Inorganic-organic composite particle as a staged delivery platform for plasmid DNA-based biopharmaceuticals

Infectious diseases such as SARS, influenza and bird flu may spread exponentially throughout communities. In fact, most infectious diseases remain major health risks due to the lack of vaccine or the lack of facilities to deliver the vaccines. Conventional vaccinations are based on damaged pathogens, live attenuated viruses and viral vectors. If the damage was not complete, the vaccination itself may cause adverse effects. Therefore, researchers have been prompted to prepare viable replacements for the attenuated vaccines that would be more effective and safer to use. DNA vaccines are generally composed of a double stranded plasmid that includes a gene encoding the target antigen under the transcriptional directory and control of a promoter region which is active in cells. Plasmid DNA (pDNA) vaccines allow the foreign genes to be expressed transiently in cells, mimicking intracellular pathogenic infection and inducing both humoral and cellular immune responses. Currently, because of their highly evolved and specialized components, viral systems are the most effective means for DNA delivery, and they achieve high efficiencies (generally >90%), for both DNA delivery and expression. As yet, viral-mediated deliveries have several limitations, including toxicity, limited DNA carrying capacity, restricted target to specific cell types, production and packing problems, and high cost. Thus, nonviral systems, particularly a synthetic DNA delivery system, are highly desirable in both research and clinical applications.

Performance of R-N(R′)-R″ functionalised poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) monolithic sorbent for plasmid DNA adsorption

High-throughput plasmid DNA (pDNA) manufacture is obstructed predominantly by the performance of conventional stationary phases. For this reason, the search for new materials for fast chromatographic separation of pDNA is ongoing. A poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) (GMA-EGDMA) monolithic material was synthesised via a thermal-free radical reaction, functionalised with different amino groups from urea, 2-chloro-N,N-diethylethylamine hydrochloride (DEAE-Cl) and ammonia in order to investigate their plasmid adsorption capacities. Physical characterisation of the monolithic polymer showed a macroporous polymer having a unimodal pore size distribution pivoted at 600 nm. Chromatographic characterisation of the functionalised polymers using pUC19 plasmid isolated from E. coli DH5α-pUC19 showed a maximum plasmid adsorption capacity of 18.73 mg pDNA/mL with a dissociation constant (KD) of 0.11 mg/mL for GMA-EGDMA/DEAE-Cl polymer. Studies on ligand leaching and degradation demonstrated the stability of GMA-EGDMA/DEAE-Cl after the functionalised polymers were contacted with 1.0 M NaOH, which is a model reagent for most 'cleaning in place' (CIP) systems. However, it is the economic advantage of an adsorbent material that makes it so attractive for commercial purification purposes. Economic evaluation of the performance of the functionalised polymers on the grounds of polymer cost (PC)/mg pDNA retained endorsed the suitability of GMA-EGDMA/DEAE-Cl polymer.

Endotoxin removal : a critical step in vaccine production

A major drawback to the immunological potency of conventional vaccines, resulting in reduced level of immune responses, tissue injury, shock and high cytotoxicity, thus making their applications contraindicated in immunodeficiency diseases, is the presence of high contaminant concentrations in vaccine titers. Vaccine contamination arises from the simultaneous occurrence of competitive pathways resulting in the formation of other bio-products during cellular metabolism aside the pathways necessary for the production of vaccine molecules. One of such vaccine contaminating molecules is endotoxins which are mainly lipopolysaccharides (LPS) complexes found in the membrane of bacterial cell wall. The structural dynamics of these molecules make their removal from vaccine titers problematic, thus making vaccine endotoxin removal a major research endeavour. This presentation will discuss a novel technique for reducing the endotoxin level of vaccines. The technique commences with the disentanglement of endotoxin-vaccine molecular bonding and then capturing the vaccine molecules on an affinity monolith to separate the vaccine molecules from the endotoxins.

Using DNA as a drug : challenges and opportunities for process engineers

The maturing of the biotechnology industry and a focus on productivity has seen a shift from discovery science to small-scale bench-top research to higher productivity, large scale production. Health companies are aggressively expanding their biopharmaceutical interests, an expansion which is facilitated by biochemical and bioprocess engineering. An area of continuous growth is vaccines. Vaccination will be a key intervention in the case of an influenza pandemic. The global manufacturing capacity for fast turn around vaccines is currently woefully inadequate at around 300 million shots. As the prevention of epidemics requires > 80 % vaccination, in theory the world should currently be aiming for the ability to produce around 5.3 billion vaccines. Presented is a production method for the creation of a fast turn around DNA vaccine. A DNA vaccine could have a production time scale of as little as two weeks. This process has been harnessed into a pilot scale production system for the creation of a pre-clinical grade malaria vaccine in a collaborative project with the Coppel Lab, Department of Microbiology, Monash University. In particular, improvements to the fermentation, chromatography and delivery stages will be discussed. Consideration will then be given as to how the fermentation stage affects the mid and downstream processing stages.

Analyzing the impact of learning inputs on near-to-far terrain traversability estimation

With the increasing need to adapt to new environments, data-driven approaches have been developed to estimate terrain traversability by learning the rover’s response on the terrain based on experience. Multiple learning inputs are often used to adequately describe the various aspects of terrain traversability. In a complex learning framework, it can be difficult to identify the relevance of each learning input to the resulting estimate. This paper addresses the suitability of each learning input by systematically analyzing the impact of each input on the estimate. Sensitivity Analysis (SA) methods provide a means to measure the contribution of each learning input to the estimate variability. Using a variance-based SA method, we characterize how the prediction changes as one or more of the input changes, and also quantify the prediction uncertainty as attributed from each of the inputs in the framework of dependent inputs. We propose an approach built on Analysis of Variance (ANOVA) decomposition to examine the prediction made in a near-to-far learning framework based on multi-task GP regression. We demonstrate the approach by analyzing the impact of driving speed and terrain geometry on the prediction of the rover’s attitude and chassis configuration in a Marsanalogue terrain using our prototype rover Mawson.

DNA molecules and future blockbuster therapeutics

Deoxyribonucleic acid molecules are heralding a new generation of reverse - engineered biopharmaceuticals. In terms of potential application in gene medicine, plasmid DNA (pDNA) vectors have exceptional therapeutic and immunological profiles as they are free from safety concerns associated with viral vectors, display non-toxicity and are simpler to develop. This presentation will discuss the potential applications of pDNA molecules in vaccine development and gene therapy, pilot-scale production of pDNA-based biopharmaceuticals and the controlled delivery of therapeutic sequences in biodegradable polymers to different target cells via the nasal route.

Do-Rank: DCG optimization for learning-to-rank in tag-based item recommendation systems

Discounted Cumulative Gain (DCG) is a well-known ranking evaluation measure for models built with multiple relevance graded data. By handling tagging data used in recommendation systems as an ordinal relevance set of {negative,null,positive}, we propose to build a DCG based recommendation model. We present an efficient and novel learning-to-rank method by optimizing DCG for a recommendation model using the tagging data interpretation scheme. Evaluating the proposed method on real-world datasets, we demonstrate that the method is scalable and outperforms the benchmarking methods by generating a quality top-N item recommendation list.

Affordances of ICTs: an environmental study of a French language unit offered at university level

This project investigates the integration of Information Communication Technologies (ICTs) into educational settings by closely looking at the uptake of the perceived affordances offered by ICTs by students enrolled in a French language course at Queensland University of Technology. This cross-disciplinary research uses the theoretical concepts of: Ecological Psychology (Gibson, 1979; Good, 2007; Reed, 1996); Ecological Linguistics (Greeno, 1994; Leather & van Dam, 2003; van Lier 2000, 2003, 2004a, 2004b); Design (Norman, 1988, 1999); Software Design/ Human-Computer Interaction (Hartson, 2003; McGrenere & Ho, 2000); Learning Design (Conole & Dyke, 2004a, 2004b; Laurillard et al. 2000;); Education (Kirschner, 2002; Salomon, 1993; Wijekumar et al., 2006) and Educational Psychology (Greeno, 1994). In order to investigate this subject, the following research questions, rooted in the theoretical foundations of the thesis, were formulated: (1) What are the learners’ attitudes towards the ICT tools used in the project?; (2) What are the affordances offered by ICTs used in a specific French language course at university level from the perspective of the teacher and from the perspective of language learners?; (3) What affordances offered by ICT tools used by the teacher within the specific teaching and learning environment have been taken up by learners?; and (4) What factors influence the uptake by learners of the affordances created by ICT tools used by the teacher within the specific teaching and learning environment? The teaching phase of this project, conducted between 2006 and 2008, used Action Research procedures (Hopkins, 2002; McNiff & Whitehead, 2002; van Lier 1994) as a research framework. The data were collected using the following combination of qualitative and quantitative methods: (1) questionnaires administered to students (Hopkins, 2002; McNiff & Whitehead, 2002) using Likert-scale questions, open questions, yes/no questions; (2) partnership classroom observations of research participants conducted by Research Participant Advocates (Hopkins, 2002; McNiff & Whitehead, 2002); and (3) a focus group with volunteering students who participated in the unit (semi-structured interview) (Hopkins, 2002; McNiff & Whitehead, 2002). The data analysis confirms the importance of a careful examination of the teaching and learning environment and reveals differences in the ways in which the opportunities for an action offered by the ICTs were perceived by teacher and students, which impacted on the uptake of affordances. The author applied the model of affordance, as described by Good (2007), to explain these differences and to investigate their consequences. In conclusion, the teacher-researcher considers that the discrepancies in perceiving the affordances result from the disparities between the frames of reference and the functional contexts of the teacher-researcher and students. Based on the results of the data analysis, a series of recommendations is formulated supporting calls for careful analysis of frames of reference and the functional contexts of all participants in the learning and teaching process. The author also suggests a modified model of affordance, outlining the important characteristics of its constituents.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Mechanisms underlying the effect of acupuncture on cognitive improvement: A systematic review of animal studies

Acupuncture has been reported to be beneficial in treating cognitive impairment in various pathological conditions. This review describes the effort to understand the signaling pathways that underlie the acupunctural therapeutic effect on cognitive function. We searched the literature in 12 electronic databases from their inception to November 2013, with full text available and language limited to English. Twenty-three studies were identified under the selection criteria. All recruited animal studies demonstrate a significant positive effect of acupuncture on cognitive impairment. Findings suggest acupuncture may improve cognitive function through modulation of signaling pathways involved in neuronal survival and function, specifically, through promoting cholinergic neural transmission, facilitating dopaminergic synaptic transmission, enhancing neurotrophin signaling, suppressing oxidative stress, attenuating apoptosis, regulating glycometabolic enzymes and reducing microglial activation. However, the quality of reviewed studies has room for improvement. Further high-quality animal studies with randomization, blinding and estimation of sample size are needed to strengthen the recognition of group differences.

External influence as an indicator of scholarly importance

Although the external influence of scholars has usually been approximated by publication and citation count, the array of scholarly activities is far more extensive. Today, new technologies, in particular Internet search engines, allow more accurate measurement of scholars' influence on societal discourse. Hence, in this article, we analyse the relation between the internal and external influence of 723 top economists using the number of pages indexed by Google and Bing as a measure of external influence. We not only identify a small association between these scholars’ internal and external influence but also a correlation between internal influence, as captured by receipt of such major academic awards as the Nobel Prize and John Bates Clark Medal, and the external prominence of the top 100 researchers (JEL Code: A11, A13, Z18).

The inner quality of an article: Will time tell?

In this paper, we assess whether quality survives the test of time in academia by comparing up to 80 years of academic journal article citations from two top journals, Econometrica and the American Economic Review. The research setting under analysis is analogous to a controlled real world experiment in that it involves a homogeneous task (trying to publish in top journals) by individuals with a homogenous job profile (academics) in a specific research environment (economics and econometrics). Comparing articles published concurrently in the same outlet at the same time (same issue) indicates that symbolic capital or power due to institutional affiliation or connection does seem to boost citation success at the beginning, giving those educated at or affiliated with leading universities an initial comparative advantage. Such advantage, however, does not hold in the long run: at a later stage,the publications of other researchers become as or even more successful.

Do great minds appear in batches?

Despite much scholarly fascination with the question of whether great minds appear in cycles, together with some empirical evidence that historical cycles exist, prior studies mostly disregard the ‘‘great minds’’ hypothesis as it relates to scientists. Rather, researchers assume a linear relation based on the argument that science is allied with the development of technology. To probe this issue further, this study uses a ranking of over 5600 scientists based on number of appearances in Google Books over a period of 200 years (1800–2000). The results point to several peak periods, particularly for scientists born in the 1850–1859, 1897–1906, or 1900–1909 periods, suggesting overall cycles of around 8 years and a positive trend in distinction that lasts around 100 years. Nevertheless,a non-parametric test to determine whether randomness can be rejected indicates that nonrandomness is less apparent, although once we analyse the greatest minds overall, rejection is more likely.