Dynamic optimization of migration topology in internet-based distributed genetic algorithms

Distributed Genetic Algorithms (DGAs) designed for the Internet have to take its high communication cost into consideration. For island model GAs, the migration topology has a major impact on DGA performance. This paper describes and evaluates an adaptive migration topology optimizer that keeps the communication load low while maintaining high solution quality. Experiments on benchmark problems show that the optimized topology outperforms static or random topologies of the same degree of connectivity. The applicability of the method on real-world problems is demonstrated on a hard optimization problem in VLSI design.

In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus

Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo.

Gene transfer vectors targeted to human prostate cancer : do we need better preclinical testing systems?

Destruction of cancer cells by genetically modified viral and nonviral vectors has been the aim of many research programs. The ability to target cytotoxic gene therapies to the cells of interest is an essential prerequisite, and the treatment has always had the potential to provide better and more long-lasting therapy than existing chemotherapies. However, the potency of these infectious agents requires effective testing systems, in which hypotheses can be explored both in vitro and in vivo before the establishment of clinical trials in humans. The real prospect of off-target effects should be eliminated in the preclinical stage, if current prejudices against such therapies are to be overcome. In this review we have set out, using adenoviral vectors as a commonly used example, to discuss some of the key parameters required to develop more effective testing, and to critically assess the current cellular models for the development and testing of prostate cancer biotherapy. Only by developing models that more closely mirror human tissues will we be able to translate literature publications into clinical trials and hence into acceptable alternative treatments for the most commonly diagnosed cancer in humans.

An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria : implications for ex vivo drug susceptibility testing

The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC50) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC50 for CQ. Our findings indicate that EC50 values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.

Are academics messy? Testing the broken windows theory with a field experiment in the work environment

We test the broken windows theory using a field experiment in a shared area of an academic workplace(the department common room). More specifically, we explore academics’ and postgraduate students’ behavior under an order condition (a clean environment) and a disorder condition (a messy environment). We find strong evidence that signs of disorderly behavior trigger littering: In 59% of the cases, subjects litter in the disorder treatment as compared to 18% in the order condition. These results remain robust in a multivariate analysis even when controlling for a large set of factors not directly examined by previous studies. Overall, when academic staff and postgraduate students observe that others have violated the social norm of keeping the common room clean, all else being equal, the probability of littering increases by around 40%.

Development and interrater reliability testing of a telephone interview training programme for Australian nurse interviewers

Summary Background The final phase of a three phase study analysing the implementation and impact of the nurse practitioner role in Australia (the Australian Nurse Practitioner Project or AUSPRAC) was undertaken in 2009, requiring nurse telephone interviewers to gather information about health outcomes directly from patients and their treating nurse practitioners. A team of several registered nurses was recruited and trained as telephone interviewers. The aim of this paper is to report on development and evaluation of the training process for telephone interviewers. Methods The training process involved planning the content and methods to be used in the training session; delivering the session; testing skills and understanding of interviewers post-training; collecting and analysing data to determine the degree to which the training process was successful in meeting objectives and post-training follow-up. All aspects of the training process were informed by established educational principles. Results Interrater reliability between interviewers was high for well-validated sections of the survey instrument resulting in 100% agreement between interviewers. Other sections with unvalidated questions showed lower agreement (between 75% and 90%). Overall the agreement between interviewers was 92%. Each interviewer was also measured against a specifically developed master script or gold standard and for this each interviewer achieved a percentage of correct answers of 94.7% or better. This equated to a Kappa value of 0.92 or better. Conclusion The telephone interviewer training process was very effective and achieved high interrater reliability. We argue that the high reliability was due to the use of well validated instruments and the carefully planned programme based on established educational principles. There is limited published literature on how to successfully operationalise educational principles and tailor them for specific research studies; this report addresses this knowledge gap.

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Preliminary reliability and validity testing of a self-efficacy questionnaire for Chinese family caregivers

Objectives: To develop and test preliminary reliability and validity of a Self-Efficacy Questionnaire for Chinese Family Caregivers (SEQCFC). Methods: A cross-sectional survey of 196 family caregivers (CGs) of people with dementia (CGs) was conducted to determine the factor structure of a SEQCFC of people with dementia. Following factor analyses, preliminary testing was performed, including internal consistency, 4-week test retest reliability, and construct and convergent validity. Results: Factor analyses with direct oblimin rotation were performed. Eight items were removed and five subscales(selfefficacy for gathering information about treatment, symptoms and health care; obtaining support; responding to behaviour disturbances; managing household, personal and medical care; and managing distress associated with caregiving) were identified. The Cronbach’s alpha coefficients for the whole scale and for each subscale were all over 0.80. The 4-week testretest reliabilities for the whole scale and for each subscale ranged from 0.64 to 0.85. The convergent validity was acceptable. Conclusions: Evidence for the preliminary testing of the SEQCFC was encouraging. A future follow-up study using confirmatory factor analysis with a new sample from different recruitment centres in Shanghai will be conducted. Future psychometric property testings of the questionnaire will be required for CGs from other regions of mainland China.

Numerical modelling and full scale testing of load bearing steel walls under real fires

Fire safety has become an important part in structural design due to the ever increasing loss of properties and lives during fires. Fire rating of load bearing wall systems made of Light gauge Steel Frames (LSF) is determined using fire tests based on the standard time-temperature curve given in ISO 834. However, modern residential buildings make use of thermoplastic materials, which mean considerably high fuel loads. Hence a detailed fire research study into the performance of load bearing LSF walls was undertaken using a series of realistic design fire curves developed based on Eurocode parametric curves and Barnett’s BFD curves. It included both full scale fire tests and numerical studies of LSF walls without any insulation, and the recently developed externally insulated composite panels. This paper presents the details of fire tests first, and then the numerical models of tested LSF wall studs. It shows that suitable finite element models can be developed to predict the fire rating of load bearing walls under real fire conditions. The paper also describes the structural and fire performances of externally insulated LSF walls in comparison to the non-insulated walls under real fires, and highlights the effects of standard and real fire curves on fire performance of LSF walls.

A taxonomy of model-based testing approaches

Model-based testing (MBT) relies on models of a system under test and/or its environment to derive test cases for the system. This paper discusses the process of MBT and defines a taxonomy that covers the key aspects of MBT approaches. It is intended to help with understanding the characteristics, similarities and differences of those approaches, and with classifying the approach used in a particular MBT tool. To illustrate the taxonomy, a description of how three different examples of MBT tools fit into the taxonomy is provided.

Genetic association of the KLK4 locus with risk of prostate cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the Ptrend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

K from zeolite : glasshouse trial for testing K availability to the plants

MesoLite, a zeolite material manufactured by NanoChem Holdings Pty Ltd is made by caustic reaction of kaolin at temperatures between 80-95°C. This material has a moderate surface area (9~12 m2/g) and very high cation exchange capacity (500meq/100g). To measure the availability of K in K-MesoLite to plants, wheat was grown with K-MesoLite or a soluble fertiliser (e.g. KCl) in non-leached pots in a glasshouse. The weights and elemental compositions of the plants were compared after four weeks growth. Plants grown with K-MesoLite were slightly larger than those grown with KCl. The elemental compositions of the plants were similar except for Si, which was significantly higher in the plants grown with K-MesoLite than in those fertilised with KCl. K from K-MesoLite is readily available to plants.

A novel testing system for a Cycloidal drive

At present, for mechanical power transmission, Cycloidal drives are most preferred - for compact, high transmission ratio speed reduction, especially for robot joints and manipulator applications. Research on drive-train dynamics of Cycloidal drives is not well-established. This paper presents a testing rig for Cycloidal drives, which would produce data for development of mathematical models and investigation of drive-train dynamics, further aiding in optimising its design

Power of QTL detection using association tests with family controls

The power of testing for a population-wide association between a biallelic quantitative trait locus and a linked biallelic marker locus is predicted both empirically and deterministically for several tests. The tests were based on the analysis of variance (ANOVA) and on a number of transmission disequilibrium tests (TDT). Deterministic power predictions made use of family information, and were functions of population parameters including linkage disequilibrium, allele frequencies, and recombination rate. Deterministic power predictions were very close to the empirical power from simulations in all scenarios considered in this study. The different TDTs had very similar power, intermediate between one-way and nested ANOVAs. One-way ANOVA was the only test that was not robust against spurious disequilibrium. Our general framework for predicting power deterministically can be used to predict power in other association tests. Deterministic power calculations are a powerful tool for researchers to plan and evaluate experiments and obviate the need for elaborate simulation studies.