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.

Reconstructing places and spaces in blended work integrated learning

This paper considers the emergence and ongoing development of an embedded, studentnegotiated work placement model of Work Integrated Learning (WIL) in the engineering and built environment disciplines at an Australian metropolitan university. The characteristics of the model and a continuous improvement strategy are provided. The model is characterised by large student cohorts independently sourcing and negotiating relevant work placements and completing at least one, mandatory credit-bearing WIL unit. Through ongoing analyses and evaluation of the model more experiential and collaborative learning approaches have been adopted. This has included the creation of blended learning spaces using technology. The paper focuses on the five year journey travelled by the teaching team as they embarked on ways to improve curriculum, pedagogy, administrative processes and assessment - effectively relocating much of their interaction with students online. The insights derived from this rich, single case study should be of interest to others considering alternative ways of responding to increasing student enrolments in WIL and the impact of blended learning in this context.

Natural and engineered plasmin inhibitors : applications and design strategies

Plasmin is the primary enzyme responsible for dissolution of fibrin in the circulatory system. Plasminogen, the zymogen of plasmin is expressed ubiquitously in the human body [1], with the predominant source being the liver [2, 3]. Plasminogen is produced as an 810 amino acid protein with a 19 amino acid leader peptide, which is cleaved during secretion to produce the mature 791 amino acid one-chain zymogen. This is converted to plasmin by cleavage of the Arg561 - Val562 scissile bond [4], resulting in an active protease consisting of two disulfide linked chains. The amino-terminal heavy chain (residues Glu1-Arg561) is comprised of a plasminogen/apple/nematode (PAN) domain [5] and five kringle domains of approximately equal size [6] while the light chain (residues Val562-Asn791) contains a serine protease domain homologous to trypsin with a catalytic triad comprising His603, Asp646 and Ser741 [7]. Both plasmin and plasminogen occur in two forms, full length and a Lys77-Lys78 activated variant produced through self catalysis (Figure 1). The former exists in a tight conformation through binding of Lys50 and/or Lys62 to kringle domain 5 [8, 9] while Lys78-plasminogen assumes a more relaxed conformation rendering it more susceptible to plasmin conversion [10, 11].

Effects of PtO2 and CeO2 additives on the microstructures of the quenched melts of Y-Ba-Cu-O materials

The microstructures of the quenched melts of samples of Y123 and Y123+15-20 mol% Y211 with PtO2 and CeO2 additives have been examined with optical microscopy, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectrometry (EDS) and X-ray Diffractometry (XRD). Significantly higher temperatures are required for the formation of dendritic or lamellar eutectic patterns throughout the samples with PtO2 and CeO2 additives as compared to samples without additives. The BaCuO2 (BCl) phase appears first in solid form and, instead of rapidly melting, is slowly dissolving or decomposing in the oxygen depleted melt. PtO2 and CeO2 additives slow down or shift to higher temperatures the dissolution or decomposition process of BCl. A larger fraction of BCl in solid form explains why samples with additives have higher viscosities and hence lower diffusivities than samples without additives. There is also a reduction in the Y solubility to about half the value in samples without additives. The mechanism that limits the Ostwald ripening of the Y211 particles is correlated to the morphology of the quenched partial melt. It is diffusion controlled for a finely mixed morphology and interface-controlled when the melt quenches into dendritic or lamellar eutectic patterns. The change in the morphology of the Y211 particles from blocky to acicular is related to an equivalent undercooling of the Y-Ba-Cu-O partial melt, particularly through the crystallization of BCl.

Graphene ripples generated by grain boundaries in highly ordered pyrolytic graphite

Atomic scale periodic ripples that extend for several nanometers on the surface of adjacent graphitic grains have been observed for the first time on highly ordered pyrolitic graphite by UHV-STM. The ripples emanate from a grain boundary, and are explained in terms of a mechanical deformation due to the elastic strain accumulated along the GB, which is relieved out-of-plane in the topmost graphene layer. We present a molecular dynamics model that accounts for the formation of similar ripples as result of the lattice mismatch induced by two different grain orientations.

A RBF meshless approach for modeling a fractal mobile/immobile transport model

A fractional differential equation is used to describe a fractal model of mobile/immobile transport with a power law memory function. This equation is the limiting equation that governs continuous time random walks with heavy tailed random waiting times. In this paper, we firstly propose a finite difference method to discretize the time variable and obtain a semi-discrete scheme. Then we discuss its stability and convergence. Secondly we consider a meshless method based on radial basis functions (RBFs) to discretize the space variable. In contrast to conventional FDM and FEM, the meshless method is demonstrated to have distinct advantages: calculations can be performed independent of a mesh, it is more accurate and it can be used to solve complex problems. Finally the convergence order is verified from a numerical example which is presented to describe a fractal model of mobile/immobile transport process with different problem domains. The numerical results indicate that the present meshless approach is very effective for modeling and simulating fractional differential equations, and it has good potential in the development of a robust simulation tool for problems in engineering and science that are governed by various types of fractional differential equations.

Visually impaired drivers who use bioptic telescopes : self-assessed driving skills and agreement with on-road driving evaluation

Purpose. To compare self-assessed driving habits and skills of licensed drivers with central visual loss who use bioptic telescopes to those of age-matched normally sighted drivers, and to examine the association between bioptic drivers' impressions of the quality of their driving and ratings by a “backseat” evaluator. Methods. Participants were licensed bioptic drivers (n = 23) and age-matched normally sighted drivers (n = 23). A questionnaire was administered addressing driving difficulty, space, quality, exposure, and, for bioptic drivers, whether the telescope was helpful in on-road situations. Visual acuity and contrast sensitivity were assessed. Information on ocular diagnosis, telescope characteristics, and bioptic driving experience was collected from the medical record or in interview. On-road driving performance in regular traffic conditions was rated independently by two evaluators. Results. Like normally sighted drivers, bioptic drivers reported no or little difficulty in many driving situations (e.g., left turns, rush hour), but reported more difficulty under poor visibility conditions and in unfamiliar areas (P < 0.05). Driving exposure was reduced in bioptic drivers (driving 250 miles per week on average vs. 410 miles per week for normally sighted drivers, P = 0.02), but driving space was similar to that of normally sighted drivers (P = 0.29). All but one bioptic driver used the telescope in at least one driving task, and 56% used the telescope in three or more tasks. Bioptic drivers' judgments about the quality of their driving were very similar to backseat evaluators' ratings. Conclusions. Bioptic drivers show insight into the overall quality of their driving and areas in which they experience driving difficulty. They report using the bioptic telescope while driving, contrary to previous claims that it is primarily used to pass the vision screening test at licensure.

Working together-apart : exploring the relationships between formal and informal care networks for people dying at home

Introduction Informal caring networks contribute significantly to end-of-life (EOL) care in the community. However, to ensure that these networks are sustainable, and unpaid carers are not exploited, primary carers need permission and practical assistance to gather networks together and negotiate the help they need. Our aim in this study was to develop an understanding of how formal and informal carers work together when care is being provided in a dying person's home. We were particularly interested in formal providers’ perceptions and knowledge of informal networks of care and in identifying barriers to the networks working together. Methods Qualitative methods, informed by an interpretive approach, were used. In February-July 2012, 10 focus groups were conducted in urban, regional, and rural Australia comprising 88 participants. Findings Our findings show that formal providers are aware, and supportive, of the vital role informal networks play in the care of the dying at home. A number of barriers to formal and informal networks working together more effectively were identified. In particular, we found that the Australian policy of health-promoting palliative is not substantially translating to practice. Conclusion Combinations of formal and informal caring networks are essential to support people and their primary carers. Formal service providers do little to establish, support, or maintain the informal networks although there is much goodwill and scope for them to do so. Further re-orientation towards a health-promoting palliative care and community capacity building approach is suggested.

Tensile properties of a boron/nitrogen-doped carbon nanotube–graphene hybrid structure

Doping is an effective approach that allows for the intrinsic modification of the electrical and chemical properties of nanomaterials. Recently, a graphene and carbon nanotube hybrid structure (GNHS) has been reported, which extends the excellent properties of carbon-based materials to three dimensions. In this paper, we carried out a first-time investigation on the tensile properties of the hybrid structures with different dopants. It is found that with the presence of dopants, the hybrid structures usually exhibit lower yield strength, Young’s modulus, and earlier yielding compared to that of a pristine hybrid structure. For dopant concentrations below 2.5% no significant reduction of Young’s modulus or yield strength could be observed. For all considered samples, the failure is found to initiate at the region where the nanotubes and graphene sheets are connected. After failure, monatomic chains are normally observed around the failure region. Dangling graphene layers without the separation of a residual CNT wall are found to adhere to each other after failure with a distance of about 3.4 Å. This study provides a fundamental understanding of the tensile properties of the doped graphene–nanotube hybrid structures, which will benefit the design and also the applications of graphene-based hybrid materials.

Chemo-enzymatic synthesis of unnatural amino acids

A general chemo-enzymatic process has been developed to prepare enantiomerically pure L- and D-amino acids in high yield by deracemisation of racemic starting materials. The method has been developed from initial academic studies to be a robust, scalable industrial process. Unnatural amino acids, in high optical purity, are a rapidly growing class of intermediates required for pharmaceuticals, agrochemicals and other fine chemical applications. However, no single method has proven sufficiently adaptable to prepare these compounds generally at large scale. Our approach uses an enantioselective oxidase biocatalyst and a non-selective chemical reducing agent to effect the stereoinversion of one enantiomer and can result in an enantiomeric excess of > 99 % from a starting racemate, and product yields over 90 %. The current approach compares very favourably to resolution methods which have a maximum single pass yield of 50 %. Efficient methods have been developed to adapt the biocatalyst used in this process towards new target compounds and to optimise key factors which improve the process efficiency and offer competitive economics at scale.

B-Raf mutation : a key player in molecular biology of cancer

B-Raf is one of the more commonly mutated proto-oncogenes implicated in the development of cancers. In this review, we consider the mechanisms and clinical impacts of B-Raf mutations in cancer and discuss the implications for the patient in melanoma, thyroid cancer and colorectal cancer, where B-Raf mutations are particularly common.

Investigation of corona sources in high voltage power lines

This paper describes the results of experiments made in the vicinity of EHV overhead lines to investigate sources of clouds of charged particles using simultaneously-recording arrays of electric field meters to measure direct electric fields produced under ion clouds. E-field measurements, made at one metre above ground level, are correlated with wind speed and direction, and with measurements from ionisation counters and audible corona effects to identify possible positions of sources of corona on adjacent power lines. Measurements made in dry conditions on EHV lines in flat remote locations with no adjacent buildings or large vegetation indicate the presence of discrete ion sources associated with high stress points on some types of line hardware such as connectors and conductor spacers. Faulty line components such as insulators and line fittings are also found to be a possible source of ion clouds.

A comparison of factors influencing perceived risk by French and Australian cyclists and drivers

Differences in the levels of risk perceived by cyclists and car drivers may contribute to the dangers in their interactions. Levels of perceived risk have been shown to vary according to personal and environmental factors and between countries. Cycling rates in France are higher than in Australia, particularly among women. This study investigated whether cultural differences between France and Australia are reflected in perceived risks for experienced adult cyclists and drivers in the two countries. In online surveys, regular cyclists (France 336, Australia 444) and drivers (France 92, Australia 151) were asked to rate the level of risk in six situations: failure to yield; going through a red light; not signalling when turning; swerving; tail-gating; and not checking traffic. The effects of type of interacting vehicle and participant type on perceived risk were similar in France and Australia. However, the influence of responsibility for the risky behaviour differed according to participant type, type of situation and nationality. When the bicycle rider committed the road rule violation, Australian cyclists and drivers gave higher risk ratings than French cyclists and drivers. In both countries, cyclists rated themselves significantly higher than drivers on the perceived control and overconfidence subscales of the perceived skill measure. The French cyclists rated themselves higher than Australian cyclists on these scales, which could be responsible for overall lower perceived risk levels when interacting with a bike. Australian cyclists rated themselves significantly lower than drivers on the incompetence subscale but French cyclists rated themselves higher than drivers. In both countries incompetence scores were positively related to levels of perceived risk. Weekly time was associated with perceived risk in Australia but not in France. Frequency of traffic violations was not associated with perceived risk in either country. In conclusion, levels of perceived risk differed between drivers and cyclists in both countries and were influenced by type of interacting vehicle, experience and perceived skill. However, some differences between the results from the two countries merit further investigation to shed light on potential improvements in safety and cycling participation.

A Tradable Permit System in an Intertemporal Economy

It is known that in an intertemporal competitive economy, a tradable permit system may not achieve efficiency without setting appropriate permit interest rates (i.e., rewards for holding permits). To find the rates, however, we need to know in advance the path of efficient permit prices, which is difficult to obtain. This study intends to solve this problem in two ways. First, we analyze a special case in which the permit interest rates are given by a simple rule. For example, if the marginal abatement cost of pollution emission is constant, then the appropriate rate is to equal the monetary interest rate. As is the case for global warming, if the damage is caused in the future far beyond the planning period of the environmental program, the appropriate rate coincides with the marginal self-recovery of environmental stock under certain conditions. As a second approach, we propose a tradable permit system with a permit bank, as a mechanism by which the permit interest rates are generated endogenously without governmental intervention other than the issuance of permits. However, we also show that this approach raises the problem of indeterminacy of the equilibrium. © 2013 Springer Science+Business Media Dordrecht.