Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes.

The influence of the motion of a rotor grid on a stator grid

In this paper we have used the method of characteristics developed for two dimensional unsteady flow problems to study a simplified axial turbine problem. The system consists of two sets of blades —the guiding vanes which are fixed and the rotor blades which move perpendicular to these vanes. The initial undisturbed constant flow in the system is perturbed by introducing a small velocity normal to the rotor blades to simulate a slight constant inclination. The resulting perturbed flow is periodic after the first three cycles. We have studied the perturbed density distribution throughout the system during a period.

Review of Nezara viridula (L.) management strategies and potential for IPM in field crops with emphasis on Australia

Nezara viridula (L.) is a cosmopolitan, polyphagous heteropteran that causes economic damage to many crop species. At present, control of N. viridula in Australia and other countries relies heavily upon insecticides, most of which are disruptive to beneficial insects, constituting a constraint on integrated pest management (IPM). Much research has been conducted into non-chemical control methods for N. viridula. This paper reviews the potential for and limitations of sterile insect technique, classical, inundative and conservation biological control, and trap cropping. None of these techniques appear to be adequate for control of N. viridula when used alone but there is scope for these non-chemical approaches to be adopted for use in integrated management of this pest. A proposal is given for one such integrated approach for future development. It includes biopesticides, trap crops and carefully targeted habitat manipulation to enhance arthropod natural enemies as well as area-wide management and grower education.

High subsoil chloride concentrations reduce soil water extraction and crop yield on Vertosols in north-eastern Australia

Salinity, sodicity, acidity, and phytotoxic levels of chloride (Cl) in subsoils are major constraints to crop production in many soils of north-eastern Australia because they reduce the ability of crop roots to extract water and nutrients from the soil. The complex interactions and correlations among soil properties result in multi-colinearity between soil properties and crop yield that makes it difficult to determine which constraint is the major limitation. We used ridge-regression analysis to overcome colinearity to evaluate the contribution of soil factors and water supply to the variation in the yields of 5 winter crops on soils with various levels and combinations of subsoil constraints in the region. Subsoil constraints measured were soil Cl, electrical conductivity of the saturation extract (ECse), and exchangeable sodium percentage (ESP). The ridge regression procedure selected several of the variables used in a descriptive model, which included in-crop rainfall, plant-available soil water at sowing in the 0.90-1.10 m soil layer, and soil Cl in the 0.90-1.10 m soil layer, and accounted for 77-85% of the variation in the grain yields of the 5 winter crops. Inclusion of ESP of the top soil (0.0-0.10 m soil layer) marginally increased the descriptive capability of the models for bread wheat, barley and durum wheat. Subsoil Cl concentration was found to be an effective substitute for subsoil water extraction. The estimates of the critical levels of subsoil Cl for a 10% reduction in the grain yield were 492 mg cl/kg for chickpea, 662 mg Cl/kg for durum wheat, 854 mg Cl/kg for bread wheat, 980 mg Cl/kg for canola, and 1012 mg Cl/kg for barley, thus suggesting that chickpea and durum wheat were more sensitive to subsoil Cl than bread wheat, barley, and canola.

Novel Self-Supported Natural and Synthetic Polymer Membranes for Air Humidification

Novel self-supported natural and synthetic polymer membranes of chitosan-hydroxy ethyl Cellulose-montmorillonite (CS-HEC-MMT) and polyvinyl alcohol (PVA)-polystyrene sulfonic acid (PSSA) are prepared by solution casting method followed by crosslinking. These membranes are employed for air humidification at varying temperatures between 30 degrees C and 70 degrees C and their performances are compared with commercial Nafion membranes. High hater fluxes with desired humidified-air output have been achieved for CS-HEC-MMT and PVA-PSSA hybrid membranes at air-flow rates of 1-10 slpm. Variation in the air/water mixing ratio, dew point, and relative humidity that ultimately results in desired water flux With respect to air-flow rates are also quantified for all the membranes. Water flux values for CS-HEC-MMT are less than those for Nafion (R) and PVA-PSSA membranes, but the operational Stability of CS-HEC-MMT membrane is higher than PVA-PSSA and comparable with Nafion (R) both of which can operate up to 70 degrees C at repetitive cycles of humidification.

Genetic erosion and changes in distribution of sorghum (Sorghum bicolor L. (Moench)) landraces in north-eastern Ethiopia

Ethiopia is believed to be the centre of origin and domestication for sorghum, where sorghum remains one of the main staple crops. Loss of biodiversity is occurring at an alarming rate in Ethiopia and crops, including sorghum, have long been recognized as vulnerable to genetic erosion. A major collection of sorghum germplasm was made in 1973 by Gebrekidan and Ejeta from north-eastern Ethiopia. A new collection of landraces was made in 2003, and these were field evaluated at Sirinka in 2004 along with representative samples from the 1973 collection. Farmer surveys and soil and climate surveys were also performed. Preliminary analysis demonstrated that some important landraces have disappeared either locally or regionally in the past 30 years and many other landraces have become marginalized. Landraces which are less preferred in terms of agronomic value and end use, and introductions, have become increasingly important. Late maturing landraces were found to be particularly vulnerable, with a number disappearing altogether. Farmers have become more risk averse, and factors such as declining soil fertility, more frequent drought and unreliable rainfall, and increased pest infestation have contributed to a change in farmer landrace selection. Data are presented on the variability and unique characters of some of the Ethiopian landraces, and implications for conservation are discussed.

Lower preoperative quality of life increases postoperative risk of adverse events in women with endometrial cancer: results from the LACE trial

Objective: To examine the association between preoperative quality of life (QoL) and postoperative adverse events in women treated for endometrial cancer. Methods: 760 women with apparent Stage I endometrial cancer were randomised into a clinical trial evaluating laparoscopic versus open surgery. This analysis includes women with preoperative QoL measurements, from the Functional Assessment of Cancer Therapy- General (FACT-G) questionnaire, and who were followed up for at least 6 weeks after surgery (n=684). The outcomes for this study were defined as (1) the occurrence of moderate to severe AEs adverse events within 6 months (Common Toxicology Criteria (CTC) grade ≥3); and (2) any Serious Adverse Event (SAE). The association between preoperative QoL and the occurrence of AE was examined, after controlling for baseline comorbidity and other factors. Results: After adjusting for other factors, odds of occurrence of AE of CTC grade ≥3 were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.00-1.03, p=0.030), which was driven by physical well-being (PWB) (OR=1.09, 95% CI 1.04-1.13, p=0.0002) and functional well-being subscales (FWB) (OR=1.04, 95% CI 1.00-1.07, p=0.035). Similarly, odds of SAE occurrence were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.01-1.04, p=0.011), baseline PWB (OR=1.11, 95% CI 1.06-1.16, p<0.0001) or baseline FWB subscales (OR=1.05, 95% CI 1.01-1.10, p=0.0077). Conclusion: Women with early endometrial cancer presenting with lower QoL prior to surgery are at higher risk of developing a serious adverse event following surgery. Funding: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council, Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women’s Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Domestication for Conservation of an Endangered Species: The Case of the Wollemi Pine

A small population of tall slender conifers was discovered in 1994 in a deep rainforest canyon of the Wollemi National Park, New SouthWales, Australia. The living trees closely resembled fossils that were more than 65 million years old, and this ‘living fossil’ was recognised as a third extant genus in the Araucariaceae (Araucaria, Agathis and now Wollemia). The species was named the Wollemi pine (W. nobilis). Extensive searches uncovered very few populations, with the total number of adult trees being less than 100. Ex situ collections were quickly established in Sydney as part of the Wollemi Pine Recovery Plan. The majority of the ex situ population was later transferred to our custom-built facility in Queensland for commercial multiplication. Domestication has relied very heavily on the species’ amenability to vegetative propagation because seed collection from the natural populations is dangerous, expensive, and undesirable for conservation reasons. Early propagation success was poor, with only about 25% of cuttings producing roots. However, small increases in propagation success have a very large impact on a domestication program because plant production can be modelled on an exponential curve where each rooted cutting develops into a mother plant that, in turn, provides more rooted cuttings. An extensive research program elevated rooting percentages to greater than 80% and also provided in vitro methods for plant multiplication. These successes have enabled international release of the Wollemi pine as a new and attractive species for ornamental horticulture.

Development and feasibility testing of an education program to improve knowledge and self-care among Aboriginal and Torres Strait Islander patients with heart failure

Background/Aim There is a 70% higher age-adjusted incidence of heart failure (HF) amongst Aboriginal and Torres Strait Islander people, three times more hospitalisations and twice as many deaths than non-Aboriginal people. There is a need to develop holistic yet individualised approaches in accord with the values of Aboriginal community healthcare to support patient education and self-care. The aim of this study was to re-design an existing HF educational resource (Fluid Watchers-Pacific Rim©) to be culturally safe for Aboriginal and Torres Strait Islander peoples, working in collaboration with the local community, and to conduct feasibility testing. Methods This study was conducted in two phases and utilised a mixed methods approach (qualitative and quantitative). Phase 1 of this study used action research methods to develop a culturally safe electronic resource to be provided to Aboriginal HF patients via a tablet computer. A HF expert panel adapted the existing resource to ensure it was evidence-based and contained appropriate language and images that reflects Aboriginal culture. A stakeholder group (which included Aboriginal workers and HF patients, as well as researchers and clinicians) then reviewed the resources and changes were made accordingly. In Phase 2, the new resource was tested on a sample of Aboriginal HF patients to assess feasibility and acceptability. Patient knowledge, satisfaction and self-care behaviours were measured using a before and after design with validated questionnaires. As this was a pilot test to determine feasibility, no statistical comparisons were made. Results - Phase 1: Throughout the process of resource development, two main themes emerged from the stakeholder consultation. These were the importance of identity, meaning that it was important to ensure that the resource accurately reflected the local community, with the appropriate clothing, skin tone and voice. The resource was adapted to reflect this and of the local community voiced the recordings for the resource. The other theme was comprehension; images were important and all text was converted to the first person and used plain language. - Phase 2: Five Aboriginal participants, mean age 61.6 ± 10.0 years, with NYHA Class III and IV heart failure were enrolled. Participants reported a high level of satisfaction with the resource (83.0%). HF knowledge (percentage of correct responses) increased from 48.0 ± 6.7% to 58.0 ± 9.7%, a 20.8% increase and results of the self-care index indicated that the biggest change was in patient confidence for self-care with a 95% increase in confidence score (46.7 ± 16.0 to 91.1 ± 11.5). Changes in management and maintenance scores varied between9275 patients. Conclusion By working in collaboration with HF experts, Aboriginal researchers and patients, a culturally safe HF resource has been developed for Aboriginal and Torres Strait Islander patients. Engaging Aboriginal researchers, capacity-building, and being responsive to local systems and structures enabled this pilot study to be successfully completed with the Aboriginal community and positive participant feedback demonstrated that the methodology used in this study was appropriate and acceptable; participants were able to engage with willingness and confidence.

Effect of sorghum ergot (Claviceps africana) on the performance of steers (Bos taurus) in a feedlot.

The effect of ergot (Claviceps africana) in naturally infected sorghum was assessed in feedlot rations. Thirty-two Hereford steers (Bos taurus) in individual pens with access to shade were adapted to feedlot conditions and then offered one of four rations containing 0, 4.4, 8.8 or 17.6 mg/kg of ergot alkaloids (84% dihydroergosine, 10% dihydroelymoclavine and 6% festuclavine), equivalent to ~0, 10, 20 or 40 g/kg ergot (sclerotia/sphacelia) in the rations. These rations were withdrawn at noon on the second day because of severe hyperthermia and almost complete feed refusal in ergot-fed steers. After recovery on ergot-free rations for 5 days, treatment groups were incrementally introduced, over a further 3–12 days, to rations containing 0, 1.1, 2.2 or 4.4 mg/kg of alkaloids (~0, 2.5, 5 or 10 g/kg ergot, respectively). Relative exposure to ergot was maintained, so that the zero- (control), low-, medium- and high-ergot groups remained so. Steers were individually fed ad libitum, and water was freely available. Steers in all ergot-fed groups had significantly elevated rectal temperatures at 0800–1000 hours, even when the temperature–humidity index was only moderate (~70), and displayed other signs of hyperthermia (increased respiration rate, mouth breathing, excessive salivation and urination), as the temperature–humidity index increased to 73–79 during the day. Plasma prolactin was significantly reduced in ergot-fed groups. Voluntary feed intakes (liveweight basis) of the ergot-fed groups were significantly reduced, averaging 94, 86 and 86%, respectively, of the feed intakes of the control group. Hair coats were rough. While the control steers grew from a mean initial liveweight of 275 kg to a suitable slaughter weight of 455 kg in 17 weeks (growth rate 1.45 kg/day), ergot-fed groups gained only 0.77–1.10 kg/day and took at least 5 weeks longer to reach the slaughter weight, despite removal of ergot at the same time as control steers were sent to slaughter. Sorghum ergot, even at low concentrations (1.1 mg alkaloids/kg feed) is severely detrimental to the performance of steers in the feedlot.

Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were: (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10), and; (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.

No evidence for genetic association with the let-7 microRNA-binding site or other common KRAS variants in risk of endometriosis

STUDY QUESTION Is there a contribution of the minor allele at the KRAS single nucleotide polymorphism (SNP) rs61764370 in the let-7 microRNA-binding site to endometriosis risk? SUMMARY ANSWER We found no evidence for association between endometriosis risk and rs61764370 or any other SNPs in KRAS. WHAT IS KNOWN ALREADY The rs61764370 SNP in the 3' untranslated region of the KRAS gene is predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA, and was recently reported to be at a high frequency (31%) in 132 women of varying ancestry with endometriosis compared with frequencies in a database of population controls (up to 7.6% depending on ancestry), suggesting a strong effect of this KRAS SNP in the aetiology of endometriosis. STUDY DESIGN, SIZE AND DURATION This was a case-control study with a total of 11 206 subjects. The study was performed between February 2012 and July 2012. PARTICIPANTS/MATERIALS, SETTINGAND METHODS We first investigated a possible association between common markers in KRAS and endometriosis risk from our genome-wide association (GWA) data in 3194 surgically confirmed endometriosis cases and 7060 controls of European ancestry. Although rs61764370 was not genotyped on the GWA arrays, five SNPs typed in the study were highly correlated with this variant. The rs61764370 and two SNPs highly correlated with rs61764370 were then genotyped in 933 endometriosis cases and 952 controls using the Sequenom MassARRAY platform. MAIN RESULTS AND THE ROLE OF CHANCE There was no evidence for an association between rs61764370 and endometriosis risk P = 0.411 and odds ratio = 1.10 (95% confidence intervals: 0.88-1.36). We also found no evidence for an association between the highly correlated SNP rs17387019 and endometriosis. Their minor allele frequencies in cases and controls were of 0.087-0.091 similar to the population frequency reported previously for this variant in controls. Analyses of endometriosis cases with revised American Fertility Society stage III/IV disease also showed no evidence for an association between these SNPs and endometriosis risk. LIMITATIONS AND REASONS FOR CAUTION The GWA and genotyped data sets were not independent since individuals and cases from some families overlap. Controls in our GWA study were not screened for endometriosis. WIDER IMPLICATIONS OF THE FINDINGS The key SNP, rs61764370, was genotyped in a subset of samples. Our results do not support the suggestion that carrying the minor allele at rs61764370 contributes to a significant number of endometriosis cases and rs61764370 is, therefore, unlikely to be a useful marker of endometriosis risk. STUDY FUNDING/COMPETING INTEREST(S) The research was funded by grants from the Australian National Health and Medical Research Council and Wellcome Trust. None of the authors has competing interests for the study.

Microstructural evolution and grain boundary sliding in a superplastic magnesium AZ31 alloy

Tensile experiments on a fine-grained single-phase Mg–Zn–Al alloy (AZ31) at 673 K revealed superplastic behavior with an elongation to failure of 475% at 1 × 10−4 s−1 and non-superplastic behavior with an elongation to failure of 160% at 1 × 10−2 s−1; the corresponding strain rate sensitivities under these conditions were 0.5 and 0.2, respectively. Measurements indicated that the grain boundary sliding (GBS) contribution to strain ξ was 30% under non-superplastic conditions; there was also a significant sharpening in texture during such deformation. Under superplastic conditions, ξ was 50% at both low and high elongations of 20% and 120%; the initial texture became more random under such conditions. In non-superplastic conditions, deformation occurred under steady-state conditions without grain growth before significant flow localization whereas, under superplastic conditions, there was grain growth during the early stages of deformation, leading to strain hardening. The grains retained equiaxed shapes under all experimental conditions. Superplastic deformation is attributed to GBS, while non-superplastic deformation is attributed to intragranular dislocation creep with some contribution from GBS. The retention of equiaxed grain shapes during dislocation creep is consistent with a model based on local recovery related to the disturbance of triple junctions.

Regenerative sustainability for the built environment – from vision to reality: An introductory chapter

Regenerative sustainability is emerging as an alternative discourse around the transition from a ‘mechanistic’ to an ‘ecological’ or living systems worldview. This view helps us to re-conceptualize relationships among humans’ technological, ecological, economic, social and political systems. Through exploration of ‘net positive’ or ‘regenerative’ development lenses and the traditional sustainability literature, the conceptualization and approaches to achieve sustainable development and ecological modernization are expanded to articulate and to explore the evolving sustainability discourse, ‘regenerative sustainability’. This Special Volume of Journal of Cleaner Production (SV) is focused upon various dimensions of regenerative sustainability (e.g. regenerative design, regenerative development, and positive development) applied to the urban built environment at scales, which range from individual buildings, neighborhoods, and urban developments to integrated regional sustainable development. The main focus is on how these approaches and developments are evolving, how they can help us to prevent or adapt to climate change and how these approaches are likely to evolve in the next two to three decades. These approaches are addressed in four themes: (1) reviewing the theoretical development of the discourse of regenerative sustainability, its emerging principles and practices, (2) explaining how it can be measured and monitored, (3) providing encouraging practical pathways and examples of its implementation in multiple cultural and climatic contexts, and (4) mapping obstacles and enablers that must be addressed to help to ensure that more rapid progress is made in implementing the transitions towards an urban built environment that supports genuinely sustainable societies.

The Influence of Bilayer Composition on the Gel to Liquid Crystalline Transition

We report molecular dynamics simulations of bilayers using a united atom model with explicit solvent molecules. The bilayer consists of the single tail cationic surfactant behenyl trimethyl ammonium chloride (BTMAC) with stearyl alcohol (SA) as the cosurfactant. We study the gel to liquid crystalline transitions in the bilayer by varying the amount of water at fixed BTMAC to SA ratio as well as by varying the BTMAC to SA ratio at fixed water content. The bilayer is found to exist in the tilted, Lβ′ phase at low temperatures, and for the compositions investigated in this study, the Lβ′ to Lα melting transition occurred in the temperature range 330−338 K. For the highest BTMAC to SA composition (2:3 molar ratio), a diffuse headgroup−water interface is observed at lower temperatures, and an increase in the d-spacing occurs prior to the melting transition. This pretransition swelling is accompanied by a sharpening in the water density variation across the headgroup region of the bilayer. Signatures of this swelling effect which can be observed in the alkane density distributions, area per headgroup, and membrane thickness are attributed to the hydrophobic effect. At a fixed bilayer composition, the transition temperature (>338 K) from the Lβ′ to Lα transition obtained for the high water content bilayer (80 wt %) is similar to that obtained with low water content (54.3 wt %), confirming that the melting transition at these water contents is dominated by chain melting.