Combinatorial Strategies by Marine Cyanobacteria: Symplostatin 4, an Antimitotic Natural Dolastatin 10/15 Hybrid that Synergizes with the Coproduced HDAC Inhibitor Largazole

Combinatorial biosynthesis meets combinatorial pharmacology, cyanobacterial style : A new antimitotic natural product with features of both dolastatins 10 and 15 was isolated from the same Floridian Symploca sp. sample that produced the histone deacetylase inhibitor largazole. Both agents in combination are more effective in inhibiting cancer cell proliferation than either agent alone.

     

Determination of Preferred pH for Root-knot Nematode Aggregation Using Pluronic F-127 Gel

Root-knot nematodes (Meloidogyne spp.) are obligate endoparasites of a wide range of plant species. The infective stage is attracted strongly to and enters host roots at the zone of elongation, but the compounds responsible for this attraction have not been identified. We developed a simple assay to investigate nematode response to chemical gradients that uses Pluronic F-127, a synthetic block copolymer that, as a 23% aqueous solution, forms a liquid at low temperature and a gel at room temperature. Test chemicals are put into a modified pipette tip, or ‘chemical dispenser,’ and dispensers are inserted into the gel in which nematodes have been dispersed. Meloidogyne hapla is attracted to pH gradients formed by acetic acid and several other Brønsted acids and aggregates between pH 4.5 and 5.4. While this pH range was attractive to all tested root-knot nematode strains and species, the level of aggregation depended on the species/strain assessed. For actively growing roots, the pH at the root surface is most acidic at the zone of elongation. This observation is consistent with the idea that low pH is an attractant for nematodes. Root-knot nematodes have been reported to be attracted to carbon dioxide, but our experiments suggest that the observed attraction may be due to acidification of solutions by dissolved CO₂ rather than to CO₂ itself. These results suggest that Pluronic F-127 gel will be broadly applicable for examining responses of a range of organisms to chemical gradients or to each other.     

Deformation-based mapping of volume change from serial brain MRI in the presence of local tissue contrast change

This paper is motivated by the analysis of serial structural magnetic resonance imaging (MRI) data of the brain to map patterns of local tissue volume loss or gain over time, using registration-based deformation tensor morphometry. Specifically, we address the important confound of local tissue contrast changes which can be induced by neurodegenerative or neurodevelopmental processes. These not only modify apparent tissue volume, but also modify tissue integrity and its resulting MRI contrast parameters. In order to address this confound we derive an approach to the voxel-wise optimization of regional mutual information (RMI) and use this to drive a viscous fluid deformation model between images in a symmetric registration process. A quantitative evaluation of the method when compared to earlier approaches is included using both synthetic data and clinical imaging data. Results show a significant reduction in errors when tissue contrast changes locally between acquisitions. Finally, examples of applying the technique to map different patterns of atrophy rate in different neurodegenerative conditions is included.     

In vitro interactions between DMSA-coated maghemite nanoparticles and human fibroblasts: A physicochemical and cyto-genotoxical study

Although the current production of oxide nanoparticles may be modest, the wide range of proposed applications and forecasted growth in production has raised questions about the potential impact of these nanoparticles on the environment and human health. Iron oxide nanoparticles have been proposed for an increasing number of biomedical applications although in vitro toxicity depending on the particles coating has been evidenced. The aim of this study was to examine the potential in vitro cyto- and genotoxicity on human dermal fibroblasts of DMSA-coated maghemite nanoparticles (NmDMSA) as a function of well-defined physicochemical states. Well-stabilized NmDMSA produced weak cytotoxic and no genotoxic effects. This is attributed in part to the DMSA coating, which serves as a barrier for a direct contact between nano-oxide and fibroblasts, inhibiting a potential toxic effect.     

Thermoplastic encapsulations of a sensor platform by high‐temperature injection molding up to 360°C

For bioprotective encapsulated Internet of Things (IoT) electronics for the medical market, especially for cost‐effective, single or multiple use, injection molding will be of major importance. The stresses from the production process pose special challenges for electronics. The aim of the study was the simulative and experimental characterization of the load spectrum from the injection molding process and its effects on electronics. General recommendations for the encapsulation of IoT electronics in polymer matrices were derived. A microcontroller‐controlled temperature sensor board and a suitable injection mold were developed. Eight circumferential NTC‐sensors measured the prevailing thermal load directly on the component during overmolding. A simulation model allowed statements on the loads to be made about individual components, validated in experimental tests. In addition to PP and PMMA, PSU with a melt temperature of 360°C was tested. The temperature influence of the melt could be described as a function of the component position. The loss of adhesion, shrinkage, distortion, cavities, and delamination were analyzed using micrograph analysis. Complete functionality of the electronics was ensured after encapsulation. Optimization strategies were developed for the design of both IoT electronics and the injection mold. Novel concepts such as interlayer or backfill vias could be derived for future research approaches. POLYM. ENG. SCI., 59:1315–1331 2019. © 2019 Society of Plastics Engineers     

Blueberries and Their Anthocyanins: Factors Affecting Biosynthesis and Properties

Abstract: Blueberry is one of the most popular fruits in North America and rich in anthocyanins. Its content in anthocyanins contributes to the health‐beneficial effects of blueberry against several chronic diseases including cardiovascular disorders, neurodegenerative diseases, diabetes, and cancer. This paper summarizes various facts presenting blueberry as a fruit with huge potential for increased future consumption as a health‐enhancing food. Factors affecting the biosynthesis of the various anthocyanins in blueberries, including agronomic and genetic factors, and the possible pathways of biosynthesis of the major anthocyanins present in this plant are discussed. The important health‐beneficial effects associated with blueberry anthocyanins, properties of these anthocyanins leading to the beneficial effects, and food processing parameters leading to the depletion of the amounts of anthocyanins present in the final processed products are also briefly discussed. Furthermore, the general methods of extraction and analyses that have been reported for being successfully applied to blueberry anthocyanins are also reviewed. Practical Application: Blueberries are well known for their nutritional and beneficial health effects, however, information concerning the physiology behind the blueberry beneficial effects is still lacking. There is little or no information on the characterization of growing conditions on anthocyanins in blueberries and research is lagging behind on advanced methods of extracting blueberry anthocyanins.     

Allele-Specific Inhibition of Histone Demethylases

Histone demethylases play a critical role in mammalian gene expression by removing methyl groups from lysine residues in degree- and site-specific manner. To specifically interrogate members and isoforms of this class of enzymes, we have developed demethylase variants with an expanded active site. The mutant enzymes are capable of performing lysine demethylation with wild-type proficiency, but are sensitive to inhibition by cofactor-competitive molecules embellished with a complementary steric “bump”. The selected inhibitors show more than 20-fold selectivity over the wild-type demethylase, thus overcoming issues typical to pharmacological and genetic approaches. The mutant–inhibitor pairs are shown to act on a physiologically relevant full-length substrate. By engineering a conserved amino acid to achieve member-specific perturbation, this study provides a general approach for studying histone demethylases in diverse cellular processes.     

Development of Phosphodiesterase–Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE–PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE–PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems—cAMP-specific PDE8–PKAR, cGMP-specific PDE5–PKG, and dual-specificity RegA–R_D complexes—and ranked inhibitors according to their inhibition potency. Targeting PDE–PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.     

An adaptive clinical decision support system for serving the elderly with chronic diseases in healthcare industry

With the increasing ageing population worldwide, providing effective nursing care planning in nursing homes is important in meeting the expectations of elderly patients and in streamlining the healthcare information process, hence maintaining high‐quality services. Instead of the traditional manual nursing care planning formulation based on expert experience and subjective judgement, this paper describes an adaptive decision support system, namely, the cloud‐based nursing care planning system, to enable decision making in formulating nursing care strategies. By integrating cloud computing technology and the case‐based reasoning (CBR) technique, medical records and documents pertaining to the elderly can be captured in real time, whereas appropriate treatment plans based on past similar treatment records can be formulated. However, the current case adaptation processes in CBR rely on domain experts to modify retrieved cases, which may not satisfy the needs of the elderly. Therefore, text mining is integrated in the case adaptation process of CBR for extracting up‐to‐date medical information from the Internet so that its efficiency can be improved. By conducting a pilot study in a nursing home, it was shown that the time for formulating applicable treatment plans for elderly patients can be reduced, and the service satisfaction level can be enhanced.     

The assessment of compositional changes in Nimonic PE16 by convergent beam electron diffraction

Lattice parameter changes can be detected by the use of a previously established technique which is based upon computer simulation of HOLZ patterns. This simulation technique is then applied to two precipitation phenomena in Nimonic PE16. Firstly, the growth of gamma prime, γ, precipitates from a solid solution is monitored via the decrease in lattice parameter of the parent phase, and secondly the lattice parameter of coarsened, overaged γ is measured for precipitates sited both at grain boundaries and within grains. The variations thus detected between intergranular and intragranular precipitates are attributed to changes in the Ti/Al ratio due to preferential γ coarsening at the grain boundary. The very subtle compositional changes inferred (～1 at. % Ti) would have been very difficult to establish by chemical analysis, but can be easily measured by convergent beam electron diffraction.