Service innovation and business models

Western economies are highly dependent on service innovation for their growth and employment. An important driver for economic growth is, therefore, the development of new, innovative services like electronic services, mobile end-user services, new financial or personalized services. Service innovation joins four trends that currently shape the western economies: the growing importance of services, the need for innovation, changes in consumer and business markets, and the advancements in information and communication technology (ICT).

Heating and plasma sheath effects in low-temperature, plasma-assisted growth of carbon nanofibers

Plasma sheath, nanostructure growth, and thermal models are used to describe carbon nanofiber (CNF) growth and heating in a low-temperature plasma. It is found that when the H2 partial pressure is increased, H atom recombination and H ion neutralization are the main mechanisms responsible for energy release on the catalyst surface. Numerical results also show that process parameters such as the substrate potential, electron temperature and number density mainly affect the CNF growth rate and plasma heating at low catalyst temperatures. In contrast, gas pressure, ion temperature, and the C2H2:H2 supply ratio affect the CNF growth at all temperatures. It is shown that plasma-related processes substantially increase the catalyst particle temperature, in comparison to the substrate and the substrate-holding platform temperatures.

Plasma heating effects in catalyzed growth of carbon nanofibres

A theoretical model describing the plasma-assisted growth of carbon nanofibres (CNFs) that accounts for the nanostructure heating by ion and etching gas fluxes from the plasma is developed. Using the model, it is shown that fluxes from the plasma environment can substantially increase the temperature of the catalyst nanoparticle located on the top of the CNF with respect to the substrate temperature. The difference between the catalyst and the substrate temperatures depends on the substrate width, the length of the CNF, the neutral gas density and temperature as well as the densities of the ions and atoms of the etching gas. In addition to the heating of the nanostructure, the ions and etching gas atoms from the ionized gas environment also strongly affect the CNF growth rates. Due to ion bombardment, the CNF growth rates in plasma enhanced chemical vapour deposition may be much higher than the rates in similar neutral gas-based thermal processes. The CNF growth model, which accounts for the nanostructure heating by the plasma-generated species, provides the growth rates that are in better agreement with the available experimental data on CNF growth than the models in which the heating effects are ignored.

A linear-elastic model of anisotropic tumour growth

This paper examines the effect of anisotropic growth on the evolution of mechanical stresses in a linear-elastic model of a growing, avascular tumour. This represents an important improvement on previous linear-elastic models of tissue growth since it has been shown recently that spatially-varying isotropic growth of linear-elastic tissues does not afford the necessary stress-relaxation for a steady-state stress distribution upon reaching a nutrient-regulated equilibrium size. Time-dependent numerical solutions are developed using a Lax-Wendroff scheme, which show the evolution of the tissue stress distributions over a period of growth until a steady-state is reached. These results are compared with the steady-state solutions predicted by the model equations, and key parameters influencing these steady-state distributions are identified. Recommendations for further extensions and applications of this model are proposed.

Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models

Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.

Conserved signaling through vascular endothelial growth (VEGF) receptor family members in murine lymphatic endothelial cells

Lymphatic vessels guide interstitial fluid, modulate immune responses by regulating leukocyte and antigen trafficking to lymph nodes, and in a cancer setting enable tumor cells to track to regional lymph nodes. The aim of the study was to determine whether primary murine lymphatic endothelial cells (mLECs) show conserved vascular endothelial growth factor (VEGF) signaling pathways with human LECs (hLECs). LECs were successfully isolated from murine dermis and prostate. Similar to hLECs, vascular endothelial growth factor (VEGF) family ligands activated MAPK and pAkt intracellular signaling pathways in mLECs. We describe a robust protocol for isolation of mLECs which, by harnessing the power of transgenic and knockout mouse models, will be a useful tool to study how LEC phenotype contributes to alterations in lymphatic vessel formation and function.

Pathways to peace : a phenomenological exploration of the processes of healing and posttraumatic growth following childhood sexual assault

This thesis explored pathways to healing in men and women who experienced traumatic sexual abuse in childhood and considered themselves to be in a place of wellness. The thesis synthesises current knowledge in this area and has produced a number of models with direct implications for clinical practice. This unique work has also contributed to advancing theoretical understanding of healing following sexual assault.

Mentor feedback : models, viewpoints and strategies

A mentor’s feedback can present professional insights to allow a mentee to reflect and develop practice. This paper positions two models for feedback that have emanated from empirical studies. It also demonstrates the diverse viewpoints of mentors and suggests strategies for providing quality feedback. In one qualitative study, 24 mentors observed a final-year preservice teacher through a professionally video-recorded lesson and wrote their observations towards giving feedback to the potential mentee. Tables illustrated in the paper, show that mentors’ positive feedback and constructive criticisms vary considerably on the same observed events. Data from this study were synthesised to posit a theoretical model for analysing mentor feedback in an interconnected, three-way Venn diagram, namely: visual, auditory and conceptual frames. Another study (n=28), which is a collection of mentor teachers’ work samples during the Mentoring for Effective Teaching (MET) program, provides strategies within six feedback practices, that is: (1) negotiated mentor-mentee expectations for providing feedback on practices, (2) reviewing teaching plans, (3) arranging for observations of practices, (4) providing oral feedback, (5) providing written feedback, and; (6) presenting opportunities for the mentee to evaluate teaching practices with consideration of the mentor’s feedback. For example, on the last mentioned practice (6) there were strategies such as “Plan a time for evaluation of practices (guided reflection)”, “Read the mentee’s reflection on practice and discuss how it aligns with your observations of their practices”, and “Highlight verbally and/or in writing where the mentee is perceptive about the reflection and how the reflection could be enhanced for future evaluations”. Developing a range of strategies that may assist the mentee in professional growth, include enlisting a community of mentors, ensuring mentors have a repertoire of strategies for articulating feedback, and using mentor feedback tools and models. This study has implications for the development of feedback models and strategies.

Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology

Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models’ initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated.

Three dimensional in-vitro models for studying cancer angiogenesis

Introduction Hydrogels prepared from star-shaped poly(ethylene glycol) (PEG) and maleimide-functionalized heparin provide a potential matrix for use in developing three dimensional (3D) models. We have previously demonstrated that these hydrogels support the cultivation of human umbilical vein endothelial cells (HUVECs). We extend this body of work to study the ability to create an extracellular matrix (ECM)-like model to study breast and prostate cancer cell growth in 3D. Also, we investigate the ability to produce a tri-culture mimicking tumour angiogenesis with cancer spheroids, HUVECs and mesenchymal stem cells (MSCs). Materials and Methods The breast cancer cell lines, MCF-7 and MDA-MB-231, and prostate cancer cell lines, LNCaP and PC3, were seeded into starPEG-heparin hydrogels and grown for 14 Days to analyze the effects of varying hydrogel stiffness on spheroid development. Resulting hydrogel constructs were analyzed via proliferation assays, light microscopy, and immunostaining. Cancer cell lines were then seeded into starPEG-heparin hydrogels functionalized with growth factors as spheroids with HUVECs and MSCs and grown as a tri-culture. Cultures were analyzed via immunostaining and observed using confocal microscopy. Results Cultures prepared in MMP-cleavable starPEG-heparin hydrogels display spheroid formation in contrast to adherent growth on tissue culture plastic. Small differences were visualized in cancer spheroid growth between different gel stiffness across the range of cell lines. Cancer cell lines were able to be co-cultivated with HUVECs and MSC. Interaction was visualized between tumours and HUVECs via confocal microscopy. Further studies intend to further optimize and mimic the ECM environment of in-situ tumour angiogenesis. Discussion Our results confirm the suitability of hydrogels constructed from starPEG-heparin for HUVEC and MSC co-cultivation with cancer cell lines to study cell-cell and cell-matrix interactions in a 3D environment. This represents a step forward in the development of 3D culture models to study the pathomechanisms of breast and prostate cancer.

Mathematical models of calcium and tight junctions in normal and reconstructed epidermis

This project investigated the calcium distributions of the skin, and the growth patterns of skin substitutes grown in the laboratory, using mathematical models. The research found that the calcium distribution in the upper layer of the skin is controlled by three different mechanisms, not one as previously thought. The research also suggests that tight junctions, which are adhesions between neighbouring skin cells, cannot be solely responsible for the differences in the growth patterns of skin substitutes and normal skin.

Accounting for management costs in sensitivity analyses of matrix population models

Traditional sensitivity and elasticity analyses of matrix population models have been used to inform management decisions, but they ignore the economic costs of manipulating vital rates. For example, the growth rate of a population is often most sensitive to changes in adult survival rate, but this does not mean that increasing that rate is the best option for managing the population because it may be much more expensive than other options. To explore how managers should optimize their manipulation of vital rates, we incorporated the cost of changing those rates into matrix population models. We derived analytic expressions for locations in parameter space where managers should shift between management of fecundity and survival, for the balance between fecundity and survival management at those boundaries, and for the allocation of management resources to sustain that optimal balance. For simple matrices, the optimal budget allocation can often be expressed as simple functions of vital rates and the relative costs of changing them. We applied our method to management of the Helmeted Honeyeater (Lichenostomus melanops cassidix; an endangered Australian bird) and the koala (Phascolarctos cinereus) as examples. Our method showed that cost-efficient management of the Helmeted Honeyeater should focus on increasing fecundity via nest protection, whereas optimal koala management should focus on manipulating both fecundity and survival simultaneously. These findings are contrary to the cost-negligent recommendations of elasticity analysis, which would suggest focusing on managing survival in both cases. A further investigation of Helmeted Honeyeater management options, based on an individual-based model incorporating density dependence, spatial structure, and environmental stochasticity, confirmed that fecundity management was the most cost-effective strategy. Our results demonstrate that decisions that ignore economic factors will reduce management efficiency. ©2006 Society for Conservation Biology.

Managing and learning with multiple models: Objectives and optimization algorithms

The quality of environmental decisions should be gauged according to managers' objectives. Management objectives generally seek to maximize quantifiable measures of system benefit, for instance population growth rate. Reaching these goals often requires a certain degree of learning about the system. Learning can occur by using management action in combination with a monitoring system. Furthermore, actions can be chosen strategically to obtain specific kinds of information. Formal decision making tools can choose actions to favor such learning in two ways: implicitly via the optimization algorithm that is used when there is a management objective (for instance, when using adaptive management), or explicitly by quantifying knowledge and using it as the fundamental project objective, an approach new to conservation.This paper outlines three conservation project objectives - a pure management objective, a pure learning objective, and an objective that is a weighted mixture of these two. We use eight optimization algorithms to choose actions that meet project objectives and illustrate them in a simulated conservation project. The algorithms provide a taxonomy of decision making tools in conservation management when there is uncertainty surrounding competing models of system function. The algorithms build upon each other such that their differences are highlighted and practitioners may see where their decision making tools can be improved. © 2010 Elsevier Ltd.

Quantifying uncertainty in parameter estimates for stochastic models of collective cell spreading using approximate Bayesian computation

Wound healing and tumour growth involve collective cell spreading, which is driven by individual motility and proliferation events within a population of cells. Mathematical models are often used to interpret experimental data and to estimate the parameters so that predictions can be made. Existing methods for parameter estimation typically assume that these parameters are constants and often ignore any uncertainty in the estimated values. We use approximate Bayesian computation (ABC) to estimate the cell diffusivity, D, and the cell proliferation rate, λ, from a discrete model of collective cell spreading, and we quantify the uncertainty associated with these estimates using Bayesian inference. We use a detailed experimental data set describing the collective cell spreading of 3T3 fibroblast cells. The ABC analysis is conducted for different combinations of initial cell densities and experimental times in two separate scenarios: (i) where collective cell spreading is driven by cell motility alone, and (ii) where collective cell spreading is driven by combined cell motility and cell proliferation. We find that D can be estimated precisely, with a small coefficient of variation (CV) of 2–6%. Our results indicate that D appears to depend on the experimental time, which is a feature that has been previously overlooked. Assuming that the values of D are the same in both experimental scenarios, we use the information about D from the first experimental scenario to obtain reasonably precise estimates of λ, with a CV between 4 and 12%. Our estimates of D and λ are consistent with previously reported values; however, our method is based on a straightforward measurement of the position of the leading edge whereas previous approaches have involved expensive cell counting techniques. Additional insights gained using a fully Bayesian approach justify the computational cost, especially since it allows us to accommodate information from different experiments in a principled way.

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

Background Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin-B2 is regulated to support both cancer promotion and angiogenesis. Methods An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. Results At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. Conclusion These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations.