Role of Neurogranin in the regulation of calcium binding to Calmodulin

Role of Neurogranin in the regulation of calcium binding to Calmodulin Anuja Chandrasekar, B.S Advisor: M. Neal Waxham, Ph.D The overall goal of my project was to gain a quantitative understanding of how the interaction between two proteins neurogranin (RC3) and calmodulin (CaM) alters a fundamental property of CaM. CaM, has been extensively studied for more than four decades due to its seminal role in almost all biological functions as a calcium signal transducer. Calcium signals in cardiac and neuronal cells are exquisitely precise and enable activation of some processes while down-regulating others. CaM, with its four calcium binding sites, serves as a central component of calcium signaling in these cells. It is aided in this role as a regulatory hub that differentially activates targets in response to a calcium flux by proteins that alter its calcium binding properties. Neurogranin, also known as RC3, is a member of a family of small neuronal IQ (SNIQ) domain proteins that was originally thought to play a ‘capacitive’ role by sequestering CaM until a calcium influx of sufficient intensity arrived. However, based on earlier work in our lab on neurogranin, we believe that this protein plays a more nuanced role in neurons than simply acting as a CaM buffer. We believe that neurogranin is one of the proteins which, by altering the kinetics of calcium binding allow CaM to decode a variety of signals with fine precision. To quantify the interaction between CaM, neurogranin and calcium, I used biophysical techniques and computational simulations. From my results, I conclude that neurogranin finely regulates the proportion of calcium-saturated CaM and thereby directs CaM’s target specificity.

A decision model for it supplier selection

En los últimos años la externalización de TI ha ganado mucha importancia en el mercado y, por ejemplo, el mercado externalización de servicios de TI sigue creciendo cada año. Ahora más que nunca, las organizaciones son cada vez más los compradores de las capacidades necesarias mediante la obtención de productos y servicios de los proveedores, desarrollando cada vez menos estas capacidades dentro de la empresa. La selección de proveedores de TI es un problema de decisión complejo. Los gerentes que enfrentan una decisión sobre la selección de proveedores de TI tienen dificultades en la elaboración de lo que hay que pensar, además en sus discursos. También de acuerdo con un estudio del SEI (Software Engineering Institute) [40], del 20 al 25 por ciento de los grandes proyectos de adquisición de TI fracasan en dos años y el 50 por ciento fracasan dentro de cinco años. La mala gestión, la mala definición de requisitos, la falta de evaluaciones exhaustivas, que pueden ser utilizadas para llegar a los mejores candidatos para la contratación externa, la selección de proveedores y los procesos de contratación inadecuados, la insuficiencia de procedimientos de selección tecnológicos, y los cambios de requisitos no controlados son factores que contribuyen al fracaso del proyecto. La mayoría de los fracasos podrían evitarse si el cliente aprendiese a comprender los problemas de decisión, hacer un mejor análisis de decisiones, y el buen juicio. El objetivo principal de este trabajo es el desarrollo de un modelo de decisión para la selección de proveedores de TI que tratará de reducir la cantidad de fracasos observados en las relaciones entre el cliente y el proveedor. La mayor parte de estos fracasos son causados por una mala selección, por parte del cliente, del proveedor. Además de estos problemas mostrados anteriormente, la motivación para crear este trabajo es la inexistencia de cualquier modelo de decisión basado en un multi modelo (mezcla de modelos adquisición y métodos de decisión) para el problema de la selección de proveedores de TI. En el caso de estudio, nueve empresas españolas fueron analizadas de acuerdo con el modelo de decisión para la selección de proveedores de TI desarrollado en este trabajo. Dos softwares se utilizaron en este estudio de caso: Expert Choice, y D-Sight. ABSTRACT In the past few years IT outsourcing has gained a lot of importance in the market and, for example, the IT services outsourcing market is still growing every year. Now more than ever, organizations are increasingly becoming acquirers of needed capabilities by obtaining products and services from suppliers and developing less and less of these capabilities in-house. IT supplier selection is a complex and opaque decision problem. Managers facing a decision about IT supplier selection have difficulty in framing what needs to be thought about further in their discourses. Also according to a study from SEI (Software Engineering Institute) [40], 20 to 25 percent of large information technology (IT) acquisition projects fail within two years and 50 percent fail within five years. Mismanagement, poor requirements definition, lack of comprehensive evaluations, which can be used to come up with the best candidates for outsourcing, inadequate supplier selection and contracting processes, insufficient technology selection procedures, and uncontrolled requirements changes are factors that contribute to project failure. The majority of project failures could be avoided if the acquirer learns how to understand the decision problems, make better decision analysis, and good judgment. The main objective of this work is the development of a decision model for IT supplier selection that will try to decrease the amount of failures seen in the relationships between the client-supplier. Most of these failures are caused by a not well selection of the supplier. Besides these problems showed above, the motivation to create this work is the inexistence of any decision model based on multi model (mixture of acquisition models and decision methods) for the problem of IT supplier selection. In the case study, nine different Spanish companies were analyzed based on the IT supplier selection decision model developed in this work. Two software products were used in this case study, Expert Choice and D-Sight.

Computational model of bladder tissue based on its measured optical properties

Urinary bladder diseases are a common problem throughout the world and often difficult to accurately diagnose. Furthermore, they pose a heavy financial burden on health services. Urinary bladder tissue from male pigs was spectrophotometrically measured and the resulting data used to calculate the absorption, transmission, and reflectance parameters, along with the derived coefficients of scattering and absorption. These were employed to create a "generic" computational bladder model based on optical properties, simulating the propagation of photons through the tissue at different wavelengths. Using the Monte-Carlo method and fluorescence spectra of UV and blue excited wavelength, diagnostically important biomarkers were modeled. Additionally, the multifunctional noninvasive diagnostics system "LAKK-M" was used to gather fluorescence data to further provide essential comparisons. The ultimate goal of the study was to successfully simulate the effects of varying excited radiation wavelengths on bladder tissue to determine the effectiveness of photonics diagnostic devices. With increased accuracy, this model could be used to reliably aid in differentiating healthy and pathological tissues within the bladder and potentially other hollow organs.

Can IT Security be improved with better IT Leadership in the 21st Century University?

Organizations generally are not responding effectively to rising IT security threats because people issues receive inadequate attention. The stark example of IT security is just the latest strategic IT priority demonstrating deficient IT leadership attention to the social dimension of IT. Universities in particular, with their devolved people organization, diverse adoption of IT, and split central/local federated approach to governance and leadership of IT, demand higher levels of interpersonal sophistication and strategic engagement from their IT leaders. An idealized model for IT leaders for the 21st century university is proposed to be developed as a framework for further investigation. The testing of this model in an action research study is proposed.

Spatial stimulus : Model making in the architectural design studio

This action research examines the enhancement of visual communication within the architectural design studio through physical model making. „It is through physical model making that designers explore their conceptual ideas and develop the creation and understanding of space,‟ (Salama & Wilkinson 2007:126). This research supplements Crowther‟s findings extending the understanding of visual dialogue to include physical models. „Architecture Design 8‟ is the final core design unit at QUT in the fourth year of the Bachelor of Design Architecture. At this stage it is essential that students have the ability to communicate their ideas in a comprehensive manner, relying on a combination of skill sets including drawing, physical model making, and computer modeling. Observations within this research indicates that students did not integrate the combination of the skill sets in the design process through the first half of the semester by focusing primarily on drawing and computer modeling. The challenge was to promote deeper learning through physical model making. This research addresses one of the primary reasons for the lack of physical model making, which was the limited assessment emphasis on the physical models. The unit was modified midway through the semester to better correlate the lecture theory with studio activities by incorporating a series of model making exercises conducted during the studio time. The outcome of each exercise was assessed. Tutors were surveyed regarding the model making activities and a focus group was conducted to obtain formal feedback from students. Students and tutors recognised the added value in communicating design ideas through physical forms and model making. The studio environment was invigorated by the enhanced learning outcomes of the students who participated in the model making exercises. The conclusions of this research will guide the structure of the upcoming iteration of the fourth year design unit.

The traditional rationale of the arm’s length approach to transfer pricing : should the separate accounting model be maintained for modern multinational entities?

This article examines the current transfer pricing regime to consider whether it is a sound model to be applied to modern multinational entities. The arm's length price methodology is examined to enable a discussion of the arguments in favour of such a regime. The article then refutes these arguments concluding that, contrary to the very reason multinational entities exist, applying arm's length rules involves a legal fiction of imagining transactions between unrelated parties. Multinational entities exist to operate in a way that independent entities would not, which the arm's length rules fail to take into account. As such, there is clearly an air of artificiality in applying the arm's length standard. To demonstrate this artificiality with respect to modern multinational entities, multinational banks are used as an example. The article concluded that the separate entity paradigm adopted by the traditional transfer pricing regime is incongruous with the economic theory of modern multinational enterprises.

A ‘service logic’ rationale for business model innovation

Successful firms use business model innovation to rethink the way they do business and transform industries. However, current research on business model innovation is lacking theoretical underpinnings and is in need of new insights. This objective of this paper is to advance our understanding of both the business model concept and business model innovation based on service logic as foundation for customer value and value creation. We present and discuss a rationale for business models based on ‘service logic’ with service as a value-supporting process and compared it with a business model based on ‘goods logic’ with goods as value-supporting resources. The implications for each of the business model dimensions: customer, value proposition, organizational architecture and revenue model, are described and discussed in detail.

Validating the design science research roadmap : through the lens of "the idealised model for theory development"

Design Science Research (DSR) has emerged as an important approach in Information Systems (IS) research. However, DSR is still in its genesis and has yet to achieve consensus on even the fundamentals, such as what methodology / approach to use for DSR. While there has been much effort to establish DSR methodologies, a complete, holistic and validated approach for the conduct of DSR to guide IS researcher (especially novice researchers) is yet to be established. Alturki et al. (2011) present a DSR ‘Roadmap’, making the claim that it is a complete and comprehensive guide for conducting DSR. This paper aims to further assess this Roadmap, by positioning it against the ‘Idealized Model for Theory Development’ (IM4TD) (Fischer & Gregor 2011). The IM4TD highlights the role of discovery and justification and forms of reasoning to progress in theory development. Fischer and Gregor (2011) have applied IM4TD’s hypothetico-deductive method to analyze DSR methodologies, which is adopted in this study to deductively validate the Alturki et al. (2011) Roadmap. The results suggest that the Roadmap adheres to the IM4TD, is reasonably complete, overcomes most shortcomings identified in other DSR methodologies and also highlights valuable refinements that should be considered within the IM4TD.

Physically sound vehicle-driver model for realistic microscopic simulation

In microscopic traffic simulators, the interaction between vehicles is considered. The dynamics of the system then becomes an emergent property of the interaction between its components. Such interactions include lane-changing, car-following behaviours and intersection management. Although, in some cases, such simulators produce realistic prediction, they do not allow for an important aspect of the dynamics, that is, the driver-vehicle interaction. This paper introduces a physically sound vehicle-driver model for realistic microscopic simulation. By building a nanoscopic traffic simulation model that uses steering angle and throttle position as parameters, the model aims to overcome unrealistic acceleration and deceleration values, as found in various microscopic simulation tools. A physics engine calculates the driving force of the vehicle, and the preliminary results presented here, show that, through a realistic driver-vehicle-environment simulator, it becomes possible to model realistic driver and vehicle behaviours in a traffic simulation.

Using a pharmacokinetic model to interpret biomonitoring data of PBDEs in the Australian population

From human biomonitoring data that are increasingly collected in the United States, Australia, and in other countries from large-scale field studies, we obtain snap-shots of concentration levels of various persistent organic pollutants (POPs) within a cross section of the population at different times. Not only can we observe the trends within this population with time, but we can also gain information going beyond the obvious time trends. By combining the biomonitoring data with pharmacokinetic modeling, we can re-construct the time-variant exposure to individual POPs, determine their intrinsic elimination half-lives in the human body, and predict future levels of POPs in the population. Different approaches have been employed to extract information from human biomonitoring data. Pharmacokinetic (PK) models were combined with longitudinal data1, with single2 or multiple3 average concentrations of a cross-sectional data (CSD), or finally with multiple CSD with or without empirical exposure data4. In the latter study, for the first time, the authors based their modeling outputs on two sets of CSD and empirical exposure data, which made it possible that their model outputs were further constrained due to the extensive body of empirical measurements. Here we use a PK model to analyze recent levels of PBDE concentrations measured in the Australian population. In this study, we are able to base our model results on four sets5-7 of CSD; we focus on two PBDE congeners that have been shown3,5,8-9 to differ in intake rates and half-lives with BDE-47 being associated with high intake rates and a short half-life and BDE-153 with lower intake rates and a longer half-life. By fitting the model to PBDE levels measured in different age groups in different years, we determine the level of intake of BDE-47 and BDE-153, as well as the half-lives of these two chemicals in the Australian population.

Feasibility of agent-based modelling of articular cartilage including a conceptual representation of its structure

Articular cartilage is a complex structure with an architecture in which fluid-swollen proteoglycans constrained within a 3D network of collagen fibrils. Because of the complexity of the cartilage structure, the relationship between its mechanical behaviours at the macroscale level and its components at the micro-scale level are not completely understood. The research objective in this thesis is to create a new model of articular cartilage that can be used to simulate and obtain insight into the micro-macro-interaction and mechanisms underlying its mechanical responses during physiological function. The new model of articular cartilage has two characteristics, namely: i) not use fibre-reinforced composite material idealization ii) Provide a framework for that it does probing the micro mechanism of the fluid-solid interaction underlying the deformation of articular cartilage using simple rules of repartition instead of constitutive / physical laws and intuitive curve-fitting. Even though there are various microstructural and mechanical behaviours that can be studied, the scope of this thesis is limited to osmotic pressure formation and distribution and their influence on cartilage fluid diffusion and percolation, which in turn governs the deformation of the compression-loaded tissue. The study can be divided into two stages. In the first stage, the distributions and concentrations of proteoglycans, collagen and water were investigated using histological protocols. Based on this, the structure of cartilage was conceptualised as microscopic osmotic units that consist of these constituents that were distributed according to histological results. These units were repeated three-dimensionally to form the structural model of articular cartilage. In the second stage, cellular automata were incorporated into the resulting matrix (lattice) to simulate the osmotic pressure of the fluid and the movement of water within and out of the matrix; following the osmotic pressure gradient in accordance with the chosen rule of repartition of the pressure. The outcome of this study is the new model of articular cartilage that can be used to simulate and study the micromechanical behaviours of cartilage under different conditions of health and loading. These behaviours are illuminated at the microscale level using the socalled neighbourhood rules developed in the thesis in accordance with the typical requirements of cellular automata modelling. Using these rules and relevant Boundary Conditions to simulate pressure distribution and related fluid motion produced significant results that provided the following insight into the relationships between osmotic pressure gradient and associated fluid micromovement, and the deformation of the matrix. For example, it could be concluded that: 1. It is possible to model articular cartilage with the agent-based model of cellular automata and the Margolus neighbourhood rule. 2. The concept of 3D inter connected osmotic units is a viable structural model for the extracellular matrix of articular cartilage. 3. Different rules of osmotic pressure advection lead to different patterns of deformation in the cartilage matrix, enabling an insight into how this micromechanism influences macromechanical deformation. 4. When features such as transition coefficient were changed, permeability (representing change) is altered due to the change in concentrations of collagen, proteoglycans (i.e. degenerative conditions), the deformation process is impacted. 5. The boundary conditions also influence the relationship between osmotic pressure gradient and fluid movement at the micro-scale level. The outcomes are important to cartilage research since we can use these to study the microscale damage in the cartilage matrix. From this, we are able to monitor related diseases and their progression leading to potential insight into drug-cartilage interaction for treatment. This innovative model is an incremental progress on attempts at creating further computational modelling approaches to cartilage research and other fluid-saturated tissues and material systems.

Higher Education and Sustainable Development : A Model for Curriculum Renewal

Responding to the global and unprecedented challenge of capacity building for twenty-first century life, this book is a practical guide for tertiary education institutions to quickly and effectively renew the curriculum towards education for sustainable development. The book begins by exploring why curriculum change has been so slow. It then describes a model for rapid curriculum renewal, highlighting the important roles of setting timeframes, formal and informal leadership, and key components and action strategies. The second part of the book provides detailed coverage of six core elements that have been trialled and peer reviewed by institutions around the world: - raising awareness among staff and students - mapping graduate attributes - auditing the curriculum - developing niche degrees, flagship courses and fully integrated programs - engaging and catalysing community and student markets - integrating curriculum with green campus operations. With input from more than seventy academics and grounded in engineering education experiences, this book will provide academic staff with tools and insights to rapidly align program offerings with the needs of present and future generations of students.

Nonlinear container ship model for the study of parametric roll resonance

Parametric roll is a critical phenomenon for ships, whose onset may cause roll oscillations up to +-40 degrees, leading to very dangerous situations and possibly capsizing. Container ships have been shown to be particularly prone to parametric roll resonance when they are sailing in moderate to heavy head seas. A Matlab/Simulink parametric roll benchmark model for a large container ship has been implemented and validated against a wide set of experimental data. The model is a part of a Matlab/Simulink Toolbox (MSS, 2007). The benchmark implements a 3rd-order nonlinear model where the dynamics of roll is strongly coupled with the heave and pitch dynamics. The implemented model has shown good accuracy in predicting the container ship motions, both in the vertical plane and in the transversal one. Parametric roll has been reproduced for all the data sets in which it happened, and the model provides realistic results which are in good agreement with the model tank experiments.

Large Scale Simulations of Hippocampal-Neocortical Interactions in a Parallel Version of Genesis

A hippocampal-CA3 memory model was constructed with PGENESIS, a recently developed version of GENESIS that allows for distributed processing of a neural network simulation. A number of neural models of the human memory system have identified the CA3 region of the hippocampus as storing the declarative memory trace. However, computational models designed to assess the viability of the putative mechanisms of storage and retrieval have generally been too abstract to allow comparison with empirical data. Recent experimental evidence has shown that selective knock-out of NMDA receptors in the CA1 of mice leads to reduced stability of firing specificity in place cells. Here a similar reduction of stability of input specificity is demonstrated in a biologically plausible neural network model of the CA3 region, under conditions of Hebbian synaptic plasticity versus an absence of plasticity. The CA3 region is also commonly associated with seizure activity. Further simulations of the same model tested the response to continuously repeating versus randomized nonrepeating input patterns. Each paradigm delivered input of equal intensity and duration. Non-repeating input patterns elicited a greater pyramidal cell spike count. This suggests that repetitive versus non-repeating neocortical inpus has a quantitatively different effect on the hippocampus. This may be relevant to the production of independent epileptogenic zones and the process of encoding new memories.