Letter to the editor : likelihood of tetraplegia after CT clearance of the cervical spine in obtunded blunt trauma patients

...the probabilistic computer simulation study by Dunham and colleagues evaluating the impact of different cervical spine management (CSM) strategies on tetraplegia and brain injury outcomes.1 Based on literature findings, expert opinion and with use of advances programming techniques the authors conclude that early collar removal without cervical spine magnetic resonance imaging (MRI) is a preferable CSM strategy for comatose, blunt trauma patients with extremity movement and a negative cervical spine computed tomography(CT) scan. Although we do not have the required expertise to comment on the applied statistical approach, we would like to comment on one of the medical assumptions raised by the authors, namely the likelihood of tetraplegia in this specific population....

The influence of glass types on the performance of air-conditioned office buildings in Australia

Windows are one of the most significant elements in the design of buildings. Whether there are small punched openings in the facade or a completely glazed curtain wall, windows are usually a dominant feature of the building's exterior appearance. From the energy use perspective, windows may also be regarded as thermal holes for a building. Therefore, window design and selection must take both aesthetics and serviceability into consideration. In this paper, using building computer simulation techniques, the effects of glass types on the thermal and energy performance of a sample air-conditioned office building in Australia are studied. It is found that a glass type with lower shading coefficient will have a lower building cooling load and total energy use. Through the comparison of results between current and future weather scenarios, it is identified that the pattern found from the current weather scenario would also exist in the future weather scenario, although the scale of change would become smaller. The possible implication of glazing selection in face of global warming is also examined. It is found that compared with its influence on building thermal performance, its influence on the building energy use is relatively small or insignificant.

Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

Sensitivity of office building zones to global warming

As global warming entails new conditions for the built environment, the thermal behavior of existing buildings, which were designed based on current weather data, may become unclear and remain a great concern. Through building computer simulation, this paper investigates the sensitivity of different office building zoning to the potential global warming. From the sample office building examined, it is found that compared with the middle and top floors, the ground floor for most cities appears to be most sensitive to the effect of global warming and has the highest tendency to having the overheating problem. From the analysis of the responses of different zone orientations to the outdoor air temperature increase, it is also found that there are widely different responses between different zone orientations, with South or Core zone being most sensitive. With an increased external air temperature, the difference between different floors or different zone orientations will become more significant.

The use of virtual prototyping for hazard identification in the early design stage

Purpose: The construction industry is well known for its high accident rate and many practitioners consider a preventative approach to be the most important means of bringing about improvements. This paper addresses previous research and the weaknesses of existing preventative approaches and a new application is described and illustrated involving the use of a multi-dimensional simulation tool - Construction Virtual Prototyping (CVP). Methodology: A literature review was conducted to investigate previous studies of hazard identification and safety management and to develop the new approach. Due to weaknesses in current practice, the research study explored the use of computer simulation techniques to create virtual environments where users can explore and identify construction hazards. Specifically, virtual prototyping technology was deployed to develop typical construction scenarios in which unsafe or hazardous incidents occur. In a case study, the users’ performance was evaluated their responses to incidents within the virtual environment and the effectiveness of the computer simulation system established though interviews with the safety project management team. Findings: The opinions and suggestions provided by the interviewees led to the initial conclusion that the simulation tool was useful in assisting the safety management team’s hazard identification process during the early design stage. Originality: The research introduces an innovative method to support the management teams’ reviews of construction site safety. The system utilises three-dimensional modelling and four-dimensional simulation of worker behaviour, a configuration that has previously not been employed in construction simulations. An illustration of the method’s use is also provided, together with a consideration of its strengths and weaknesses.

Modified beam theories for bending properties of nanowires considering surface/intrinsic effects and axial extension effect

Several studies of the surface effect on bending properties of a nanowire (NW) have been conducted. However, these analyses are mainly based on theoretical predictions, and there is seldom integration study in combination between theoretical predictions and simulation results. Thus, based on the molecular dynamics (MD) simulation and different modified beam theories, a comprehensive theoretical and numerical study for bending properties of nanowires considering surface/intrinsic stress effects and axial extension effect is conducted in this work. The discussion begins from the Euler-Bernoulli beam theory and Timoshenko beam theory augmented with surface effect. It is found that when the NW possesses a relatively small cross-sectional size, these two theories cannot accurately interpret the true surface effect. The incorporation of axial extension effect into Euler-Bernoulli beam theory provides a nonlinear solution that agrees with the nonlinear-elastic experimental and MD results. However, it is still found inaccurate when the NW cross-sectional size is relatively small. Such inaccuracy is also observed for the Euler-Bernoulli beam theory augmented with both contributions from surface effect and axial extension effect. A comprehensive model for completely considering influences from surface stress, intrinsic stress, and axial extension is then proposed, which leads to good agreement with MD simulation results. It is thus concluded that, for NWs with a relatively small cross-sectional size, a simple consideration of surface stress effect is inappropriate, and a comprehensive consideration of the intrinsic stress effect is required.

A fundamental numerical and theoretical study for the vibrational properties of nanowires

Based on the molecular dynamics (MD) simulation and the classical Euler-Bernoulli beam theory, a fundamental study of the vibrational performance of the Ag nanowire (NW) is carried out. A comprehensive analysis of the quality (Q)-factor, natural frequency, beat vibration, as well as high vibration mode is presented. Two excitation approaches, i.e., velocity excitation and displacement excitation, have been successfully implemented to achieve the vibration of NWs. Upon these two kinds of excitations, consistent results are obtained, i.e., the increase of the initial excitation amplitude will lead to a decrease to the Q-factor, and moderate plastic deformation could increase the first natural frequency. Meanwhile, the beat vibration driven by a single relatively large excitation or two uniform excitations in both two lateral directions is observed. It is concluded that the nonlinear changing trend of external energy magnitude does not necessarily mean a nonconstant Q-factor. In particular, the first order natural frequency of the Ag NW is observed to decrease with the increase of temperature. Furthermore, comparing with the predictions by Euler- Bernoulli beam theory, the MD simulation provides a larger and smaller first vibration frequencies for the clamped-clamped and clamped-free thin Ag NWs, respectively. Additionally, for thin NWs, the first order natural frequency exhibits a parabolic relationship with the excitation magnitudes. The frequencies of the higher vibration modes tend to be low in comparison to Euler-Bernoulli beam theory predictions. A combined initial excitation is proposed which is capable to drive the NW under a multi-mode vibration and arrows the coexistence of all the following low vibration modes. This work sheds lights on the better understanding of the mechanical properties of NWs and benefits the increasing utilities of NWs in diverse nano-electronic devices.

Human activity-induced vibration in slender structural systems

Human activity-induced vibrations in slender structural sys tems become apparent in many different excitation modes and consequent action effects that cause discomfort to occupants, crowd panic and damage to public infrastructure. Resulting loss of public confidence in safety of structures, economic losses, cost of retrofit and repairs can be significant. Advanced computational and visualisation techniques enable engineers and architects to evolve bold and innovative structural forms, very often without precedence. New composite and hybrid materials that are making their presence in structural systems lack historical evidence of satisfactory performance over anticipated design life. These structural systems are susceptible to multi-modal and coupled excitation that are very complex and have inadequate design guidance in the present codes and good practice guides. Many incidents of amplified resonant response have been reported in buildings, footbridges, stadia a nd other crowded structures with adverse consequences. As a result, attenuation of human-induced vibration of innovative and slender structural systems very ofte n requires special studies during the design process. Dynamic activities possess variable characteristics and thereby induce complex responses in structures that are sensitive to parametric variations. Rigorous analytical techniques are available for investigation of such complex actions and responses to produce acceptable performance in structural systems. This paper presents an overview and a critique of existing code provisions for human-induced vibration followed by studies on the performance of three contrasting structural systems that exhibit complex vibration. The dynamic responses of these systems under human-induced vibrations have been carried out using experimentally validated computer simulation techniques. The outcomes of these studies will have engineering applications for safe and sustainable structures and a basis for developing design guidance.

Virtual prototyping for planning bridge construction

4D simulation, building information modeling, virtual construction, computer simulation and virtual prototyping are emerging topics in the building construction industry. These techniques not only relate to the buildings themselves, but can also be applied to other forms of construction, including bridges. Since bridge construction is a complex process involving multiple types of plant and equipment, applying such virtual methods benefits the understanding of all parties in construction practice. This paper describes the relationship between temporary platforms, plant and equipment resources and a proposed-built model in the construction planning and use of Virtual Prototyping Simulation (VPS) to implement different construction scenarios in order to help planners identify an optimal construction plan. A case study demonstrates the use of VPS integrated with temporary platform design and plant and equipment-resource allocation to generate different construction scenarios.

Excess power circulation in distribution networks containing distributed energy resources

The presence of large number of single-phase distributed energy resources (DERs) can cause severe power quality problems in distribution networks. The DERs can be installed in random locations. This may cause the generation in a particular phase exceeds the load demand in that phase. Therefore the excess power in that phase will be fed back to the transmission network. To avoid this problem, the paper proposes the use of distribution static compensator (DSTATCOM) that needs to be connected at the first bus following a substation. When operated properly, the DSTATCOM can facilitate a set of balanced current flow from the substation, even when excess power is generated by DERs. The proposals are validated through extensive digital computer simulation studies using PSCAD and MATLAB.

A self-tuning feedforward active noise control system

This paper proposes a self-tuning feedforward active noise control (ANC) system with online secondary path modeling. The step-size parameters of the controller and modeling filters have crucial rule on the system performance. In literature, these parameters are adjusted by trial-and-error. In other words, they are manually initialized before system starting, which require performing extensive experiments to ensure the convergence of the system. Hence there is no guarantee that the system could perform well under different situations. In the proposed method, the appropriate values for the step-sizes are obtained automatically. Computer simulation results indicate the effectiveness of the proposed method.

An efficient online secondary path estimation for feedback active noise control systems

In practical cases for active noise control (ANC), the secondary path has usually a time varying behavior. For these cases, an online secondary path modeling method that uses a white noise as a training signal is required to ensure convergence of the system. The modeling accuracy and the convergence rate are increased when a white noise with a larger variance is used. However, the larger variance increases the residual noise, which decreases performance of the system and additionally causes instability problem to feedback structures. A sudden change in the secondary path leads to divergence of the online secondary path modeling filter. To overcome these problems, this paper proposes a new approach for online secondary path modeling in feedback ANC systems. The proposed algorithm uses the advantages of white noise with larger variance to model the secondary path, but the injection is stopped at the optimum point to increase performance of the algorithm and to prevent the instability effect of the white noise. In this approach, instead of continuous injection of the white noise, a sudden change in secondary path during the operation makes the algorithm to reactivate injection of the white noise to correct the secondary path estimation. In addition, the proposed method models the secondary path without the need of using off-line estimation of the secondary path. Considering the above features increases the convergence rate and modeling accuracy, which results in a high system performance. Computer simulation results shown in this paper indicate effectiveness of the proposed method.

Prediction of IBD based on population history for fine gene mapping

A novel multiple regression method (RM) is developed to predict identity-by-descent probabilities at a locus L (IBDL), among individuals without pedigree, given information on surrounding markers and population history. These IBDL probabilities are a function of the increase in linkage disequilibrium (LD) generated by drift in a homogeneous population over generations. Three parameters are sufficient to describe population history: effective population size (Ne), number of generations since foundation (T), and marker allele frequencies among founders (p). IBD L are used in a simulation study to map a quantitative trait locus (QTL) via variance component estimation. RM is compared to a coalescent method (CM) in terms of power and robustness of QTL detection. Differences between RM and CM are small but significant. For example, RM is more powerful than CM in dioecious populations, but not in monoecious populations. Moreover, RM is more robust than CM when marker phases are unknown or when there is complete LD among founders or Ne is wrong, and less robust when p is wrong. CM utilises all marker haplotype information, whereas RM utilises information contained in each individual marker and all possible marker pairs but not in higher order interactions. RM consists of a family of models encompassing four different population structures, and two ways of using marker information, which contrasts with the single model that must cater for all possible evolutionary scenarios in CM.

An optimized online secondary path modeling method for single-channel feedback ANC systems

This paper proposes a new method for online secondary path modeling in feedback active noise control (ANC) systems. In practical cases, the secondary path is usually time varying. For these cases, online modeling of secondary path is required to ensure convergence of the system. In literature the secondary path estimation is usually performed offline, prior to online modeling, where in the proposed system there is no need for using offline estimation. The proposed method consists of two steps: a noise controller which is based on an FxLMS algorithm, and a variable step size (VSS) LMS algorithm which is used to adapt the modeling filter with the secondary path. In order to increase performance of the algorithm in a faster convergence and accurate performance, we stop the VSS-LMS algorithm at the optimum point. The results of computer simulation shown in this paper indicate effectiveness of the proposed method.

Memory effect in the deposition of C20 fullerenes on a diamond surface

In this paper, the deposition of C-20 fullerenes on a diamond (001)-(2x1) surface and the fabrication of C-20 thin film at 100 K were investigated by a molecular dynamics (MD) simulation using the many-body Brenner bond order potential. First, we found that the collision dynamic of a single C-20 fullerene on a diamond surface was strongly dependent on its impact energy. Within the energy range 10-45 eV, the C-20 fullerene chemisorbed on the surface retained its free cage structure. This is consistent with the experimental observation, where it was called the memory effect in "C-20-type" films [P. Melion , Int. J. Mod. B 9, 339 (1995); P. Milani , Cluster Beam Synthesis of Nanostructured Materials (Springer, Berlin, 1999)]. Next, more than one hundred C-20 (10-25 eV) were deposited one after the other onto the surface. The initial growth stage of C-20 thin film was observed to be in the three-dimensional island mode. The randomly deposited C-20 fullerenes stacked on diamond surface and acted as building blocks forming a polymerlike structure. The assembled film was also highly porous due to cluster-cluster interaction. The bond angle distribution and the neighbor-atom-number distribution of the film presented a well-defined local order, which is of sp(3) hybridization character, the same as that of a free C-20 cage. These simulation results are again in good agreement with the experimental observation. Finally, the deposited C-20 film showed high stability even when the temperature was raised up to 1500 K.