution pattern of surfactant (4 ml/kg). In bothsurfactant treatment groups, a high mortality was observed with theventilation strategy used for group 3.We conclude that the distribution of exogenous surfactant affects theresponse to different ventilatory strategies in this model of acutelung injury.

     

Differences in the Direction of Change of Cerebral Function Parameters Are Evident over Three Years in HIV-Infected Individuals Electively Commencing Initial cART

BackgroundChanges in cerebral metabolite ratios (CMR) measured on ¹H-MRS and changes in cognitive function (CF) are described in subjects commencing combination antiretroviral therapy (cART), although the dynamics of such changes are poorly understood.MethodsNeuroasymptomatic, HIV-infected subjects electively commencing cART were eligible. CMR were assessed in three anatomical voxels and CF assessed at baseline, week 48 and week 144. Overall differences in absolute change in CMRs and CF parameters between 0–48 and 48–144 weeks were assessed.ResultsTwenty-two subjects completed study procedures. Plasma HIV-RNA was <50 copies/mL in all at week 48 and in all, but two subjects at week 144. In general, between weeks 0–48 a rise in N-acetyl-aspartate(NAA)/Creatine(Cr) ratio and a decline in myo-Inositol(mI)/Cr ratio were observed. Between weeks 48–144, small rises in NAA/Cr ratio were observed in two anatomical voxels, whereas a rise in mI/Cr ratio was observed in all anatomical locations (0.31 (0.66) and -0.27 (1.35) between weeks 0–48 and 0.13 (0.91) and 1.13 (1.71) between weeks 48–144 for absolute changes in NAA/Cr and mI/Cr (SD) in frontal-grey voxel, respectively). Global CF score improved between weeks 0–48 and then declined between weeks 48–144 (0.63 (1.16) and -0.63 (0.1.41) for mean absolute change (SD) between weeks 0–48 and weeks 48–144, respectively).ConclusionsThe direction of change of cerebral function parameters differs over time in HIV-infected subjects commencing cART, highlighting the need for long-term follow-up in such studies. The changes we have observed between weeks 48–144 may represent the initial development of cerebral toxicities from cART.     

Desperate Prawns: Drivers of Behavioural Innovation Vary across Social Contexts in Rock Pool Crustaceans

Innovative behaviour may allow animals to cope with changes in their environment. Innovative propensities are known to vary widely both between and within species, and a growing body of research has begun to examine the factors that drive individuals to innovate. Evidence suggests that individuals are commonly driven to innovate by necessity; for instance by hunger or because they are physically unable to outcompete others for access to resources. However, it is not known whether the factors that drive individuals to innovate are stable across contexts. We examined contextual variation in the drivers of innovation in rock pool prawns (Palaemon spp), invertebrates that face widely fluctuating environments and may, through the actions of tides and waves, find themselves isolated or in groups. Using two novel foraging tasks, we examined the effects of body size and hunger in prawns tested in solitary and group contexts. When tested alone, small prawns were significantly more likely to succeed in a spatial task, and faster to reach the food in a manipulation task, while hunger state had no effect. In contrast, size had no effect when prawns were tested in groups, but food-deprived individuals were disproportionately likely to innovate in both tasks. We suggest that contextual variation in the drivers of innovation is likely to be common in animals living in variable environments, and may best be understood by considering variation in the perception of relative risks and rewards under different conditions.     

SBOL Visual: A Graphical Language for Genetic Designs

Synthetic Biology Open Language (SBOL) Visual is a graphical standard for genetic engineering. It consists of symbols representing DNA subsequences, including regulatory elements and DNA assembly features. These symbols can be used to draw illustrations for communication and instruction, and as image assets for computer-aided design. SBOL Visual is a community standard, freely available for personal, academic, and commercial use (Creative Commons CC0 license). We provide prototypical symbol images that have been used in scientific publications and software tools. We encourage users to use and modify them freely, and to join the SBOL Visual community: http://www.sbolstandard.org/visual.     

Molecular Cloning,Functional Characterization,and Evolutionary Analysis of Vitamin D Receptors Isolated from Basal Vertebrates

The vertebrate genome is a result of two rapid and successive rounds of whole genome duplication, referred to as 1R and 2R. Furthermore, teleost fish have undergone a third whole genome duplication (3R) specific to their lineage, resulting in the retention of multiple gene paralogs. The more recent 3R event in teleosts provides a unique opportunity to gain insight into how genes evolve through specific evolutionary processes. In this study we compare molecular activities of vitamin D receptors (VDR) from basal species that diverged at key points in vertebrate evolution in order to infer derived and ancestral VDR functions of teleost paralogs. Species include the sea lamprey (Petromyzon marinus), a 1R jawless fish; the little skate (Leucoraja erinacea), a cartilaginous fish that diverged after the 2R event; and the Senegal bichir (Polypterus senegalus), a primitive 2R ray-finned fish. Saturation binding assays and gel mobility shift assays demonstrate high affinity ligand binding and classic DNA binding characteristics of VDR has been conserved across vertebrate evolution. Concentration response curves in transient transfection assays reveal EC₅₀ values in the low nanomolar range, however maximum transactivational efficacy varies significantly between receptor orthologs. Protein-protein interactions were investigated using co-transfection, mammalian 2-hybrid assays, and mutations of coregulator activation domains. We then combined these results with our previous study of VDR paralogs from 3R teleosts into a bioinformatics analysis. Our results suggest that 1, 25D₃ acts as a partial agonist in basal species. Furthermore, our bioinformatics analysis suggests that functional differences between VDR orthologs and paralogs are influenced by differential protein interactions with essential coregulator proteins. We speculate that we may be observing a change in the pharmacodynamics relationship between VDR and 1, 25D₃ throughout vertebrate evolution that may have been driven by changes in protein-protein interactions between VDR and essential coregulators.     

Common Variation at 1q24.1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer

So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (P _combined =2.30x10^-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; P _combined =2.73x10^-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.     

Algae in Fish Feed: Performances and Fatty Acid Metabolism in Juvenile Atlantic Salmon

Algae are at the base of the aquatic food chain, producing the food resources that fish are adapted to consume. Previous studies have proven that the inclusion of small amounts (<10% of the diet) of algae in fish feed (aquafeed) resulted in positive effects in growth performance and feed utilisation efficiency. Marine algae have also been shown to possess functional activities, helping in the mediation of lipid metabolism, and therefore are increasingly studied in human and animal nutrition. The aim of this study was to assess the potentials of two commercially available algae derived products (dry algae meal), Verdemin (derived from Ulva ohnoi) and Rosamin (derived from diatom Entomoneis spp.) for their possible inclusion into diet of Atlantic Salmon (Salmo salar). Fish performances, feed efficiency, lipid metabolism and final product quality were assessed to investigated the potential of the two algae products (in isolation at two inclusion levels, 2.5% and 5%, or in combination), in experimental diets specifically formulated with low fish meal and fish oil content. The results indicate that inclusion of algae product Verdemin and Rosamin at level of 2.5 and 5.0% did not cause any major positive, nor negative, effect in Atlantic Salmon growth and feed efficiency. An increase in the omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) content in whole body of fish fed 5% Rosamin was observed.