Mastering the canonical loop of serine protease inhibitors : enhancing potency by optimising the internal hydrogen bond network

Background Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. Methodology/Principal Findings In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. Conclusion/Significance These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Granule mining and its application for network traffic characterization

Decision table and decision rules play an important role in rough set based data analysis, which compress databases into granules and describe the associations between granules. Granule mining was also proposed to interpret decision rules in terms of association rules and multi-tier structure. In this paper, we further extend granule mining to describe the relationships between granules not only by traditional support and confidence, but by diversity and condition diversity as well. Diversity measures how diverse of a granule associated with the other ganules, it provides a kind of novel knowledge in databases. Some experiments are conducted to test the proposed new concepts for describing the characteristics of a real network traffic data collection. The results show that the proposed concepts are promising.

Sustainable Road Management in Texas : network-level flexible pavement structural condition analysis using data mining techniques

The research team recognized the value of network-level Falling Weight Deflectometer (FWD) testing to evaluate the structural condition trends of flexible pavements. However, practical limitations due to the cost of testing, traffic control and safety concerns and the ability to test a large network may discourage some agencies from conducting the network-level FWD testing. For this reason, the surrogate measure of the Structural Condition Index (SCI) is suggested for use. The main purpose of the research presented in this paper is to investigate data mining strategies and to develop a prediction method of the structural condition trends for network-level applications which does not require FWD testing. The research team first evaluated the existing and historical pavement condition, distress, ride, traffic and other data attributes in the Texas Department of Transportation (TxDOT) Pavement Maintenance Information System (PMIS), applied data mining strategies to the data, discovered useful patterns and knowledge for SCI value prediction, and finally provided a reasonable measure of pavement structural condition which is correlated to the SCI. To evaluate the performance of the developed prediction approach, a case study was conducted using the SCI data calculated from the FWD data collected on flexible pavements over a 5-year period (2005 – 09) from 354 PMIS sections representing 37 pavement sections on the Texas highway system. The preliminary study results showed that the proposed approach can be used as a supportive pavement structural index in the event when FWD deflection data is not available and help pavement managers identify the timing and appropriate treatment level of preventive maintenance activities.

Strategizing public sector human resource management : the implications of working network

Networks have come to the fore as a means by which government can achieve its strategic objectives, particularly when addressing complex or “wicked” issues. Such joined-up arrangements differ in their operations from other forms of organizing as they require collaborative effort to deliver the collaborative advantage. Strategic Human Resource Management is concerned with the matching of human resource practices to the strategic direction of organizations. It is argued that the strategic direction of government has been towards network involvement and that, as a result, a reconfiguration of Human Resource Management practices is needed to support this new direction. Drawing on eight network case studies findings are presented in relation to the roles government is expected to play in networks and conclusions are drawn about what types of human resource management practices would best support those roles. Implications for Strategic Human Resource Management are posited.

An interpretation of current progress towards an industry model for Queensland's surveying and mapping industry

A strongly progressive surveying and mapping industry depends on a shared understanding of the industry as it exists, some shared vision or imagination of what the industry might become, and some shared action plan capable of bringing about a realisation of that vision. The emphasis on sharing implies a need for consensus reached through widespread discussion and mutual understanding. Unless this occurs, concerted action is unlikely. A more likely outcome is that industry representatives will negate each other's efforts in their separate bids for progress. The process of bringing about consensual viewpoints is essentially one of establishing an industry identity. Establishing the industry's identity and purpose is a prerequisite for rational development of the industry's education and training, its promotion and marketing, and operational research that can deal .with industry potential and efficiency. This paper interprets evolutionary developments occurring within Queensland's surveying and mapping industry within a framework that sets out logical requirements for a viable industry.

Large scale monocular vision-only mapping from a fixed-wing sUAS

This paper presents the application of a monocular visual SLAMon a fixed-wing small Unmanned Aerial System (sUAS) capable of simultaneous estimation of aircraft pose and scene structure. We demonstrate the robustness of unconstrained vision alone in producing reliable pose estimates of a sUAS, at altitude. It is ultimately capable of online state estimation feedback for aircraft control and next-best-view estimation for complete map coverage without the use of additional sensors.We explore some of the challenges of visual SLAM from a sUAS including dealing with planar structure, distant scenes and noisy observations. The developed techniques are applied on vision data gathered from a fast-moving fixed-wing radio control aircraft flown over a 1×1km rural area at an altitude of 20-100m.We present both raw Structure from Motion results and a SLAM solution that includes FAB-MAP based loop-closures and graph-optimised pose. Timing information is also presented to demonstrate near online capabilities. We compare the accuracy of the 6-DOF pose estimates to an off-the-shelfGPS aided INS over a 1.7kmtrajectory.We also present output 3D reconstructions of the observed scene structure and texture that demonstrates future applications in autonomous monitoring and surveying.

Bi-objective bundle adjustment: towards large-scale visual sea-floor mapping with a minimal sensor suite

Visual sea-floor mapping is a rapidly growing application for Autonomous Underwater Vehicles (AUVs). AUVs are well-suited to the task as they remove humans from a potentially dangerous environment, can reach depths human divers cannot, and are capable of long-term operation in adverse conditions. The output of sea-floor maps generated by AUVs has a number of applications in scientific monitoring: from classifying coral in high biological value sites to surveying sea sponges to evaluate marine environment health.