Modeling of Complex and Diverse Aircraft Trajectories with the Trajectory Synthesizer Generalized Profile Interface

A flexible method to describe and generate aircraft trajectories called GenProf was developed for the Center TRACON Automation System (CTAS) software research platform. Generally CTAS is used to prototype new air traffic management decision support tools and concepts. Beyond this purpose, the GenProf methodology has enabled a variety of research and validation tasks to be performed. This paper briefly describes the methodology and details these applications

Battlespace Next™: Developing a Serious Game to Explore Multi-domain Operations

Changes in the geopolitical landscape and increasing technological complexity have prompted the U.S. Military to coin the terms Multi-Domain Operations (MDO) and Joint All-Domain Command and Control (JADC2) as over-arching strategy to frame the complexity of warfare across both traditional and emerging warfighting domains. Teaching new concepts associated with these terms requires both innovation as well as distinct education and training tools in order to realize the cultural change advocated by senior military leaders. Battlespace Next™ (BSN) is a serious game designed to teach concepts integral to MDO and initiate discussion on military strategy while conserving time, money, and manpower. BSN, a Collectable Card Game (CCG), is engineered to provide an engaging learning tool that educates on capabilities in a multi-domain conflict. This paper proposes an extensible game framework for modeling and reasoning about MDO concepts and presents our empirical feedback from over 120 military play testers evaluating a moderate to difficult version of the game. Results reveal the game teaches MDO concepts and delivers an engaging, hands-on learning experience. Specifically, we provide evidence it improved military readiness in seven areas of MDO in at least 62% of participants and 76% of respondents reported they enjoyed playing the game

The structure of human 5-lipoxygenase

The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). 5-LOX activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. We identified a 5-LOX-specific destabilizing sequence that is involved in orienting the carboxyl terminus, which binds the catalytic iron. Here, we report the crystal structure at 2.4 angstrom resolution of human 5-LOX stabilized by replacement of this sequence

A covalent linker allows for membrane targeting of an oxylipin biosynthetic complex

A naturally occurring bifunctional protein from Plexaura homomalla links sequential catalytic activities in an oxylipin biosynthetic pathway. The C-terminal lipoxygenase (LOX) portion of the molecule catalyzes the transformation of arachidonic acid (AA) to the corresponding 8R-hydroperoxide, and the N-terminal allene oxide synthase (AOS) domain promotes the conversion of the hydroperoxide intermediate to the product allene oxide (AO). Small-angle X-ray scattering data indicate that in the absence of a covalent linkage the two catalytic domains that transform AA to AO associate to form a complex that recapitulates the structure of the bifunctional protein. The SAXS data also support a model for LOX and AOS domain orientation in the fusion protein inferred from a low-resolution crystal structure. However, results of membrane binding experiments indicate that covalent linkage of the domains is required for Ca2+-dependent membrane targeting of the sequential activities, despite the noncovalent domain association. Furthermore, membrane targeting is accompanied by a conformational change as monitored by specific proteolysis of the linker that joins the AOS and LOX domains. Our data are consistent with a model in which Ca2+-dependent membrane binding relieves the noncovalent interactions between the AOS and LOX domains and suggests that the C2-like domain of LOX mediates both protein-protein and protein-membrane interactions. © 2008 American Chemical Society

Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663

The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca 2+-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A4 from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5-LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down-regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation. © FASEB

Survey and scoping of wildcat priority areas

This report summarises the findings of three complementary projects commissioned by SNH to inform the selection of Priority Areas for wildcat conservation; as proposed in the Scottish Wildcat Conservation Action Plan 2013. The scoping projects combined field surveys, taxonomic and genetic assessments, population modelling and a questionnaire survey of public attitudes to wildcat conservation measures. The report makes a recommendations for six wildcat Priority Areas from the nine areas pre-selected by SNH for survey. The sites recommended as Priority Areas all had evidence of cats that were classified as wildcats based on their appearance. However, domestic cats or hybrids (between domestic cats and wildcats) were also found, highlighting the need for conservation actions to reduce the risks they pose to wildcats from hybridisation and disease

Screening a protein kinase inhibitor library against <i>Plasmodium falciparum</i>

Abstract Background Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. Results As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. Discussion This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. Conclusions Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library

A Motion Planning Approach to Automatic Obstacle Avoidance during Concentric Tube Robot Teleoperation

Abstract-Concentric tube robots are thin, tentacle-like devices that can move along curved paths and can potentially enable new, less invasive surgical procedures. Safe and effective operation of this type of robot requires that the robot&apos;s shaft avoid sensitive anatomical structures (e.g., critical vessels and organs) while the surgeon teleoperates the robot&apos;s tip. However, the robot&apos;s unintuitive kinematics makes it difficult for a human user to manually ensure obstacle avoidance along the entire tentacle-like shape of the robot&apos;s shaft. We present a motion planning approach for concentric tube robot teleoperation that enables the robot to interactively maneuver its tip to points selected by a user while automatically avoiding obstacles along its shaft. We achieve automatic collision avoidance by precomputing a roadmap of collision-free robot configurations based on a description of the anatomical obstacles, which are attainable via volumetric medical imaging. We also mitigate the effects of kinematic modeling error in reaching the goal positions by adjusting motions based on robot tip position sensing. We evaluate our motion planner on a teleoperated concentric tube robot and demonstrate its obstacle avoidance and accuracy in environments with tubular obstacles

Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

BACKGROUND: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. METHODS: Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. RESULTS: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. CONCLUSIONS: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding