Workflow resource pattern simulation and visualization

This thesis addresses the process simulation and validation in Business Process Management. It proposes that the hybrid Multi Agent System (MAS) / 3D Virtual World approach is a valid method for better simulating the behaviour of human resources in business processes, supporting a wide range of rich visualization applications that can facilitate communication between business analysts and stakeholders. It is expected that the findings of this thesis may be fruitfully extended from BPM to other application domains, such as social simulation in video games and computer-based training animations.

The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

Computational simulation of the early stage of bone healing under different configurations of locking compression plates

Flexible fixation or the so-called ‘biological fixation’ has been shown to encourage the formation of fracture callus, leading to better healing outcomes. However, the nature of the relationship between the degree of mechanical stability provided by a flexible fixation and the optimal healing outcomes has not been fully understood. In this study, we have developed a validated quantitative model to predict how cells in fracture callus might respond to change in their mechanical microenvironment due to different configurations of locking compression plate (LCP) in clinical practice, particularly in the early stage of healing. The model predicts that increasing flexibility of the LCP by changing the bone–plate distance (BPD) or the plate working length (WL) could enhance interfragmentary strain in the presence of a relatively large gap size (.3 mm). Furthermore, conventional LCP normally results in asymmetric tissue development during early stage of callus formation, and the increase of BPD or WL is insufficient to alleviate this problem.

Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways

Purpose Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities. Experimental Design Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers. Results Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing-induced apoptosis. K-Ras-mutated, c-Met-amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing-induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Conclusion Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. ©2011 AACR.

Is foot ulcer simulation training (FUST) really effective? Participants’ supervisors speak out

Background Foot ulcers are a common reason for diabetes-related hospitalisation. Foot ulcer simulation training (FUST) programs have increased podiatry participants self-confidence to manage foot ulcers. However, supervisors’ perspectives on their participants attending these simulation programs have not been investigated. This mixed method (quantitative and qualitative) study aimed to investigate home clinical supervisors’ perspectives on any changes to their participants’ competence and practice following FUST. Methods Clinical supervisors of fifteen podiatrists, who participated in a two-day Foot Ulcer Simulation Training (FUST) course, were recruited. Supervisors completed quantitative surveys evaluating their participants’ foot ulcer competence pre-FUST and 6-months post-FUST, via a purposed designed 21-item survey using a five-point Likert scale (1=Very limited, 5=Highly competent). Supervisors also attended a semi-structured qualitative group interview to investigate supervisors’ perspectives on FUST. Results Supervisors surveys returned were pre-FUST (n=10) and post-FUST (n=12). Significant competence improvements were observed at the 6-month survey (mean scores 2.84 cf. 3.72, p < 0.05). Five supervisors attended the group interview. Five sub-themes emerged: i) FUST provided a good foundation for future learning, ii) FUST modelled good clinical behaviour, iii) clinical practice improvement was evident in most participants, iv) clinical improvements were dependent on participant’s willingness to change and existing workplace culture, v) FUST needs to be reinforced back in the home clinic. Conclusion Overall, supervisors of FUST participants indicated that the course improved their participants’ competence and clinical practice. However, the degree of improvement appears dependant on the participants’ home workplace culture and willingness to embrace change.

Foot ulcer simulation training (FUST) : are podiatrists FUST with long-term clinical confidence?

Background Foot ulcers are a leading cause of diabetes-related hospitalisations. Clinical training has been shown to be beneficial in foot ulcer management. Recently, improved self-confidence in podiatrists was reported immediately after foot ulcer simulation training (FUST) pilot programs. This study aimed to investigate the longer-term impacts of the FUST program on podiatrists’ self-confidence over 12 months in a larger sample. Methods Participants were podiatrists attending a two-day FUST course comprising web-based interactive learning, low-fidelity part-tasks and high-fidelity full clinical scenarios. Primary outcome measures included participants’ self-confidence measured pre-, (immediately) post-, 6-month post- and 12-month post-course via a purpose designed 21-item survey using a five-point Likert scale (1=Very limited, 5=Highly confident). Participants’ perceptions of knowledge gained, satisfaction, relevance and fidelity were also investigated. ANOVA and post hoc tests were used to test any differences between groups. Results Thirty-four participants completed FUST. Survey response rates were 100% (pre), 82% (post), 74% (6-month post), and 47% (12-month post). Overall mean scores were 3.13 (pre), 4.49 (post), 4.35 (6-month post) and 4.30 (12-month post) (p < 0.05); post hoc tests indicated no differences between the immediately, 6-month and 12-month post group scores (p > 0.05). Satisfaction, knowledge, relevance and fidelity were all rated highly. Conclusion This study suggests that significant short-term improvements in self-confidence to manage foot ulcers via simulation training are retained over the longer term. It is likely that improved self-confidence leads to improved foot ulcer clinical practice and outcomes; although this requires further research.

Tailoring the resonance of bilayer graphene sheets by interlayer sp3 bonds

Graphene-based resonators are envisioned to build the ultimate limit of two-dimensional nanoelectromechanical system due to their ultrasensitive detection of mass, force, pressure and charge. However, such application has been greatly impeded by their extremely low quality factor. In the present work, we explore, using the large-scale molecular dynamics simulation, the possibility of tailoring the resonance properties of a bilayer graphene sheet (GS) with interlayer sp3 bonds. For the bilayer GS resonator with interlayer sp3 bonds, we discovered that the sp3 bonds can either degrade or enhance the resonance properties of the resonator depending on their density and location. It is found that the distribution of sp3 bonds only along the edges of either pristine or hydrogenated bilayer GS, leads to a greatly enhanced quality factor. A quality factor of ~1.18×105 is observed for a 3.07×15.31 nm2 bilayer GS resonator with sp3 bonds, which is more than 30 times larger comparing with that of a pristine bilayer GS. The present study demonstrates that the resonance properties of a bilayer GS resonator can be tuned by introducing sp3 bonds. This finding provides a useful guideline for the synthesis of the bilayer GS for its application as a resonator component.

Effect of defects on fracture strength of graphene sheets

With a hexagonal monolayer network of carbon atoms, graphene has demonstrated exceptional electrical 22 and mechanical properties. In this work, the fracture of graphene sheets with Stone–Wales type defects and vacancies were investigated using molecular dynamics simulations at different temperatures. The initiation of defects via bond rotation was also investigated. The results indicate that the defects and vacancies can cause significant strength loss in graphene. The fracture strength of graphene is also affected by temperature and loading directions. The simulation results were compared with the prediction from the quantized fracture mechanics.

The potential role of lycopene for the prevention and therapy of prostate cancer : from molecular mechanisms to clinical evidence

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have linked increased lycopene consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that lycopene not only enhances the antioxidant response of prostate cells, but that it is even able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, there is still no clearly proven clinical evidence supporting the use of lycopene in the prevention or treatment of prostate cancer, due to the only limited number of published randomized clinical trials and the varying quality of existing studies. The scope of this article is to discuss the potential impact of lycopene on prostate cancer by giving an overview about its molecular mechanisms and clinical effects. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Eph receptors and their ligands : promising molecular biomarkers and therapeutic targets in prostate cancer

Although at present, there is a high incidence of prostate cancer, particularly in the Western world, mortality from this disease is declining and occurs primarily only from clinically significant late stage tumors with a poor prognosis. A major current focus of this field is the identification of new biomarkers which can detect earlier, and more effectively, clinically significant tumors from those deemed “low risk”, as well as predict the prognostic course of a particular cancer. This strategy can in turn offer novel avenues for targeted therapies. The large family of Receptor Tyrosine Kinases, the Ephs, and their binding partners, the ephrins, has been implicated in many cancers of epithelial origin through stimulation of oncogenic transformation, tumor angiogenesis, and promotion of increased cell survival, invasion and migration. They also show promise as both biomarkers of diagnostic and prognostic value and as targeted therapies in cancer. This review will briefly discuss the complex roles and biological mechanisms of action of these receptors and ligands and, with regard to prostate cancer, highlight their potential as biomarkers for both diagnosis and prognosis, their application as imaging agents, and current approaches to assessing them as therapeutic targets. This review demonstrates the need for future studies into those particular family members that will prove helpful in understanding the biology and potential as targets for treatment of prostate cancer.

A stochastic thermostat algorithm for coarse-grained thermomechanical modeling of large-scale soft matters : theory and application to microfilaments

As all-atom molecular dynamics method is limited by its enormous computational cost, various coarse-grained strategies have been developed to extend the length scale of soft matters in the modeling of mechanical behaviors. However, the classical thermostat algorithm in highly coarse-grained molecular dynamics method would underestimate the thermodynamic behaviors of soft matters (e.g. microfilaments in cells), which can weaken the ability of materials to overcome local energy traps in granular modeling. Based on all-atom molecular dynamics modeling of microfilament fragments (G-actin clusters), a new stochastic thermostat algorithm is developed to retain the representation of thermodynamic properties of microfilaments at extra coarse-grained level. The accuracy of this stochastic thermostat algorithm is validated by all-atom MD simulation. This new stochastic thermostat algorithm provides an efficient way to investigate the thermomechanical properties of large-scale soft matters.

A simulation-based large deflection and inelastic analysis of steel frames under fire

This paper presents an accurate and robust geometric and material nonlinear formulation to predict structural behaviour of unprotected steel members at elevated temperatures. A fire analysis including large displacement effects for frame structures is presented. This finite element formulation of beam-column elements is based on the plastic hinge approach to model the elasto-plastic strain-hardening material behaviour. The Newton-Raphson method allowing for the thermal-time dependent effect was employed for the solution of the non-linear governing equations for large deflection in thermal history. A combined incremental and total formulation for determining member resistance is employed in this nonlinear solution procedure for the efficient modeling of nonlinear effects. Degradation of material strength with increasing temperature is simulated by a set of temperature-stress-strain curves according to both ECCS and BS5950 Part 8, which implicitly allows for creep deformation. The effects of uniform or non-uniform temperature distribution over the section of the structural steel member are also considered. Several numerical and experimental verifications are presented.

Strategies and challenges for systematically mapping biologically significant molecular pathways regulating carcinoma epithelial-mesenchymal transition

Enormous progress has been made towards understanding the role of specific factors in the process of epithelial-mesenchymal transition (EMT); however, the complex underlying pathways and the transient nature of the transition continues to present significant challenges. Targeting tumour cell plasticity underpinning EMT is an attractive strategy to combat metastasis. Global gene expression profiling and high-content analyses are among the strategies employed to identify novel EMT regulators. In this review, we highlight several approaches to systematically interrogate key pathways involved in EMT, with particular emphasis on the features of multiparametric, high-content imaging screening strategies that lend themselves to the systematic discovery of highly significant modulators of tumour cell plasticity.

Blast response of reinforced concrete pile using fully coupled computer simulation techniques

Pile foundations transfer loads from superstructures to stronger sub soil. Their strength and stability can hence affect structural safety. This paper treats the response of reinforced concrete pile in saturated sand to a buried explosion. Fully coupled computer simulation techniques are used together with five different material models. Influence of reinforcement on pile response is investigated and important safety parameters of horizontal deformations and tensile stresses in the pile are evaluated. Results indicate that adequate longitudinal reinforcement and proper detailing of transverse reinforcement can reduce pile damage. Present findings can serve as a benchmark reference for future analysis and design.