Effects of Relative Positions of Defect to Inclusion on Nanocomposite Strength.

It is generally accepted that material inhomogeneity causes stress concentrations at the interface and thus reduces the overall strength of a composite. To overcome this reduction in strength, some groups experimented on coating the nanoinclusions with a layer of rubbery material, aiming for higher energy absorption. However, representative volume element (RVE) nanocomposite models, established with randomly distributed core-shell nanoparticles and single nanoparticle cells, show that the enhancement in strength observed in some experiments remains elusive computationally. By including a pre-existing crack in the matrix of the RVE, the stress concentration at the crack tip is reduced for cases where the nanoparticle and precrack are aligned away from the loading direction. This suggests that stress concentrations around inherent defects in materials can sometimes be reduced by adding nanoparticles to improve material strength. The effect is reversed if the crack and nanoparticle are aligned towards the loading direction. Parametric studies were also carried out in terms of the relative stiffness of the nanoparticle to the matrix and crack length. Validation tests were performed on 3D RVEs with an elliptical crack as the initial defect, and the results match with the 2D findings.

High density mechanical energy storage with carbon nanothread bundle.

The excellent mechanical properties of carbon nanofibers bring promise for energy-related applications. Through in silico studies and continuum elasticity theory, here we show that the ultra-thin carbon nanothreads-based bundles exhibit a high mechanical energy storage density. Specifically, the gravimetric energy density is found to decrease with the number of filaments, with torsion and tension as the two dominant contributors. Due to the coupled stresses, the nanothread bundle experiences fracture before reaching the elastic limit of any individual deformation mode. Our results show that nanothread bundles have similar mechanical energy storage capacity compared to (10,10) carbon nanotube bundles, but possess their own advantages. For instance, the structure of the nanothread allows us to realize the full mechanical energy storage potential of its bundle structure through pure tension, with a gravimetric energy density of up to 1.76 MJ kg-1, which makes them appealing alternative building blocks for energy storage devices.

A theoretical and numerical study on the mechanics of vibro-acoustic modulation.

Vibro-acoustic modulation (VAM) is a form of a non-destructive testing technique used in nonlinear acoustic methods for the detection of defects. It comprises of exciting the structure with a dual frequency sinusoidal signal and studying the interaction of this wave with the underlying defect. In this work a theoretical study on the mechanics of VAM is presented for a generic material body. The roles of different types of defect on the response of the material are analyzed. The theoretical analysis shows the origins of the nonlinear frequencies in the form of higher harmonics and sidebands commonly observed in the output response of VAM excitation. In addition, the analysis provides insights on the relationships between the magnitudes of the nonlinear responses and those of the input vibrations, and on the physical origins of the nonlinear responses. For a physical visualization of the nonlinear vibrations associated with the theory a finite element analysis of VAM is also performed. The model looks into the plausibility of using VAM for the mapping of damage in physical structures. The model is also used to investigate the effects of the defect size and defect depth on the nonlinear mechanism of VAM.

The best features of diamond nanothread for nanofibre applications.

Carbon fibres have attracted interest from both the scientific and engineering communities due to their outstanding physical properties. Here we report that recently synthesized ultrathin diamond nanothread not only possesses excellent torsional deformation capability, but also excellent interfacial load-transfer efficiency. Compared with (10,10) carbon nanotube bundles, the flattening of nanotubes is not observed in diamond nanothread bundles, which leads to a high-torsional elastic limit that is almost three times higher. Pull-out tests reveal that the diamond nanothread bundle has an interface transfer load of more than twice that of the carbon nanotube bundle, corresponding to an order of magnitude higher in terms of the interfacial shear strength. Such high load-transfer efficiency is attributed to the strong mechanical interlocking effect at the interface. These intriguing features suggest that diamond nanothread could be an excellent candidate for constructing next-generation carbon fibres.

Finite element modeling of nonlinear acoustics/ultrasonics for the detection of closed delaminations in composites.

Linear ultrasonics methods based on the principle of reflection, transmission, dissipation of sound waves have been traditionally used to detect delaminations in composite structures. However, when the delamination is in very early stages such that it is almost closed, or closed due to a compressive load, the linear methods may fail to detect such cases of delaminations. Nonlinear acoustics/ultrasonics have shown potential to identify damages in composite structures which are difficult to detect using conventional linear ultrasonic methods. The nonlinear method involves exciting the structure with a sinusoidal signal of certain (or multiple) frequency and observing the vibrations of the structure. The vibrations of the damage region differ significantly from intact regions and can be used to identify the damage. However due to the complex and varying nature of the nonlinear phenomena created by the interaction between the exciting signal and the damage, there are many variables at play which can lead to success or failure of the method. While experiments lead to the establishment of the method to be used as a damage detection technique, numerical simulations can help to explain the various phenomena associated with nonlinearity. This work presents a quick approach to model the nonlinear behavior caused by closed delaminations. The model is validated with a previously available approach for nonlinear vibrations modeling and a comparison is made between the two. The local nature of the nonlinearity enables to map out the area of damage in the structure. Additionally, a few parametric studies are performed to study the effect of various parameters related to the nonlinear phenomenon.

From brittle to ductile: a structure dependent ductility of diamond nanothread.

As a potential building block for the next generation of devices/multifunctional materials that are spreading in almost every technology sector, one-dimensional (1D) carbon nanomaterial has received intensive research interests. Recently, a new ultra-thin diamond nanothread (DNT) has joined this palette, which is a 1D structure with poly-benzene sections connected by Stone-Wales (SW) transformation defects. Using large-scale molecular dynamics simulations, we found that this sp(3) bonded DNT can transition from brittle to ductile behaviour by varying the length of the poly-benzene sections, suggesting that DNT possesses entirely different mechanical responses than other 1D carbon allotropes. Analogously, the SW defects behave like a grain boundary that interrupts the consistency of the poly-benzene sections. For a DNT with a fixed length, the yield strength fluctuates in the vicinity of a certain value and is independent of the "grain size". On the other hand, both yield strength and yield strain show a clear dependence on the total length of DNT, which is due to the fact that the failure of the DNT is dominated by the SW defects. Its highly tunable ductility together with its ultra-light density and high Young's modulus makes diamond nanothread ideal for the creation of extremely strong three-dimensional nano-architectures.

First BRET-based screening assay performed in budding yeast leads to the discovery of CDK5/p25 interaction inhibitors.

The protein kinase CDK5 (cyclin-dependent kinase 5) is activated through its association with a cyclin-like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up-regulates the kinase activity and modifies the substrate specificity. ATP-mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)-based screening assay in yeast to discover protein-protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high-specificity drug candidates.

An in silico approach for the discovery of CDK5/p25 interaction inhibitors.

The lack of selectivity of all existing ATP competitive inhibitors for a single cyclin-dependent kinase (CDK) has led us to redirect the structure-based molecule design from targeting the classic ATP-binding pocket in CDK5 toward the CDK5/p25 interface. The aim was to seek novel inhibition mechanisms to interrupt protein-protein interactions. A combined strategy of alanine-scanning calculations for locating binding sites, virtual screening for small molecules, molecular dynamics simulations for examining the binding stability of virtual screening hits and bio-assays for testing the level of inhibition was set up and used to explore novel inhibitors capable of interrupting the interactions between the proteins, and consequently of inhibiting the kinase activity. Two compounds were shown to inhibit the complex formation between CDK5 and p25 through p25 binding. They could open avenues for the discovery of new types of structures that prevent interactions between CDK5 and p25 or other CDK and activator proteins, and, more importantly, provide leads in the development of selective inhibitors among CDKs.

Mechanism of CDK5 activation revealed by steered molecular dynamics simulations and energy calculations.

In the current work, CDK5/p25 complexes were pulled apart by applying external forces with steered molecular dynamics (SMD) simulations. The crucial interactions between the kinase and the activation protein were investigated and the SMD simulations showed that several activation-relevant motifs of CDK5 leave p25 in sequence during the pulling and lead to an apo-CDK2 like CDK5 structure after separation. Based on systematic examination of hydrogen bond breaking and classical MD/molecular mechanics-generalized Born/surface area) (MM-GBSA) calculations, a CDK5 activation mechanism by p25 is suggested. This is the first step towards the systemic development of CDK inhibitors and the mechanism proposed could lead to a better understanding of the protein-protein recognition characteristics between the kinase and its activator.

Explaining the inhibition of cyclin-dependent kinase 5 by peptides derived from p25 with molecular dynamics simulations and MM-PBSA.

A cyclin-dependent kinase (CDK) 5 inhibitory peptide (CIP) from p25 was recently reported to inhibit CDK5/p25 activity in vitro but had no effect on endogenous cdc2 kinase activity. This may lead to a specific CDK5 inhibition strategy in the treatment of neurodegeneration. However, the mechanism of the inhibition remains unclear. In this work, molecular dynamics simulations and energy decomposition calculation models were set up to investigate the deregulation mechanisms of CIP on CDK5 activity. The results show that truncation of the N, and C terminals of p25 introduces important conformational changes into a hydrophobic pocket that is crucial for accommodating Ile153 on the activation loop of CDK5. In addition, such truncations lead to distortion and displacement of the activation loop and consequently affect binding of the substrate peptide. New inhibition sites for selectively inhibiting the activity of CDK5 are also suggested.

Synthesis and evaluation of functionalized isoindigos as antiproliferative agents.

A series of functionalized isoindigos structurally related to meisoindigo (1-methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1-(p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3'-oxime on leukemic K562 and liver HuH7 cells were identified. Structure-activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition.

Geometry dependent I-V characteristics of silicon nanowires.

The current-voltage (I-V) characteristics of small-diameter hydrogenated and pristine silicon nanowires (SiNWs) are calculated by nonequilibrium Green's function combined with density functional theory. We show that the I-V characteristics depend strongly on length, growth orientation, and surface modification of the SiNWs. In particular, a length of 3 nm is suggested for the nanowires to retrieve its intrinsic conducting properties from the influences of both the electrodes and metal/semiconductor mismatched surface contact; surface reconstruction would enhance the conductance in hydrogenated SiNW, which is explained by the extra conducting eigenchannel found in the transmission spectrum, suggesting possible surface conducting channel. Discussions with available experimental data are given.

Structure-mechanical property of individual cobalt oxide nanowires.

We present a comprehensive approach to address the correlation between mechanical properties of nanowires (NWs) with their characteristic size, microstructure, and chemical composition. Using this technique, the Young's modulus of Co3O4 NWs with different sizes was evaluated. Thermal annealing in inert atmosphere was found to induce chemical reduction of as-grown Co3O4 NWs into CoO NWs without modifying their geometrical shape. Both Co3O4 and CoO NWs exhibited a size-dependent variation in Young's modulus.

One-dimensional iron-cyclopentadienyl sandwich molecular wire with half metallic, negative differential resistance and high-spin filter efficiency properties.

We present a theoretical study on a series of novel organometallic sandwich molecular wires (SMWs), which are constructed with alternating iron atoms and cyclopentadienyl (Cp) rings, using DFT and nonequilibrium Green's function techniques. It is found that that the SMWs are stable, flexible structures having half-metallic (HM) properties with 100% negative spin polarization near the Fermi level in the ground state. Some SMWs of finite size show a nearly perfect spin filter effect (SFE) when coupled between ferromagnetic electrodes. Moreover, their I-V curves exhibit negative differential resistance (NDR), which is essential for certain electronic applications. The SMWs are the first linear molecules with HM, high SFE, and NDR and can be easily synthesized. In addition, we also analyze the underlying mechanisms via the transmission spectra and spin-dependent calculations. These findings strongly suggest that the SMWs are promising materials for application in molecular electronics.

Study of the inhibition of cyclin-dependent kinases with roscovitine and indirubin-3'-oxime from molecular dynamics simulations.

Molecular dynamics simulations were performed to elucidate the interactions of CDK2 and CDK5 complexes with three inhibitors: R-roscovitine, S-roscovitine, and indirubin-3'-oxime. The preference of the two complexes for R-roscovitine over the S enantiomer, as reported by the experiment, was also found by the simulations. More importantly, the simulations showed that the cause of the stronger affinity for the R enantiomer is the presence of an important hydrogen bond between R-roscovitine and the kinases not found with S-roscovitine. The simulations also showed two amino acid mutations in the active site of CDK5/R-roscovitine that favor binding-enhanced electrostatic contributions, making the inhibitor more effective for CDK5 than for CDK2. This suggests that the effectiveness of roscovitine-like inhibitors can be improved by enhancing their electrostatic interaction with the kinases. Finally, molecular mechanics-Possion-Boltzmann/surface area calculations of the CDK5/indirubin-3'-oxime system in both water-excluded and water-included environments gave significantly different electrostatic contributions to the binding. The simulations detected the displacement of a water molecule in the active site of the water-included CDK/indirubin-3'-oxime system. This resulted in a more conserved binding pattern than the water-excluded structure. Hence, in the design of new indirubin-like inhibitors, it is important to include the water molecule in the analysis.

Molecular dynamics simulations on the inhibition of cyclin-dependent kinases 2 and 5 in the presence of activators.

Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.

Creating polymer structures of tunable electric functionality by nanoscale discharge-assisted cross-linking and oxygenation.

We report the creation of polymeric micro/nanostructures which exhibit distinct chemical and physical characteristics from the matrix poly(N-vinyl carbazole) (PVK). The structure formation is based on atomic force microscopy (AFM) facilitated cross-linking and oxygenation. The reaction of PVK with AFM lithographically induced nanoscale discharge produces raised structures in which bridge oxygen links neighboring carbazole groups. The cross-linking by bridge oxygen converts the initially insulating PVK matrix to chemically modified conducting patterns through the formation of extended pi-conjugations. A comprehensive AFM, PES (photoelectron spectroscopy), FTIR (Fourier transform infrared spectroscopy), and DFT (density functional theory) analysis is presented to address the chemophysical identity of the patterned structures. Our results demonstrate new capabilities of AFM nanolithography in generating heterogeneous functional structures in a polymer matrix.