Modelling the surface energetics of patchy arctic tundra snowcover

A combination of field observations and measurements were used to study the energy-balance of a patchy arctic tundra snow-cover during the winter of 2003/2004 at a mountain tundra site in Northern Sweden. To quantify the effect of patchy snow-cover on surface energetic, the Met. Office Surface Exchange Scheme (MOSES 2) was employed to simulate surface snow dynamics. Surface snow patchiness was controlled by the interaction of blowing snow with surface topography and vegetation, with deep drifts forming in topographic hollows and tall shrub beds. Some exposed ridge tops remained exposed for the majority of the winter. The surface patchiness was found to significantly alter the surface energetics, and the interaction between snow and snow-free surfaces was critical to accurately numerically simulating snow-cover ablation. The assumption of uniform snow- covers in large-scale atmospheric models may lead to significant errors in model simulations. It was found that for large-scale models, heterogeneous snow-covers can be adequately represented by the use of separate energy-balances for snow and snow-free surfaces respectively with a single underlying soil layer. The proportions of each surface can be represented using a snow covered fraction which is a parameterisation of the distribution of snow depths. Simulated surface fluxes, particularly surface runoff and heat and water vapour, were found to be highly sensitive to the exact form of this parameterisation. No field evidence was found for the advection of turbulent energy between snow and snow-free surface

Comparative analysis of haplotype association mapping algorithms

BACKGROUND: Finding the genetic causes of quantitative traits is a complex and difficult task. Classical methods for mapping quantitative trail loci (QTL) in miceuse an F2 cross between two strains with substantially different phenotype and an interval mapping method to compute confidence intervals at each position in the genome. This process requires significant resources for breeding and genotyping, and the data generated are usually only applicable to one phenotype of interest. Recently, we reported the application of a haplotype association mapping method which utilizes dense genotyping data across a diverse panel of inbred mouse strains and a marker association algorithm that is independent of any specific phenotype. As the availability of genotyping data grows in size and density, analysis of these haplotype association mapping methods should be of increasing value to the statistical genetics community. RESULTS: We describe a detailed comparative analysis of variations on our marker association method. In particular, we describe the use of inferred haplotypes from adjacent SNPs, parametric and nonparametric statistics, and control of multiple testing error. These results show that nonparametric methods are slightly better in the test cases we study, although the choice of test statistic may often be dependent on the specific phenotype and haplotype structure being studied. The use of multi-SNP windows to infer local haplotype structure is critical to the use of a diverse panel of inbred strains for QTL mapping. Finally, because the marginal effect of any single gene in a complex disease is often relatively small, these methods require the use of sensitive methods for controlling family-wise error. We also report our initial application of this method to phenotypes cataloged in the Mouse Phenome Database. CONCLUSION: The use of inbred strains of mice for QTL mapping has many advantages over traditional methods. However, there are also limitations in comparison to the traditional linkage analysis from F2 and RI lines. Application of these methods requires careful consideration of algorithmic choices based on both theoretical and practical factors. Our findings suggest general guidelines, though a complete evaluation of these methods can only be performed as more genetic data in complex diseases becomes available

Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively

Uncontrolled cell growth in Tuberous Sclerosis Complex occurs due to inappropriate activation of mechanistic (mammalian) target of rapamycin complex 1 (mTORC1). The current therapy, rapamycin, produced promising clinical trial results, but patient tumours regrow if treatment is discontinued, revealing rapamycin has cytostatic properties rather than a cytotoxic effect. Taking advantage of the enhanced levels of endoplasmic reticulum (ER) stress present in TSC2-null cells, we investigated drug combinations producing a cytotoxic response. We found a nelfinavir and salinomycin combination specifically killed TSC2-deficient, mTORC1 hyperactive cells. Cytotoxicity was rescued by reducing protein synthesis, either through mTORC1 inhibition or cycloheximide treatment. This indicates that the drug combination targets the cells by tipping the protein homeostasis balance of the already metabolically stressed TSC2-deficient cells in favour of cell death. Furthermore, this drug combination also inhibited tumour formation in TSC2-deficient cell models and caused tumour spheroid death in 3D culture. Importantly, the 3D assay could differentiate the cytostatic agent, rapamycin, from the cytotoxic nelfinavir/salinomycin combination. Sporadic cancer cell lines with hyperactive mTORC1 signalling were also susceptible to this nelfinavir/salinomycin drug combination. This work indicates that the protein homeostasis pathway is an attractive therapeutic target in both Tuberous Sclerosis Complex and mTORC1-driven sporadic cancers

A lost decade? Service delivery and reforms in Papua New Guinea 2002 – 2012

Papua New Guinea has experienced an unprecedented resource boom over the last decade that has led to a rapid rise in revenue and subsequent increases in public expenditure. The PNG Government and its donors have also implemented major reforms aimed at improving access to basic services across the country. However, the question remains as to whether our nation’s booming mineral wealth has translated into services for ordinary people. In an effort to provide some answers to these important questions, the joint NRI-ANU Promoting Effective Public Expenditure (PEPE) Project completed extensive expenditure tracking and facility surveys across eight provinces at the end of 2012. Survey teams visited 216 primary schools and 142 health clinics from the nation’s capital to some of PNG’s most remote and isolated communities. Altogether 1,276 interviews were completed, making it one of the largest and most comprehensive service delivery surveys completed in PNG. The PEPE survey was subject to difficulties and logistical problems associated with the large scale of the survey and the need for survey teams to operate in very remote parts of the country. The success of the survey was dependent not only on extensive planning but on the dedication, commitment and effort of the surveyors. Many of the same schools and health clinics were visited in a similar survey conducted in 2002 that was also undertaken by NRI. By combining findings from both surveys, this report can compare changes in schools and health clinics between 2002 and 2012. The aim is to provide the basic information, which not only the Government of Papua New Guinea but also the people need to assess progress and suggest changes for better spending in the future. This report and the unique data set on which it is based will be an invaluable resource for PNG’s policy makers and people.PEPE is supported by the Australian aid program, through the Economic and Public Sector Program (EPSP). EPSP is managed by Coffey on behalf of the Australian Government

Reconfigurable quantum metamaterials

By coupling controllable quantum systems into larger structures we introduce the concept of a quantum metamaterial. Conventional meta-materials represent one of the most important frontiers in optical design, with applications in diverse fields ranging from medicine to aerospace. Up until now however, metamaterials have themselves been classical structures and interact only with the classical properties of light. Here we describe a class of dynamic metamaterials, based on the quantum properties of coupled atom-cavity arrays, which are intrinsically lossless, reconfigurable, and operate fundamentally at the quantum level. We show how this new class of metamaterial could be used to create a reconfigurable quantum superlens possessing a negative index gradient for single photon imaging. With the inherent features of quantum superposition and entanglement of metamaterial properties, this new class of dynamic quantum metamaterial, opens a new vista for quantum science and technology.Comment: 16 pages, 8 figure

A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety-like behavior

Glyoxalase 1 (Glo1) has been implicated in anxiety-like behavior in mice and in multiple psychiatric diseases in humans. We used mouse Affymetrix exon arrays to detect copy number variants (CNV) among inbred mouse strains and thereby identified a approximately 475 kb tandem duplication on chromosome 17 that includes Glo1 (30,174,390-30,651,226 Mb; mouse genome build 36). We developed a PCR-based strategy and used it to detect this duplication in 23 of 71 inbred strains tested, and in various outbred and wild-caught mice. Presence of the duplication is associated with a cis-acting expression QTL for Glo1 (LOD>30) in BXD recombinant inbred strains. However, evidence for an eQTL for Glo1 was not obtained when we analyzed single SNPs or 3-SNP haplotypes in a panel of 27 inbred strains. We conclude that association analysis in the inbred strain panel failed to detect an eQTL because the duplication was present on multiple highly divergent haplotypes. Furthermore, we suggest that non-allelic homologous recombination has led to multiple reversions to the non-duplicated state among inbred strains. We show associations between multiple duplication-containing haplotypes, Glo1 expression and anxiety-like behavior in both inbred strain panels and outbred CD-1 mice. Our findings provide a molecular basis for differential expression of Glo1 and further implicate Glo1 in anxiety-like behavior. More broadly, these results identify problems with commonly employed tests for association in inbred strains when CNVs are present. Finally, these data provide an example of biologically significant phenotypic variability in model organisms that can be attributed to CNVs.These studies were funded by MH070933, MH79103 and MH020065

Robust Ecosystem Demography (RED version 1.0): a parsimonious approach to modelling vegetation dynamics in Earth system models

A significant proportion of the uncertainty in climate projections arises from uncertainty in the representation of land carbon uptake. Dynamic global vegetation models (DGVMs) vary in their representations of regrowth and competition for resources, which results in differing responses to changes in atmospheric CO2 and climate. More advanced cohort-based patch models are now becoming established in the latest DGVMs. These models typically attempt to simulate the size distribution of trees as a function of both tree size (mass or trunk diameter) and age (time since disturbance). This approach can capture the overall impact of stochastic disturbance events on the forest structure and biomass – but at the cost of increasing the number of parameters and ambiguity when updating the probability density function (pdf) in two dimensions. Here we present the Robust Ecosystem Demography (RED), in which the pdf is collapsed onto the single dimension of tree mass. RED is designed to retain the ability of more complex cohort DGVMs to represent forest demography, while also being parameter sparse and analytically solvable for the steady state. The population of each plant functional type (PFT) is partitioned into mass classes with a fixed baseline mortality along with an assumed power-law scaling of growth rate with mass. The analytical equilibrium solutions of RED allow the model to be calibrated against observed forest cover using a single parameter – the ratio of mortality to growth for a tree of a reference mass (μ0). We show that RED can thus be calibrated to the ESA LC_CCI (European Space Agency Land Cover Climate Change Initiative) coverage dataset for nine PFTs. Using net primary productivity and litter outputs from the UK Earth System Model (UKESM), we are able to diagnose the spatially varying disturbance rates consistent with this observed vegetation map. The analytical form for RED circumnavigates the need to spin up the numerical model, making it attractive for application in Earth system models (ESMs). This is especially so given that the model is also highly parameter sparse

Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis.

BACKGROUND: The incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda. METHODS: We retrieved and tested paired serum aliquots for 101 HIV-TB co-infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP®; and Aspergillus-specific IgG and total serum IgE using Immulite® immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics. RESULTS: 10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus-specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/μl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP® Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x-ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24. CONCLUSION: These results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis. TRIAL REGISTRATION: The SOUTH trial was registered prospectively. ClinicalTrials.gov Identifier: NCT01782950 ; Registration date: 4th February 2013; Last verified: 13th April 2015

Virological outcome of patients with HIV drug resistance attending an urban out-patient clinic in Uganda: a need for structured adherence counselling and third line treatment options

BACKGROUND HIV drug resistance and suboptimal adherence are the main reasons for treatment failure among HIV-infected individuals. As genotypic resistance testing is not routinely available in resource-limited settings such as Uganda, data on transmitted and acquired resistance is sparse. METHODS This observational follow-up study assessed the virological outcomes of patients diagnosed with virological failure or transmitted HIV drug resistance in 2015 at the adults' out-patient clinic of the Infectious Diseases Institute in Kampala, Uganda. Initially, 2430 patients on antiretroviral therapy (ART) underwent virological monitoring, of which 190 had virological failure and were subsequently eligible for this follow-up study. Nine patients diagnosed with transmitted drug resistance were eligible. In patients with a viral load > 1000 copies/mL genotypic resistance testing was done. RESULTS Of 190 eligible patients, 30 (15.8%) had either died or were lost to follow-up. A total of 148 (77.9%) were included, of which 98 had had a change of ART regimen, and 50 had received adherence counselling only. The majority was now on 2-line ART (N=130, 87.8%). The median age was 39 years (interquartile range: 32-46) and 109 (73.6%) were female. Virological failure was diagnosed in 29 (19.6%) patients, of which 24 (82.8%) were on 2-line ART. Relevant drug resistance was found in 25 (86.2%) cases, of which 12 (41.3%) carried dual and 7 (24.1%) triple drug resistance. CONCLUSION Two years after initial virological failure, most patients followed up by this study had a successful virological outcome. However, a significant proportion either continued to fail or died or was lost to follow-up