InFlo: a novel systems biology framework identifies cAMP-CREB1 axis as a key modulator of platinum resistance in ovarian cancer.

Characterizing the complex interplay of cellular processes in cancer would enable the discovery of key mechanisms underlying its development and progression. Published approaches to decipher driver mechanisms do not explicitly model tissue-specific changes in pathway networks and the regulatory disruptions related to genomic aberrations in cancers. We therefore developed InFlo, a novel systems biology approach for characterizing complex biological processes using a unique multidimensional framework integrating transcriptomic, genomic and/or epigenomic profiles for any given cancer sample. We show that InFlo robustly characterizes tissue-specific differences in activities of signalling networks on a genome scale using unique probabilistic models of molecular interactions on a per-sample basis. Using large-scale multi-omics cancer datasets, we show that InFlo exhibits higher sensitivity and specificity in detecting pathway networks associated with specific disease states when compared to published pathway network modelling approaches. Furthermore, InFlo's ability to infer the activity of unmeasured signalling network components was also validated using orthogonal gene expression signatures. We then evaluated multi-omics profiles of primary high-grade serous ovarian cancer tumours (N=357) to delineate mechanisms underlying resistance to frontline platinum-based chemotherapy. InFlo was the only algorithm to identify hyperactivation of the cAMP-CREB1 axis as a key mechanism associated with resistance to platinum-based therapy, a finding that we subsequently experimentally validated. We confirmed that inhibition of CREB1 phosphorylation potently sensitized resistant cells to platinum therapy and was effective in killing ovarian cancer stem cells that contribute to both platinum-resistance and tumour recurrence. Thus, we propose InFlo to be a scalable and widely applicable and robust integrative network modelling framework for the discovery of evidence-based biomarkers and therapeutic targets.

Mechanical properties of carbon nanotube/polymer composites.

The remarkable mechanical properties of carbon nanotubes, such as high elastic modulus and tensile strength, make them the most ideal and promising reinforcements in substantially enhancing the mechanical properties of resulting polymer/carbon nanotube composites. It is acknowledged that the mechanical properties of the composites are significantly influenced by interfacial interactions between nanotubes and polymer matrices. The current challenge of the application of nanotubes in the composites is hence to determine the mechanical properties of the interfacial region, which is critical for improving and manufacturing the nanocomposites. In this work, a new method for evaluating the elastic properties of the interfacial region is developed by examining the fracture behavior of carbon nanotube reinforced poly (methyl methacrylate) (PMMA) matrix composites under tension using molecular dynamics simulations. The effects of the aspect ratio of carbon nanotube reinforcements on the elastic properties, i.e. Young's modulus and yield strength, of the interfacial region and the nanotube/polymer composites are investigated. The feasibility of a three-phase micromechanical model in predicting the elastic properties of the nanocomposites is also developed based on the understanding of the interfacial region.

Process synthesis and optimization for the production of carbon nanostructures.

A swirled fluidized bed chemical vapour deposition (SFCVD) reactor has been manufactured and optimized to produce carbon nanostructures on a continuous basis using in situ formation of floating catalyst particles by thermal decomposition of organometallic ferrocene. During the process optimization, carbon nanoballs were produced in the absence of a catalyst at temperatures higher than 1000 degrees C, while carbon nanofibres, single-walled carbon nanotubes, helical carbon nanotubes, multi-walled carbon nanotubes (MWCNTs) and carbon nanofibres (CNFs) were produced in the presence of a catalyst at lower temperatures of between 750 and 900 degrees C. The optimum conditions for producing carbon nanostructures were a temperature of 850 degrees C, acetylene flow rate of 100 ml min(-1), and acetylene gas was used as the carbon source. All carbon nanostructures produced have morphologies and diameters ranging from 15 to 200 nm and wall thicknesses between 0.5 and 0.8 nm. In comparison to the quantity of MWCNTs produced with other methods described in the literature, the SFCVD technique was superior to floating catalytic CVD (horizontal fixed bed) and microwave CVD but inferior to rotary tube CVD.

Nanoelectronic interface for lab-on-a-chip devices.

Innovations in microfabricated analytical devices integrated with microelectronic circuits and biological cells show promising results in detection, diagnosis and analysis. Planar metallic microelectrodes are widely used for the electrical interface with the biological cells. Issues with the current microelectrode array design are the difficulty in selective integration with a cell, the size dependency of its impedance and the large amount of noise in the circuit due to this mismatch. It is quite evident that an approach utilising nanotechnology can solve some of these problems by yielding efficient electrical interconnections. The design and development of a planar microelectrode array integrated with vertically aligned nanowires for lab-on-a-chip (LoC) device applications are presented. The nanowire integrated microelectrode arrays for LoC devices show promising results with respect to impedance control due to increased surface area. The authors have fabricated nanowire integrated microelectrode arrays on silicon and flexible polymer substrates using the template method. A high degree of specific growth is achieved by controlling the nanowire synthesis parameters. An attempt has been made to integrate biological cells into the nanowires by culturing endothelial cells onto the microelectrode array.

Shape identification of underwater objects using backscattered frequency signals.

The inverse problems in the area of the acoustic scattering often concern the determination of the size, shape, and orientation of an object using the scattered field data. This paper presents a method to retrieve the shape information of an underwater object using illuminated lengths, which can be obtained from the ramp response signatures of the object. An ellipsoidal object submerged in water is considered. Both the low and high backscattered frequency data have been employed to calculate the illuminated lengths. The calculated results show that the illuminated lengths will be more accurate, if only the high-frequency-range data are employed. For ellipsoidal objects, any three illuminated lengths that are not of a same plane can in theory fully determine the shape of the ellipsoid. As the calculated illuminated lengths contain numerical errors, the calculated results of the three semiaxes of the ellipsoid will deteriorate and become unreliable, especially when the three incident directions of the illuminated lengths become close. The reason is that the condition number of the coefficient matrix becomes big in such situations, which leads to an increase of the relative error upper limit in the calculated results. To avoid such errors in close incident wave cases, it is found that the use of more than three incident waves works very well in the shape identification of an underwater object.

Simple expressions for scattering by a chiral elliptic cylinder of small cross-sectional dimensions.

An integral-equation method is used to derive simple expressions for the field scattered by infinitely long chiral cylinders of elliptic cross sections; the derived expressions are applicable when the cross-sectional dimensions are electrically small. Reductions for the scattering of plane waves are obtained. The derived results can be extended to thin strips.

Dilute random distribution of small chiral spheres.

The problem solved here consists of estimating the effective-medium properties of a chiral composite made of a dilute concentration of small noninteracting chiral spheres, randomly suspended in free space. Volume integral equations, to determine the scattering characteristics of an inhomogeneous chiral scatterer, are obtained. These equations are used to derive the general electromagnetic polarizability matrix of a small, homogeneous, chiral sphere embedded in free space. Finally, from the polarizability matrix, several conclusions regarding the effective properties of the chiral composite are obtained.

Time-harmonic and time-dependent dyadic Green's functions for some uniaxial gyroelectromagnetic media.

Time-harmonic and time-dependent Green's functions are derived for a lossless, uniaxial gyroelectromagnetic medium whose permeability tensor is a scalar multiple of its permittivity tensor, and their properties are investigated.

Scattered intensity of a wave propagating in a discrete random medium.

The present paper aims at a computational scheme to obtain numerical results for the second moment (average intensity) of a wave field propagating in a medium consisting of randomly distributed scatterers, not necessarily simple in shape. A formalism is presented that parallels the diagram method and shows the approximations made in the intensity computation of anisotropic scattering whenever finite size scatterers with a considerable concentration are considered. The back and forth scattering between a pair of scatterers, which has been neglected in the ladder approximation, automatically appears in our formalism taking into account all the multiple scattering between two particles through the pair statistics. Sample numerical results for average intensity scattered by particles are presented and compared to some microwave and optical measurements.