Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Planning, development and management of sustainable cities: A commentary from the guest editors

Cities are the most dramatic manifestations of human activities on the surface of the earth. These human-dominated organisms—i.e., cities—degrade natural habitats, simplify species composition, disrupt hydrological systems, and modify energy flow and nutrient cycling. Today, these consequential impacts of human activities, originated from population increase, rapid urbanization, high private motor vehicle dependency, deregulated industrialization and mass livestock production, are increasing exponentially and causing great deal of environmental, social, and economic challenges both at global and local scales. In such a situation, establishment of sustainable cities, through sustainable urban development practices, is seen as a potential panacea to combat these challenges responsibly, effectively, and efficiently. This paper offers a critical review of the key literature on the issues relating to planning, development and management of sustainable cities, introduces the contributions from the Special Issue, and speculates on the prospective research directions to place necessary mechanisms to secure a sustainable urban future for all.

Model Predictive Static Programming: A Computationally Efficient Technique For Suboptimal Control Design

Combining the philosophies of nonlinear model predictive control and approximate dynamic programming, a new suboptimal control design technique is presented in this paper, named as model predictive static programming (MPSP), which is applicable for finite-horizon nonlinear problems with terminal constraints. This technique is computationally efficient, and hence, can possibly be implemented online. The effectiveness of the proposed method is demonstrated by designing an ascent phase guidance scheme for a ballistic missile propelled by solid motors. A comparison study with a conventional gradient method shows that the MPSP solution is quite close to the optimal solution.

Developments in phosphine resistance in China and possible implications for Australia

Resistance to phosphine was characterised in strains of rice weevil, Sirophilus oryzae, and the psocids Liposcelis entomophila and L. decolor from China and Australia. Mixed-age cultures (containing all life stages) of insects were tested using a flow-through apparatus. The criterion of response was 'time to population extinction' defined as the exposure period, in days, at which 100% mortality of adults and no live progeny were achieved. Chinese S. oryzae took 11 and 7 days for population extinction at 200 and 700 ppm phosphine, respectively, compared with the Australian strain, which was controlled in 7 and 5 days, respectively. Similarly, the Chinese strains L. Enfornophila and L. decolor were generally more difficult to control than the corresponding Australian strains. The Chinese strains of L. decolor showed resistance levels stronger than any grain storage insect pest species so far detected in Australia. This research allows us to evaluate the likely significance of potential new resistance to the Australian grain industry and to prepare effective fumigation dosages and resistance management strategies to combat new strong resistances before they emerge here.

The story of … the military jacket

Fashion and war don’t seem an obvious pairing, but the military jacket is a fashion staple. It may take the form of a double-breasted dress uniform with brass buttons and epaulettes, trimmed in rock star braid, or it may be a khaki combat jacket, worn with Doc Martens and a scowl. Here I explore how these two forms of the military jacket were frogmarched into fashion...

Bysanttilaisten ja Akhaian ruhtinaskunnan väliset sotatoimet vuosina 1259-83 : Tapaustutkimus myöhäis-bysanttilaisesta sodankäynnistä

In my master thesis I analyse Byzantine warfare in the late period of the empire. I use military operations between Byzantines and crusader Principality of Achaia (1259–83) as a case study. Byzantine strategy was based (in “oriental manner”) on using ambushes, diplomacy, surprise attacks, deception etc. Open field battles that were risky in comparison with their benefits were usually avoided, but the Byzantines were sometimes forced to seek open encounter because their limited ability to keep strong armies in field for long periods of time. Foreign mercenaries had important place in Byzantine armies and they could simply change sides if their paymasters ran out of resources. The use of mercenaries with short contracts made it possible that the composition of an army was flexible but on the other hand heterogeneous – in result Byzantine armies were sometimes ineffective and prone to confusion. In open field battles Byzantines used formation that was made out from several lines placed one after another. This formation was especially suitable for cavalry battles. Byzantines might have also used other kinds of formations. The Byzantines were not considered equal to Latins in close combat. West-Europeans saw mainly horse archers and Latin mercenaries on Byzantine service as threats to themselves in battle. The legitimacy of rulers surrounding the Aegean sea was weak and in many cases political intrigues and personal relationships can have resolved the battles. Especially in sieges the loyalty of population was decisive. In sieges the Byzantines used plenty of siege machines and archers. This made fast conquests possible, but it was expensive. The Byzantines protected their frontiers by building castles. Military operations against the Principality of Achaia were mostly small scale raids following an intensive beginning. Byzantine raids were mostly made by privateers and mountaineers. This does not fit to the traditional picture that warfare belonged to the imperial professional army. It’s unlikely that military operations in war against the Principality of Achaia caused great demographic or economic catastrophe and some regions in the warzone might even have flourished. On the other hand people started to concentrate into villages which (with growing risks for trade) probably caused disturbance in economic development and in result birth rates might have decreased. Both sides of war sought to exchange their prisoners of war. These were treated according to conventional manners that were accepted by both sides. It was possible to sell prisoners, especially women and children, to slavery, but the scale of this trade does not seem to be great in military operations treated in this theses.

Subsoil constraints to grain production in the cropping soils of the north-eastern region of Australia: an overview

In dryland agricultural systems of the subtropical, semi-arid region of north-eastern Australia, water is the most limiting resource. Crop productivity depends on the efficient use of rainfall and available water stored in the soil during fallow. Agronomic management practices including a period of fallow, stubble retention, and reduced tillage enhance reserves of soil water. However, access to stored water in these soils may be restricted by the presence of growth-limiting conditions in the rooting zone of the crop. These have been termed as subsoil constraints. Subsoil constraints may include compacted or gravel layers (physical), sodicity, salinity, acidity, nutrient deficiencies, presence of toxic elements (chemical) and low microbial activity (biological). Several of these constraints may occur together in some soils. Farmers have often not been able to obtain the potential yield determined by their prevailing climatic conditions in the marginal rainfall areas of the northern grains region. In the past, the adoption of soil management practices had been largely restricted to the top 100 mm soil layer. Exploitation of the subsoil as a source of water and nutrients has largely been overlooked. The key towards realising potential yields would be to gain better understanding of subsoils and their limitations, then develop options to manage them practically and economically. Due to the complex nature of the causal factors of these constraints, efforts are required for a combination of management approaches rather than individual options, with the aim to combat these constraints for sustainable crop production, managing natural resources and avoiding environmental damage.

New annual and short-lived perennial pasture legumes for Australian agriculture--15 years of revolution

Fifteen years ago subterranean clover (Trifolium subterraneum) and annual medics (Medicago spp.) dominated annual pasture legume sowings in southern Australia, while limited pasture legume options existed for cropping areas of subtropical Australia. Since then a number of sustainability and economic challenges to existing farming systems have emerged, exposing shortcomings in these species and the lack of legume biodiversity. Public breeding institutions have responded to these challenges by developing 58 new annual and short-lived perennial pasture legumes with adaptation to both existing and new farming systems. This has involved commercialisation of new species and overcoming deficiencies in traditional species. Traits incorporated in legumes of Mediterranean Basin origin for the Mediterranean, temperate and southern subtropical climates of Australia include deeper root systems, protection from false breaks (germination-inducing rainfall events followed by death from drought), a range of hardseed levels, acid-soil tolerant root nodule symbioses, tolerance to pests and diseases and provision of lower cost seed through ease of seed harvesting and processing. Ten new species, French serradella (Ornithopus sativus), biserrula (Biserrula pelecinus), sulla (Hedysarum coronarium), gland (Trifolium glanduliferum), arrowleaf (Trifolium vesiculosum), eastern star (Trifolium dasyurum) and crimson (Trifolium incarnatum) clovers and sphere (Medicago sphaerocarpos), button (Medicago orbicularis) and hybrid disc (Medicago tornata x Medicago littoralis) medics have been commercialised. Improved cultivars have also been developed of subterranean (T. subterraneum), balansa (Trifolium michelianum), rose (Trifolium hirtum), Persian (Trifolium resupinatum) and purple (Trifolium purpureum) clovers, burr (Medicago polymorpha), strand (M. littoralis), snail (Medicago scutellata) and barrel (Medicago truncatula) medics and yellow serradella (Ornithopus compressus). New tropical legumes for pasture phases in subtropical cropping areas include butterfly pea (Clitoria ternatea), burgundy bean (Macroptilium bracteatum) and perennial lablab (Lablab purpureus). Other species and cultivars of Mediterranean species are likely to be released soon. The contributions of genetic resources, rhizobiology, pasture ecology and agronomy, plant pathology, entomology, plant chemistry and animal science have been paramount to this success. A farmer survey in Western Australia has shown widespread adoption of the new pasture legumes, while adoption of new tropical legumes has also been high in cropping areas of the subtropics. This trend is likely to increase due to the increasing cost of inorganic nitrogen, the need to combat herbicide-resistant crop weeds and improved livestock prices. Mixtures of these legumes allows for more robust pastures buffered against variable seasons, soils, pests, diseases and management decisions. This paper discusses development of the new pasture legumes, their potential use and deficiencies in the current suite. 'Ground–breaking Stuff’- Proceedings of the 13th Australian Society of Agronomy Conference, 10-14 September 2006, Perth, Western Australia.

The social supply of cannabis among young people in Australia

Cannabis is the most prolifically used illicit drug in Australia, however, there is a gap in our understanding concerning the social interactions and friendships formed around its supply and use. The authors recruited cannabis users aged between 18 and 30 years throughout Australia, to explore the impact of supply routes on young users and their perceived notions of drug dealing in order to provide valuable insight into the influence that reciprocal relationships have on young people’s access to cannabis. Findings reveal that the supply of cannabis revolves around pre-existing connections and relationships formed through associates known to be able to readily source cannabis. It was found that motivations for proffering cannabis in a shared environment were related more to developing social capital than to generating financial gain. Given this, often those involved in supply do not perceive that they are breaking the law or that they are ‘dealers’. This social supply market appears to be built on trust and social interactions and, as such, presents several challenges to law enforcement. It is suggested that there would be benefit in providing targeted education campaigns to combat social supply dealing among young adults.

Social supply of cannabis in Australia

While cannabis is the most prolifically used illicit drug in Australia, there is a gap in our understanding concerning the social interactions and friendships formed around its supply and use. The authors recruited cannabis users aged between 18 and 30 years throughout Australia, to explore the impact of supply routes on young users and their perceived notions of drug dealing in order to provide valuable insight into the influence that reciprocal relationships have on young people’s access to cannabis. Findings reveal that the supply of cannabis revolves around pre-existing connections and relationships formed through associates known to be able to readily source cannabis. It was found that motivations for proffering cannabis in a shared environment were related more to developing social capital than to generating financial gain. Given this, often those involved in supply do not perceive that they are breaking the law or that they are ‘dealers’. This social supply market appears to be built on trust and social interactions and, as such, presents several challenges to law enforcement. It is suggested that there would be benefit in providing targeted education campaigns to combat social supply dealing among young adults.

Molecular Background of Common Dyslipidemias

The leading cause of death in the Western world continues to be coronary heart disease (CHD). At the root of the disease process is dyslipidemia an aberration in the relevant amounts of circulating blood lipids. Cholesterol builds up in the arterial wall and following rupture of these plaques, myocardial infarction or stroke can occur. Heart disease runs in families and a number of hereditary forms are known. The leading cause of adult dyslipidemia presently however is overweight and obesity. This thesis work presents an investigation of the molecular genetics of common, hereditary dyslipidemia and the tightly related condition of obesity. Familial combined hyperlipidemia (FCHL) is the most common hereditary dyslipidemia in man with an estimated population prevalence of 1-6%. This complex disease is characterized by elevated levels of serum total cholesterol, triglycerides or both and is observed in about 20% of individuals with premature CHD. Our group identified the disease to be associated with genetic variation in the USF1 transcription factor gene. USF1 has a key role in regulating other genes that control lipid and glucose metabolism as well as the inflammatory response all central processes in the progression of atherosclerosis and CHD. The first two works of this thesis aimed at understanding how these USF1 variants result in increased disease risk. Among the many, non-coding single-nucleotide polymorphisms (SNPs) that associated with the disease, one was found to have a functional effect. The risk-enhancing allele of this SNP seems to eradicate the ability of the important hormone insulin to induce the expression of USF1 in peripheral tissues. The resultant changes in the expression of numerous USF1 target genes over time probably enhance and accelerate the atherogenic processes. Dyslipidemias often represent an outcome of obesity and in the final work of this thesis we wanted to address the metabolic pathways related to acquired obesity. It is recognized that active processes in adipose tissue play an important role in the development of dyslipidemia, insulin resistance and other pathological conditions associated with obesity. To minimize the confounding effects of genetic differences present in most human studies, we investigated a rare collection of identical twins that differed significantly in the amount of body fat. In the obese, but otherwise healthy young adults, several notable changes were observed. In addition to chronic inflammation, the adipose tissue of the obese co-twins was characterized by a marked (47%) decrease in amount of mitochondrial DNA (mtDNA) a change associated with mitochondrial dysfunction. The catabolism of branched chain amino acids (BCAAs) was identified as the most down-regulated process in the obese co-twins. A concordant increase in the serum level of these insulin secretagogues was identified. This hyperaminoacidemia may provide the feed-back signal from insulin resistant adipose tissue to the pancreas to ensure an appropriately augmented secretory response. The down regulation of BCAA catabolism correlated closely with liver fat accumulation and insulin. The single most up-regulated gene (5.9 fold) in the obese co-twins was osteopontin (SPP1) a cytokine involved in macrophage recruitment to adipose tissue. SPP1 is here implicated as an important player in the development of insulin resistance. These studies of exceptional study samples provide better understanding of the underlying pathology in common dyslipidemias and other obesity associated diseases important for future improvement of intervention strategies and treatments to combat atherosclerosis and coronary heart disease.

An Online Implementable Differential Evolution Tuned Optimal Guidance Law

This paper proposes a novel application of differential evolution to solve a difficult dynamic optimisation or optimal control problem. The miss distance in a missile-target engagement is minimised using differential evolution. The difficulty of solving it by existing conventional techniques in optimal control theory is caused by the nonlinearity of the dynamic constraint equation, inequality constraint on the control input and inequality constraint on another parameter that enters problem indirectly. The optimal control problem of finding the minimum miss distance has an analytical solution subject to several simplifying assumptions. In the approach proposed in this paper, the initial population is generated around the seed value given by this analytical solution. Thereafter, the algorithm progresses to an acceptable final solution within a few generations, satisfying the constraints at every iteration. Since this solution or the control input has to be obtained in real time to be of any use in practice, the feasibility of online implementation is also illustrated.

Molecular Details of Serum Resistance of Yersinia enterocolitica

In complement activation, Factor H (FH) and C4b-binding protein (C4bp) are the key regulators that prevent the complement cascade from attacking host tissues. Some bacteria may bind and deposit these regulators on their own surfaces and thus provide themselves with an efficient means to avoid complement activation. In consequence, bacteria resist complement-mediated lysis and opsonin-dependent phagocytosis. This study has demonstrated that Y. enterocolitica, similar to many other pathogens, recruits both FH and C4bp to its surface to ensure protection against the complement-mediated killing. YadA and Ail, the most crucial serum resistance factors of Y.enterocolitica, mediate the binding of FH and C4bp. FH - YadA interaction involves multiple higher structural motifs on the YadA stalk and the short consensus repeats (SCRs) of the entire polypeptide chain of FH. The Ail binding site on FH has been located to SCRs 6 and 7. The binding site for FH on Ail, however, remains undetermined. Both YadA- and Ail-bound regulators display full cofactor activity for FI-mediated cleavage of C3b/C4b. FH/C4bp-binding characteristics do, however, differ between YadA and Ail. In addition, Ail captures the regulators only in the absence of blocking lipopolysaccharide O-antigen and outer core, whereas YadA binds FH/C4bp independent of the presence of other surface factors Independent of mode of binding, however, YadA and Ail provide Y. enterocolitica a means to avoid complement-mediated lysis, enhancing chances for the bacteria to survive in the host during various phases of infection.

Women, environmental changes and forestry-related development : Gender-affected roles of rural people in land degradation and environmental rehabilitation in a dry region of Sudan

The purpose of the present study was to increase understanding of the interaction of rural people and, specifically, women with the environment in a dry area in Sudan. The study that included both nomadic pastoralists and farmers aimed at answering two main research questions, namely: What kinds of roles have the local people, and the women in particular, had in land degradation in the study area and what kinds of issues would a gender-sensitive, forestry-related environmental rehabilitation intervention need to consider there? The study adopted the definition of land degradation as proposed by the United Nations Convention to Combat Desertification (UNCCD), which describes land degradation as reduction or loss the biological or economic productivity and complexity of land in arid, semi-arid and dry sub-humid areas. The Convention perceives desertification as land degradation. The dry study area in Sudan, South of the Sahara, has been the subject of land degradation or desertification discussions since the 1970s, and other studies have been also conducted to assess the degradation in the area. Nevertheless, the exact occurrence, scale and local significance of land degradation in the area is still unclear. This study explored how the rural population whose livelihood depended on the area, perceived environmental changes occurring there and compared their conceptions with other sources of information of the area such as research reports. The main fieldwork methods included interviews with open-ended questions and observation of people and the environment. The theoretical framework conceptualised the rural population as land users whose choices of environmental activities are affected by multiple factors in the social and biophysical contexts in which they live. It was emphasised that these factors have their own specific characteristics in different contexts, simultaneously recognising that there are also factors that generally affect environmental practices in various areas such as the land users' environmental literacy (conceptions of the environment), gender and livelihood needs. The people studied described that environmental changes, such as reduced vegetation cover and cropland production, had complicated the maintenance of their livelihoods in the study area. Some degraded sites were also identified through observations during the fieldwork. Whether a large-scale reduction of cropland productivity had occurred in the farmers' croplands remained, however, unclear. The study found that the environmental impact of the rural women's activities varied and was normally limited. The women's most significant environmental impact resulted from their cutting of trees, which was likely to contribute, at least in some places, to land degradation, affecting the environment together with climate and livestock. However, when a wider perspective is taken, it becomes questionable whether the women have really played roles in land degradation, since gender, poverty and the need to maintain livelihood had caused them to conduct environmentally harmful activities. The women have had, however, no power to change the causes of their activities. The findings further suggested that an inadequate availability of food was the most critical problem in the study area. Therefore, an environmental programme in the area was suggested to include technical measures to increase the productivity of croplands, opportunities for income generation and readiness to co-operate with other programmes to improve the local people's abilities to maintain their livelihoods. In order to protect the environment and alleviate the women's work burden, the introduction of fuel-saving stoves was also suggested. Furthermore, it was suggested that increased planting of trees on homesteads would be supported by an easy availability of tree seedlings. Planting trees on common property land was, however, perceived as extremely demanding in the study area, due to scarcity of such land. In addition, it became apparent that the local land users, and women in particular, needed to allocate their labour to maintain the immediate livelihood of their families and were not motivated to allocate their labour solely for environmental rehabilitation. Nonetheless, from the point of view of the existing social structures, women's active participation in a community-based environmental programme would be rather natural, particularly among the farmer women who had already formed a women's group and participated in communal decision making. Forming of a women group or groups was suggested to further support both the farmer women's and pastoral women's active participation within an environmental programme and their general empowerment. An Environmental programme would need to acknowledge that improving rural people's well-being and maintaining their livelihood in the study area requires development and co-operation with various sectors in Sudan.

Resistance Struggle Against Nazis Commemorative Medal

Obverse: The symbol of the World Assembly to Commemorate Jewish Resistance and Combat Against Nazis. Man and woman wearing a stylized Star of David. Reverse: Symbol of the State of Israel, inscription. Emblem of 35 years of the state of Israel.