Evolving noisy oscillatory dynamics in genetic regulatory networks

We introduce a genetic programming (GP) approach for evolving genetic networks that demonstrate desired dynamics when simulated as a discrete stochastic process. Our representation of genetic networks is based on a biochemical reaction model including key elements such as transcription, translation and post-translational modifications. The stochastic, reaction-based GP system is similar but not identical with algorithmic chemistries. We evolved genetic networks with noisy oscillatory dynamics. The results show the practicality of evolving particular dynamics in gene regulatory networks when modelled with intrinsic noise.

Population genetic structure and patterns of dispersal in the Giant Long-Armed Prawn, Macrobrachium lar (Fabricius, 1798) (Decapoda : Palaemonidae)

The Giant Long-Armed Prawn, Macrobrachium lar is a freshwater species native to the Indo-Pacific. M. lar has a long-lived, passive, pelagic marine larval stage where larvae need to colonise freshwater within three months to complete their development. Dispersal is likely to be influenced by the extensive distances larvae must transit between small oceanic islands to find suitable freshwater habitat, and by prevailing east to west wind and ocean currents in the southern Pacific Ocean. Thus, both intrinsic and extrinsic factors are likely to influence wild population structure in this species. The present study sought to define the contemporary broad and fine-scale population genetic structure of Macrobrachium lar in the south-western Pacific Ocean. Three polymorphic microsatellite loci were used to assess patterns of genetic variation within and among 19 wild adult sample sites. Statistical procedures that partition variation implied that at both spatial scales, essentially all variation was present within sample sites and differentiation among sites was low. Any differentiation observed also was not correlated with geographical distance. Statistical approaches that measure genetic distance, at the broad-scale, showed that all south-western Pacific Islands were essentially homogeneous, with the exception of a well supported divergent Cook Islands group. These findings are likely the result of some combination of factors that may include the potential for allelic homoplasy, through to the effects of sampling regime. Based on the findings, there is most likely a divergent M. lar Cook Islands clade in the south-western Pacific Ocean, resulting from prevailing ocean currents. Confirmation of this pattern will require a more detailed analysis of nDNA variation using a larger number of loci and, where possible, use of larger population sizes.

A mathematical model for genetic regulation of the lactose operon

In this paper we construct a mathematical model for the genetic regulatory network of the lactose operon. This mathematical model contains transcription and translation of the lactose permease (LacY) and a reporter gene GFP. The probability of transcription of LacY is determined by 14 binding states out of all 50 possible binding states of the lactose operon based on the quasi-steady-state assumption for the binding reactions, while we calculate the probability of transcription for the reporter gene GFP based on 5 binding states out of 19 possible binding states because the binding site O2 is missing for this reporter gene. We have tested different mechanisms for the transport of thio-methylgalactoside (TMG) and the effect of different Hill coefficients on the simulated LacY expression levels. Using this mathematical model we have realized one of the experimental results with different LacY concentrations, which are induced by different concentrations of TMG.

Evolving genetic regulatory networks performing as stochastic switches

Recent studies have shown that small genetic regulatory networks (GRNs) can be evolved in silico displaying certain dynamics in the underlying mathematical model. It is expected that evolutionary approaches can help to gain a better understanding of biological design principles and assist in the engineering of genetic networks. To take the stochastic nature of GRNs into account, our evolutionary approach models GRNs as biochemical reaction networks based on simple enzyme kinetics and simulates them by using Gillespie’s stochastic simulation algorithm (SSA). We have already demonstrated the relevance of considering intrinsic stochasticity by evolving GRNs that show oscillatory dynamics in the SSA but not in the ODE regime. Here, we present and discuss first results in the evolution of GRNs performing as stochastic switches.

Screening, isolation, and decolonisation strategies in the control of meticillin resistant Staphylococcus aureus in intensive care units : cost effectiveness evaluation

Objective: To assess the cost-effectiveness of screening, isolation and decolonisation strategies in the control of methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs). Design: Economic evaluation. Setting: England and Wales. Population: ICU patients. Main outcome measures: Infections, deaths, costs, quality adjusted life years (QALYs), incremental cost-effectiveness ratios for alternative strategies, net monetary benefits (NMBs). Results: All strategies using isolation but not decolonisation improved health outcomes but increased costs. When MRSA prevalence on admission to the ICU was 5% and the willingness to pay per QALY gained was between £20,000 and £30,000, the best such strategy was to isolate only those patients at high risk of carrying MRSA (either pre-emptively or following identification by admission and weekly MRSA screening using chromogenic agar). Universal admission and weekly screening using polymerase chain reaction (PCR)-based MRSA detection coupled with isolation was unlikely to be cost-effective unless prevalence was high (10% colonised with MRSA on admission to the ICU). All decolonisation strategies improved health outcomes and reduced costs. While universal decolonisation (regardless of MRSA status) was the most cost-effective in the short-term, strategies using screening to target MRSA carriers may be preferred due to reduced risk of selecting for resistance. Amongst such targeted strategies, universal admission and weekly PCR screening coupled with decolonisation with nasal mupirocin was the most cost-effective. This finding was robust to ICU size, MRSA admission prevalence, the proportion of patients classified as high-risk, and the precise value of willingness to pay for health benefits. Conclusions: MRSA control strategies that use decolonisation are likely to be cost-saving in an ICU setting provided resistance is lacking, and combining universal PCR-based screening with decolonisation is likely to represent good value for money if untargeted decolonisation is considered unacceptable. In ICUs where decolonisation is not implemented there is insufficient evidence to support universal MRSA screening outside high prevalence settings.

QoS-aware web service composition using genetic algorithms

Web service technology is increasingly being used to build various e-Applications, in domains such as e-Business and e-Science. Characteristic benefits of web service technology are its inter-operability, decoupling and just-in-time integration. Using web service technology, an e-Application can be implemented by web service composition — by composing existing individual web services in accordance with the business process of the application. This means the application is provided to customers in the form of a value-added composite web service. An important and challenging issue of web service composition, is how to meet Quality-of-Service (QoS) requirements. This includes customer focused elements such as response time, price, throughput and reliability as well as how to best provide QoS results for the composites. This in turn best fulfils customers’ expectations and achieves their satisfaction. Fulfilling these QoS requirements or addressing the QoS-aware web service composition problem is the focus of this project. From a computational point of view, QoS-aware web service composition can be transformed into diverse optimisation problems. These problems are characterised as complex, large-scale, highly constrained and multi-objective problems. We therefore use genetic algorithms (GAs) to address QoS-based service composition problems. More precisely, this study addresses three important subproblems of QoS-aware web service composition; QoS-based web service selection for a composite web service accommodating constraints on inter-service dependence and conflict, QoS-based resource allocation and scheduling for multiple composite services on hybrid clouds, and performance-driven composite service partitioning for decentralised execution. Based on operations research theory, we model the three problems as a constrained optimisation problem, a resource allocation and scheduling problem, and a graph partitioning problem, respectively. Then, we present novel GAs to address these problems. We also conduct experiments to evaluate the performance of the new GAs. Finally, verification experiments are performed to show the correctness of the GAs. The major outcomes from the first problem are three novel GAs: a penaltybased GA, a min-conflict hill-climbing repairing GA, and a hybrid GA. These GAs adopt different constraint handling strategies to handle constraints on interservice dependence and conflict. This is an important factor that has been largely ignored by existing algorithms that might lead to the generation of infeasible composite services. Experimental results demonstrate the effectiveness of our GAs for handling the QoS-based web service selection problem with constraints on inter-service dependence and conflict, as well as their better scalability than the existing integer programming-based method for large scale web service selection problems. The major outcomes from the second problem has resulted in two GAs; a random-key GA and a cooperative coevolutionary GA (CCGA). Experiments demonstrate the good scalability of the two algorithms. In particular, the CCGA scales well as the number of composite services involved in a problem increases, while no other algorithms demonstrate this ability. The findings from the third problem result in a novel GA for composite service partitioning for decentralised execution. Compared with existing heuristic algorithms, the new GA is more suitable for a large-scale composite web service program partitioning problems. In addition, the GA outperforms existing heuristic algorithms, generating a better deployment topology for a composite web service for decentralised execution. These effective and scalable GAs can be integrated into QoS-based management tools to facilitate the delivery of feasible, reliable and high quality composite web services.

An improved genetic algorithm and graph theory based method for optimal sectionalizer switch placement in distribution networks with DG

In this paper a new graph-theory and improved genetic algorithm based practical method is employed to solve the optimal sectionalizer switch placement problem. The proposed method determines the best locations of sectionalizer switching devices in distribution networks considering the effects of presence of distributed generation (DG) in fitness functions and other optimization constraints, providing the maximum number of costumers to be supplied by distributed generation sources in islanded distribution systems after possible faults. The proposed method is simulated and tested on several distribution test systems in both cases of with DG and non DG situations. The results of the simulations validate the proposed method for switch placement of the distribution network in the presence of distributed generation.

Impacts of traditional husbandry practices on exploitable levels of genetic diversity in cultured 'Tra' catfish (Pangasianodon hypophthalmus) in the Mekong Delta, Vietnam

Sutchi catfish (Pangasianodon hypophthalmus) – known more universally by the Vietnamese name ‘Tra’ is an economically important freshwater fish in the Mekong Delta in Vietnam that constitutes an important food resource. Artificial propagation technology for Tra catfish has only recently been developed along the main branches of the Mekong River where more than 60% of the local human population participate in fishing or aquaculture. Extensive support for catfish culture in general, and that of Tra (P. hypophthalmus) in particular, has been provided by the Vietnamese government to increase both the scale of production and to develop international export markets. In 2006, total Vietnamese catfish exports reached approximately 286,602 metric tons (MT) and were valued at 736.87 $M with a number of large new export destinations being developed. Total value of production from catfish culture has been predicted to increase to approximately USD 1 billion by 2020. While freshwater catfish culture in Vietnam has a promising future, concerns have been raised about long-term quality of fry and the effectiveness of current brood stock management practices, issues that have been largely neglected to date. In this study, four DNA markers (microsatellite loci: CB4, CB7, CB12 and CB13) that were developed specifically for Tra (P. hypophthalmus) in an earlier study were applied to examine the genetic quality of artificially propagated Tra fry in the Mekong Delta in Vietnam. The goals of the study were to assess: (i) how well available levels of genetic variation in Tra brood stock used for artificial propagation in the Mekong Delta of Vietnam (breeders from three private hatcheries and Research Institute of Aquaculture No2 (RIA2) founders) has been conserved; and (ii) whether or not genetic diversity had declined significantly over time in a stock improvement program for Tra catfish at RIA2. A secondary issue addressed was how genetic markers could best be used to assist industry development. DNA was extracted from fins of catfish collected from the two main branches of the Mekong River inf Vietnam, three private hatcheries and samples from the Tra improvement program at RIA2. Study outcomes: i) Genetic diversity estimates for Tra brood stock samples were similar to, and slightly higher than, wild reference samples. In addition, the relative contribution by breeders to fry in commercial private hatcheries strongly suggest that the true Ne is likely to be significantly less than the breeder numbers used; ii) in a stock improvement program for Tra catfish at RIA2, no significant differences were detected in gene frequencies among generations (FST=0.021, P=0.036>0.002 after Bonferroni correction); and only small differences were observed in alleles frequencies among sample populations. To date, genetic markers have not been applied in the Tra catfish industry, but in the current project they were used to evaluate the levels of genetic variation in the Tra catfish selective breeding program at RIA2 and to undertake genetic correlations between genetic marker and trait variation. While no associations were detected using only four loci, they analysis provided training in the practical applications of the use of molecular markers in aquaculture in general, and in Tra culture, in particular.

Reduced variance in monozygous twins for multiple MR parameters : implications for disease studies and the genetic basis of brain structure

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest. Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation. Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA). This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

Possible genetic predisposition to lymphedema after breast cancer

Background: Known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicate a number of potential candidate genes to explore in relation to secondary lymphedema. Methods and Results: We undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n=22) and those without lymphedema serving as controls (n=98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM and PROX1 were selected for genotyping. Multiple SNPs within three receptor genes, VEGFR2, VEGFR3 and RORC, were associated with lymphedema defined by statistical significance (p<0.05) or extreme risk estimates (OR<0.5 or >2.0). Conclusions: These provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger datasets.

The development of a conceptual framework for a district 4-Year Pavement Management Plan, implementation of network-level project screening process

The Texas Department of Transportation (TxDOT) is concerned about the widening gap between preservation needs and available funding. Funding levels are not adequate to meet the preservation needs of the roadway network; therefore projects listed in the 4-Year Pavement Management Plan must be ranked to determine which projects should be funded now and which can be postponed until a later year. Currently, each district uses locally developed methods to prioritize projects. These ranking methods have relied on less formal qualitative assessments based on engineers’ subjective judgment. It is important for TxDOT to have a 4-Year Pavement Management Plan that uses a transparent, rational project ranking process. The objective of this study is to develop a conceptual framework that describes the development of the 4-Year Pavement Management Plan. It can be largely divided into three Steps; 1) Network-Level project screening process, 2) Project-Level project ranking process, and 3) Economic Analysis. A rational pavement management procedure and a project ranking method accepted by districts and the TxDOT administration will maximize efficiency in budget allocations and will potentially help improve pavement condition. As a part of the implementation of the 4-Year Pavement Management Plan, the Network-Level Project Screening (NLPS) tool including the candidate project identification algorithm and the preliminary project ranking matrix was developed. The NLPS has been used by the Austin District Pavement Engineer (DPE) to evaluate PMIS (Pavement Management Information System) data and to prepare a preliminary list of candidate projects for further evaluation.

Screening to identify large truck potential blackspots : methodological issues and concerns

1. Overview of hotspot identification (HSID)methods 2. Challenges with HSID 3. Bringing crash severity into the ‘mix’ 4. Case Study: Truck Involved Crashes in Arizona 5. Conclusions • Heavy duty trucks have different performance envelopes than passenger cars and have more difficulty weaving, accelerating, and braking • Passenger vehicles have extremely limited sight distance around trucks • Lane and shoulder widths affect truck crash risk more than passenger cars • Using PDOEs to model truck crashes results in a different set of locations to examine for possible engineering and behavioral problems • PDOE models point to higher societal cost locations, whereas frequency models point to higher crash frequency locations • PDOE models are less sensitive to unreported crashes • PDOE models are a great complement to existing practice

Validity of the malnutrition screening tool for older adults at high risk of hospital readmission

Malnutrition is a serious problem in older adults, particularly for those at risk of hospital readmission. The essential step in managing malnutrition is early identification using a valid nutrition screening tool. The purpose of this study was to validate the Malnutrition Screening Tool (MST) in older adults at high risk of hospital readmission. Two registered nurses administered the MST to identify malnutrition risk, and compared it to the comprehensive Subjective Global Assessment (SGA) to assess nutritional status for patients aged 65 years who had at least one risk factor for hospital readmission. The MST demonstrates substantial sensitivity, specificity and agreement with the SGA. These findings indicate that nursing staff can use the MST as a valid tool for routine screening and rescreening to identify patients at risk of malnutrition. Use of the MST may prevent hospital-acquired malnutrition for acute hospitalized older adults at high risk of readmission.

Genetic evidence for the vital function of osterix in cementogenesis

To date, attempts to regenerate a complete tooth, including the critical periodontal tissues associated with the tooth root, have not been successful. Controversy still exists regarding the origin of the cell source for cellular cementum (epithelial or mesenchymal). This disagreement may be partially due to a lack of understanding of the events leading to the initiation and development of the tooth roots and supportive tissues, such as the cementum. Osterix (OSX) is a transcriptional factor essential for osteogenesis, but its role in cementogenesis has not been addressed. In the present study, we first documented a close relationship between the temporal- and spatial-expression pattern of OSX and the formation of cellular cementum. We then generated 3.6 Col 1-OSX transgenic mice, which displayed accelerated cementum formation vs. WT controls. Importantly, the conditional deletion of OSX in the mesenchymal cells with two different Cre systems (the 2.3 kb Col 1 and an inducible CAG-CreER) led to a sharp reduction in cellular cementum formation (including the cementum mass and mineral deposition rate) and gene expression of dentin matrix protein 1 (DMP1) by cementocytes. However, the deletion of the OSX gene after cellular cementum formed did not alter the properties of the mature cementum as evaluated by backscattered SEM and resin-cast SEM. Transient transfection of Osx in the cementoblasts in vitro significantly inhibited cell proliferation and increased cell differentiation and mineralization. Taken together, these data support 1) the mesenchymal origin of cellular cementum (from PDL progenitor cells); 2) the vital role of OSX in controlling the formation of cellular cementum; and 3) the limited remodeling of cellular cementum in adult mice.

Screening for alcohol and drug use in pregnancy

Objective - this study examined the clinical utility and precision of routine screening for alcohol and other drug use among women attending a public antenatal service. Study design - a survey of clients and audit of clinical charts. Participants and setting - clients attending an antenatal clinic of a large tertiary hospital in Queensland, Australia, from October to December 2009. Measurements and findings - data were collected from two sources. First, 32 women who reported use of alcohol or other drugs during pregnancy at initial screening were then asked to complete a full substance use survey. Second, data were collected from charts of 349 new clients who attended the antenatal clinic during the study period. Both sensitivity (86%, 67%) and positive predictive value (100%, 92%) for alcohol and other drug use respectively, were high. Only 15% of surveyed women were uncomfortable about being screened for substance use in pregnancy, yet the chart audit revealed poor staff compliance. During the study period, 25% of clients were either not screened adequately or not at all. Key conclusions and implications for practise - despite recommended universal screening in pregnancy and the apparent acceptance by our participants, alcohol and other drug (A&OD) screening in the antenatal setting remains problematic. Investigation into the reasons behind, and ways to overcome, the low screening rate could improve health outcomes for mothers and children in this at-risk group. Targeted education and training for midwives may form part of the solution as these clinicians have a key role in implementing prevention and early intervention strategies.