Synthesis and Application of Methyl N,O-Hydroxylamine Muramyl Peptides

The innate immune system's interaction with bacterial cells plays a pivotal role in a variety of human diseases. Carbohydrate units derived from a component of bacterial cell wall, peptidoglycan (PG), are known to stimulate an immune response. Nonetheless, access to modified late-stage peptidoglycan intermediates is limited due to their synthetic complexity. A method to rapidly functionalize PG fragments is needed to better understand the natural host–PG interactions. Here methyl N,O-hydroxylamine linkers are incorporated onto a synthetic PG derivative, muramyl dipeptide (MDP). The modification of MDP maintained the ability to stimulate a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) immune response dependent on the expression of nucleotide-binding oligomerization domain-containing protein 2 (Nod2). Intrigued by this modification's maintenance of biological activity, several applications were explored. Methyl N,O-hydroxylamine MDP was amendable to N-hydroxylsuccinimide (NHS) chemistry for bioconjugation to fluorophores as well as a self-assembled monolayer for Nod2 surface plasmon resonance analysis. Finally, linker incorporation was applicable to larger PG fragments, both enzymatically generated from Escherichia coli or chemically synthesized. This methodology provides rapid access to PG probes in one step and allows for the installation of a variety of chemical handles to advance the molecular understanding of PG and the innate immune system.     

Sensory characteristics and storage quality indicators of surimi franks nutritionally enhanced with omega‐3 rich flaxseed oil and salmon oil

Surimi franks were fortified with flaxseed or salmon oil at 2 g/100 g sample, franks without added oil served as a control. Thiobarbituric acid reactive substances values were highest (P < 0.001) in salmon oil franks; however, these values did not change over the 21‐day storage period regardless of frank type (P > 0.05). Frank pH decreased over time (P = 0.011) for all frank types. There were differences in textural properties between frank types (P < 0.05), with the flaxseed franks being softer and less gummy, cohesive and chewy than the control franks. Participants (n = 79; age 18–35) evaluated visual appeal, colour, aroma, texture, flavour and acceptability on a hedonic scale; there were no differences (P > 0.05) between franks. Fifty‐four panellists reported consuming sausage on a weekly to monthly basis, and most (50/79) indicated interest in purchasing this type product. The surimi franks were accepted by young adult consumers, which may indicate market potential of these types of products.     

Translating moral orders: putting moral conflict theory in conversation with actor–network theory

Moral conflict theory explains deep moral differences and patterns of communication commonly associated with such conflicts. Moral conflict is defined as a struggle between humans, but we argue that the objects of contention in such intractable conflicts, including texts, physical objects, and places, assume a force of their own. We use actor–network theory to help explain this eventuality and to expand our understanding of moral conflict. Combining actor–network theory literature with moral conflict theory literature helps us understand the complexity of moral orders and the networks of actors involved in the construction of moral conflict. This expansion of literature also allows us to conceive of more possibilities for transcendent discourse.     

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

Influence of polyimide precursor synthesis route and ortho-position functional group on thermally rearranged (TR) polymer properties: Conversion and free volume

Thermal rearrangement of polyimides with ortho-position groups to polybenzoxazoles and related structures has been of recent interest for producing gas separation membranes. This study explores the influence of synthesis route and ortho-position functional group on the thermal rearrangement process and the fractional free volume of thermally rearranged (TR) polymers produced from polyimides derived from 3,3′-dihydroxy-4,4′-diamino-biphenyl and 2,2′-bis-(3,4-dicarboxyphenyl) hexafluoropropane dianhydride (HAB–6FDA). Acetate, propanoate, and pivalate ortho-position functional groups were considered. Thermogravimetric analysis (TGA) was used to study thermal rearrangement at temperatures between 350 and 450 °C, and evolved gases from TGA were analyzed via mass spectrometry to characterize the byproducts of thermal rearrangement and thermal degradation. CO₂ was the major byproduct of thermal rearrangement for all samples, and its evolution began well before the onset of thermal degradation. When non-hydroxyl ortho-position groups were present in the polymers, several byproducts other than CO₂ were also observed due to the loss of these ortho-position groups before thermal rearrangement. Free volume generally increased with increasing extent of thermal rearrangement, but precise values of free volume could not be accurately determined for polymers with propanoate and pivalate ortho-position functional groups due to uncertainties in the chemical structure of partially converted materials. For polymers with acetate and hydroxyl ortho-position groups, free volume could be determined within the uncertainty of density measurements. Thermal rearrangement behavior and free volume results for acetate containing polymers synthesized via different routes were very similar. Based on these results, the chemical structure of the ortho-position functional group has a larger impact on TR polymer properties than the polyimide precursor synthesis route.     

Crystallization of Stoichiometric SbSI Glass

Congruent crystallization of antimony sulphoiodide (SbSI) glass of stoichiometric composition, which is prepared successfully for the first time using rapid melt‐quenching, has been investigated using differential scanning calorimetry (DSC). The results for glass powder show a glass transition at 127°C and two separate exothermal peaks with maxima around 140°C and 190°C. The ratio of the intensities of the exothermal peak at ~190°C to the peak at ~140°C increases as the particle size and heating rate are increased, but their total enthalpy remains constant at 62 ± 2 J/g for all DSC runs. Surface heating of the glass induced by a 520 nm CW laser shows two contracted regions: needle‐like crystalline formations at low temperature and bulk crystallization at high temperature. The observed phenomena and DSC results suggest two different kinds of crystallization of the SbSI phase: one‐dimensional crystallization at low temperature which starts from the sample surface and three‐dimensional bulk crystallization that continues the transformation to crystalline state at higher temperatures. The origin of the two different crystallizations can be traced to the strong anisotropy of the SbSI crystal structure due to the weak van der Waals interaction between covalent‐ionic chains (Sb₂S₂I₂)_n.     

Specificity of a UDP‐GalNAc Pyranose–Furanose Mutase: A Potential Therapeutic Target for Campylobacter jejuni Infections

Pyranose–furanose mutases are essential enzymes in the life cycle of a number of microorganisms, but are absent in mammalian systems, and hence represent novel targets for drug development. To date, all such mutases show preferential recognition of a single substrate (e.g., UDP‐Gal). We report here the detailed structural characterization of the first bifunctional pyranose–furanose mutase, which recognizes both UDP‐Gal and UDP‐GalNAc. The enzyme under investigation (cjUNGM) is involved in the biosynthesis of capsular polysaccharides (CPSs) in Campylobacter jejuni 11168. These CPSs are known virulence factors that are required for adhesion and invasion of human epithelial cells. Using a combination of UV/visible spectroscopy, X‐ray crystallography, saturation transfer difference NMR spectroscopy, molecular dynamics and CORCEMA‐ST calculations, we have characterized the binding of the enzyme to both UDP‐Galp and UDP‐GalpNAc, and compared these interactions with those of a homologous monofunctional mutase enzyme from E. coli (ecUGM). These studies reveal that two arginines in cjUNGM, Arg59 and Arg168, play critical roles in the catalytic mechanism of the enzyme and in controlling its specificity to ultimately lead to a GalfNAc‐containing CPS. In ecUGM, these arginines are replaced with histidine and lysine, respectively, and this results in an enzyme that is selective for UDP‐Gal. We propose that these changes in amino acids allow C. jejuni 11168 to produce suitable quantities of the sugar nucleotide substrate required for the assembly of a CPS containing GalfNAc, which is essential for viability.     

Conversion of polyhydroxybutyrate (PHB) to methyl crotonate for the production of biobased monomers

Within the concept of the replacement of fossil with biobased resources, bacterial polyhydroxybutyrate (PHB) can be obtained from volatile fatty acids (VFAs) from agro‐food waste streams and used as an intermediate toward attractive chemicals. Here we address a crucial step in this process, the conversion of PHB to methyl crotonate (MC), which can be converted via cross‐metathesis with ethylene to methyl acrylate and propylene, two important monomers for the plastics industry. The conversion of PHB to MC proceeds via a thermolysis of PHB to crotonic acid (CA), followed by an esterification to MC. At pressures below 18 bar, the thermolysis of PHB to CA is the rate‐determining step, where above 18 bar, the esterification of CA to MC becomes rate limiting. At 200°C and 18 bar, a full conversion and 60% selectivity to MC is obtained. This conversion circumvents processing and application issues of PHB as a polymer and allows PHB to be used as an intermediate to produce biobased chemicals. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42462.