Computational micromodel for epigenetic mechanisms

Characterization of the epigenetic profile of humans since the initial breakthrough on the human genome project has strongly established the key role of histone modifications and DNA methylation. These dynamic elements interact to determine the normal level of expression or methylation status of the constituent genes in the genome. Recently, considerable evidence has been put forward to demonstrate that environmental stress implicitly alters epigenetic patterns causing imbalance that can lead to cancer initiation. This chain of consequences has motivated attempts to computationally model the influence of histone modification and DNA methylation in gene expression and investigate their intrinsic interdependency. In this paper, we explore the relation between DNA methylation and transcription and characterize in detail the histone modifications for specific DNA methylation levels using a stochastic approach.

Cell type-dependent, infection-induced, aberrant DNA methylation in gastric cancer

Epigenetic changes correspond to heritable modifications of the chromatin structure, which do not involve any alteration of the DNA sequence but nonetheless affect gene expression. These mechanisms play an important role in cell differentiation, but aberrant occurrences are also associated with a number of diseases, including cancer and neural development disorders. In particular, aberrant DNA methylation induced by H. Pylori has been found to be a significant risk factor in gastric cancer. To investigate the sensitivity of different genes and cell types to this infection, a computational model of methylation in gastric crypts is developed. In this article, we review existing results from physical experiments and outline their limitations, before presenting the computational model and investigating the influence of its parameters.

Computational analysis of epigenetic information in human DNA sequences

Over the last few years, investigations of human epigenetic profiles have identified key elements of change to be Histone Modifications, stable and heritable DNA methylation and Chromatin remodeling. These factors determine gene expression levels and characterise conditions leading to disease. In order to extract information embedded in long DNA sequences, data mining and pattern recognition tools are widely used, but efforts have been limited to date with respect to analyzing epigenetic changes, and their role as catalysts in disease onset. Useful insight, however, can be gained by investigation of associated dinucleotide distributions. The focus of this paper is to explore specific dinucleotides frequencies across defined regions within the human genome, and to identify new patterns between epigenetic mechanisms and DNA content. Signal processing methods, including Fourier and Wavelet Transformations, are employed and principal results are reported.

Building cross-scale models of epigenetic mechanisms

Epigenetic changes correspond to heritable modifications of the chromosome structure, which do not involve alteration of the DNA sequence but do affect gene expression. These mechanisms play an important role in normal cell differentiation, but aberration is associated also with several diseases, including cancer and neural disorders. In consequence, despite intensive studies in recent years, the contribution of modifications remains largely unquantified due to overall system complexity and insufficient data. Computational models can provide powerful auxiliary tools to experimentation, not least as scales from the sub-cellular through cell populations (or to networks of genes) can be spanned. In this paper, the challenges to development, of realistic cross-scale models, are discussed and illustrated with respect to current work.

Web crippling tests of cold-formed steel channels under two flange load cases

Cold-formed steel members have many advantages over hot-rolled steel members. However, they are susceptible to various buckling modes at stresses below the yield stress of the member because of their relatively high width-to-thickness ratio. Web crippling is a form of localized failure mode that can occur when the members are subjected to transverse high concentrated loadings and/or reactions. The four common loading conditions are the end-one-flange (EOF), interior-one-flange (IOF), end-two-flange (ETF) and interior-two-flange (ITF) loadings. Recently a test method has been proposed by AISI to obtain the web crippling capacities under these four loading conditions. Using this test method 42 tests were conducted in this research to investigate the web crippling behaviour and strengths of unlipped channels with stocky webs under ETF and ITF cases. DuraGal sections having a nominal yield stress of 450 MPa were tested with different web slenderness and bearing lengths. The flanges of these channel sections were not fastened to the supports. In this research the suitability of the currently available design rules for unlipped channels subject to web crippling was investigated, and suitable modifications were proposed where necessary. In addition to this, a new design rule was proposed based on the direct strength method to predict the web crippling capacities of tested beams. This paper presents the details of this experimental study and the results.

An upstream open reading frame is essential for feedback regulation of ascorbate biosynthesis in arabidopsis

Ascorbate (vitamin C) is an essential antioxidant and enzyme cofactor in both plants and animals. Ascorbate concentration is tightly regulated in plants, partly to respond to stress. Here, we demonstrate that ascorbate concentrations are determined via the posttranscriptional repression of GDP-l-galactose phosphorylase (GGP), a major control enzyme in the ascorbate biosynthesis pathway. This regulation requires a cis-acting upstream open reading frame (uORF) that represses the translation of the downstream GGP open reading frame under high ascorbate concentration. Disruption of this uORF stops the ascorbate feedback regulation of translation and results in increased ascorbate concentrations in leaves. The uORF is predicted to initiate at a noncanonical codon (ACG rather than AUG) and encode a 60- to 65-residue peptide. Analysis of ribosome protection data from Arabidopsis thaliana showed colocation of high levels of ribosomes with both the uORF and the main coding sequence of GGP. Together, our data indicate that the noncanonical uORF is translated and encodes a peptide that functions in the ascorbate inhibition of translation. This posttranslational regulation of ascorbate is likely an ancient mechanism of control as the uORF is conserved in GGP genes from mosses to angiosperms.

A low-cost attack on branch-based software watermarking schemes

In 2005, Ginger Myles and Hongxia Jin proposed a software watermarking scheme based on converting jump instructions or unconditional branch statements (UBSs) by calls to a fingerprint branch function (FBF) that computes the correct target address of the UBS as a function of the generated fingerprint and integrity check. If the program is tampered with, the fingerprint and integrity checks change and the target address will not be computed correctly. In this paper, we present an attack based on tracking stack pointer modifications to break the scheme and provide implementation details. The key element of the attack is to remove the fingerprint and integrity check generating code from the program after disassociating the target address from the fingerprint and integrity value. Using the debugging tools that give vast control to the attacker to track stack pointer operations, we perform both subtractive and watermark replacement attacks. The major steps in the attack are automated resulting in a fast and low-cost attack.

Substation Automation Systems – Future possibilities for commissioning

Substation Automation Systems have undergone many transformational changes triggered by improvements in technologies. Prior to the digital era, it made sense to confirm that the physical wiring matched the schematic design by meticulous and laborious point to point testing. In this way, human errors in either the design or the construction could be identified and fixed prior to entry into service. However, even though modern secondary systems today are largely computerised, we are still undertaking commissioning testing using the same philosophy as if each signal were hard wired. This is slow and tedious and doesn’t do justice to modern computer systems and software automation. One of the major architectural advantages of the IEC 61850 standard is that it “abstracts” the definition of data and services independently of any protocol allowing the mapping of them to any protocol that can meet the modelling and performance requirements. On this basis, any substation element can be defined using these common building blocks and are made available at the design, configuration and operational stages of the system. The primary advantage of accessing data using this methodology rather than the traditional position method (such as DNP 3.0) is that generic tools can be created to manipulate data. Self-describing data contains the information that these tools need to manipulate different data types correctly. More importantly, self-describing data makes the interface between programs robust and flexible. This paper proposes that the improved data definitions and methods for dealing with this data within a tightly bound and compliant IEC 61850 Substation Automation System could completely revolutionise the need to test systems when compared to traditional point to point methods. Using the outcomes of an undergraduate thesis project, we can demonstrate with some certainty that it is possible to automatically test the configuration of a protection relay by comparing the IEC 61850 configuration extracted from the relay against its SCL file for multiple relay vendors. The software tool provides a quick and automatic check that the data sets on a particular relay are correct according to its CID file, thus ensuring that no unexpected modifications are made at any stage of the commissioning process. This tool has been implemented in a Java programming environment using an open source IEC 61850 library to facilitate the server-client association with the relay.

Fire design rules for load bearing cold-formed steel frame walls exposed to realistic design fire curves

Light gauge Steel Frame (LSF) walls are extensively used in the building industry due to the many advantages they provide over other wall systems. Although LSF walls have been used widely, fire design of LSF walls is based on approximate prescriptive methods based on limited fire tests. Also these fire tests were conducted using the standard fire curve [1] and the applicability of available design rules to realistic design fire curves has not been verified. This paper investigates the accuracy of existing fire design rules in the current cold-formed steel standards and the modifications proposed by previous researchers. Of these the recently developed design rules by Gunalan and Mahendran [2] based on Eurocode 3 Part 1.3 [3] and AS/NZS 4600 [4] for standard fire exposure [1] were investigated in detail to determine their applicability to predict the axial compression strengths and fire resistance ratings of LSF walls exposed to realistic design fire curves. This paper also presents the fire performance results of LSF walls exposed to a range of realistic fire curves obtained using a finite element analysis based parametric study. The results from the parametric study were used to develop a simplified design method based on the critical hot flange temperature to predict the fire resistance ratings of LSF walls exposed to realistic fire curves. Finally, the stud failure times (fire resistance rating) obtained from the fire design rules and the simplified design method were compared with parametric study results for LSF walls lined with single and double plasterboards, and externally insulated with rock fibres under realistic fire curves.

Translating road safety research on night-time visibility to the context of mining

In recent years a significant amount of research has been undertaken in collision avoidance and personnel location technology in order to reduce the number of incidents involving pedestrians and mobile plant equipment which are a high risk in underground coal mines. Improving the visibility of pedestrians to drivers would potentially reduce the likelihood of these incidents. In the road safety context, a variety of approaches have been used to make pedestrians more conspicuous to drivers at night (including vehicle and roadway lighting technologies and night vision enhancement systems). However, emerging research from our group and others has demonstrated that clothing incorporating retroreflective markers on the movable joints as well as the torso can provide highly significant improvements in pedestrian visibility in reduced illumination. Importantly, retroreflective markers are most effective when positioned on the moveable joints creating a sensation of “biological motion”. Based only on the motion of points on the moveable joints of an otherwise invisible body, observers can quickly recognize a walking human form, and even correctly judge characteristics such as gender and weight. An important and as yet unexplored question is whether the benefits of these retroreflective clothing configurations translate to the context of mining where workers are operating under low light conditions. Given that the benefits of biomotion clothing are effective for both young and older drivers, as well as those with various eye conditions common in those >50 years reinforces their potential application in the mining industry which employs many workers in this age bracket. This paper will summarise the visibility benefits of retroreflective markers in a biomotion configuration for the mining industry, highlighting that this form of clothing has the potential to be an affordable and convenient way to provide a sizeable safety benefit. It does not involve modifications to vehicles, drivers, or infrastructure. Instead, adding biomotion markings to standard retroreflective vests can enhance the night-time conspicuity of mining workers by capitalising on perceptual capabilities that have already been well documented.

Practice patterns of radiation therapy technology in Australia: Results of a national audit

This article presents the results of a single-day census of radiation therapy (RT) treatment and technology use in Australia. The primary aim of the study was to ascertain patterns of RT practice and technology in use across Australia. These data were primarily collated to inform curriculum development of academic programs, thereby ensuring that training is matched to workforce patterns of practice. Methods: The study design was a census method with all 59 RT centres in Australia being invited to provide quantitative summary data relating to patient case mix and technology use on a randomly selected but common date. Anonymous and demographic-free data were analysed using descriptive statistics. Results: Overall data were provided across all six Australian States by 29 centres of a possible 59, yielding a response rate of 49% and representing a total of 2743 patients. Findings from this study indicate the increasing use of emerging intensity-modulated radiotherapy (IMRT), image fusion and image-guided radiation therapy (IGRT) technology in Australian RT planning and delivery phases. IMRT in particular was used for 37% of patients, indicating a high uptake of the technology in Australia when compared to other published data. The results also highlight the resource-intensive nature of benign tumour radiotherapy. Conclusions: In the absence of routine national data collection, the single-day census method offers a relatively convenient means of measuring and tracking RT resource utilisation. Wider use of this tool has the potential to not only track trends in technology implementation but also inform evidence-based guidelines for referral and resource planning.

The ASAS criteria for axial spondyloarthritis: Strengths, weaknesses, and proposals for a way forward

Classification criteria should facilitate selection of similar patients for clinical and epidemiologic studies, therapeutic trials, and research on etiopathogenesis to enable comparison of results across studies from different centers. We critically appraise the validity and performance of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA). It is still debatable whether all patients fulfilling these criteria should be considered as having true axSpA. Patients with radiographically evident disease by the ASAS criteria are not necessarily identical with ankylosing spondylitis (AS) as classified by the modified New York criteria. The complex multi-arm selection design of the ASAS criteria induces considerable heterogeneity among patients so classified, and applying them in settings with a low prevalence of axial spondyloarthritis (SpA) greatly increases the proportion of subjects falsely classified as suffering from axial SpA. One of the unmet needs in non-radiographic form of axial SpA is to have reliable markers that can identify individuals at risk for progression to AS and thereby facilitate early intervention trials designed to prevent such progression. We suggest needed improvements of the ASAS criteria for axSpA, as all criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances.

Learner driver mentor programs: Stakeholder perspectives on an ideal program

This study investigated the development and operation of Learner Driver Mentor Programs (LDMPs). LDMPs are used throughout Australia to assist young learner drivers to gain supervised on-road driving experience through coordinated access to vehicles and supervisors. There is a significant lack of research regarding these programs. In this study, 41 stakeholders including representatives from existing or ceased LDMPs as well as representatives of other groups completed a questionnaire in either survey or interview format. The questionnaire sought information about the objectives of LDMPs, any social problems that were targeted as well as the characteristics of an ideal program and what could be done to improve them. Stakeholders indicated that LDMPs were targeted at local communities and, therefore, there should be a clear local need for the program as well as community ownership and involvement in the program. Additionally, the program needed to be accessible and provide clear positive outcomes for mentees. The most common suggestion to improve LDMPs related to the provision of greater funding and sponsorship, particularly in relation to the vehicles used within the programs. LDMPs appear to have an important role in facilitating young learner drivers to acquire the appropriate number of supervised hours of driving practice. However, while a number of factors appear related to a successful program, the program must remain flexible and suitable for its local community. There is a clear need to complete evaluations of existing programs to ensure that future LDMPs and modifications to existing programs are evidence-based.

LibVM: An architecture for shared library sandboxing

Many software applications extend their functionality by dynamically loading libraries into their allocated address space. However, shared libraries are also often of unknown provenance and quality and may contain accidental bugs or, in some cases, deliberately malicious code. Most sandboxing techniques which address these issues require recompilation of the libraries using custom tool chains, require significant modifications to the libraries, do not retain the benefits of single address-space programming, do not completely isolate guest code, or incur substantial performance overheads. In this paper we present LibVM, a sandboxing architecture for isolating libraries within a host application without requiring any modifications to the shared libraries themselves, while still retaining the benefits of a single address space and also introducing a system call inter-positioning layer that allows complete arbitration over a shared library’s functionality. We show how to utilize contemporary hardware virtualization support towards this end with reasonable performance overheads and, in the absence of such hardware support, our model can also be implemented using a software-based mechanism. We ensure that our implementation conforms as closely as possible to existing shared library manipulation functions, minimizing the amount of effort needed to apply such isolation to existing programs. Our experimental results show that it is easy to gain immediate benefits in scenarios where the goal is to guard the host application against unintentional programming errors when using shared libraries, as well as in more complex scenarios, where a shared library is suspected of being actively hostile. In both cases, no changes are required to the shared libraries themselves.

Comparison of Radiation Doses for Catheter Ablation Procedures for Atrial Fibrillation with Percutaneous Coronary Intervention Cases

Background: Catheter ablation procedures for atrial fibrillation (AF) may frequently require long fluoroscopic times. We sought to undertake a review of radiation safety practice in our Cardiac Electrophysiology Laboratory and implement changes to minimize fluoroscopic doses. We also sought to compare the results with radiation doses for percutaneous coronary intervention (PCI) cases performed in our hospital. Methods: Fluoroscopic times and doses for AF ablation procedures performed by a single operator on a Philips Integris H3000 image-intensifier were analysed for 11-month period. Results were compared with all PCI procedures performed over a similar period by multiple operators on a Philips Integris Allura FD system. Comprehensive review of radiation practice in the Electrophysiology laboratory identified the potential to reduce pulse frame rates and doses, and to narrow the field of interest without impacting the performance of the procedure. These changes were implemented and results analysed after a further 11 months. Results: In the pre-intervention period 50 AF catheter ablations had a mean fluoroscopic time of 86.4 min and mean fluoroscopic dose 68.4 Gy/cm2. Post-intervention 75 procedures had a mean fluorosocopic time of 68.9 min (p < 0.0001) and mean dose of 14.3 Gy/cm2 (p < 0.0001) 128 PCI procedures had a mean combined fluoroscopic and image acquisition time of 10.0 min and mean total dose 38.8 Gy/cm2. Conclusions: Catheter ablation procedures for AF may require lengthy use of fluoroscopy but simple modifications to radiation practice can result in marked reductions in radiation dose that compare favourably with PCI case doses