Investigation of the binding network of IGF-I on the cavity surface of IGFBP4

Insulin-like growth factor-binding proteins (IGFBPs) control bioactivity and distribution of insulin-like growth factors (IGFs) through high-affinity complex of IGFBP and IGF. To get more insight into the binding interaction of IGF system, the site-directed mutagenesis and force-driving desorption methods were employed to study the interaction mechanism of IGFBP4 and IGF-I by molecular dynamics (MD) simulation. In IGF-I, residues Gly7 to Asp12 were found to be the hot spots and they mainly anchored on the N-domain of IGFBP4. The contact area, the shape and size of protein, the surroundings of the binding site, the hydrophobic and electrostatic interaction between the two proteins worked as a complex network to regulate the protein-protein interaction. It was also found that the unfolding of the helix was not inevitable in the mutant, and it could be regulated by careful selection of the substituted amino acid.

Interplay between human microglia and neural stem/progenitor cells in an allogeneic co‐culture model

Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co‐culture model. In co‐cultures, both NPCs and microglia showed increased survival and proliferation compared with mono‐cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono‐cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co‐cultures, whereas the release of transforming growth factor‐β was increased suggesting anti‐inflammatory features of the co‐cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.     

First-principles study of the structural transformation, electronic structure, and optical properties of crystalline 2,6-diamino-3,5-dinitropyrazine-1-oxide under high pressure

Periodic first-principles calculations have been performed to study the effect of high pressure on the geometric, electronic, and absorption properties of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) under hydrostatic pressures of 0–50 GPa. Obvious irregular changes in lattice constants, unit-cell angles, bond lengths, bond angles, and band gaps showed that crystalline LLM-105 undergoes four structural transformations at 8, 17, 25, and 42 GPa, respectively. The intramolecular H-bonds were strong at pressures of 0–41 GPa but weakened in the range 42–50 GPa. The lengths of the intermolecular H-bonds (<1.47 Å) indicated that these H-bonds have covalent character and tend to induce the formation of a new twelve-membered ring. Analysis of the DOS showed that the interactions between electrons, especially the valence electrons, strengthen under the influence of pressure. The p states play a very important role in chemical reactions of LLM-105. The absorption spectrum of LLM-105 displayed more bands—as well as stronger bands—in the fundamental absorption region when the pressure was high rather than low. A new absorption peak due to O–H stretching appeared at 18.3 eV above 40 GPa, indicating that covalent O–H bonds and a new twelve-membered ring are present in LLM-105.     

Periodic density functional theory study of the high-pressure behavior of energetic crystalline 1,4-dinitrofurazano[3, 4-b]piperazine

A detailed study of the structural, electronic, and optical absorption properties of crystalline 1,4-dinitrofurazano[3,4-b]piperazine (DNFP) under hydrostatic pressures of 0–100 GPa was performed using periodic density functional theory. As the pressure increases, the lattice constants and cell volumes calculated by LDA gradually approach those obtained by GGA-PW91. It was found that the structure of DNFP is much stiffer in the b direction than along the a and c axes, indicating that the compressibility of the crystal is anisotropic. As the pressure increases, the band gap gradually decreases, and this decrease is more pronounced in the low-pressure range than in the high-pressure region. An analysis of the density of states showed that the electronic delocalization in DNFP gradually increases under the influence of pressure. DNFP exhibits relatively high optical activity at high pressure. As the pressure increases, the bands in the fundamental absorption region of the absorption spectrum of DNFP become more numerous and intense.     

Molecular dynamics study on the correlation between structure and sensitivity for defective RDX crystals and their PBXs

Molecular dynamics simulation was applied to investigate the sensitivities of perfect and defective RDX (cyclotrimethylene trinitramine) crystals, as well as their PBXs (polymer-bonded explosives) with the polymeric binder F₂₃₁₁, in the NPT (constant number of particles, constant pressure, constant temperature) ensemble using the COMPASS force field. Five kinds of defects—two dislocations, one vacancy, and two types of doping—were considered separately. The bond length distribution and the maximum (L _max) and average (L _ave) bond lengths of the N–NO₂ trigger bonds in RDX were obtained and their relationships to the sensitivities of RDX and PBXs are discussed. L _max was found to be an important structural parameter for judging the relative sensitivity, and defects were observed to have little effect on the sensitivities of PBXs, due to the strong desensitizing effect of the polymer F₂₃₁₁.     

Theoretical investigations on the synthesis mechanism of cyanuric acid from NH3 and CO2

In the synthesis of cyanuric acid from NH₃ and CO₂, urea and isocyanic acid OCNH are two pivotal intermediates. Based on density functional theory (DFT) calculations, the synthesis mechanism of cyanuric acid from NH₃ + CO₂ was investigated systematically. Urea can be synthesized from NH₃ and CO₂, and cyanuric acid can be obtained from urea or NH₃ + CO₂. In the stepwise mechanism of cyanuric acid from urea or NH₃ + CO₂, the energy barriers are relatively high, and the condition of high pressure and temperature does not decrease the energy barriers. Our theoretical model shows that cyanuric acid is actually acquired from OCNH via a one-step cycloaddition reaction.

A knowledge-based halogen bonding scoring function for predicting protein-ligand interactions

Halogen bonding, a non-covalent interaction between the halogen σ-hole and Lewis bases, could not be properly characterized by majority of current scoring functions. In this study, a knowledge-based halogen bonding scoring function, termed XBPMF, was developed by an iterative method for predicting protein-ligand interactions. Three sets of pairwise potentials were derived from two training sets of protein-ligand complexes from the Protein Data Bank. It was found that two-dimensional pairwise potentials could characterize appropriately the distance and angle profiles of halogen bonding, which is superior to one-dimensional pairwise potentials. With comparison to six widely used scoring functions, XBPMF was evaluated to have moderate power for predicting protein-ligand interactions in terms of “docking power”, “ranking power” and “scoring power”. Especially, it has a rather satisfactory performance for the systems with typical halogen bonds. To the best of our knowledge, XBPMF is the first halogen bonding scoring function that is not dependent on any dummy atom, and is practical for high-throughput virtual screening. Therefore, this scoring function should be useful for the study and application of halogen bonding interactions like molecular docking and lead optimization.

Evaluation of the performance and accuracy of Global Positioning System bug transmitters deployed on a small mammal

Recent technological advances in Global Positioning System (GPS) telemetry have allowed the production of lightweight devices suitable for use on small mammals. We evaluated the use of GPS bugs on the European hedgehog (Erinaceus europaeus) in a series of static and field tests. Static tests were conducted in five different rural habitats, affording different degrees of obstruction to satellites. GPS bug performance was good in all habitats (fix success rate (FSR): median ≥?66.8 %; location error (LE): mean ≤?13.5 m), except woodland (FSR?=?37.7 %; LE?=?15.6 m), with performance highest in the open pasture habitat (FSR?=?100 %; LE?=?6.4 m). Field tests revealed mean FSR was high (84.6 %), with the use of nesting habitats, the probable cause of most failed fixes. Despite being more expensive, GPS bugs require less survey effort and substantially lower labour costs with unlimited longevity permitting re-use in multiple seasons. We recommend the use of GPS bugs in the spatial ecological study of any small mammal in a rural environment, providing accurate and unbiased movement data. Further performance testing is recommended before deployment on species inhabiting forested habitats where reduced FSR and high LE support the alternative use of very high frequency tracking.