Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition

The ever‐growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as‐yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba‐α‐d ‐glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN‐mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self‐cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.     

Influence of shear thinning and material flow on robotic dispensing of poly(ethylene glycol) diacrylate/poloxamer 407 hydrogels

Robotic dispensing of hydrogels offers a direct way for generating complex hydrogel shapes. For this, there is a general need for hydrogel formulations with suitable rheological properties. In this contribution, hydrogel formulations containing poly(ethylene glycol) diacrylate (PEG‐DA) and Poloxamer 407 are characterized regarding their flow behavior during robotic dispensing. Formulations contain between 15% and 20% PEG‐DA and 22.5% and 25% Poloxamer 407. All formulations show shear thinning which can be described using a power law with a power law index between 0.10 and 0.11 and calculated shear rates at the wall of the dispensing needle of 379 s^?1 with a dispensing speed of 8 mm s^?1 and a dispensing needle inner diameter of 0.51 mm. Thus, facilitating the generation of smooth hydrogel strands, three‐dimensional hydrogel objects can be prepared without flow after robotic dispensing and can be cured afterward to elastic hydrogels, retaining the shape of the dispensed object. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134 , 45083.     

Cover Image,Volume 66, Issue 3

The cover image, by Katia Sparnacci et al., is based on the Research Article High temperature surface neutralization process with random copolymers for block copolymer self‐assembly, DOI: 10.1002/pi.5285 .

     

Electrically insulating polymeric nanocomposites with enhanced thermal conductivity by visible‐light curing of epoxy–boron nitride nanotube formulations

Epoxy–boron nitride nanotube (BNNT) composites were prepared using visible light through a radical‐induced cationic polymerization method activated by camphorquinone. The fully cured films showed an enhancement of glass transition temperature in the presence of the filler. Electrical characterization showed a slight dielectric constant decrease with BNNT content. Finally, thermal conductivity measured using nano‐flash analysis showed a linear increase in the thermal conductivity of the materials with increasing BNNT content in the photocurable formulations. © 2017 Society of Chemical Industry     

Quantitative Assessment of Affinity Selection Performance by Using DNA-Encoded Chemical Libraries

DNA-encoded chemical libraries are often used for the discovery of ligands against protein targets of interest. These large collections of DNA-barcoded chemical compounds are typically screened by using affinity capture methodologies followed by PCR amplification and DNA sequencing procedures. However, the performance of individual steps in the selection procedures has been scarcely investigated, so far. Herein, the quantitative analysis of selection experiments, by using three ligands with different affinity to carbonic anhydrase IX as model compounds, is described. In the first set of experiments, quantitative PCR (qPCR) procedures are used to evaluate the recovery and selectivity for affinity capture procedures performed on different solid-phase supports, which are commonly used for library screening. In the second step, both qPCR and analysis of DNA sequencing results are used to assess the recovery and selectivity of individual carbonic anhydrase IX ligands in a library, containing 360 000 compounds. Collectively, this study reveals that selection procedures can be efficient for ligands with sub-micromolar dissociation constants to the target protein of interest, but also that selection performance dramatically drops if 10⁴ copies per library member are used as the input.     

A statistical model for the failure of glass plates due to nickel sulfide inclusions

Nickel Sulfide (NiS) inclusions can provoke the rupture of thermally treated glass due to a phase transformation with volume increase that stresses the surrounding glass. Starting from a Pareto statistics for the population of inclusion sizes, from an assumed kinetics of the phase transformation, a micro-mechanically motivated model provides the statistical characterization of the probability of spontaneous failure of glass during lifetime. A distinction based upon the composition of NiS is used to discuss the effects of the heat soak test (HST), where glass remains at high temperature for a certain time to speed-up the phase transformation and destroy those elements with critical inclusions. Three functions à la Weibull for the probability of spontaneous rupture during lifetime are theoretically derived for the case of no HST, short HST, and long HST. In particular, the probability of collapse for long HSTs depends upon the holding time in the oven. An explanatory example shows the potentiality of the model for optimizing the HST parameters toward a target probability of failure, but experimental campaigns are needed for a proper calibration.     

Lipid characteristics of RSV-transformed Balb/c 3T3 cell lines with different spontaneous metastatic potentials

To determine whether a metastatic phenotype may be corelated with a characteristic lipid pattern, we compared the lipid composition of low metastasizing Balb/c 3T3 cells transformed by the B77 strain of Rous sarcoma virus (B77-3T3 cells) with that of a subclone isolated by growth in 0.6% agar, the B77-AA6 cells, which exhibit a high capacity for spontaneous metastasis. B77-3T3 cells revealed characteristics in their lipid composition common to other systems of transformed cells, i.e., an accumulation of ether-linked lipids, a reduction of the more complex gangliosides, an increase of oleic acid (18∶1) and a decrease of arachidonic (20∶4) and C22 polyunsaturated fatty acids in phospholipids. High metastatic B77-AA6 cells showed: a) an even more marked decrease of complex gangliosides; b) a more pronounced increase of 18∶1 and decrease of 20∶4 and 22 polyunsaturated fatty acids in certain phospholipid classes; and c) a higher percentage of alkyl-acyl subfractions in both phosphatidylcholine and phosphatidylethanolamine than B77-3T3 cells. Comparing the data for other systems of metastatic cells with those of lipid studies of spontaneously metastasizing B77-AA6 cell system leads us to conclude that the metastatic phenotype is characterized by a change in ether-linked lipids, rather than in fatty acids.     

Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach

The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.     

Synthesis of novel DC-SIGN ligands with an alpha-fucosylamide anchor

The dendritic cell-specific intercellular adhesion molecule (ICAM) 3-grabbing nonintegrin (DC-SIGN) is a C-type lectin that appears to perform several different functions. Besides mediating adhesion between dendritic cells and T lymphocytes, DC-SIGN recognizes several pathogens some of which, including HIV, appear to exploit it to invade host organisms. The intriguing diversity of the roles attributed to DC-SIGN and their therapeutic implications have stimulated the search for new ligands that could be used as biological probes and possibly as lead compounds for drug development. The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. Using the known 3D structure of the Lewis-x trisaccharide, we have identified some monovalent alpha-fucosylamides that bind to DC-SIGN with inhibitory constants 0.4-0.5 mM, as determined by SPR, and have characterized their interaction with the protein by STD NMR spectroscopy. This work establishes for the first time alpha-fucosylamides as functional mimics of chemically and enzymatically unstable alpha-fucosides and describes interesting candidates for the preparation of multivalent systems able to block the receptor DC-SIGN with high affinity and with potential biomedical applications.