A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery

SiViT

The Signalling Visualisation Toolkit (SiViT), is a cancer cell signalling network visualisation tool that provides an intuitive games-based real-time interactive interface to models of cancer cell dynamics. SiViT provides a games-technology approach to unlocking the complexities of cancer cells to anti-cancer drugs. SiViT can load a wide range of biological models in the form of SBML, but the work focuses on the Abertay Cancer cell model. SiViT allows clinicians and biologists to directly interact with the cancer cell model, introducing drugs or mutations. SiViT animates the effects of these introductions on the internal elements of the cell pathways and nodes. Showing how the cell network responds to these introductions such as increased or decreased activity, or re-rerouting to bypass the effected region of the network. Indicating the effectiveness of drugs, drug resistance and suggesting area for further experimentation.Offering bi-directional interaction and explorations. With drug inserts updating the model in real-time. Timings of drug introduction or mutations is crucial and SiViT allows for changes to occur at specific timings and model the result. This is critical in the exploration of combination therapees. SiViT follows the visual guidelines from existing literature on cell networking and dynamics, with ongoing HCI work being conducted to ensure information is visualised accessibly. SiViT was part of the UKRI Main Exhibition Stand at the American Association for the Advancement of Science 2019 conference. SiViT was the catalyst for a new 4-year project led by Macmillan Cancer Support on optimising health and social care service provision through interactive network visualisation.<br/

Age-dependent effect of Alzheimer’s risk variant of CLU on EEG alpha rhythm in non-demented adults

Polymorphism in the genomic region harboring the CLU gene (rs11136000) has been associated with the risk for Alzheimer’s disease (AD). CLU C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated CLU genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20–80) divided into young (age range 20–50) and old (age range 51–80) cohorts and stratified by CLU polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ε4 allele were included in the study. The homozygous presence of the AD risk variant CLU CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of CLU genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the CLU genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the CLU CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD

A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery:SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling byclinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery

Photonic Bandgap Quasi-Crystals for Integrated WDM Devices

ABSTRACT A novel concept of Photonic Bandgap Quasi-Crystal (PBQC) as a platform for planar integrated WDM optical devices is proposed. The PBQC can be lithographically fabricated in a planar waveguide as a computer-generated two-dimensional hologram. In this approach the spectral selectivity of Bragg gratings, f ocusing properties of elliptical mirrors, superposition properties of thick holograms, photonic bandgaps of periodic structures, and flexibility of lithography on planar waveguides are combined. In distinction to conventional combination of independent planar Bragg gratings, in PBQC we create multiple bandgaps by synthesizing a synergetic super-grating of a number of individual sub-gratings. The device spectral selectivity is determined by those of the sub-gratings. The super-grating comprises million(s) of dashes etched on an interface of a planar waveguide. Each dash is a binary feature placed by a computer program to serve simultaneously many channels. For realization of PBQC devices the software for generating super-gratings (GDS-II format) and 2-D simu lation of its transfer function was developed. Direct e-beam writing and photolithography were used for manufacturing PBQC structures. For verification of the ideas behind the concept a number of multichannel MUX/DEMUX devices have been manufactured and experimentally tested. The results of detailed experimental study of 4-and 16-channel devices will be presented. Channel isolation ~30 dB was achieved in 4-channel devices. The applications of PBQC platform for integrated light wave circuits are discussed