A random forest model for predicting the crystallisability of organic molecules

A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ∼70% accuracy. The predictive model is based on calculated molecular descriptors and published experimental crystallisation propensities of a library of substituted acylanilides

Carbamazepine on a carbamazepine monolayer forms unique 1D supramolecular assemblies

High-resolution STM imaging of the structures formed by carbamazepine molecules adsorbed onto a pseudo-ordered carbamazepine monolayer on Au(111) shows the formation of previously unreported 1-dimensional supramolecular assemblies

Degradation behavior of silk nanoparticles – enzyme responsiveness

Silk nanoparticles are viewed as promising vectors for intracellular drug delivery as they can be taken up into cells by endocytosis and trafficked to lysosomes, where lysosomal enzymes and the low pH trigger payload release. However, the subsequent degradation of the silk nanoparticles themselves still requires study. Here, we report the responsiveness of native and PEGylated silk nanoparticles to degradation following exposure to proteolytic enzymes (protease XIV and α-chymotrypsin) and papain, a cysteine protease. Both native and PEGylated silk nanoparticles showed similar degradation behavior over a 20 day exposure period (degradation rate: protease XIV > papain >> chymotrypsin). Within 1 day, the silk nanoparticles were rapidly degraded by protease XIV, resulting in a ~50% mass loss, an increase in particle size, and a reduction in the amorphous content of the silk secondary structure. By contrast, 10 days of papain treatment was necessary to observe any significant change in nanoparticle properties, and chymotrypsin treatment had no effect on silk nanoparticle characteristics over the 20-day study period. Silk nanoparticles were also exposed ex vivo to mammalian lysosomal enzyme preparations to mimic the complex lysosomal microenvironment. Preliminary results indicated a 45% reduction in the silk nanoparticle size over a 5-day exposure. Overall, the results demonstrate that silk nanoparticles undergo enzymatic degradation, but the extent and kinetics are enzyme specific

Degradation Behavior of Silk Nanoparticles - Enzyme Responsiveness

Silk nanoparticles are viewed as promising vectors for intracellular drug delivery as they can be taken up into cells by endocytosis and trafficked to lysosomes, where lysosomal enzymes and the low pH trigger payload release. However, the subsequent degradation of the silk nanoparticles themselves still requires study. Here, we report the responsiveness of native and PEGylated silk nanoparticles to degradation following exposure to proteolytic enzymes (protease XIV and α-chymotrypsin) and papain, a cysteine protease. Both native and PEGylated silk nanoparticles showed similar degradation behavior over a 20 day exposure period (degradation rate: protease XIV > papain ≫ α-chymotrypsin). Within 1 day, the silk nanoparticles were rapidly degraded by protease XIV, resulting in a ∼50% mass loss, an increase in particle size, and a reduction in the amorphous content of the silk secondary structure. By contrast, 10 days of papain treatment was necessary to observe any significant change in nanoparticle properties, and α-chymotrypsin treatment had no effect on silk nanoparticle characteristics over the 20-day study period. Silk nanoparticles were also exposed ex vivo to mammalian lysosomal enzyme preparations to mimic the complex lysosomal microenvironment. Preliminary results indicated a 45% reduction in the silk nanoparticle size over a 5-day exposure. Overall, the results demonstrate that silk nanoparticles undergo enzymatic degradation, but the extent and kinetics are enzyme-specific

Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.publishedVersio

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

Changes to inhaled corticosteroid dose when initiating combination inhaler therapy in long-acting β agonist-naive patients with asthma : a retrospective database analysis

Retrospective prescribing data were obtained from 46 general practice surgeries in NHS Scotland. Patients with asthma who were naïve to previous long-acting β agonist therapy and initiated combination inhaler therapy in 2008–2009 were classified according to the inhaled corticosteroid (ICS) dose in their combination inhaler compared with the highest dose of ICS they received before initiation. Among the 685 patients (541 (79.0%) who had been prescribed an ICS previously), those originally on low-, medium- or high-dose ICS were changed to high-dose combination therapy in 122/250 (48.8%), 94/151 (62.3%) or 85/113 (75.2%) cases in each ICS dose category, respectively. These results suggest that evaluation of appropriate high-dose ICS prescribing in general practice is needed

Manufacture and drug delivery applications of silk nanoparticles

Silk is a promising biopolymer for biomedical and pharmaceutical applications due to its outstanding mechanical properties, biocompatibility and biodegradability, as well its ability to protect and subsequently release its payload in response to a trigger. While silk can be formulated into various material formats, silk nanoparticles are emerging as promising drug delivery systems. Therefore, this article covers the procedures for reverse engineering silk cocoons to yield a regenerated silk solution that can be used to generate stable silk nanoparticles. These nanoparticles are subsequently characterized, drug loaded and explored as a potential anticancer drug delivery system. Briefly, silk cocoons are reverse engineered first by degumming the cocoons, followed by silk dissolution and clean up, to yield an aqueous silk solution. Next, the regenerated silk solution is subjected to nanoprecipitation to yield silk nanoparticles – a simple but powerful method that generates uniform nanoparticles. The silk nanoparticles are characterized according to their size, zeta potential, morphology and stability in aqueous media, as well as their ability to entrap a chemotherapeutic payload and kill human breast cancer cells. Overall, the described methodology yields uniform silk nanoparticles that can be readily explored for a myriad of applications, including their use as a potential nanomedicine

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