Genome-wide co-expression analysis in multiple tissues

Expression quantitative trait loci (eQTLs) represent genetic control points of gene expression, and can be categorized as cis- and trans-acting, reflecting local and distant regulation of gene expression respectively. Although there is evidence of co-regulation within clusters of trans-eQTLs, the extent of co-expression patterns and their relationship with the genotypes at eQTLs are not fully understood. We have mapped thousands of cis- and trans-eQTLs in four tissues (fat, kidney, adrenal and left ventricle) in a large panel of rat recombinant inbred (RI) strains. Here we investigate the genome-wide correlation structure in expression levels of eQTL transcripts and underlying genotypes to elucidate the nature of co-regulation within cis- and trans-eQTL datasets. Across the four tissues, we consistently found statistically significant correlations of cis-regulated gene expression to be rare (<0.9% of all pairs tested). Most (>80%) of the observed significant correlations of cis-regulated gene expression are explained by correlation of the underlying genotypes. In comparison, co-expression of trans-regulated gene expression is more common, with significant correlation ranging from 2.9%-14.9% of all pairs of trans-eQTL transcripts. We observed a total of 81 trans-eQTL clusters (hot-spots), defined as consisting of > or =10 eQTLs linked to a common region, with very high levels of correlation between trans-regulated transcripts (77.2-90.2%). Moreover, functional analysis of large trans-eQTL clusters (> or =30 eQTLs) revealed significant functional enrichment among genes comprising 80% of the large clusters. The results of this genome-wide co-expression study show the effects of the eQTL genotypes on the observed patterns of correlation, and suggest that functional relatedness between genes underlying trans-eQTLs is reflected in the degree of co-expression observed in trans-eQTL clusters. Our results demonstrate the power of an integrative, systematic approach to the analysis of a large gene expression dataset to uncover underlying structure, and inform future eQTL studies

Spectroscopic biomedical imaging with the Medipix2 detector

This study confirms that the Medipix2 x-ray detector enables spectroscopic bio-medical plain radiography. We show that the detector has the potential to provide new, useful information beyond the limited spectroscopic information of modern dual-energy computed tomography (CT) scanners. Full spectroscopic 3D-imaging is likely to be the next major technological advance in computed tomography, moving the modality towards molecular imaging applications. This paper focuses on the enabling technology which allows spectroscopic data collection and why this information is useful. In this preliminary study we acquired the first spectroscopic images of human tissue and other biological samples obtained using the Medipix2 detector. The images presented here include the clear resolution of the 1.4mm long distal phalanx of a 20 week old miscarried foetus, showing clear energy-dependent variations. The opportunities for further research using the forthcoming Medipix3 detector are discussed and a prototype spectroscopic CT scanner (MARS, Medipix All Resolution System) is briefly described

Intermobility of barium, strontium, and lead in chloride and sulfate leach solutions

Production of radionuclide-free copper concentrates is dependent on understanding and controlling the deportment of daughter radionuclides (RNs) produced from 238U decay, specifically 226Ra, 210Pb, and 210Po. Sulfuric acid leaching is currently employed in the Olympic Dam processing plant (South Australia) to remove U and fluorine from copper concentrates prior to smelting but does not adequately remove the aforementioned RN. Due to chemical similarities between lead and alkaline earth metals (including Ra), two sets of experiments were designed to understand solution interactions between Sr, Ba, and Pb at various conditions. Nanoscale secondary ion mass spectrometry (NanoSIMS) isotopic spatial distribution maps and laser ablation inductively coupled-plasma mass spectrometry transects were performed on laboratory-grown crystals of baryte, celestite, and anglesite which had been exposed to different solutions under different pH and reaction time conditions. Analysis of experimental products reveals three uptake mechanisms: overgrowth of nearly pure SrSO4 and PbSO4 on baryte; incorporation of minor of Pb and Ba into celestite due to diffusion; and extensive replacement of Pb by Sr (and less extensive replacement of Pb by Ba) in anglesite via coupled dissolution-reprecipitation reactions. The presence of H2SO4 either enhanced or inhibited these reactions. Kinetic modelling supports the experimental results, showing potential for extrapolating the (Sr, Ba, Pb)SO4 system to encompass RaSO4. Direct observation of grain-scale element distributions by nanoSIMS aids understanding of the controlling conditions and mechanisms of replacement that may be critical steps for Pb and Ra removal from concentrates by allowing construction of a cationic replacement scenario targeting Pb or Ra, or ideally all insoluble sulfates. Experimental results provide a foundation for further investigation of RN uptake during minerals processing, especially during acid leaching. The new evidence enhances understanding of micro- to nanoscale chemical interactions and not only aids determination of where radionuclides reside during each processing stage but also guides development of flowsheets targeting their removal.Mark Rollog, Nigel J. Cook, Paul Guagliardo, Kathy Ehrig, Sarah E. Gilbert and Matt Kilbur

Nanoscale study of titanomagnetite from the Panzhihua Layered Intrusion, southwest China: multistage exsolutions record ore formation

Titanomagnetite from Fe-Ti-V ores of the Lanjiahuoshan deposit, Panzhihua layered intrusion, Southwest China, was investigated at the nanoscale. The objectives were to establish the composition of exsolution phases and their mutual relationships in order to evaluate the sequence of exsolution among oxide phases, and assess mechanisms of ore formation during magma emplacement. At the micron-scale, titanomagnetite shows crosscutting sets of exsolutions with ilmenite and Al-Mg-Fe-spinel (pleonaste), as well as overprint, both in terms of phase re-equilibration and remobilization of trace elements. Most complex textures were found in titanomagnetite surrounded by ilmenite and this was selected for high-angle annular dark field scanning transmission electron microscopy (HAADF STEM) imaging and STEM energy-dispersive X-ray spectrometry (EDS) spot analysis and mapping on a thin foil prepared in situ on a focused ion beam scanning electron microscope platform. Titanomagnetite revealed two sequential sets of exsolutions, {111} crosscutting {100}, which are associated with changes in phase speciation and trace element distribution patterns. Qandilite is the dominant spinel phase inside titanomagnetite; magnesioferrite is also identified. In contrast, Fe-poor, Al-rich, Mg-bearing spinel is present within ilmenite outside the grain. Vanadium enrichment in newly-formed magnetite lamellae is clear evidence for trace element remobilization. This V-rich magnetite shows epitaxial relationships with ilmenite at the contact with titanomagnetite. Two-fold super-structuring in ilmenite is evidence for non-redox re-equilibration between titanomagnetite and ilmenite, supporting published experimental data. In contrast, the transformation of cubic Ti-rich spinel into rhombohedral ilmenite imaged at the nanoscale represents the “oxy-exsolution” model of titanomagnetite–ilmenite re-equilibration via formation of a transient ulvöspinel species. Nanoscale disorder is encountered as vacancy layers in Ti-rich spinel, and lower symmetry in the Fe-poor, Al-Mg phase, suggesting that slow cooling rates can preserve small-scale phase equilibration. The cooling history of titanomagnetite ore can be reconstructed as three distinct stages, concordant with published models for the magma plumbing system: equilibrium crystallization of Al-rich, Mg-bearing titanomagnetite from cumulus melts at ~55 km, with initial exsolutions occurring above 800 °C at moderate fO2 conditions (Stage 1); crosscutting {111} exsolutions resulting in formation of qandilite, attributable to temperature increase due to emplacement of another batch of melt affecting the interstitial cumulus during uplift. Formation of 2-fold superstructure ilmenite + V-rich magnetite exsolution pairs representing non-redox equilibration indicates resetting of the cooling path at this stage (Stage 2); and ilmenite formation from pre-existing Ti-rich spinel and ulvöspinel, illustrative of redox-driven cooling paths at <10 km (Stage 3). HAADF STEM provides direct imaging of atomic arrangements, allowing recognition of processes not recognizable at the micron-scale, and can thus be used to constrain exsolution models during ore formation.Wenyuan Gao, Cristiana L. Ciobanu, Nigel J. Cook, Ashley Slattery, Fei Huang and Dan Son

Mineralogy of zirconium in iron‐oxides: a micron‐ to nanoscale study of hematite ore from peculiar Knob, South Australia

Zirconium is an element of considerable petrogenetic significance but is rarely found in hematite at concentrations higher than a few parts-per-million (ppm). Coarse-grained hematite ore from the metamorphosed Peculiar Knob iron deposit, South Australia, contains anomalous concentrations of Zr and has been investigated using microanalytical techniques that can bridge the micron- to nanoscales to understand the distribution of Zr in the ore. Hematite displays textures attributable to annealing under conditions of high-grade metamorphism, deformation twins (r~85° to hematite elongation), relict magnetite and fields of sub-micron-wide inclusions of baddeleyite as conjugate needles with orientation at ~110°/70°. Skeletal and granoblastic zircon, containing only a few ppm U, are both present interstitial to hematite. Using laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) spot analysis and mapping, the concentration of Zr in hematite is determined to be ~260 ppm on average (up to 680 ppm). The Zr content is, however, directly attributable to nm-scale inclusions of baddeleyite pervasively distributed throughout the hematite rather than Zr in solid solution. Distinction between nm-scale inclusions and lattice-bound trace element substitutions cannot be made from LA-ICP-MS data alone and requires nanoscale characterization. Scandium-rich (up to 0.18 wt. % Sc2O3) cores in zircon are documented by microprobe analysis and mapping. Using high-angle annular dark field scanning transmission electron microscopy imaging (HAADF-STEM) and energy-dispersive spectrometry STEM mapping of foils prepared in-situ by focused ion beam methods, we identify [ 01¯1 ]baddeleyite epitaxially intergrown with [ 22¯.1 ]hematite. Lattice vectors at 84–86° underpinning the epitaxial intergrowth orientation correspond to directions of r-twins but not to the orientation of the needles, which display a ~15° misfit. This is attributable to directions of trellis exsolutions in a precursor titanomagnetite. U–Pb dating of zircon gives a 206Pb/238U weighted mean age of 1741 ± 49 Ma (sensitive high-resolution ion microprobe U–Pb method). Based on the findings presented here, detrital titanomagnetite from erosion of mafic rocks is considered the most likely source for Zr, Ti, Cr and Sc. Whether such detrital horizons accumulated in a basin with chemical precipitation of Fe-minerals (banded iron formation) is debatable, but such Fe-rich sediments clearly included detrital horizons. Martitization during the diagenesis-supergene enrichment cycle was followed by high-grade metamorphism during the ~1.73–1.69 Ga Kimban Orogeny during which martite recrystallized as granoblastic hematite. Later interaction with hydrothermal fluids associated with ~1.6 Ga Hiltaba-granitoids led to W, Sn and Sb enrichment in the hematite. By reconstructing the evolution of the massive orebody at Peculiar Knob, we show how application of complimentary advanced microanalytical techniques, in-situ and on the same material but at different scales, provides critical constraints on ore-forming processes.William Keyser, Cristiana L. Ciobanu, Nigel J. Cook, Holly Feltus, Geoff Johnson, Ashley Slattery, Benjamin P. Wade and Kathy Ehri

Silician Magnetite: Si–Fe-nanoprecipitates and other mineral inclusions in magnetite from the Olympic Dam deposit, South Australia

A comprehensive nanoscale study on magnetite from samples from the outer, weakly mineralized shell at Olympic Dam, South Australia, has been undertaken using atom-scale resolution High Angle Annular Dark Field Scanning Transmission Electron Microscopy (HAADF STEM) imaging and STEM energy-dispersive X-ray spectrometry mapping and spot analysis, supported by STEM simulations. Silician magnetite within these samples is characterized and the significance of nanoscale inclusions in hydrothermal and magmatic magnetite addressed. Silician magnetite, here containing Si–Fe-nanoprecipitates and a diverse range of nanomineral inclusions [(ferro)actinolite, diopside and epidote but also U-, W-(Mo), Y-As- and As-S-nanoparticles] appears typical for these samples. We observe both silician magnetite nanoprecipitates with spinel-type structures and a γ-Fe₁.₅SiO₄ phase with maghemite structure. These are distinct from one another and occur as bleb-like and nm-wide strips along d₁₁₁ in magnetite, respectively. Overprinting of silician magnetite during transition from K-feldspar to sericite is also expressed as abundant lattice-scale defects (twinning, faults) associated with the transformation of nanoprecipitates with spinel structure into maghemite via Fe-vacancy ordering. Such mineral associations are characteristic of early, alkali-calcic alteration in the iron-oxide copper gold (IOCG) system at Olympic Dam. Magmatic magnetite from granite hosting the deposit is quite distinct from silician magnetite and features nanomineral associations of hercynite-ulvöspinel-ilmenite. Silician magnetite has petrogenetic value in defining stages of ore deposit evolution at Olympic Dam and for IOCG systems elsewhere. The new data also add new perspectives into the definition of silician magnetite and its occurrence in ore deposits.Cristiana L. Ciobanu, Max R. Verdugo-Ihl, Ashley Slattery, Nigel J. Cook, Kathy Ehrig, Liam Courtney-Davies, and Benjamin P. Wad

Deterministic and stochastic descriptions of gene expression dynamics

A key goal of systems biology is the predictive mathematical description of gene regulatory circuits. Different approaches are used such as deterministic and stochastic models, models that describe cell growth and division explicitly or implicitly etc. Here we consider simple systems of unregulated (constitutive) gene expression and compare different mathematical descriptions systematically to obtain insight into the errors that are introduced by various common approximations such as describing cell growth and division by an effective protein degradation term. In particular, we show that the population average of protein content of a cell exhibits a subtle dependence on the dynamics of growth and division, the specific model for volume growth and the age structure of the population. Nevertheless, the error made by models with implicit cell growth and division is quite small. Furthermore, we compare various models that are partially stochastic to investigate the impact of different sources of (intrinsic) noise. This comparison indicates that different sources of noise (protein synthesis, partitioning in cell division) contribute comparable amounts of noise if protein synthesis is not or only weakly bursty. If protein synthesis is very bursty, the burstiness is the dominant noise source, independent of other details of the model. Finally, we discuss two sources of extrinsic noise: cell-to-cell variations in protein content due to cells being at different stages in the division cycles, which we show to be small (for the protein concentration and, surprisingly, also for the protein copy number per cell) and fluctuations in the growth rate, which can have a significant impact.Comment: 23 pages, 5 figures; Journal of Statistical physics (2012

Anthropogenic alteration of nutrient supply increases the global freshwater carbon sink

Lakes have a disproportionate effect on the global carbon (C) cycle relative to their area, mediating C transfer from land to atmosphere, and burying organic-C in their sediments. The magnitude and temporal variability of C burial is, however, poorly constrained, and the degree to which humans have influenced lake C cycling through landscape alteration has not been systematically assessed. Here, we report global and biome specific trajectories of lake C sequestration based on 516 lakes and show that some lake C burial rates (i.e., those in tropical forest and grassland biomes) have quadrupled over the last 100 years. Global lake C-sequestration (~0.12 Pg year-1) has increased by ~72 Tg year-1 since 1900, offsetting 20% of annual CO2 freshwater emissions rising to ~30% if reservoirs are included and contributing to the residual continental C sink. Nutrient availability explains ~70% of the observed increase, while rising temperatures have a minimal effect