Binding to DNA Protects Neisseria meningitidis Fumarate and Nitrate Reductase Regulator (FNR) from Oxygen

Here, we report the overexpression, purification, and characterization of the transcriptional activator fumarate and nitrate reductase regulator from the pathogenic bacterium Neisseria meningitidis (NmFNR). Like its homologue from Escherichia coli (EcFNR), NmFNR binds a 4Fe-4S cluster, which breaks down in the presence of oxygen to a 2Fe-2S cluster and subsequently to apo-FNR. The kinetics of NmFNR cluster disassembly in the presence of oxygen are 2–3× slower than those previously reported for wild-type EcFNR, but similar to constitutively active EcFNR* mutants, consistent with earlier work in which we reported that the activity of FNR-dependent promoters in N. meningitidis is only weakly inhibited by the presence of oxygen (Rock, J. D., Thomson, M. J., Read, R. C., and Moir, J. W. (2007) J. Bacteriol. 189, 1138–1144). NmFNR binds to DNA containing a consensus FNR box sequence, and this binding stabilizes the iron-sulfur cluster in the presence of oxygen. Partial degradation of the 4Fe-4S cluster to a 3Fe-4S occurs, and this form remains bound to the DNA. The 3Fe-4S cluster is converted spontaneously back to a 4Fe-4S cluster under subsequent anaerobic reducing conditions in the presence of ferrous iron. The finding that binding to DNA stabilizes FNR in the presence of oxygen such that it has a half-life of ∼30 min on the DNA has implications for our appreciation of how oxygen switches off FNR activatable genes in vivo.

Brain targeted PLGA nanocarriers alleviating amyloid-Β expression and preserving basal survivin in degenerating mice model

The chronic systemic administration of d-Galactose in C57BL/6J mice showed a relatively high oxidative stress, amyloid-β expression and neuronal cell death. Enhanced expression of pyknotic nuclei, caspase-3 and reduced expression of neuronal integrity markers further confirmed the aforesaid insults. However, concomitant treatment with the recombinant protein (SurR9-C84A) and the anti-transferrin receptor antibody conjugated SurR9-C84A (SurR9+TFN) nanocarriers showed a significant improvement in the disease status and neuronal health. The beauty of this study is that the biodegradable Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA) nanocarriers enhanced the biological half-life and the efficacy of the treatments. The nanocarriers were effective in lowering the amyloid-β expression, enhancing the neuronal integrity markers and maintaining the basal levels of endogenous survivin that is essential for evading the caspase activation and apoptosis. The current study herein reports for the first time that the brain targeted SurR9-C84A nanocarriers alleviated the d-Galactose induced neuronal insults and has potential for future brain targeted nanomedicine application.

Testing for convergence in carbon dioxide emissions using a century of panel data

This paper tests the convergence in per-capita carbon dioxide emissions for a collection of developed and developing countries using data spanning the period 1870-2002. For this purpose, three recently developed panel unit root tests that permit for dependence among the individual countries are employed. The results lend strong support in favor of convergence for the panel as a whole. Estimates of the speed of this convergence is also provided. © 2007 Springer Science+Business Media B.V.

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

Food security: one of a number of ‘securities’ we need for a full life: an Australian perspective

Although agriculture in Australia is very productive, the current food supply systems in Australia fail to deliver healthy diets to all Australians and fail to protect the natural resources on which they depend. The operation of the food systems creates ‘collateral damage’ to the natural environment including biodiversity loss. In coming decades, Australia’s food supply systems will be increasingly challenged by resource price inflation and climate change. Australia exports more than half of its current agricultural production. Government and business are aiming to substantially increase production to bolster exports. This will increase pressure on agricultural resources and exacerbate ‘collateral’ damage to the environment. The Australian public have a deep and ongoing interest in a very wide range of issues associated with the food systems including the environment, health and sustainability. Food is something we require in order to live and a good diet is something we have to have to be healthy. For health over a life-time we need food security. However, we also require a range of other material goods and social arrangements in order to develop and flourish as human beings. And we need these other things to be secure over a life-time. Food is therefore one security among a range of other securities we need in order to flourish. The paper outlines a number of approaches, as examples, that help to identify what these other goods and arrangements might be. The approaches mentioned in this paper include human rights, national securities, human needs, authentic happiness, capabilities, sustainability and environmental ethics. The different approaches provide a way of evaluating the current situation and indicating a direction for change within the food systems that will address the problems. However, changing large systems such as those involved in food supply is difficult because inertias and vested interests make the current food supply systems resilient to change. The paper suggests that one of the first and ongoing tasks is to develop an understanding of the situation from a comprehensive social–ecological systems perspective. The paper also suggests that a practical leverage point for system change is restructuring the flow of information on the health, natural resources and biodiversity loss issues related to the food supply systems.

Invasive carnivores alter ecological function and enhance complementarity in scavenger assemblages on ocean beaches

Species composition is expected to alter ecological function in assemblages if species traits differ strongly. Such effects are often large and persistent for nonnative carnivores invading islands. Alternatively, high similarity in traits within assemblages creates a degree of functional redundancy in ecosystems. Here we tested whether species turnover results in functional ecological equivalence or complementarity, and whether invasive carnivores on islands significantly alter such ecological function. The model system consisted of vertebrate scavengers (dominated by raptors) foraging on animal carcasses on ocean beaches on two Australian islands, one with and one without invasive red foxes (Vulpes vulpes). Partitioning of scavenging events among species, carcass removal rates, and detection speeds were quantified using camera traps baited with fish carcasses at the dune–beach interface. Complete segregation of temporal foraging niches between mammals (nocturnal) and birds (diurnal) reflects complementarity in carrion utilization. Conversely, functional redundancy exists within the bird guild where several species of raptors dominate carrion removal in a broadly similar way. As predicted, effects of red foxes were large. They substantially changed the nature and rate of the scavenging process in the system: (1) foxes consumed over half (55%) of all carrion available at night, compared with negligible mammalian foraging at night on the fox-free island, and (2) significant shifts in the composition of the scavenger assemblages consuming beach-cast carrion are the consequence of fox invasion at one island. Arguably, in the absence of other mammalian apex predators, the addition of red foxes creates a new dimension of functional complementarity in beach food webs. However, this functional complementarity added by foxes is neither benign nor neutral, as marine carrion subsidies to coastal red fox populations are likely to facilitate their persistence as exotic carnivores.

Omega 6 to omega 3 fatty acid imbalance early in life leads to persistant reductions in DHA levels in glycerophospholipids in rat hypothalamus even after long-term omega 3 fatty acid repletion

Failure to provide omega 3 fatty acids in the perinatal period results in alterations in nerve growth factor levels, dopamine production and  permanent elevations in blood pressure. The present study investigated whether changes in brain (i.e., hypothalamus) glycerophospholipid fatty acid profiles induced by a diet rich in omega 6 fatty acids and very low in alpha-linolenic acid (ALA) during pregnancy and the perinatal period could be reversed by subsequent feeding of a diet containing ALA. Female rats (6 per group) were mated and fed either a low ALA diet or a control diet containing ALA throughout pregnancy and until weaning of the pups at 3 weeks. At weaning, the pups (20 per group) remained on the diet of their mothers until 9 weeks, when half the pups were switched onto the other diet, thus generating four groups of animals. At 33 weeks, pups were killed, the hypothalamus dissected from the male rats and analysed for glycerophospholipid fatty acids. In the animals fed the diet with very little ALA and then re-fed the control diet containing high levels of ALA for 24 weeks, the DHA levels were still significantly less than the control values in PE, PS and PI fractions, by 9%, 18% and 34%, respectively. In this group, but not in the other dietary groups, ALA was detected in all glycerophospholipid classes at 0.2–1.7% of the total fatty acids. The results suggest that omega 6–3 PUFA imbalance early in life leads to irreversible changes in hypothalamic composition. The increased ALA and reduced DHA proportions in the animals re-fed ALA in later life are consistent with a dysfunction or down-regulation of the conversion of ALA to 18:4n-3 by the delta-6 desaturase.

Increased blood pressure later in life may be associated with perinatal n-3 fatty acid deficiency

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Previous work in both animals and humans with high blood pressure has demonstrated the antihypertensive effects of n−3 polyunsaturated fatty acids (PUFA), although it is not known whether these nutrients are effective in preventing hypertension. The predominant n−3 PUFA in the mammalian nervous system, docosahexaenoic acid (DHA), is deposited into synaptic membranes at a high rate during the perinatal period, and recent observations indicate that the perinatal environment is important for the normal development of blood pressure control. This study investigated the importance of perinatal n−3 PUFA supply in the control of blood pressure in adult Sprague-Dawley rats. Pregnant rat dams were fed semisynthetic diets that were either deficient in (DEF) or supplemented with (CON) n−3 PUFA. Offspring were fed the same diets as their mothers until 9 wk; then, half of the rats from each group were crossed over to the opposite diet, creating four groups, i.e., CON-CON; CON-DEF; DEF-DEF, DEF-CON. Mean arterial blood pressures (MAP) were measured directly, at 33 wk of age, by cannulation of the femoral artery. The phospholipid fatty acid profile of the hypothalamic region was determined by capillary gas-liquid chromatography. The tissue phospholipid fatty acid profile reflected the diet that the rats were consuming at the time of testing. Both groups receiving DEF after 9 wk of age (i.e., DEF-DEF and CON-DEF) had similar profiles with a reduction in DHA levels of 30%, compared with rats receiving CON (i.e., CON-CON and DEF-CON). DEF-DEF rats had significantly raised MAP compared with all other groups, with differences as great as 17 mm Hg. DEF-CON rats had raised MAP compared with CON-CON rats, and DEF-DEF rats had higher MAP than CON-DEF rats, despite the fact that their respective fatty acid profiles were not different. These findings indicate that inadequate levels of DHA in the perinatal period are associated with altered blood pressure control in later life. The way in which these long-term effects are produced remains to be elucidated.

"So that's when I thought to myself : 'my life is just horrible'" : everyday judgements of life satisfaction

Objectives : The study was designed to investigate life satisfaction (l.s.) judgments as they occur spontaneously in everyday life, rather than being constructed in response to a researcher's question.
Methods : A convenience sample of 50 adults from Melbourne, Australia, was employed.
Half had at least some university education; the other half did not. In an in-depth, structured interview, participants were asked to recall – if they could do so – an occasion when they had spontaneously made a judgment about their l.s. The circumstances in which the judgment had been made and the thoughts that had entered into it were elicited.
Results : Main findings included :
(a) All participants were able to recall an occasion when they had spontaneously made a l.s.
judgment.
(b) Judgments that life was good and that life was bad were equally common.
(c) Judgments invariably involved comparisons with various standards (e.g., what one had versus
what one wanted, what one had versus what one deserved, what one had versus what one
expected to have).
(d) However, upward and downward social comparisons were relatively rare.
(e) Judgments were commonly based on events relating to just one or two areas of life, rather
than a review of many different areas.
(f) The areas of life involved were invariably those impacting very directly on participants.
(g) While the thoughts entering into the judgment generally went beyond consideration just of a
specific situation, they usually did not encompass large sweeps of time.
(h) There was very little to distinguish judgments of more- and less-educated participants.
Conclusions : Findings are compared and contrasted with those typically obtained using the more standard approach of asking participants to rate their 1.s.

Knowledge of late-life depression : an empirical investigation of aged care staff

Objectives: This study examined knowledge of late-life depression among staff working in residential and community aged care settings, as well as their previous training in caring for older people with depression.

Method: A sample of 320 aged care staff (mean age = 42 years) completed a survey questionnaire. Participants included direct care staff, registered nurses and Care Managers from nursing and residential homes and community aged care services.

Results: Less than half of the participating aged care staff had received any training in depression, with particularly low rates in residential care. Although aware of the importance of engaging with depressed care recipients and demonstrating moderate knowledge of the symptoms of depression, a substantial proportion of staff members saw depression as a natural consequence of bereavement, aging or relocation to aged care.

Conclusion: Experience in aged care appears to be insufficient for staff to develop high levels of knowledge of depression. Specific training in depression is recommended for staff working in aged care settings in order to improve the detection and management of late-life depression, particularly among direct carers, who demonstrated least knowledge of this common disorder.

Why do young women drop out of sport and physical activity? A social ecological approach

This study explored significant individual, social, and environmental factors and how they interact to influence participation in physical activity for adolescent young women. These factors were explored at two transitional life stages: from primary to secondary school and from middle to upper years at secondary school. Ten focus groups with young women and 10 interviews with teachers were conducted and multiple, interrelated themes emerged. Our findings indicated that there are a number of strategies that could be undertaken to increase the participation of young women in physical activity. These include: (1) enhancing intrinsic motivation for sport and physical activity; (2) appealing to young women’s need for socialising through opportunities for informal physical activity; (3) educating parents about the benefits of sport and physical activity; (4) overcoming gender stereotypes about what is acceptable behaviour for young women; (5) improving physical education teachers’ understanding of gender issues and motivating less physically active students; (6) the provision of accessible sport and physical activity facilities, programs, and services in schools; and (7) prioritorisation of sport and physical activity in the school curriculum. These strategies are not ‘quick fixes’, but rather require a whole-ofcommunity approach and, in some cases, a reorientation of societal values.

Decision making to support an integrated infrastructure supply chain industrial ecological approach within public private partnerships

Supply chains are complex adaptive systems for which final performance depends upon numerous interdependent decisions made by numerous firms which synthesise inputs from various resources systems.  The dynamic interdependent behaviour of social, economic, material and informational resource systems within eco-industrial settings that support the built environment life cycle supply chains can be studied at the supply chain level.  The impact of megaprojects is significant and holds promise to explore the impact of decisions on various systems as it combines project and system boundaries.  Megaoprojects considered as major events within systems can produce critical revolutionary impacts on the systems within which they are embedded.  The decisions that are made on megaprojects are central to risk management.  typically major infrastructure projects are procured through a form of public private partnership (PPP).  The core principle of PPP is value for money which refers to the best available outcome attempting to take account of all benefits, costs and risks over the whole life of the procurement.  In this paper the focus is on Australia where there has been considerable acitivity in the use of PPPs.  With recent national infrastucture packages proposed to stimulate the economy due to the global financial crisis, decision modelling on risks is a revelant and critical matter not only in practice but also in the research community.  PPPs encourage the whole-of-lifecycle approach in the procurement and management of public sector assets by transparently recognising the costs and risks associated with the whole life of the required service or facility, thus integrated whole of life supply chains can be considered.  By creating a single point of responsibility for an entire project from inception through operation, a strong incentive is created for thinking about the effects that a design or construction decision will have on the effectiveness and efficiency of managing and maintaining a facility during its operational life.  The decision to procure holistic supply chains becomes a much more viable commercial reality in the PPP environment than previously considered in the usual commercial construction spot transactional approach.  These types of decisions tend to be imprecise, approximate and complex requireing justification and reasoning logic rather than the classical 'truth' logic.  The purpose of this paper is to develop a theoretical decision framework which combines interdependency and multi-values logic for supply chain procurement modelling.