Computer-Aided Business Model Design

There is a lack of dedicated tools for business model design at a strategic level. However, in today's economic world the need to be able to quickly reinvent a company's business model is essential to stay competitive. This research focused on identifying the functionalities that are necessary in a computer-aided design (CAD) tool for the design of business models in a strategic context. Using design science research methodology a series of techniques and prototypes have been designed and evaluated to offer solutions to the problem. The work is a collection of articles which can be grouped into three parts: First establishing the context of how the Business Model Canvas (BMC) is used to design business models and explore the way in which CAD can contribute to the design activity. The second part extends on this by proposing new technics and tools which support elicitation, evaluation (assessment) and evolution of business models design with CAD. This includes features such as multi-color tagging to easily connect elements, rules to validate coherence of business models and features that are adapted to the correct business model proficiency level of its users. A new way to describe and visualize multiple versions of a business model and thereby help in addressing the business model as a dynamic object was also researched. The third part explores extensions to the business model canvas such as an intermediary model which helps IT alignment by connecting business model and enterprise architecture. And a business model pattern for privacy in a mobile environment, using privacy as a key value proposition. The prototyped techniques and proposition for using CAD tools in business model modeling will allow commercial CAD developers to create tools that are better suited to the needs of practitioners.

Business model design: an evaluation of paper-based and computer-aided canvases

In recent years, Business Model Canvas design has evolved from being a paper-based activity to one that involves the use of dedicated computer-aided business model design tools. We propose a set of guidelines to help design more coherent business models. When combined with functionalities offered by CAD tools, they show great potential to improve business model design as an ongoing activity. However, in order to create complex solutions, it is necessary to compare basic business model design tasks, using a CAD system over its paper-based counterpart. To this end, we carried out an experiment to measure user perceptions of both solutions. Performance was evaluated by applying our guidelines to both solutions and then carrying out a comparison of business model designs. Although CAD did not outperform paper-based design, the results are very encouraging for the future of computer-aided business model design.

Distal dendrites of frog motor neurons: a computer-aided electron microscopic study of cobalt-filled cells.

With the aid of the cobalt labelling technique, frog spinal cord motor neuron dendrites of the subpial dendritic plexus have been identified in serial electron micrographs. Computer reconstructions of various lengths (2.5-9.8 micron) of dendritic segments showed the contours of these dendrites to be highly irregular, and to present many thorn-like projections 0.4-1.8 micron long. Number, size and distribution of synaptic contacts were also determined. Almost half of the synapses occurred at the origins of the thorns and these synapses had the largest contact areas. Only 8 out of 54 synapses analysed were found on thorns and these were the smallest. For the total length of reconstructed dendrites there was, on average, one synapse per 1.2 micron, while 4.4% of the total dendritic surface was covered with synaptic contacts. The functional significance of these distal dendrites and their capacity to influence the soma membrane potential is discussed.

Synapses on motoneuron dendrites in the brachial section of the frog spinal cord: a computer-aided electron microscopic study of cobalt-filled cells.

Cobalt-labelled motoneuron dendrites of the frog spinal cord at the level of the second spinal nerve were photographed in the electron microscope from long series of ultrathin sections. Three-dimensional computer reconstructions of 120 dendrite segments were analysed. The samples were taken from two locations: proximal to cell body and distal, as defined in a transverse plane of the spinal cord. The dendrites showed highly irregular outlines with many 1-2 microns-long 'thorns' (on average 8.5 thorns per 100 microns 2 of dendritic area). Taken together, the reconstructed dendrite segments from the proximal sites had a total length of about 250 microns; those from the distal locations, 180 microns. On all segments together there were 699 synapses. Nine percent of the synapses were on thorns, and many more close to their base on the dendritic shaft. The synapses were classified in four groups. One third of the synapses were asymmetric with spherical vesicles; one half were symmetric with spherical vesicles; and one tenth were symmetric with flattened vesicles. A fourth, small class of asymmetric synapses had dense-core vesicles. The area of the active zones was large for the asymmetric synapses (median value 0.20 microns 2), and small for the symmetric ones (median value 0.10 microns 2), and the difference was significant. On average, the areas of the active zones of the synapses on thin dendrites were larger than those of synapses on large calibre dendrites. About every 4 microns 2 of dendritic area received one contact. There was a significant difference between the areas of the active zones of the synapses at the two locations. Moreover, the number per unit dendritic length was correlated with dendrite calibre. On average, the active zones covered more than 4% of the dendritic area; this value for thin dendrites was about twice as large as that of large calibre dendrites. We suggest that the larger active zones and the larger synaptic coverage of the thin dendrites compensate for the longer electrotonic distance of these synapses from the soma.

Computer Aided Detection and measurement of peripheral artery disease.

Computer-Aided Tomography Angiography (CTA) images are the standard for assessing Peripheral artery disease (PAD). This paper presents a Computer Aided Detection (CAD) and Computer Aided Measurement (CAM) system for PAD. The CAD stage detects the arterial network using a 3D region growing method and a fast 3D morphology operation. The CAM stage aims to accurately measure the artery diameters from the detected vessel centerline, compensating for the partial volume effect using Expectation Maximization (EM) and a Markov Random field (MRF). The system has been evaluated on phantom data and also applied to fifteen (15) CTA datasets, where the detection accuracy of stenosis was 88% and the measurement accuracy was with an 8% error.

Computer-aided volume measurement of posttraumatic orbits reconstructed with AO titanium mesh plates: accuracy and reliability

PURPOSE: To prospectively evaluate the accuracy and reliability of "freehand" posttraumatic orbital wall reconstruction with AO (Arbeitsgemeinschaft Osteosynthese) titanium mesh plates by using computer-aided volumetric measurement of the bony orbits. METHODS: Bony orbital volume was measured in 12 patients from coronal CT scan slices using OsiriX Medical Image software. After defining the volumetric limits of the orbit, the segmentation of the bony orbital region of interest of each single slice was performed. At the end of the segmentation process, all regions of interest were grouped and the volume was computed. The same procedure was performed on both orbits, and thereafter the volume of the contralateral uninjured orbit was used as a control for comparison. RESULTS: In all patients, the volume data of the reconstructed orbit fitted that of the contralateral uninjured orbit with accuracy to within 1.85 cm3 (7%). CONCLUSIONS: This preliminary study has demonstrated that posttraumatic orbital wall reconstruction using "freehand" bending and placement of AO titanium mesh plates results in a high success rate in re-establishing preoperative bony volume, which closely approximates that of the contralateral uninjured orbit.

A new training set-up for trans-apical aortic valve replacement.

Trans-apical aortic valve replacement (AVR) is a new and rapidly growing therapy. However, there are only few training opportunities. The objective of our work is to build an appropriate artificial model of the heart that can replace the use of animals for surgical training in trans-apical AVR procedures. To reduce the necessity for fluoroscopy, we pursued the goal of building a translucent model of the heart that has nature-like dimensions. A simplified 3D model of a human heart with its aortic root was created in silico using the SolidWorks Computer-Aided Design (CAD) program. This heart model was printed using a rapid prototyping system developed by the Fab@Home project and dip-coated two times with dispersion silicone. The translucency of the heart model allows the perception of the deployment area of the valved-stent without using heavy imaging support. The final model was then placed in a human manikin for surgical training on trans-apical AVR procedure. Trans-apical AVR with all the necessary steps (puncture, wiring, catheterization, ballooning etc.) can be realized repeatedly in this setting.

Investigation of high-resolution functional magnetic resonance imaging by means of surface and array radiofrequency coils at 7 T.

In this investigation, high-resolution, 1x1x1-mm(3) functional magnetic resonance imaging (fMRI) at 7 T is performed using a multichannel array head coil and a surface coil approach. Scan geometry was optimized for each coil separately to exploit the strengths of both coils. Acquisitions with the surface coil focused on partial brain coverage, while whole-brain coverage fMRI experiments were performed with the array head coil. BOLD sensitivity in the occipital lobe was found to be higher with the surface coil than with the head array, suggesting that restriction of signal detection to the area of interest may be beneficial for localized activation studies. Performing independent component analysis (ICA) decomposition of the fMRI data, we consistently detected BOLD signal changes and resting state networks. In the surface coil data, a small negative BOLD response could be detected in these resting state network areas. Also in the data acquired with the surface coil, two distinct components of the positive BOLD signal were consistently observed. These two components were tentatively assigned to tissue and venous signal changes.

Shielding requirements in helical tomotherapy.

Helical tomotherapy is a relatively new intensity-modulated radiation therapy (IMRT) treatment for which room shielding has to be reassessed for the following reasons. The beam-on-time needed to deliver a given target dose is increased and leads to a weekly workload of typically one order of magnitude higher than that for conventional radiation therapy. The special configuration of tomotherapy units does not allow the use of standard shielding calculation methods. A conventional linear accelerator must be shielded for primary, leakage and scatter photon radiations. For tomotherapy, primary radiation is no longer the main shielding issue since a beam stop is mounted on the gantry directly opposite the source. On the other hand, due to the longer irradiation time, the accelerator head leakage becomes a major concern. An analytical model based on geometric considerations has been developed to determine leakage radiation levels throughout the room for continuous gantry rotation. Compared to leakage radiation, scatter radiation is a minor contribution. Since tomotherapy units operate at a nominal energy of 6 MV, neutron production is negligible. This work proposes a synthetic and conservative model for calculating shielding requirements for the Hi-Art II TomoTherapy unit. Finally, the required concrete shielding thickness is given for different positions of interest.

Structure-Based, Rational Design of T Cell Receptors.

Adoptive cell transfer using engineered T cells is emerging as a promising treatment for metastatic melanoma. Such an approach allows one to introduce T cell receptor (TCR) modifications that, while maintaining the specificity for the targeted antigen, can enhance the binding and kinetic parameters for the interaction with peptides (p) bound to major histocompatibility complexes (MHC). Using the well-characterized 2C TCR/SIYR/H-2K(b) structure as a model system, we demonstrated that a binding free energy decomposition based on the MM-GBSA approach provides a detailed and reliable description of the TCR/pMHC interactions at the structural and thermodynamic levels. Starting from this result, we developed a new structure-based approach, to rationally design new TCR sequences, and applied it to the BC1 TCR targeting the HLA-A2 restricted NY-ESO-1157-165 cancer-testis epitope. Fifty-four percent of the designed sequence replacements exhibited improved pMHC binding as compared to the native TCR, with up to 150-fold increase in affinity, while preserving specificity. Genetically engineered CD8(+) T cells expressing these modified TCRs showed an improved functional activity compared to those expressing BC1 TCR. We measured maximum levels of activities for TCRs within the upper limit of natural affinity, K D = ∼1 - 5 μM. Beyond the affinity threshold at K D < 1 μM we observed an attenuation in cellular function, in line with the "half-life" model of T cell activation. Our computer-aided protein-engineering approach requires the 3D-structure of the TCR-pMHC complex of interest, which can be obtained from X-ray crystallography. We have also developed a homology modeling-based approach, TCRep 3D, to obtain accurate structural models of any TCR-pMHC complexes when experimental data is not available. Since the accuracy of the models depends on the prediction of the TCR orientation over pMHC, we have complemented the approach with a simplified rigid method to predict this orientation and successfully assessed it using all non-redundant TCR-pMHC crystal structures available. These methods potentially extend the use of our TCR engineering method to entire TCR repertoires for which no X-ray structure is available. We have also performed a steered molecular dynamics study of the unbinding of the TCR-pMHC complex to get a better understanding of how TCRs interact with pMHCs. This entire rational TCR design pipeline is now being used to produce rationally optimized TCRs for adoptive cell therapies of stage IV melanoma.

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.