Review : alternative splicing (AS) of genes as an approach for generating protein complexity

Prior to the completion of the human genome project, the human genome was thought to have a greater number of genes as it seemed structurally and functionally more complex than other simpler organisms. This along with the belief of “one gene, one protein”, were demonstrated to be incorrect. The inequality in the ratio of gene to protein formation gave rise to the theory of alternative splicing (AS). AS is a mechanism by which one gene gives rise to multiple protein products. Numerous databases and online bioinformatic tools are available for the detection and analysis of AS. Bioinformatics provides an important approach to study mRNA and protein diversity by various tools such as expressed sequence tag (EST) sequences obtained from completely processed mRNA. Microarrays and deep sequencing approaches also aid in the detection of splicing events. Initially it was postulated that AS occurred only in about 5%; of all genes but was later found to be more abundant. Using bioinformatic approaches, the level of AS in human genes was found to be fairly high with 35-59%; of genes having at least one AS form. Our ability to determine and predict AS is important as disorders in splicing patterns may lead to abnormal splice variants resulting in genetic diseases. In addition, the diversity of proteins produced by AS poses a challenge for successful drug discovery and therefore a greater understanding of AS would be beneficial.

Blast induced ground shock effects on pile foundations

Due to increased number of terrorist attacks in recent years, loads induced by explosions need to be incorporated in building designs. For safer performance of a structure, its foundation should have sufficient strength and stability. Therefore, prior to any reconstruction or rehabilitation of a building subjected to blast, it is important to examine adverse effects on the foundation caused by blast induced ground shocks. This paper evaluates the effects of a buried explosion on a pile foundation. It treats the dynamic response of the pile in saturated sand, using explicit dynamic nonlinear finite element software LS-DYNA. The blast induced wave propagation in the soil and the horizontal deformation of pile are presented and the results are discussed. Further, a parametric study is carried out to evaluate the effect of varying the explosive shape on the pile response. This information can be used to evaluate the vulnerability of piled foundations to credible blast events as well as develop guidance for their design.

Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis

Background Chaperonin 10 (Cpn10) is a mitochondrial molecule involved in protein folding. The aim of this study was to determine the safety profile of Cpn10 in patients with multiple sclerosis (MS). Methods A total of 50 patients with relapse-remitting or secondary progressive MS were intravenously administered 5 mg or 10 mg of Cpn10 weekly for 12 weeks in a double-blind, randomized, placebo controlled, phase II trial. Clinical reviews, including Expanded Disability Status Scale and magnetic resonance imaging (MRI) with Gadolinium, were undertaken every 4 weeks. Stimulation of patient peripheral blood mononuclear cells with lipopolysaccharide ex vivo was used to measure the in vivo activity of Cpn10. Results No significant differences in the frequency of adverse events were seen between treatment and placebo arms. Leukocytes from both groups of Cpn10-treated patients produced significantly lower levels of critical proinflammatory cytokines. A trend toward improvement in new Gadolinium enhancing lesions on MRI was observed, but this difference was not statistically significant. No differences in clinical outcome measures were seen. Conclusions Cpn10 is safe and well tolerated when administered to patients with MS for 3 months, however, a further extended phase II study primarily focused on efficacy is warranted.

Modeling electricity price events as point processes

Energy prices are highly volatile and often feature unexpected spikes. It is the aim of this paper to examine whether the occurrence of these extreme price events displays any regularities that can be captured using an econometric model. Here we treat these price events as point processes and apply Hawkes and Poisson autoregressive models to model the dynamics in the intensity of this process.We use load and meteorological information to model the time variation in the intensity of the process. The models are applied to data from the Australian wholesale electricity market, and a forecasting exercise illustrates both the usefulness of these models and their limitations when attempting to forecast the occurrence of extreme price events.

Detecting anomalous events at railway level crossings

Collisions between pedestrians and vehicles continue to be a major problem throughout the world. Pedestrians trying to cross roads and railway tracks without any caution are often highly susceptible to collisions with vehicles and trains. Continuous financial, human and other losses have prompted transport related organizations to come up with various solutions addressing this issue. However, the quest for new and significant improvements in this area is still ongoing. This work addresses this issue by building a general framework using computer vision techniques to automatically monitor pedestrian movements in such high-risk areas to enable better analysis of activity, and the creation of future alerting strategies. As a result of rapid development in the electronics and semi-conductor industry there is extensive deployment of CCTV cameras in public places to capture video footage. This footage can then be used to analyse crowd activities in those particular places. This work seeks to identify the abnormal behaviour of individuals in video footage. In this work we propose using a Semi-2D Hidden Markov Model (HMM), Full-2D HMM and Spatial HMM to model the normal activities of people. The outliers of the model (i.e. those observations with insufficient likelihood) are identified as abnormal activities. Location features, flow features and optical flow textures are used as the features for the model. The proposed approaches are evaluated using the publicly available UCSD datasets, and we demonstrate improved performance using a Semi-2D Hidden Markov Model compared to other state of the art methods. Further we illustrate how our proposed methods can be applied to detect anomalous events at rail level crossings.

Metrological performances of a diffusion charger particle counter for personal monitoring

Airborne particles have been shown to be associated with a wide range of adverse health effects, which has led to a recent increase in medical research to gain better insight into their health effects. However, accurate evaluation of the exposure-dose-response relationship is highly dependent on the ability to track actual exposure levels of people to airborne particles. This is quite a complex task, particularly in relation to submicrometer and ultrafine particles, which can vary quite significantly in terms of particle surface area and number concentrations. Therefore, suitable monitors that can be worn for measuring personal exposure to these particles are needed. This paper presents an evaluation of the metrological performance of six diffusion charger sensors, NanoTracer (Philips Aerasense) monitors, when measuring particle number and surface area concentrations, as well as particle number distribution mean when compared to reference instruments. Tests in the laboratory (by generating monodisperse and polydisperse aerosols) and in the field (using natural ambient particles) were designed to evaluate the response of these devices under both steady-state and dynamics conditions. Results showed that the NanoTracers performed well when measuring steady state aerosols, however they strongly underestimated actual concentrations during dynamic response testing. The field experiments also showed that, when the majority of the particles were smaller than 20 nm, which occurs during particle formation events in the atmosphere, the NanoTracer underestimated number concentration quite significantly. Even though the NanoTracer can be used for personal monitoring of exposure to ultrafine particles, it also has limitations which need to be considered in order to provide meaningful results.

Pten and Ndufb8 aberrations in cervical cancer tissue

Cervical cancer is one of the world's major health issues. Despite many studies in this field, the carcinogenetic events of malignant conversion in cervical tumours have not been significantly characterised. The first aim of this project was to investigate the mutation status of the tumour suppressor gene- Phosphatase and Tension Homolog (PTEN)- in cervical cancer tissue. The second aim of this study was the analysis in the same cervical cancer tissue for aberrations in the mitochondrial electron transport chain subunit gene NDUFB8, which is localised to the same chromosomal contig as PTEN. The third aim was the evaluation of the potential therapeutic anti-cancer drug 2,4-Thiazolidinediones (TZDs) and its affect in regulating the PTEN protein in a cervical cancer cell line (HeLa). To approach the aims, paraffin-embedded cancerous cervical tissue and non-cancerous cervical tissue were obtained. DNA recovered from those tissues was then used to investigate the putative genomic changes regarding the NDUFB8 gene utilising SYBR Green I Real-Time PCR. The PTEN gene was studied via Dual-Labelled probe Real-Time PCR. To investigate the protein expression change of the PTEN protein, HeLa cells were firstly treated with different concentrations of 2,4-Thiazolidinediones and the level of PTEN protein expression was then observed utilising standard protein assays. Results indicated that there were putative copy-number changes between the cancerous cervical tissue and non-cancerous cervical tissue, with regard to the PTEN locus. This implies a potential gain of the PTEN gene in cancerous cervical tissue. With regards to normal cervical tissue versus cancerous cervical tissue no significant melting temperature differences were observed with the SYBR Green I Real-Time PCR in respect to the NDUFB8 gene. A putative up-regulation of PTEN protein was observed in TZD treated HeLa cells. © 2008 Springer Science+Business Media, LLC.

Analysis of Sdhd and Mmp12 in an affected solar keratosis and control cohort

The incidence of Squamous Cell Carcinoma (SCG) is growing in certain populations to the extent that it is now the most common skin lesion in young men and women in high ultraviolet exposure regions such as Queensland. In terms of incidence up to 40% of the Australian population over 40 years of age is thought to possess the precancerous Solar Keratosis (SK) lesion and with a small, but significant, chance of progression into SCC, understanding the genetic events that play a role in this process is essential. The major aims of this study were to analyse whole blood derived samples for DNA aberrations in genes associated with tumour development and cellular maintenance, with the ultimate aim of identifying genes associated with non-melanoma skin cancer development. More specifically the first aim of this project was to analyse the SDHD and MMP12 genes via Dual-Labelled Probe Real-Time PCR for copy number aberrations in an affected Solar Keratosis and control cohort. It was found that 12 samples had identifiable copy-number aberrations in either the SDHD or MMP12 gene (this means that a genetic section of either of these two genes is aberrantly amplified or deleted), with five of the samples exhibiting aberrations in both genes. The significance of this study is the contribution to the knowledge of the genetic pathways that are malformed in the progression and development of the pre-cancerous skin lesion Solar Keratosis. © 2008 Springer Science+Business Media, LLC.

Selecting rainfall events for effective Water Sensitive Urban Design (WSUD) implementation

The current approach for protecting the receiving water environment from urban stormwater pollution is the adoption of structural measures commonly referred to as Water Sensitive Urban Design (WSUD). The treatment efficiency of WSUD measures closely depends on the design of the specific treatment units. As stormwater quality can be influenced by rainfall characteristics, the selection of appropriate rainfall events for treatment design is essential to ensure the effectiveness of WSUD systems. Based on extensive field investigation of four urban residential catchments and computer modelling, this paper details a technically robust approach for the selection of rainfall events for stormwater treatment design using a three-component model. The modelling outcomes indicate that selecting smaller average recurrence interval (ARI) events with high intensity-short duration as the threshold for the treatment system design is the most feasible since these events cumulatively generate a major portion of the annual pollutant load compared to the other types of rainfall events, despite producing a relatively smaller runoff volume. This implies that designs based on small and more frequent rainfall events rather than larger rainfall events would be appropriate in the context of efficiency in treatment performance, cost-effectiveness and possible savings in land area needed.

A novel representation of bioacoustic events for content-based search in field audio data

Bioacoustic data can provide an important base for environmental monitoring. To explore a large amount of field recordings collected, an automated similarity search algorithm is presented in this paper. A region of an audio defined by frequency and time bounds is provided by a user; the content of the region is used to construct a query. In the retrieving process, our algorithm will automatically scan through recordings to search for similar regions. In detail, we present a feature extraction approach based on the visual content of vocalisations – in this case ridges, and develop a generic regional representation of vocalisations for indexing. Our feature extraction method works best for bird vocalisations showing ridge characteristics. The regional representation method allows the content of an arbitrary region of a continuous recording to be described in a compressed format.

Governing drug use among young people : crime, harm and contemporary drug use practices

Taking an empirical, critical approach to the problem of drugs, this thesis explores the interaction of drug policies and young people's drug use in Brisbane. The research argues that criminalising drug users does not usually prevent harmful drug use, but it can exacerbate harm and change how young people use drugs. Contemporary understandings of drug use as either recreational or addictive can create a false binary, and influence how illicit drugs are used. These understandings interact with policy responses to the drug problem, with some very real implications for the lived experiences of drug users. This research opens up possibilities for new directions in drug research and allows for a redefinition of drug related harm.

Gene expression profiling in human breast cancer – toward personalised therapeutics?

The most integrated approach toward understanding the multiple molecular events and mechanisms by which cancer may develop is the application of gene expression profiling using microarray technologies. As molecular alterations in breast cancer are complex and involve cross-talk between multiple cellular signalling pathways, microarray technology provides a means of capturing and comparing the expression patterns of the entire genome across multiple samples in a high throughput manner. Since the development of microarray technologies, together with the advances in RNA extraction methodologies, gene expression studies have revolutionised the means by which genes suitable as targets for drug development and individualised cancer treatment can be identified. As of the mid-1990s, expression microarrays have been extensively applied to the study of cancer and no cancer type has seen as much genomic attention as breast cancer. The most abundant area of breast cancer genomics has been the clarification and interpretation of gene expression patterns that unite both biological and clinical aspects of tumours. It is hoped that one day molecular profiling will transform diagnosis and therapeutic selection in human breast cancer toward more individualised regimes. Here, we review a number of prominent microarray profiling studies focussed on human breast cancer and examine their strengths, their limitations, clinical implications including prognostic relevance and gene signature significance along with potential improvements for the next generation of microarray studies.

MS-based metabolomics facilitates the discovery of in vivo functional small molecules with a diversity of biological contexts

In vivo small molecules as necessary intermediates are involved in numerous critical metabolic pathways and biological processes associated with many essential biological functions and events. There is growing evidence that MS-based metabolomics is emerging as a powerful tool to facilitate the discovery of functional small molecules that can better our understanding of development, infection, nutrition, disease, toxicity, drug therapeutics, gene modifications and host-pathogen interaction from metabolic perspectives. However, further progress must still be made in MS-based metabolomics because of the shortcomings in the current technologies and knowledge. This technique-driven review aims to explore the discovery of in vivo functional small molecules facilitated by MS-based metabolomics and to highlight the analytic capabilities and promising applications of this discovery strategy. Moreover, the biological significance of the discovery of in vivo functional small molecules with different biological contexts is also interrogated at a metabolic perspective.

Research trends of post disaster reconstruction : the past and the future

Natural disasters can have adverse effect on human lives. To raise the awareness of research and better combat future events, it is important to identify recent research trends in the area of post disaster reconstruction (PDR). The authors used a three-round literature review strategy to study journal papers published in the last decade that are related to PDR with specific conditions using the Scopus search engine. A wide range of PDR related papers from a general perspective was examined in the first two rounds while the final round established 88 papers as target publications through visual examination of the abstracts, keywords and as necessary, main texts. These papers were analysed in terms of research origins, active researchers, research organisations, most cited papers, regional concerns, major themes and deliverables, for clues of the past trends and future directions. The need for appropriate PDR research is increasingly recognised. The publication number multiplied 5 times from 2002 to 2012. For PDR research with a construction perspective, the increase is sixfold. Developing countries such as those in Asia attract almost 50% researchers' attention for regional concerns while the US is the single most concentrated (24%) country. Africa is hardly represented. Researchers in developed countries lead in worldwide PDR research. This contrasts to the need for expertise in developing countries. Past works focused on waste management, stakeholder analysis, resourcing, infrastructure issue, resilience and vulnerability, reconstruction approach, sustainable reconstruction and governance issues. Future research should respond to resourcing, integrated development, sustainability and resilience building to cover the gaps. By means of a holistic summary and structured analysis of key patterns, the authors hope to provide a streamlined access to existing research findings and make predictions of future trends. They also hope to encourage a more holistic approach to PDR research and international collaborations.

Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis : protocol for a randomised controlled trial

Background Recurrent protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis are characterised by a chronic wet cough and are important causes of childhood respiratory morbidity globally. Haemophilus influenzae and Streptococcus pneumoniae are the most commonly associated pathogens. As respiratory exacerbations impair quality of life and may be associated with disease progression, we will determine if the novel 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) reduces exacerbations in these children. Methods A multi-centre, parallel group, double-blind, randomised controlled trial in tertiary paediatric centres from three Australian cities is planned. Two hundred six children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis will be randomised to receive either two doses of PHiD-CV or control meningococcal (ACYW(135)) conjugate vaccine 2 months apart and followed for 12 months after the second vaccine dose. Randomisation will be stratified by site, age (<6 years and >= 6 years) and aetiology (recurrent PBB or CSLD/bronchiectasis). Clinical histories, respiratory status (including spirometry in children aged >= 6 years), nasopharyngeal and saliva swabs, and serum will be collected at baseline and at 2, 3, 8 and 14 months post-enrolment. Local and systemic reactions will be recorded on daily diaries for 7 and 30 days, respectively, following each vaccine dose and serious adverse events monitored throughout the trial. Fortnightly, parental contact will help record respiratory exacerbations. The primary outcome is the incidence of respiratory exacerbations in the 12 months following the second vaccine dose. Secondary outcomes include: nasopharyngeal carriage of H. influenzae and S. pneumoniae vaccine and vaccine-related serotypes; systemic and mucosal immune responses to H. influenzae proteins and S. pneumoniae vaccine and vaccine-related serotypes; impact upon lung function in children aged >= 6 years; and vaccine safety. Discussion As H. influenzae is the most common bacterial pathogen associated with these chronic respiratory diseases in children, a novel pneumococcal conjugate vaccine that also impacts upon H. influenzae and helps prevent respiratory exacerbations would assist clinical management with potential short- and long-term health benefits. Our study will be the first to assess vaccine efficacy targeting H. influenzae in children with recurrent PBB, CSLD and bronchiectasis.