This report describes the design and synthesis of a series of a V b 3 integrin-directed monomeric, dimeric and tetrameric cyclo [Arg-Gly-Asp-D-Phe-Lys] dendrimers using "click chemistry". It was found that the unprotected N-e-azido derivative of cyclo[Arg-Gly-Asp-D-Phe-Lys] underwent a highly chemoselective conjugation to amino acid-based dendrimers bearing terminal alkynes using a microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition. The a V b 3 binding characteristics of the dendrimers were determined in vitro and their in vivo a V b 3 targeting properties were assessed in nude mice with subcutaneously growing human SK-RC-52 tumors. The multivalent RGD-dendrimers were found to have enhanced affinity toward the a V b 3 integrin receptor as compared to the monomeric derivative as determined in an in vitro binding assay. In case of the DOTA-conjugated 111 In-labeled RGD-dendrimers, it was found that the radiolabeled multimeric dendrimers showed specifically enhanced uptake in a V b 3 integrin expressing tumors in vivo. These studies showed that the tetrameric RGD-dendrimer had better tumor targeting properties than its dimeric and monomeric congeners.
Trimethylation of lysine residue K4 of histone H3 (H3K4me3) strongly correlates with active promoters for RNA polymerase II-transcribed genes. Several reader proteins, including the basal transcription factor TFIID, for this nucleosomal mark have been identified. Its TAF3 subunit specifically binds the H3K4me3 mark via its conserved plant homeodomain (PHD) finger. Here, we report the solution structure of the TAF3-PHD finger and its complex with an H3K4me3 peptide. Using a combination of NMR, mutagenesis, and affinity measurements, we reveal the structural basis of binding affinity, methylation-state specificity, and crosstalk with asymmetric dimethylation of R2. A unique local structure rearrangement in the K4me3-binding pocket of TAF3 due to a conserved sequence insertion underscores the requirement for cation-pi interactions by two aromatic residues. Interference by asymmetric dimethylation of arginine 2 suggests that a H3R2/K4 "methyl-methyl" switch in the histone code dynamically regulates TFIID-promoter association.
The root bacterial microbiome is important for the general health of the plant. Additionally, it can enhance tolerance to abiotic stresses, exemplified by plant species found in extreme ecological niches like deserts. These complex microbe-plant interactions can be simplified by constructing synthetic bacterial communities or SynComs from the root microbiome. Furthermore, SynComs can be applied as biocontrol agents to protect crops against abiotic stresses such as high salinity. However, there is little knowledge on the design of a SynCom that offers a consistent protection against salt stress for plants growing in a natural and, therefore, non-sterile soil which is more realistic to an agricultural setting. Here we show that a SynCom of five bacterial strains, originating from the root of the desert plant Indigofera argentea, protected tomato plants growing in a non-sterile substrate against a high salt stress. This phenotype correlated with the differential expression of salt stress related genes and ion accumulation in tomato. Quantification of the SynCom strains indicated a low penetrance into the natural soil used as the non-sterile substrate. Our results demonstrate how a desert microbiome could be engineered into a simplified SynCom that protected tomato plants growing in a natural soil against an abiotic stress.
Lignin is a key factor limiting saccharification of lignocellulosic feedstocks. In this comparative study, various lignin methods-including acetyl bromide lignin (ABL), acid detergent lignin (ADL), Klason lignin (KL), and modified ADL and KL determination methods-were evaluated for their potential to assess saccharification efficiency. Six diverse accessions of the bioenergy crop miscanthus were used for this analysis, which included accessions of Miscanthus sinensis, Miscanthus sacchariflorus, and hybrid species. Accessions showed large variation in lignin content. Lignin estimates were different between methods, but (highly) correlated to each other (0.54≤r≤0.94). The strength of negative correlations to saccharification efficiency following either alkaline or dilute acid pretreatment differed between lignin estimates. The strongest and most consistent correlations (−0.48≤r≤ −0.85) were obtained with a modified Klason lignin method. This method is suitable for high throughput analysis and was the most effective in detecting differences in lignin content (p<0.001) between accessions.
The optimized reaction conditions for the Cu(I)-catalyzed N-->C polymerization of azido-phenylalanyl-alanyl-propargyl amide to yield either high molecular weight linear polymers or medium-sized cyclic polymers is described. These reaction conditions will be applied to tailor the synthesis, properties, and structure of biologically relevant peptide-based biopolymers.
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