Metabolic reprogramming of macrophages exposed to silk, poly(lactic-co-glycolic acid) and silica nanoparticles

Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. We describe the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of pre-clinical and clinical development for drug delivery applications. We used 1H NMR analysis of cell extracts and culture media to quantify the changes in the intracellular and extracellular metabolomes of macrophages in response to nanoparticle exposure. Increased glycolytic activity, an altered tricarboxylic acid cycle and reduced ATP generation were consistent with a pro-inflammatory phenotype. Furthermore, amino acids possibly arising from autophagy, the creatine kinase/phosphocreatine system and a few osmolytes and antioxidants emerged as important players in the metabolic reprogramming of macrophages exposed to nanoparticles. This metabolic signature was a common response to all nanoparticles tested; however, the direction and magnitude of some variations were clearly nanoparticle specific, indicating material-induced biological specificity. Overall, metabolic reprogramming of macrophages can be achieved with nanoparticle treatments, modulated through the choice of the material, and monitored using 1H NMR metabolomics

Structural investigation and compression of a co-crystal of indomethacin and saccharin

The co-crystalline structure of the non-steroidal, anti-inflammatory indomethacin with the non-toxic, Generally Regarded As Safe (GRAS) sweetener component saccharin was investigated up to 6.33 GPa using a Diamond Anvil Cell (DAC). Single crystal X-ray diffraction measurements show that the co-crystal remains in the same triclinic, P-1, phase throughout the compression with a significant reduction in void space (155.69 to 55.61Å3). Information on the response of different types of intermolecular interactions to external force at the same time is enabled by the use of a co-crystal. We have rationalised that the length and compression rate of the saccharin amide dimer in the co-crystal is caused by the dimer sitting in a ‘pocket’ surrounded by the indomethacin framework. This framework reduces the effects of molecular packing on the dimer allowing for an ideal hydrogen bonding geometry

Unraveling the Impact of High-Order Silk Structures on Molecular Drug Binding and Release Behaviors

Silk continues to amaze: over the past decade, new research threads have emerged that include the use of silk fibroin for advanced pharmaceutics, including its suitability for drug delivery. Despite this ongoing interest, the details of silk fibroin structures and their subsequent drug interactions at the molecular level remain elusive, primarily because of the difficulties encountered in modeling the silk fibroin molecule. Here, we generated an atomistic silk model containing amorphous and crystalline regions. We then exploited advanced well-tempered metadynamics simulations to generate molecular conformations that we subsequently exposed to classical molecular dynamics simulations to monitor both drug binding and release. Overall, this study demonstrated the importance of the silk fibroin primary sequence, electrostatic interactions, hydrogen bonding, and higher-order conformation in the processes of drug binding and release. © Copyright © 2019 American Chemical Society

Long-lived space observatories for astronomy and astrophysics

NASA's plan to build and launch a fleet of long-lived space observatories that include the Hubble Space Telescope (HST), the Gamma Ray Observatory (GRO), the Advanced X Ray Astrophysics Observatory (AXAF), and the Space Infrared Telescope Facility (SIRTF) are discussed. These facilities are expected to have a profound impact on the sciences of astronomy and astrophysics. The long-lived observatories will provide new insights about astronomical and astrophysical problems that range from the presence of planets orbiting nearby stars to the large-scale distribution and evolution of matter in the universe. An important concern to NASA and the scientific community is the operation and maintenance cost of the four observatories described above. The HST cost about $1.3 billion (1984 dollars) to build and is estimated to require$160 million (1986 dollars) a year to operate and maintain. If HST is operated for 20 years, the accumulated costs will be considerably more than those required for its construction. Therefore, it is essential to plan carefully for observatory operations and maintenance before a long-lived facility is constructed. The primary goal of this report is to help NASA develop guidelines for the operations and management of these future observatories so as to achieve the best possible scientific results for the resources available. Eight recommendations are given

Microfluidic-assisted silk nanoparticle tuning

Silk is now making inroads into advanced pharmaceutical and biomedical applications. Both bottom-up and top-down approaches can be applied to silk and the resulting aqueous silk solution can be processed into a range of material formats, including nanoparticles. Here, we demonstrate the potential of microfluidics for the continuous production of silk nanoparticles with tuned particle characteristics. Our microfluidic-based design ensured efficient mixing of different solvent phases at the nanoliter scale, in addition to controlling the solvent ratio and flow rates. The total flow rate and aqueous : solvent ratios were important parameters affecting yield (1 mL min−1 > 12 mL min−1). The ratios also affected size and stability; a solvent : aqueous total flow ratio of 5 : 1 efficiently generated spherical nanoparticles 110 and 215 nm in size that were stable in water and had a high beta-sheet content. These 110 and 215 nm silk nanoparticles were not cytotoxic (IC50 > 100 μg mL−1) but showed size-dependent cellular trafficking. Overall, microfluidic-assisted silk nanoparticle manufacture is a promising platform that allows control of the silk nanoparticle properties by manipulation of the processing variables

Assessing the impact of the physical properties of industrially produced carbon nanotubes on their interaction with human primary macrophages in vitro

Currently it is not fully understood how carbon nanotubes (CNTs) may affect human health. Despite this, CNTs are produced at a tonne mass scale yearly. Due to their large production and intended use within a variety of applications it is imperative that a clear understanding of the hazard potential of CNTs is gained. The aim of this study therefore was to assess the impact of five different industrially produced CNTs which varied in their physical properties on the viability of human monocyte derived macrophages (MDM), and subsequently, at sub-lethal concentrations (0.005-0.02 mg/mL), their ability to cause oxidative stress and a pro-inflammatory response in these important immune cells over a 24-h period. None of the CNTs caused significant cytotoxicity up to 0.02 mg/mL after 24 h. Only the long multi-walled CNTs (MWNCTs) caused a significant, dose-dependent (0.005-0.02 mg/mL) reactive oxygen species production, whilst bundled MWCNTs showed a significant tumor necrosis factor alpha release after 24 h exposure at 0.02 mg/mL. No effects were observed for either tangled MWCNTs or short MWCNTs. It can be concluded from the findings of the present study that the industrially produced CNTs studied can cause hazardous effects in vitro that may be associated with their physical propertie

Pulsar magnetic alignment and the pulsewidth-age relation

Using pulsewidth data for 872 isolated radio pulsars we test the hypothesis that pulsars evolve through a progressive narrowing of the emission cone combined with progressive alignment of the spin and magnetic axes. The new data provide strong evidence for the alignment over a time-scale of about 1 Myr with a log standard deviation of around 0.8 across the observed population. This time-scale is shorter than the time-scale of about 10 Myr found by previous authors, but the log standard deviation is larger. The results are inconsistent with models based on magnetic field decay alone or monotonic counter-alignment to orthogonal rotation. The best fits are obtained for a braking index parameter n_gamma approximately equal to 2.3, consistent the mean of the six measured values, but based on a much larger sample of young pulsars. The least-squares fitted models are used to predict the mean inclination angle between the spin and magnetic axes as a function of log characteristic age. Comparing these predictions to existing estimates it is found that the model in which pulsars are born with a random angle of inclination gives the best fit to the data. Plots of the mean beaming fraction as a function of characteristic age are presented using the best-fitting model parameters.Comment: 13 pages, 11 figures, Accepted for publication in MNRA

Unraveling the impact of high-order silk structures on molecular drug binding and release behaviors

Silk continues to amaze: over the past decade, new research threads have emerged that include the use of silk fibroin for advanced pharmaceutics, including its suitability for drug delivery. Despite this ongoing interest, the details of silk fibroin structures and their subsequent drug interactions at the molecular level remain elusive, primarily because of the difficulties encountered in modeling the silk fibroin molecule. Here, we generated an atomistic silk model containing amorphous and crystalline regions. We then exploited advanced well-tempered metadynamics simulations to generate molecular conformations that we subsequently exposed to classical molecular dynamics simulations to monitor both drug binding and release. Overall, this study demonstrated the importance of the silk fibroin primary sequence, electrostatic interactions, hydrogen bonding, and higher order conformation in the processes of drug binding and release