Stretchable Polymerized High Internal Phase Emulsion Separators for High Performance Soft Batteries

Powering soft embodiments of robots, machines and electronics is a key issue that impacts emerging human friendly forms of technologies. Batteries as energy source enable their untethered operation at high power density but must be rendered elastic to fully comply with (soft) robots and human beings. Current intrinsically stretchable batteries typically show decreased performance when deformed due to design limitations, mainly imposed by the separator material. High quality stretchable separators such as gel electrolytes represent a key component of soft batteries that affects power, internal resistance, and capacity independently of battery chemistry. Here, polymerized high internal phase emulsions (polyHIPEs) are introduced as highly ionically conductive separators in stretchable (rechargeable) batteries. Highly porous (>80%) separators result in electrolyte to polyHIPE conductivity ratios of below 2, while maintaining stretchability of ≈50% strain. The high stretchability, tunable porosity, and fast ion transport enable stretchable batteries with internal resistance below 3 Ω and 16.8 mAh cm^?2 capacity that power on‐skin processing and communication electronics. The battery/separator architecture is universally applicable to boost battery performance and represents a step towards autonomous operation of conformable electronic skins for healthcare, robotics, and consumers.     

9-[2-(R)-(Phosphonomethoxy)propyl]-2,6-diaminopurine (R)-PMPDAP and its prodrugs: Optimized preparation,including identification of by-products formed,and antiviral evaluation in vitro

New large-scale synthetic approach to antiretroviral agent 9-[2-(R)-(phosphonomethoxy)propyl]-2,6-diaminopurine, (R)-PMPDAP, was developed. Reaction of (R)-propanediol carbonate with 2,6-diaminopurine afforded exclusively (R)-9-(2-hydroxypropyl)-2,6-diaminopurine which was subsequently used for introduction of a phosphonomethyl residue using TsOCH₂P(O)(OiPr)₂ or BrCH₂P(O)(OiPr)₂ followed by deprotection of ester groups. All minor ingredients and by-products formed during the process were identified and further studied. The final product was obtained in high yield and its high enantiomeric purity (>99%) was confirmed by chiral capillary electrophoretic analysis using β-cyclodextrin as a chiral selector. Antiretroviral activity data of (R)-PMPDAP and its diverse prodrugs against HIV and FIV were investigated. Akin to (R)-PMPDAP, both prodrugs inhibit FIV replication in a selective manner. Compared to the parent molecule, the amidate prodrug was 10-fold less active against FIV in cell culture, whereas the alkoxyalkyl ester prodrug was 200-fold more potent in inhibiting FIV replication in vitro.     

Purification and kinetic characterization of human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and discovery of selective IDO1 inhibitors

Indoleamine 2,3-dioxygenase (IDO1) catalyzes the first step in tryptophan breakdown along the kynurenine pathway. Therapeutic inhibition of IDO1 is receiving much attention due to its proposed role in the pathogenesis of several diseases including cancer, hypotension and neurodegenerative disorders. A related enzyme, IDO2 has recently been described. We report the first purification and kinetic characterization of human IDO2 using a facile l-tryptophan consumption assay amenable to high throughput screening. We found that the K(m) of human IDO2 for l-tryptophan is much higher than that of IDO1. We also describe the identification and characterization of a new IDO1 inhibitor compound, Amg-1, by high throughput screening, and compare the inhibition profiles of IDO1 and IDO2 with Amg-1 and previously described compounds. Our data indicate that human IDO1 and IDO2 have different kinetic parameters and different inhibition profiles. Docking of Amg-1 and related analogs to the known structure of IDO1 and to homology-modeled IDO2 suggests possible rationales for the different inhibition profiles of IDO1 and IDO2.     

Relationship between tumor vascularity and vascular endothelial growth factor as prognostic factors for patients with neuroblastoma

Although the role of angiogenesis in tumor progression and response to treatment is generally well-characterized, for neuroblastomas clinical data regarding the contribution of angiogenesis and its predictive capacity remain unclear. The aim of this study was to evaluate whether tumor vascularity in the combination with expression of vascular endothelial growth factor (VEGF) represent prognostic factors for patients with neuroblastoma. Immunohistochemistry using anti-CD34 and anti-VEGF antibodies was used to analyze paraffin-embedded primary tumor tissues from 56 patients diagnosed with neuroblastoma. Tumor vascularity was estimated by calculating the tumor vascular volume fraction (TVVF), and VEGF expression was determined using semi-quantitative scoring. Statistical analyses including multivariate analysis were performed and compared with these two factors. Tumor vascularity had impact on survival of high VEGF expression neuroblastoma patients. Combination of high VEGF expression and TVVF value < or = 5% was independent predictor of overall survival (p-value = 0.0041, odds ratio (OR) (95% CI) = 8.67 (1.99-37.69) by the Cox proportional hazards model). This study revealed for the first time a group of extremely high-risk neuroblastoma with both high VEGF expression and poor vascularity. For these patients reduced rates of survival were observed (37% vs. 92.5%) (p < 0.0001). These patients did not experience a significant improvement following hematopoietic stem cell transplantation, and could be candidates for receiving novel therapies. These results indicate the importance of the mutual relationship between tumor vascularity and VEGF, because it gives better insight into the prognosis of patients with neuroblastoma.     

Aurora Kinase A Is Not Involved in CPEB1 Phosphorylation and cyclin B1 mRNA Polyadenylation during Meiotic Maturation of Porcine Oocytes

Regulation of mRNA translation by cytoplasmic polyadenylation is known to be important for oocyte maturation and further development. This process is generally controlled by phosphorylation of cytoplasmic polyadenylation element binding protein 1 (CPEB1). The aim of this study is to determine the role of Aurora kinase A in CPEB1 phosphorylation and the consequent CPEB1-dependent polyadenylation of maternal mRNAs during mammalian oocyte meiosis. For this purpose, we specifically inhibited Aurora kinase A with MLN8237 during meiotic maturation of porcine oocytes. Using poly(A)-test PCR method, we monitored the effect of Aurora kinase A inhibition on poly(A)-tail extension of long and short cyclin B1 encoding mRNAs as markers of CPEB1-dependent cytoplasmic polyadenylation. Our results show that inhibition of Aurora kinase A activity impairs neither cyclin B1 mRNA polyadenylation nor its translation and that Aurora kinase A is unlikely to be involved in CPEB1 activating phosphorylation.     

A simple method for the preparation of (5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid enantiomers and the corresponding 14,15-dehydro analogues: role of the 16-hydroxy group for the lipoxygenase reaction

(5Z,8Z,11Z,13E)-15-Hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) is not well oxygenated by arachidonate 15-lipoxygenases because of two structural reasons: (i) it contains a hydrophilic OH-group in close proximity to its methyl end and (ii) it lacks the bisallylic methylene at C(13). We synthesized racemic (5Z,8Z,11Z,14Z)-16-hydroxy-5,8,11,14-eicosatetraenoic acid (16-HETE) which still contains the bisallylic C(13), separated the enantiomers reaching an optical purity of >99% and tested them as substrates for 5- and 15-lipoxygenases. Our synthetic pathway, which is based on stereospecific hydrogenation of a polyacetylenic precursor, yielded substantial amounts (30%) of 14,15-dehydro-16-HETE in addition to 16-HETE. When 16-HETE was tested as lipoxygenase substrate, we found that it is well oxygenated by the soybean 15-lipoxygenase and by the recombinant human 5-lipoxygenase. Analysis of the reaction products suggested an arachidonic acid-like alignment at the active site of the two enzymes. In contrast, the product pattern of 16-HETE methyl ester oxygenation by the soybean lipoxygenase (5-lipoxygenation) may be explained by an inverse head to tail substrate orientation.     

Imidazoline-modified benzylimidazolines as h5-HT(1D/1B) serotonergic ligands

Sumatriptan, a h5-HT1D and h5-HT1B receptor agonist used clinically as a migraine-abortive, produces certain side effects thought to result from its affinity for h5-HT1B receptors. The present investigation extends our work with benzylimidazolines as novel non-tryptamine h5-HT(1D/1B) ligands. The effect of N-methylation, N-benzylation, ring-aromatization, and variation of the imidazoline ring on affinity both at h5-HT1D and h5-HT1B receptors was examined. Several compounds were identified with good affinity and enhanced (i.e., > 100-fold) h5-HT1D versus hS-HT1B selectivity.