Irreversible compressible work and APE dissipation in turbulent stratified fluid

Although it plays a key role in the theory of stratified turbulence, the concept of available potential energy (APE) dissipation has remained until now a rather mysterious quantity, owing to the lack of rigorous result about its irreversible character or energy conversion type. Here, we show by using rigorous energetics considerations rooted in the analysis of the Navier-Stokes for a fully compressible fluid with a nonlinear equation of state that the APE dissipation is an irreversible energy conversion that dissipates kinetic energy into internal energy, exactly as viscous dissipation. These results are established by showing that APE dissipation contributes to the irreversible production of entropy, and by showing that it is a part of the work of expansion/contraction. Our results provide a new interpretation of the entropy budget, that leads to a new exact definition of turbulent effective diffusivity, which generalizes the Osborn-Cox model, as well as a rigorous decomposition of the work of expansion/contraction into reversible and irreversible components. In the context of turbulent mixing associated with parallel shear flow instability, our results suggests that there is no irreversible transfer of horizontal momentum into vertical momentum, as seems to be required when compressible effects are neglected, with potential consequences for the parameterisations of momentum dissipation in the coarse-grained Navier-Stokes equations.

Flavonoids as prospective compounds for anti-cancer therapy

Flavonoids, which are polyphenolic compounds, are a class of plant secondary metabolites possessing a broad spectrum of pharmacological activity including anti-cancer activities. They have been reported to interfere in the initiation, promotion and progression of cancer by modulating different enzymes and receptors in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. Due to their multiple molecular mechanisms of action, flavonoids (both natural and synthetic analogs) are being investigated for their potential applications in anti-cancer therapies. In this review article, the main molecular mechanisms of action of flavonoids attributing to their potential anti-cancer activities have been discussed and the key structural features required for their activity are highlighted.

Global-scale climate impact functions: the relationship between climate forcing and impact

Although there is a strong policy interest in the impacts of climate change corresponding to different degrees of climate change, there is so far little consistent empirical evidence of the relationship between climate forcing and impact. This is because the vast majority of impact assessments use emissions-based scenarios with associated socio-economic assumptions, and it is not feasible to infer impacts at other temperature changes by interpolation. This paper presents an assessment of the global-scale impacts of climate change in 2050 corresponding to defined increases in global mean temperature, using spatially-explicit impacts models representing impacts in the water resources, river flooding, coastal, agriculture, ecosystem and built environment sectors. Pattern-scaling is used to construct climate scenarios associated with specific changes in global mean surface temperature, and a relationship between temperature and sea level used to construct sea level rise scenarios. Climate scenarios are constructed from 21 climate models to give an indication of the uncertainty between forcing and response. The analysis shows that there is considerable uncertainty in the impacts associated with a given increase in global mean temperature, due largely to uncertainty in the projected regional change in precipitation. This has important policy implications. There is evidence for some sectors of a non-linear relationship between global mean temperature change and impact, due to the changing relative importance of temperature and precipitation change. In the socio-economic sectors considered here, the relationships are reasonably consistent between socio-economic scenarios if impacts are expressed in proportional terms, but there can be large differences in absolute terms. There are a number of caveats with the approach, including the use of pattern-scaling to construct scenarios, the use of one impacts model per sector, and the sensitivity of the shape of the relationships between forcing and response to the definition of the impact indicator.

Impact of the enhanced permeability and retention (EPR) effect and cathepsins levels on the activity of polymer-drug conjugates

Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.

Challenges in quantifying changes in the global water cycle

Understanding observed changes to the global water cycle is key to predicting future climate changes and their impacts. While many datasets document crucial variables such as precipitation, ocean salinity, runoff, and humidity, most are uncertain for determining long-term changes. In situ networks provide long time-series over land but are sparse in many regions, particularly the tropics. Satellite and reanalysis datasets provide global coverage, but their long-term stability is lacking. However, comparisons of changes among related variables can give insights into the robustness of observed changes. For example, ocean salinity, interpreted with an understanding of ocean processes, can help cross-validate precipitation. Observational evidence for human influences on the water cycle is emerging, but uncertainties resulting from internal variability and observational errors are too large to determine whether the observed and simulated changes are consistent. Improvements to the in situ and satellite observing networks that monitor the changing water cycle are required, yet continued data coverage is threatened by funding reductions. Uncertainty both in the role of anthropogenic aerosols, and due to large climate variability presently limits confidence in attribution of observed changes.

The impacts of climate change across the globe: a multi-sectoral assessment

The overall global-scale consequences of climate change are dependent on the distribution of impacts across regions, and there are multiple dimensions to these impacts.This paper presents a global assessment of the potential impacts of climate change across several sectors, using a harmonised set of impacts models forced by the same climate and socio-economic scenarios. Indicators of impact cover the water resources, river and coastal flooding, agriculture, natural environment and built environment sectors. Impacts are assessed under four SRES socio-economic and emissions scenarios, and the effects of uncertainty in the projected pattern of climate change are incorporated by constructing climate scenarios from 21 global climate models. There is considerable uncertainty in projected regional impacts across the climate model scenarios, and coherent assessments of impacts across sectors and regions therefore must be based on each model pattern separately; using ensemble means, for example, reduces variability between sectors and indicators. An example narrative assessment is presented in the paper. Under this narrative approximately 1 billion people would be exposed to increased water resources stress, around 450 million people exposed to increased river flooding, and 1.3 million extra people would be flooded in coastal floods each year. Crop productivity would fall in most regions, and residential energy demands would be reduced in most regions because reduced heating demands would offset higher cooling demands. Most of the global impacts on water stress and flooding would be in Asia, but the proportional impacts in the Middle East North Africa region would be larger. By 2050 there are emerging differences in impact between different emissions and socio-economic scenarios even though the changes in temperature and sea level are similar, and these differences are greater in 2080. However, for all the indicators, the range in projected impacts between different climate models is considerably greater than the range between emissions and socio-economic scenarios.

Exploring quercetin and luteolin derivatives as antiangiogenic agents

The formation of new blood vessels from the pre-existing vasculature (angiogenesis) is a crucial stage in cancer progression and, indeed, angiogenesis inhibitors are now used as anticancer agents, clinically. Here we have explored the potential of flavonoid derivatives as antiangiogenic agents. Specifically, we have synthesised methoxy and 4-thio derivatives of the natural flavones quercetin and luteolin, two of which (4-thio quercetin and 4-thio luteolin) had never been previously reported. Seven of these compounds showed significant (P<0.05) antiangiogenic activity in an in vitro scratch assay. Their activity ranged from an 86% inhibition of the vascular endothelium growth factor (VEGF)-stimulated migration (observed for methoxyquercetin at 10 µM and for luteolin at 1 µM) to a 36% inhibition (for thiomethoxy quercetin at 10 µM). Western blotting studies showed that most (4 out of 7) compounds inhibited phosphorylation of the VEGF receptor-2 (VEGFR2), suggesting that the antiangiogenic activity was due to an interference with the VEGF/VEGFR2 pathway. Molecular modelling studies looking at the affinity of our compounds towards VEGFR and/or VEGF confirmed this hypothesis, and indeed the compound with the highest antiangiogenic activity (methoxyquercetin) showed the highest affinity towards VEGFR and VEGF. As reports from others have suggested that structurally similar compounds can elicit biological responses via a non-specific, promiscuous membrane perturbation, potential interactions of the active compounds with a model lipid bilayer were assessed via DSC. Luteolin and its derivatives did not perturb the model membrane even at concentrations 10 times higher than the biologically active concentration and only subtle interactions were observed for quercetin and its derivatives. Finally, cytotoxicity assessment of these flavonoid derivatives against MCF-7 breast cancer cells demonstrated also a direct anticancer activity albeit at generally higher concentrations than those required for an antiangiogenic effect (10 fold higher for the methoxy analogues). Taken together these results show promise for flavonoid derivatives as antiangiogenic agents.

Sialic acids in biological and therapeutic processes: opportunities and challenges

It is now well documented that carbohydrates play multiple roles in biological processes, and hence are interesting targets for chemical biology and medicinal chemistry programmes. This review focuses on a subset of carbohydrates, specifically sialic acid containing carbohydrates. It highlights their occurrence and diversity, and presents evidence for their roles in a range of biological pathways. It illustrates that they are targets for novel medicinal chemistry strategies for a range of therapeutic areas, including cancer and immunity. Case studies highlight opportunities and challenges in this area, and sialic acid based drugs that have entered clinical practice, and are promising candidates for future disease intervention schemes, are discussed. The review concludes by highlighting perspectives and emerging roles for these targets.

An efficient and rapid microwave-assisted synthesis of 1-acetyl-1H-indol-3-YL acetates

An efficient and rapid synthesis of 1-acetyl-1H-indol-3-yl acetate 1 and its derivatives 7 via the microwave-assisted cyclisation and decarboxylation of 2-[(carboxymethyl)amino]benzoic acids 5 is described. The latter were left to react with acetic anhydride using triethylamine as the base and were subjected to microwave irradiation for 1 minute, at 80 °C with initial power of 300 W. The target 1-acetyl-1H-indol-3-yl acetate 1 and derivatives 7 were isolated in 34-71% yield. In particular, synthesis of 1-acetyl-6-(trifluoromethyl)-1H-indol-3-yl acetate 7f and 1-acetyl-3-methyl-1H-indol-3-yl acetate 7h is reported for the first time.

Synthesis and biological analysis of novel glycoside derivatives of L-AEP, as targeted antibacterial agents

To develop targeted methods for treating bacterial infections, the feasibility of using glycoside derivatives of the antibacterial compound L-R-aminoethylphosphonic acid (L-AEP) has been investigated. These derivatives are hypothesized to be taken up by bacterial cells via carbohydrate uptake mechanisms, and then hydrolysed in situ by bacterial borne glycosidase enzymes, to selectively afford L-AEP. Therefore the synthesis and analysis of ten glycoside derivatives of L-AEP, for selective targeting of specific bacteria, is reported. The ability of these derivatives to inhibit the growth of a panel of Gram-negative bacteria in two different media is discussed. β-Glycosides (12a) and (12b) that contained L-AEP linked to glucose or galactose via a carbamate linkage inhibited growth of a range of organisms with the best MICs being <0.75 mg/ml; for most species the inhibition was closely related to the hydrolysis of the equivalent chromogenic glycosides. This suggests that for (12a) and (12b), release of L-AEP was indeed dependent upon the presence of the respective glycosidase enzyme.

Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

With many cancers showing resistance to current chemotherapies, the search for novel anti-cancer agents is attracting considerable attention. Natural flavonoids have been identified as useful leads in such programmes. However, since an in-depth understanding of the structural requirements for optimum activity is generally lacking, further research is required before the full potential of flavonoids as anti-proliferative agents can be realised. Herein a broad library of 76 methoxy and hydroxy flavones, and their 4-thio analogues, was constructed and their structure-activity relationships for anti-proliferative activity against the breast cancer cell lines MCF-7 (ER+ve), MCF-7/DX (ER+ve, anthracycline resistant) and MDA-MB-231 (ER-ve) were probed. Within this library, 42 compounds were novel, and all compounds were afforded in good yields and > 95% purity. The most promising lead compounds, specifically the novel hydroxy 4-thioflavones 15f and 16f, were further evaluated for their anti-proliferative activities against a broader range of cancer cell lines by the National Cancer Institute (NCI), USA and displayed significant growth inhibition profiles (e.g Compound-15f: MCF-7 (GI50 = 0.18 μM), T-47D (GI50 = 0.03 μM) and MDA-MB-468 (GI50 = 0.47 μM) and compound-16f: MCF-7 (GI50 = 1.46 μM), T-47D (GI50 = 1.27 μM) and MDA-MB-231 (GI50 = 1.81 μM). Overall, 15f and 16f exhibited 7-46 fold greater anti-proliferative potency than the natural flavone chrysin (2d). A systematic structure-activity relationship study against the breast cancer cell lines highlighted that free hydroxyl groups and the B-ring phenyl groups were essential for enhanced anti-proliferative activities. Substitution of the 4-C=O functionality with a 4-C=S functionality, and incorporation of electron withdrawing groups at C4’ of the B-ring phenyl, also enhanced activity. Molecular docking and mechanistic studies suggest that the anti-proliferative effects of flavones 15f and 16f are mediated via ER-independent cleavage of PARP and downregulation of GSK-3β for MCF-7 and MCF-7/DX cell lines. For the MDA-MB-231 cell line, restoration of the wild-type p53 DNA binding activity of mutant p53 tumour suppressor gene was indicated.

Warrock collection: original line drawings by fourth year Deakin University architecture students of the Warrock Homestead, a local heritage listed property in Victoria

This collection includes the original line drawings by fourth year Deakin University architecture students of a well known local heritage listed property, the Warrock homestead. The Warrock homestead consisted of detailed original timber structures of the 19th century. The drawings are the result of a conservation project funded by the Commonwealth Government of Australia National Estate Grants program. In 1999 a further deposit of original reports relating to individual buildings on the property was received. The collection consists of monographs, photographs and photograph negatives, architectural drawings, VHS tapes and ephemera.

A clustered randomised trial examining the effect of social marketing and community mobilisation on the age of uptake and levels of alcohol consumption by Australian adolescents

Introduction
Throughout the world, alcohol consumption is common among adolescents. Adolescent alcohol use and misuse have prognostic significance for several adverse long-term outcomes, including alcohol problems, alcohol dependence, school disengagement and illicit drug use. The aim of this study was to evaluate whether randomisation to a community mobilisation and social marketing intervention reduces the proportion of adolescents who initiate alcohol use before the Australian legal age of 18, and the frequency and amount of underage adolescent alcohol consumption.
Method and analysis
The study comprises 14 communities matched with 14 non-contiguous communities on socioeconomic status (SES), location and size. One of each pair was randomly allocated to the intervention. Baseline levels of adolescent alcohol use were estimated through school surveys initiated in 2006 (N=8500). Community mobilisation and social marketing interventions were initiated in 2011 to reduce underage alcohol supply and demand. The setting is communities in three Australian states (Victoria, Queensland and Western Australia). Students (N=2576) will complete school surveys in year 8 in 2013 (average age 12). Primary outcomes: (1) lifetime initiation and (2) monthly frequency of alcohol use. Reports of social marketing and family and community alcohol supply sources will also be assessed. Point estimates with 95% CIs will be compared for student alcohol use in intervention and control communities. Changes from 2006 to 2013 will be examined; multilevel modelling will assess whether random assignment of communities to the intervention reduced 2013 alcohol use, after accounting for community level differences. Analyses will also assess whether exposure to social marketing activities increased the intervention target of reducing alcohol supply by parents and community members.

Effectiveness of Milorganite® as a Repellent to Protect Ornamental and Agronomic Plants From Deer Over-Browsing

When deer populations become locally overabundant, browsing of ornamental and agronomic plants negatively affects plant establishment, survival, and productivity. Milorganite® is a slow-release, organic fertilizer produced from human sewage. We tested Milorganite® as a deer repellent on chrysanthemums (Chrysanthemums morifolium) in an urban/suburban environment, and soybeans (Gycine max) in a rural agriculture environment. Six beds of chrysanthemums at two sites were monitored for 28 to 35 days. Treatment plants received a top dressing of 104 grams of Milorganite® (1120.9 kg/ha). Milorganite® treated plants had more (P < 0.001) terminal buds and achieved greater height (P < 0.002) compared to controls at one site, however damage observed was similar at the second site. In a second experiment, 0.2-ha plots of soybeans (Glycine max) were planted on five rural properties in northeastern Georgia and monitored for ≥ 30 days. Treated areas received 269 kg/ha of Milorganite®. In 4 of 5 sites, Milorganite® delayed browsing on treated plants from 1 week to > 5 weeks post-planting. Duration of the protection appeared to be related to the difference in deer density throughout most of the study areas. Results of this study indicate Milorganite® has potential use as a deer repellent.

High-resolution paleoclimatology of the last millennium: a review of current status and future prospects

This review of late-Holocene palaeoclimatology represents the results from a PAGES/CLIVAR Intersection Panel meeting that took place in June 2006. The review is in three parts: the principal high-resolution proxy disciplines (trees, corals, ice cores and documentary evidence), emphasizing current issues in their use for climate reconstruction; the various approaches that have been adopted to combine multiple climate proxy records to provide estimates of past annual-to-decadal timescale Northern Hemisphere surface temperatures and other climate variables, such as large-scale circulation indices; and the forcing histories used in climate model simulations of the past millennium. We discuss the need to develop a framework through which current and new approaches to interpreting these proxy data may be rigorously assessed using pseudo-proxies derived from climate model runs, where the `answer' is known. The article concludes with a list of recommendations. First, more raw proxy data are required from the diverse disciplines and from more locations, as well as replication, for all proxy sources, of the basic raw measurements to improve absolute dating, and to better distinguish the proxy climate signal from noise. Second, more effort is required to improve the understanding of what individual proxies respond to, supported by more site measurements and process studies. These activities should also be mindful of the correlation structure of instrumental data, indicating which adjacent proxy records ought to be in agreement and which not. Third, large-scale climate reconstructions should be attempted using a wide variety of techniques, emphasizing those for which quantified errors can be estimated at specified timescales. Fourth, a greater use of climate model simulations is needed to guide the choice of reconstruction techniques (the pseudo-proxy concept) and possibly help determine where, given limited resources, future sampling should be concentrated.