Microtubulin binding sites as target for developing anticancer agents

Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made α−and β−tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA

CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups—a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q2 = 0.699, r2 = 0.991, PC = 6, S.E.E. = 0.343 and F = 185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand–receptor interactions. The results obtained from the CoMSIA studies were: q2 = 0.535, r2 = 0.983, PC = 5, S.E.E. = 0.452 and F = 127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood–brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.

Synthesis and applications of carbon nanomaterials for energy generation and storage

The world is facing an energy crisis due to exponential population growth and limited availability of fossil fuels. Carbon, one of the most abundant materials found on earth, and its allotrope forms have been proposed in this project for novel energy generation and storage devices. This studied investigated the synthesis and properties of these carbon nanomaterials for applications in organic solar cells and supercapacitors.

The structural basis of DNA binding by the single-stranded DNA-binding protein from Sulfolobus solfataricus

Canonical single-stranded DNA-binding proteins (SSBs) from the oligosaccharide/oligonucleotide-binding (OB) domain family are present in all known organisms and are critical for DNA replication, recombination and repair. The SSB from the hyperthermophilic crenarchaeote Sulfolobus solfataricus (SsoSSB) has a ‘simple’ domain organization consisting of a single DNA-binding OB fold coupled to a flexible C-terminal tail, in contrast with other SSBs in this family that incorporate up to four OB domains. Despite the large differences in the domain organization within the SSB family, the structure of the OB domain is remarkably similar all cellular life forms. However, there are significant differences in the molecular mechanism of ssDNA binding. We have determined the structure of the SsoSSB OB domain bound to ssDNA by NMR spectroscopy. We reveal that ssDNA recognition is modulated by base-stacking of three key aromatic residues, in contrast with the OB domains of human RPA and the recently discovered human homologue of SsoSSB, hSSB1. We also demonstrate that SsoSSB binds ssDNA with a footprint of five bases and with a defined binding polarity. These data elucidate the structural basis of DNA binding and shed light on the molecular mechanism by which these ‘simple’ SSBs interact with ssDNA.

The expected and unexpected consequences of implementing energy efficient vehicle incentives

Completed as part of a Joint PhD program between Queensland University of Technology and the Royal Institute of Technology in Stockholm, Sweden, this thesis examines the effects of different government incentive policies on the demand, usage and pricing of energy efficient vehicles. This study outlines recommendations for policy makers aiming to increase the uptake of energy efficient vehicles. The study finds that whilst many government incentives have been successful in encouraging the uptake of energy efficient vehicles, policy makers need to both recognise and attempt to minimise the potential unintended consequences of such initiatives.

Energy Transformed: Sustainable Energy Solutions for Climate Change Mitigation

This 600+ page online education program provides free access to a comprehensive education and training package that brings together the knowledge of how countries, specifically Australia, can achieve at least 60 percent cuts to greenhouse gas emissions by 2050. This resource has been developed in line with the activities of the CSIRO Energy Transformed Flagship research program which is focused on research that will assist Australia to achieve this target. This training package provides industry, governments, business and households with the knowledge they need to realise at least 30 percent energy efficiency savings in the short term while providing a strong basis for further improvement. It also provides an updated overview of advances in low carbon technologies, renewable energy and sustainable transport to help achieve a sustainable energy future. Whist this education and training package has an Australian focus, it outlines sustainable energy strategies and provide links to numerous online reports which will assist climate change mitigation efforts globally. This training program seeks to compliment other initiatives seeking to encourage the reduction of greenhouse gas emissions through behaviour change, sustainable consumption, and constructive changes in economic incentives and policy.

Re-engineering higher education for energy efficiency solutions

Emerging 21st century challenges require higher education institutions (HEIs) to play a key role in developing graduates and professionals, particularly in engineering and design, who can forge sustainable solutions. The trouble is there’s currently a significant lag in the preparedness of HEIs to provide the stream of professionals needed. Addressing energy efficiency competencies is one critical area.

Hawai’i, clean energy, and climate action

Hawai’i is a leader in clean energy and climate action in the Pacific and the United States. With the Mauna Loa Observatory, Hawai’i has been at the forefront of climate research. The state has a special vulnerability to the impacts of climate change — particularly in respect of the marine environment, water resources, biodiversity, and human costs. Hawaii has promoted a Clean Energy initiative and passed legislation on climate adaptation. State and national leaders — most notably, United States Senator Brian Schatz — have shown great initiative in respect of clean energy and climate action. As such, it is worthwhile considering Hawaii as a case study of climate leadership in the Pacific and the United States.

Intellectual property and biofuels: The energy crisis, food security, and climate change

In light of larger public policy debates over intellectual property and climate change, this article considers patent practice, law, and policy in respect of biofuels. This debate has significant implications for public policy discussions in respect of energy independence, food security, and climate change. The first section of the paper provides a network analysis of patents in respect of biofuels across the three generations. It provides empirical research in respect of patent subject matter, ownership, and strategy in respect of biofuels. The second section provides a case study of significant patent litigation over biofuels. There is an examination of the biofuels patent litigation between the Danish company Novozymes, and Danisco and DuPont. The third section examines flexibilities in respect of patent law and clean technologies in the context of the case study of biofuels. In particular, it explores the debate over substantive doctrinal matters in respect of biofuels – such as patentable subject matter, technology transfer, patent pools, compulsory licensing, and disclosure requirements. The conclusion explores the relevance of the debate over patent law and biofuels to the larger public policy discussions over energy independence, food security, and climate change.

Influence of habitual physical activity on gastric emptying in healthy males and relationships with body composition and energy expenditure

Although a number of studies have examined the role of gastric emptying (GE) in obesity, the influences of habitual physical activity level, body composition and energy expenditure (EE) on GE have received very little consideration. In this study, we have compared GE in active and inactive males, and we have characterised relationships with body composition (fat and fat free mass) and EE. Forty-four males (Active: n=22, Inactive: n=22; range BMI 21-36kg/m2; range percent fat mass 9-42%) were studied, with GE of a standardised (1676 kJ) pancake meal being assessed by 13C-octanoic acid breath test, body composition by air displacement plethysmography, resting metabolic rate (RMR) by indirect calorimetry and activity EE (AEE) by accelerometry. Results showed that GE was faster in active compared to inactive males (mean ±SD half time (t1/2): Active: 157±18 and Inactive: 179±21 min, p<0.001). When data from both groups were pooled, GE t1/2 was associated with percent fat mass (r=0.39, p<0.01) and AEE (r =-0.46, p<0.01). After controlling for habitual physical activity status, the association between AEE and GE remained, but not that for percent fat mass and GE. BMI and RMR were not associated with GE. In summary, faster GE is considered to be a marker of a habitually active lifestyle in males, and is associated with a higher AEE and lower percent fat mass. The possibility that GE contributes to a gross physiological regulation (or dysregulation) of food intake with physical activity level deserves further investigation.

Substrate effects in the supramolecular assembly of 1,3,5-benzene tricarboxylic acid on graphite and graphene

The behavior of small molecules on a surface depends critically on both molecule–substrate and intermolecular interactions. We present here a detailed comparative investigation of 1,3,5-benzene tricarboxylic acid (trimesic acid, TMA) on two different surfaces: highly oriented pyrolytic graphite (HOPG) and single-layer graphene (SLG) grown on a polycrystalline Cu foil. On the basis of high-resolution scanning tunnelling microscopy (STM) images, we show that the epitaxy matrix for the hexagonal TMA chicken wire phase is identical on these two surfaces, and, using density functional theory (DFT) with a non-local van der Waals correlation contribution, we identify the most energetically favorable adsorption geometries. Simulated STM images based on these calculations suggest that the TMA lattice can stably adsorb on sites other than those identified to maximize binding interactions with the substrate. This is consistent with our net energy calculations that suggest that intermolecular interactions (TMA–TMA dimer bonding) are dominant over TMA–substrate interactions in stabilizing the system. STM images demonstrate the robustness of the TMA films on SLG, where the molecular network extends across the variable topography of the SLG substrates and remains intact after rinsing and drying the films. These results help to elucidate molecular behavior on SLG and suggest significant similarities between adsorption on HOPG and SLG.

Innovation in energy efficiency education for engineers

Energy efficiency as a concept has gained significant attention over the last few decades, as governments and industries around the world have grappled with issues such as rapid population growth and expanding needs for energy, the cost of supplying infrastructure for growing spikes in peak demand, the finite nature of fossil based energy reserves, and managing transition timeframes for expanding renewable energy supplies. Over the last decade in particular, there has been significant growth in understanding the complexity and interconnectedness of these issues, and the centrality of energy efficiency to the engineering profession. Furthermore, there has been a realisation amongst various government departments and education providers that associated knowledge and skill sets to achieve energy efficiency goals are not being sufficiently developed in vocational or higher education. Within this context, this poster discusses the emergence of a national energy efficiency education agenda in Australia, to support embedding such knowledge throughout the engineering curriculum, and throughout career pathways. In particular, the posterprovides insights into the national priorities for capacity building in Australia, and how this is influencing the engineering education community, from undergraduate education through to postgraduate studies and professional development. The poster is intended to assist in raising awareness about the central role of energy efficiency within engineering, significant initiatives by major government, professional, and training organisations, and the increasing availability of high quality energy efficiency engineering education resources. The authors acknowledge the support for and contributions to this poster by the federal Department of Resources, Energy and Tourism, through members of the national Energy Efficiency Advisory Group for engineering education.

Consultation: Energy efficiency and engineering education

This report provides the Commonwealth Department of Resources, Energy and Tourism (RET) with a summary of consultation undertaken with representatives from industry and academia around Australia regarding mainstreaming energy efficiency within engineering education. Specifically, the report documents the purpose of the consultation process, key messages and emerging themes, industry-perceived gaps in energy efficiency related knowledge and skills, and academic considerations regarding graduate attributes and learning pathways to close these gaps. This information complements previous reports by presenting the current thoughts and ideas of more than 100 engineering academic and practising professionals who are actively involved in building capacity through the education system or implementing energy efficiency improvements in companies/the workplace. Furthermore, the report describes the emergence of a potential ‘community of practice’ in energy efficiency capacity building that arose during the project.

State of Education for Energy Efficiency in Australian Engineering Education - Summary of Questionnaire Results

In 2007 the National Framework for Energy Efficiency provided funding for the first survey of energy efficiency education across all Australian universities teaching engineering education. The survey asked the question, ‘What is the state of education for energy efficiency in Australian engineering education?’. There was an excellent response to the survey, with 48 course responses from lecturers across 27 universities from every state and territory in Australia, and 260 student responses from 18 courses across 8 universities from all 6 states. It is concluded from the survey findings that the state of education for energy efficiency in Australian engineering education is currently highly variable and ad hoc across universities and engineering disciplines.

Service composition and binding

Service composition enables the creation of services previously unavailable through the aggregation of existing services. The result is called a service composition. Exposing a service composition as a service, the result is called a composed service. It can be distinguished from atomic services. Service composition approaches can be differentiated along two axes: point in time of composition and degree of automation. With design-time and run-time we can identify two different points in time for doing a composition. Additionally we can distinguish between three different degrees of automation: manual, assisted, and automated service composition. © 2008 Springer Berlin Heidelberg.