Synthesis,Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short-Chain Fatty Acid Derivatives

Short-chain fatty acids (SCFAs) have a range of effects in metabolism and immune regulation. We have observed that delivery of SCFAs to lysosomes has potent immune regulatory effects, possibly as a surrogate signal for the presence of anaerobic organisms. To better understand the pharmacology of lysosomal SCFA donors, we investigated the distribution and metabolism of propionate and butyrate donors. Each analog ( 1 a and 2 a ) can donate three SCFA equivalents via ester hydrolysis through six intermediate metabolites. The compounds are stabilized by low pH, and stability in cells is usually higher than in medium, but is cell-type specific. Butyrate derivatives were found to be more stable than propionates. Tri-esters were more stable than di- or mono-esters. The donors were surprisingly stable in vivo, and hydrolysis of each position was organ specific. Jejunum and liver caused rapid loss of 4’’ esters. The gut metabolite pattern by i. v. differed from that of p.o. application, suggesting luminal and apical enzyme effects in the gut epithelium. Central organs could de-esterify the 11-position. Levels in lung relative to other organs were higher by p.o. than via i. v., suggesting that delivery route can influence the observed pharmacology and that gut metabolites distribute differently. The donors were largely eliminated by 24 h, following near linear decline in organs. The observed levels and distribution were found to be consistent with pharmacodynamic effects, particularly in the gut.     

Feed Restriction Modulates Growth,Gut Morphology and Gene Expression in Zebrafish

A reduction in daily caloric or nutrient intake has been observed to promote health benefits in mammals and other vertebrates. Feed Restriction (FR), whereby the overall food intake of the organism is reduced, has been explored as a method to improve metabolic and immune health, as well as to optimize productivity in farming. However, less is known regarding the molecular and physiological consequences of FR. Using the model organism, Danio rerio, we investigated the impact of a short-term (month-long) FR on growth, gut morphology and gene expression. Our data suggest that FR has minimal effects on the average growth rates, but it may affect weight and size heterogeneity in a sex-dependent manner. In the gut, we observed a significant reduction in gut circumference and generally lower mucosal heights, whereas other parameters remained unchanged. Gene Ontology (GO), EuKaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified numerous metabolic, reproductive, and immune response pathways that were affected by FR. These results broaden our understanding of FR and contribute towards growing knowledge of its effects on vertebrate health.     

Mannose‐Decorated Multicomponent Supramolecular Polymers Trigger Effective Uptake into Antigen‐Presenting Cells

A modular route to prepare functional self‐assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen‐presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylene glycol)s (TEGs) or labeled with a Cy3 fluorescent probe. Experiments on the uptake of the multifunctional supramolecular particles into murine macrophages (Mφs) were monitored by confocal microscopy and fluorescence‐activated cell sorting. Mannose‐decorated supramolecular polymers trigger a significantly higher cellular uptake and distribution, relative to TEG carrying bare polymers. No cytotoxicity or negative impact on cytokine production of the treated Mφs was observed, which emphasized their biocompatibility. The modular nature of the multicomponent supramolecular polymer coassembly protocol is a promising platform to develop fully synthetic multifunctional vaccines, for example, in cancer immunotherapy.     

Synthetic MUC1 Antitumor Vaccine with Incorporated 2,3‐Sialyl‐T Carbohydrate Antigen Inducing Strong Immune Responses with Isotype Specificity

The endothelial glycoprotein MUC1 is known to underlie alterations in cancer by means of aberrant glycosylation accompanied by changes in morphology. The heavily shortened glycans induce a collapse of the peptide backbone and enable accessibility of the latter to immune cells, rendering it a tumor‐associated antigen. Synthetic vaccines based on MUC1 tandem repeat motifs, comprising tumor‐associated 2,3‐sialyl‐T antigen, conjugated to the immunostimulating tetanus toxoid, are reported herein. Immunization with these vaccines in a simple water/oil emulsion produced a strong immune response in mice to which stimulation with complete Freund's adjuvant (CFA) was not superior. In both cases, high levels of IgG1 and IgG2a/b were induced in C57BL/6 mice. Additional glycosylation in the immunodominant PDTRP domain led to improved binding of the induced antisera to MCF‐7 breast tumor cells, compared with that of the monoglycosylated peptide vaccine.     

Oxime crosslinked polymer networks: Is every reversible covalent bond suitable to create self‐healing polymers?

The incorporation of reversible covalent bonds into polymeric materials offers the possibility to generate polymers with self‐healing ability. For this purpose, three new oxime crosslinkers are synthesized and crosslinked by the copolymerization with different commercially available methacrylates via a photo‐polymerization process. These crosslinked materials are investigated regarding a potential self‐healing behavior. Moreover, the influence of different additives (polymerizable acids, photo acids, and acid developers) to enable self‐healing is studied in detail. Thereby, the limit of self‐healing based on reversible covalent bonds is reached in these materials. Due to the high stability of the oxime bonds in bulk materials no exchange reactions as well as no self‐healing behavior could be observed. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44168.     

Biocompatible porous ceramics for the cultivation of hematopoietic cells

Porous ceramics made of alumina and hydroxyapatite were created using a protein foaming method. Porosity and pore size distribution were successfully varied by means of chemical modification of the foaming protein Bovine serum albumin (BSA). The effectiveness of the BSA and of its chemical modifications as well as the influence of the dispersing agent were investigated using synchrotron tomography. Resulting porous ceramic materials were used as three-dimensional substrates for the cultivation of human peripheral stem cells. The cells proliferated and differentiated in culture. Five cell lines consistent with human blood cell lines were observed.     

Proximity-effect-induced superconductivity at millikelvin temperatures

A systematic study is reported of the proximity effect in superconductivity of thick Cu layers (4d _n105 µm) in contact with Nb or Nb-Ti (46D _s1041 µm) from measurements of the ac susceptibility and of the thermal conductivity. The induced superconducting properties of Cu are studied as a function of temperature (7 mKT1 K), field (0.4 mGH 10 G), and electronic mean free path (0.2l14 µm). The Meissner screening length in Cu increases faster than the coherence length with decreasing temperature and eventually saturates, making the Cu fully superconducting. In this case, superconductivity can be destroyed sharply at a breakdown fieldH _b; the transition atH _b is hysteretic. The data are in agreement with numerical solutions of the de Gennes/Ginzburg-Landau theory, as demonstrated by the dependence of the Meissner screening length and of the breakdown field on temperature, field, and electronic mean free path. The data indicate that observation of a reduction in thermal conductivity requires a substantially larger induced pair potential than is necessary even for total field shielding. The concentration of Cooper pairs in Cu in contact to Nb is larger than in Cu in contact to Nb-Ti, even for Nb-Ti/Cu samples with a larger electron mean free path in the Cu part. No measurable superconducting field screening could be induced in the investigated temperature range in Pd (26d _n72 µm) in contact to Nb/Cu or to Nb (D _s5d _n). This is explained by the fact that the coherence length is at least an order of magnitude smaller in Pd than in Cu. Evaporating a layer of Fe on Cu in the Nb/Cu samples results in a strong depression of the proximity effect.