Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production

BACKGROUND Tubulointerstitial lesions, characterized by tubular injury, interstitial fibrosis and the appearance of myofibroblasts, are the strongest predictors of the degree and progression of chronic renal failure. These lesions are typically preceded by macrophage infiltration of the tubulointerstitium, raising the possibility that these inflammatory cells promote progressive renal disease through fibrogenic actions on resident tubulointerstitial cells. The aim of the present study, therefore, was to investigate the potentially fibrogenic mechanisms of interleukin-1beta (IL-1beta), a macrophage-derived pro-inflammatory cytokine, on human proximal tubule cells (PTC). METHODS Confluent, quiescent, passage 2 PTC were established in primary culture from histologically normal segments of human renal cortex (N = 11) and then incubated in serum- and hormone-free media supplemented with either IL-1beta (0 to 4 ng/mL) or vehicle (control). RESULTS IL-1beta significantly enhanced fibronectin secretion by up to fourfold in a time- and concentration-dependent fashion. This was accompanied by significant (2.5- to 6-fold) increases in alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor beta (TGF-beta1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1beta. NG-methyl-l-arginine (L-NMMA; 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1beta-stimulated fibronectin secretion. In contrast, a pan-specific TGF-beta neutralizing antibody significantly blocked the effects of IL-1beta on PTC fibronectin secretion (IL-1beta, 268.1 +/- 30.6 vs. IL-1beta+alphaTGF-beta 157.9 +/- 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1beta 81.0 +/- 6.7% vs. IL-1beta+alphaTGF-beta 93.4 +/- 2.1%, of control values, P < 0.01). CONCLUSION IL-1beta acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote alpha-smooth muscle actin expression. These actions appear to be mediated by a TGF-beta1 dependent mechanism and are independent of nitric oxide release.

Assessing the immediate and short-term impact of flooding on residential property participant behaviour

The past decade has seen an increase in the number of significant natural disasters that have caused considerable loss of life as well as damage to all property markets in the affected areas. In many cases, these natural disasters have not only caused significant property damage, but in numerous cases, have resulted in the total destruction of the property in the location. With these disasters attracting considerable media attention, the public are more aware of where these affected property markets are, as well as the overall damage to properties that have been damaged or destroyed. This heightened level of awareness has to have an impact on the participants in the property market, whether a developer, vendor seller or investor. To assess this issue, a residential property market that has been affected by a significant natural disaster over the past 2 years has been analysed to determine the overall impact of the disaster on buyer, renter and vendor behaviour, as well as prices in these residential markets. This paper is based on data from the Brisbane flood in January 2011. This natural disaster resulted in loss of life and partial and total devastation of considerable residential property sectors. Data for the research have been based on the residential sales and rental listings for each week of the study period to determine the level of activity in the specific property sectors, and these are also compared to the median house prices for the various suburbs for the same period based on suburbs being either flood affected or flood free. As there are 48 suburbs included in the study, it has been possible to group these suburbs on a socio-economic basis to determine possible differences due to location and value. Data were accessed from realestate.com.au, a free real estate site that provides details of current rental and sales listings on a suburb basis, RP Data a commercial property sales database and the Australian Bureau of Statistics. The paper found that sales listings fell immediately after the flood in the affected areas, but there was no corresponding fall or increase in sales listings in the flood-free suburbs. There was a significant decrease in the number of rental listings follow the flood as affected parties sought alternate accommodation. The greatest fall in rental listings was in areas close to the flood-affected suburbs indicating the desire to be close to the flooded property during the repair period.

Atmospheric gas plasma–induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis

Atmospheric gas plasmas (AGPs) are able to selectively induce apoptosis in cancer cells, offering a promising alternative to conventional therapies that have unwanted side effects such as drug resistance and toxicity. However, the mechanism of AGP-induced cancer cell death is unknown. In this study, AGP is shown to up-regulate intracellular reactive oxygen species (ROS) levels and induce apoptosis in melanoma but not normal melanocyte cells. By screening genes involved in apoptosis, we identify tumor necrosis factor (TNF)-family members as the most differentially expressed cellular genes upon AGP treatment of melanoma cells. TNF receptor 1 (TNFR1) antagonist-neutralizing antibody specifically inhibits AGP-induced apoptosis signal, regulating apoptosis signal-regulating kinase 1 (ASK1) activity and subsequent ASK1-dependent apoptosis. Treatment of cells with intracellular ROS scavenger N-acetyl-l-cysteine also inhibits AGP-induced activation of ASK1, as well as apoptosis. Moreover, depletion of intracellular ASK1 reduces the level of AGP-induced oxidative stress and apoptosis. The evidence for TNF-signaling dependence of ASK1-mediated apoptosis suggests possible mechanisms for AGP activation and regulation of apoptosis-signaling pathways in tumor cells.

Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.

Circulating fragments of N-Terminal Pro-B-Type Natriuretic Peptides in plasma of heart failure patients

BACKGROUND: The use of nonstandardized N-terminal pro-B-type natriuretic peptide (NT-proBNP) assays can contribute to the misdiagnosis of heart failure (HF). Moreover, there is yet to be established a common consensus regarding the circulating forms of NT-proBNP being used in current assays. We aimed to characterize and quantify the various forms of NT-proBNP in the circulation of HF patients. METHODS: Plasma samples were collected from HF patients (n = 20) at rest and stored at -80 degrees C. NT-proBNP was enriched from HF patient plasma by use of immunoprecipitation followed by mass spectrometric analysis. Customized homogeneous sandwich AlphaLISA (R) immunoassays were developed and validated to quantify 6 fragments of NT-proBNP. RESULTS: Mass spectrometry identified the presence of several N- and C-terminally processed forms of circulating NT-proBNP, with physiological proteolysis between Pro2-Leu3, Leu3-Gly4, Pro6-Gly7, and Pro75-Arg76. Consistent with this result, AlphaLISA immunoassays demonstrated that antibodies targeting the extreme N or C termini measured a low apparent concentration of circulating NT-proBNP. The apparent circulating NT-proBNP concentration was increased with antibodies targeting nonglycosylated and nonterminal epitopes (P < 0.05). CONCLUSIONS: In plasma collected from HF patients, immunoreactive NT-proBNP was present as multiple N- and C-terminally truncated fragments of the full length NT-proBNP molecule. Immunodetection of NT-proBNP was significantly improved with the use of antibodies that did not target these terminal regions. These findings support the development of a next generation NT-proBNP assay targeting nonterminal epitopes as well as avoiding the central glycosylated region of this molecule. (c) 2013 American Association for Clinical Chemistry

Barbadocladius Cranston & Krosch, a new genus of Orthocladiinae (Diptera : Chironomidae) from South America.

Barbadocladius n. gen. is erected and described in larval, pupal and adult stages for two species: B. andinus sp. nov. and B. limay sp. nov., from Andean streams. The larva is distinctive by virtue of the very large ventromental 'beard' and the anterior parapods with a 'sleeve' of hooklets in addition to apical pectinate claws. The pupa has hooklets on some tergal and sternal intersegmental membranes. The adult, reported only in teneral specimens has hairy eyes, no antennal apical strong seta, no acrostichals, bare and unmarked wings, cylindrical 4th tarsomere subequal in length to the 5th, pulvilli about half the claw length, and hypopygium with anal point, lacking a virga. Molecular phylogenetic analysis eliminates relationships directly to the Eukiefferiella complex (which also have pupal hooklets), or to the Cricotopus group (adults also with hairy eyes), suggesting instead a sister group relationship to a suite of predominantly austral genera of Orthocladiinae.

Accounting for management costs in sensitivity analyses of matrix population models

Traditional sensitivity and elasticity analyses of matrix population models have been used to inform management decisions, but they ignore the economic costs of manipulating vital rates. For example, the growth rate of a population is often most sensitive to changes in adult survival rate, but this does not mean that increasing that rate is the best option for managing the population because it may be much more expensive than other options. To explore how managers should optimize their manipulation of vital rates, we incorporated the cost of changing those rates into matrix population models. We derived analytic expressions for locations in parameter space where managers should shift between management of fecundity and survival, for the balance between fecundity and survival management at those boundaries, and for the allocation of management resources to sustain that optimal balance. For simple matrices, the optimal budget allocation can often be expressed as simple functions of vital rates and the relative costs of changing them. We applied our method to management of the Helmeted Honeyeater (Lichenostomus melanops cassidix; an endangered Australian bird) and the koala (Phascolarctos cinereus) as examples. Our method showed that cost-efficient management of the Helmeted Honeyeater should focus on increasing fecundity via nest protection, whereas optimal koala management should focus on manipulating both fecundity and survival simultaneously. These findings are contrary to the cost-negligent recommendations of elasticity analysis, which would suggest focusing on managing survival in both cases. A further investigation of Helmeted Honeyeater management options, based on an individual-based model incorporating density dependence, spatial structure, and environmental stochasticity, confirmed that fecundity management was the most cost-effective strategy. Our results demonstrate that decisions that ignore economic factors will reduce management efficiency. ©2006 Society for Conservation Biology.

Cost-effective suppression and eradication of invasive predators

Introduced predators can have pronounced effects on naïve prey species; thus, predator control is often essential for conservation of threatened native species. Complete eradication of the predator, although desirable, may be elusive in budget-limited situations, whereas predator suppression is more feasible and may still achieve conservation goals. We used a stochastic predator-prey model based on a Lotka-Volterra system to investigate the cost-effectiveness of predator control to achieve prey conservation. We compared five control strategies: immediate eradication, removal of a constant number of predators (fixed-number control), removal of a constant proportion of predators (fixed-rate control), removal of predators that exceed a predetermined threshold (upper-trigger harvest), and removal of predators whenever their population falls below a lower predetermined threshold (lower-trigger harvest). We looked at the performance of these strategies when managers could always remove the full number of predators targeted by each strategy, subject to budget availability. Under this assumption immediate eradication reduced the threat to the prey population the most. We then examined the effect of reduced management success in meeting removal targets, assuming removal is more difficult at low predator densities. In this case there was a pronounced reduction in performance of the immediate eradication, fixed-number, and lower-trigger strategies. Although immediate eradication still yielded the highest expected minimum prey population size, upper-trigger harvest yielded the lowest probability of prey extinction and the greatest return on investment (as measured by improvement in expected minimum population size per amount spent). Upper-trigger harvest was relatively successful because it operated when predator density was highest, which is when predator removal targets can be more easily met and the effect of predators on the prey is most damaging. This suggests that controlling predators only when they are most abundant is the "best" strategy when financial resources are limited and eradication is unlikely. © 2008 Society for Conservation Biology.

Making robust decisions for conservation with restricted money and knowledge

1. In conservation decision-making, we operate within the confines of limited funding. Furthermore, we often assume particular relationships between management impact and our investment in management. The structure of these relationships, however, is rarely known with certainty - there is model uncertainty. We investigate how these two fundamentally limiting factors in conservation management, money and knowledge, impact optimal decision-making. 2. We use information-gap decision theory to find strategies for maximizing the number of extant subpopulations of a threatened species that are most immune to failure due to model uncertainty. We thus find a robust framework for exploring optimal decision-making. 3. The performance of every strategy decreases as model uncertainty increases. 4. The strategy most robust to model uncertainty depends not only on what performance is perceived to be acceptable but also on available funding and the time horizon over which extinction is considered. 5. Synthesis and applications. We investigate the impact of model uncertainty on robust decision-making in conservation and how this is affected by available conservation funding. We show that subpopulation triage can be a natural consequence of robust decision-making. We highlight the need for managers to consider triage not as merely giving up, but as a tool for ensuring species persistence in light of the urgency of most conservation requirements, uncertainty and the poor state of conservation funding. We illustrate this theory by a specific application to allocation of funding to reduce poaching impact on the Sumatran tiger Panthera tigris sumatrae in Kerinci Seblat National Park. © 2008 The Authors.

Subpopulation triage: How to allocate conservation effort among populations

Threatened species often exist in a small number of isolated subpopulations. Given limitations on conservation spending, managers must choose from strategies that range from managing just one subpopulation and risking all other subpopulations to managing all subpopulations equally and poorly, thereby risking the loss of all subpopulations. We took an economic approach to this problem in an effort to discover a simple rule of thumb for optimally allocating conservation effort among subpopulations. This rule was derived by maximizing the expected number of extant subpopulations remaining given n subpopulations are actually managed. We also derived a spatiotemporally optimized strategy through stochastic dynamic programming. The rule of thumb suggested that more subpopulations should be managed if the budget increases or if the cost of reducing local extinction probabilities decreases. The rule performed well against the exact optimal strategy that was the result of the stochastic dynamic program and much better than other simple strategies (e.g., always manage one extant subpopulation or half of the remaining subpopulation). We applied our approach to the allocation of funds in 2 contrasting case studies: reduction of poaching of Sumatran tigers (Panthera tigris sumatrae) and habitat acquisition for San Joaquin kit foxes (Vulpes macrotis mutica). For our estimated annual budget for Sumatran tiger management, the mean time to extinction was about 32 years. For our estimated annual management budget for kit foxes in the San Joaquin Valley, the mean time to extinction was approximately 24 years. Our framework allows managers to deal with the important question of how to allocate scarce conservation resources among subpopulations of any threatened species. © 2008 Society for Conservation Biology.

Using conservation evidence to guide management

Almost 10 years ago, Pullin and Knight (2001) called for an “effectiveness revolution in conservation” to be enabled by the systematic evaluation of evidence for conservation decision making. Drawing from the model used in clinicalmedicine, they outlined the concept of “evidencebased conservation” in which existing information, or evidence, from relevant and rigorous research is compiled and analyzed in a systematic manner to inform conservation actions (Cochrane 1972). The promise of evidencebased conservation has generated significant interest; 25 systematic reviews have been completed since 2004 and dozens are underway (Collaboration for Environmental Evidence 2010). However we argue that an “effectiveness revolution” (Pullin & Knight 2001) in conservation will not be possible unless mechanisms are devised for incorporating the growing evidence base into decision frameworks. For conservation professionals to accomplish the missions of their organizations they must demonstrate that their actions actually achieve objectives (Pullin & Knight 2009). Systematic evaluation provides a framework for objectively evaluating the effectiveness of actions. To leverage the benefit of these evaluations, we need resource-allocation systems that are responsive to their outcomes. The allocation of conservation resources is often the product of institutional priorities or reliance on intuition (Sutherland et al. 2004; Pullin & Knight 2005; Cook et al. 2010). We highlight the NICE technologyappraisal process because it provides an example of formal integration of systematic-evidence evaluation with provision of guidance for action. The transparent process, which clearly delineates costs and benefits of each alternative action, could also provide the public with new insight into the environmental effects of different decisions. This insight could stimulate a wider discussion about investment in conservation by demonstrating how changes in funding might affect the probability of achieving conservation objectives. ©2010 Society for Conservation Biology

The Why, What, and How of Global Biodiversity Indicators Beyond the 2010 Target

The 2010 biodiversity target agreed by signatories to the Convention on Biological Diversity directed the attention of conservation professionals toward the development of indicators with which to measure changes in biological diversity at the global scale. We considered why global biodiversity indicators are needed, what characteristics successful global indicators have, and how existing indicators perform. Because monitoring could absorb a large proportion of funds available for conservation, we believe indicators should be linked explicitly to monitoring objectives and decisions about which monitoring schemes deserve funding should be informed by predictions of the value of such schemes to decision making. We suggest that raising awareness among the public and policy makers, auditing management actions, and informing policy choices are the most important global monitoring objectives. Using four well-developed indicators of biological diversity (extent of forests, coverage of protected areas, Living Planet Index, Red List Index) as examples, we analyzed the characteristics needed for indicators to meet these objectives. We recommend that conservation professionals improve on existing indicators by eliminating spatial biases in data availability, fill gaps in information about ecosystems other than forests, and improve understanding of the way indicators respond to policy changes. Monitoring is not an end in itself, and we believe it is vital that the ultimate objectives of global monitoring of biological diversity inform development of new indicators. ©2010 Society for Conservation Biology.

Heritability of working memory brain activation

Although key to understanding individual variation in task-related brain activation, the genetic contribution to these individual differences remains largely unknown. Here we report voxel-by-voxel genetic model fitting in a large sample of 319 healthy, young adult, human identical and fraternal twins (mean ± SD age, 23.6 ±1.8 years) who performed an n-back working memory task during functional magnetic resonance imaging (fMRI) at a high magnetic field (4 tesla). Patterns of task-related brain response (BOLD signal difference of 2-back minus 0-back) were significantly heritable, with the highest estimates (40 - 65%) in the inferior, middle, and superior frontal gyri, left supplementary motor area, precentral and postcentral gyri, middle cingulate cortex, superior medial gyrus, angular gyrus, superior parietal lobule, including precuneus, and superior occipital gyri. Furthermore, high test-retest reliability for a subsample of 40 twins indicates that nongenetic variance in the fMRI brain response is largely due to unique environmental influences rather than measurement error. Individual variations in activation of the working memory network are therefore significantly influenced by genetic factors. By establishing the heritability of cognitive brain function in a large sample that affords good statistical power, and using voxel-by-voxel analyses, this study provides the necessary evidence for task-related brain activation to be considered as an endophenotype for psychiatric or neurological disorders, and represents a substantial new contribution to the field of neuroimaging genetics. These genetic brain maps should facilitate discovery of gene variants influencing cognitive brain function through genome-wide association studies, potentially opening up new avenues in the treatment of brain disorders.

Relationship of a variant in the NTRK1 gene to white matter microstructure in young adults

The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importantce of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-acommondiffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p=0.038 forNTRK1-Tand0.013 for rs4661063-A). In each half-sample, theNTRK1-T effectwasreplicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.