The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to ...leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1α (HIF1α), activation of HIF1αtargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1α a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel–Lindau syndrome.
We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened ...controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻⁷), SP4 (P=7.68 x 10⁻⁷) and GRM7 (P=1.11 x 10⁻⁶). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.
► The Se content and species in flour and bread produced from biofortified wheat was assessed. ► Total Se in flour increased by ∼170ng/g with 10g/ha selenate application to wheat crop. ► The ...relationship between Se added to crop and the content in flour and bread was linear. ► The major species of extractable Se in enriched flour and bread was selenomethionine. ► Biofortification of wheat may provide an appropriate strategy to increase the intake of bioavailable Se.
The retention and speciation of selenium in flour and bread was determined following experimental applications of selenium fertilisers to a high-yielding UK wheat crop. Flour and bread were produced using standard commercial practices. Total selenium was measured using inductively coupled plasma-mass spectrometry (ICP-MS) and the profile of selenium species in the flour and bread were determined using high performance liquid chromatography (HPLC) ICP-MS. The selenium concentration of flour ranged from 30ng/g in white flour and 35ng/g in wholemeal flour from untreated plots up to >1800ng/g in white and >2200ng/g in wholemeal flour processed from grain treated with selenium (as selenate) at the highest application rate of 100g/ha. The relationship between the amount of selenium applied to the crop and the amount of selenium in flour and bread was approximately linear, indicating minimal loss of Se during grain processing and bread production. On average, application of selenium at 10g/ha increased total selenium in white and wholemeal bread by 155 and 185ng/g, respectively, equivalent to 6.4 and 7.1μg selenium per average slice of white and wholemeal bread, respectively. Selenomethionine accounted for 65–87% of total extractable selenium species in Se-enriched flour and bread; selenocysteine, Se-methylselenocysteine selenite and selenate were also detected. Controlled agronomic biofortification of wheat crops for flour and bread production could provide an appropriate strategy to increase the intake of bioavailable selenium.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer lacking specific biomarkers that can be correlated to disease onset, promotion and progression. To assess whether tumor cell ...electrophysiology may serve as a marker for PDAC tumorigenicity, we use multi-frequency impedance cytometry at high throughput (∼350 cells/s) to measure the electrical phenotype of single PDAC tumor cells from xenografts, which are derived from primary pancreatic tumors versus those from liver metastases of different patients. A novel phase contrast metric based on variations in the high and low frequency impedance phase responses that is related to electrophysiology of the cell interior is found to be systematically altered as a function of tumorigenicity. PDAC cells of higher tumorigenicity exhibited lowered interior conductivity and enhanced permittivity, which is validated by the dielectrophoresis on the respective cell types. Using genetic analysis, we suggest the role of dysregulated Na+ transport and removal of Ca2+ ions from the cytoplasm on key oncogenic KRAS-driven processes that may be responsible for lowering of the interior cell conductivity. We envision that impedance cytometry can serve as a tool to quantify phenotypic heterogeneity for rapidly stratifying tumorigenicity. It can also aid in protocols for dielectrophoretic isolation of cells with a particular phenotype for prognostic studies on patient survival and to tailor therapy selection to specific patients.
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•High-throughput (∼350 cells/s) impedance cytometry to measure ∼10,000 cells/sample.•Samples of patient-derived pancreatic tumor xenografts of varying tumorigenicity.•Impedance phase due to electrophysiology of cell interior varies with tumorigenicity.•Lowered interior conductivity and enhanced permittivity for cells of higher tumorigenicity.•Validated based on level of positive dielectrophoresis and its crossover frequency.
The shutdown of star formation in galaxies is generally termed "quenching." This paper addresses quenching by searching for traces of possible quenching processes through their effects on galaxy ...structural parameters such as stellar mass (M sub(*)), M sub(*)/r sub(e), surface stellar mass density (~M sub(*)/r super(2) sub(e)), and Sersic index (n). We analyze the rest-frame U-B color correlations versus these structural parameters using a sample of galaxies in the redshift range 0.5 < or =, slant z < 0.8 from the DEEP2/AEGIS survey. We assess the tightness of the color relationships by measuring their "overlap regions," defined as the area in color-parameter space in which red and blue galaxies overlap; the parameter that minimizes these overlap regions is considered to be the most effective color discriminator. We discuss a two-stage model for quenching in which galaxy star formation rates are controlled by their dark halos while they are still in the blue cloud and a second quenching process sets in later, associated with the central stellar mass buildup.
Field trials were undertaken to investigate the effect of the application of metal mobilizing agents, different sowing strategies and length of growing season on the extraction of Cd and Zn from ...soils by
Thlaspi caerulescens and
Arabidopsis halleri. None of the mobilizing agents used enhanced metal accumulation by
T. caerulescens. Between 1998 and 2000, on average across plots where Cd or Zn exceeded allowable limits,
T. caerulescens removed 1.3 and 0.3% of the total soil Cd and Zn. In one season when
T. caerulescens was grown for 14
months, 21.7 and 4.4% of the total soil Cd and Zn was removed. This was larger than values found when
T. caerulescens was grown for 4
months.
A. halleri accumulated similar concentrations of Zn, but lower Cd concentrations than
T.
caerulescens. The results indicate that metal phytoextraction using
T. caerulescens can be used to clean up soils moderately contaminated by Cd.
The hyperaccumulator Thlaspi caerulescens (the Ganges ecotype) is more efficient at phytoextracting Cd than Zn from contaminated soil.
We evaluated the effectiveness of lime and red mud (by-product of aluminium manufacturing) to reduce metal availability to
Festuca rubra and to allow re-vegetation on a highly contaminated ...brown-field site. Application of both lime and red mud (at 3 or 5%) increased soil pH and decreased metal availability.
Festuca rubra failed to establish in the control plots, but grew to a near complete vegetative cover on the amended plots. The most effective treatment in decreasing grass metal concentrations in the first year was 5% red mud, but by year two all amendments were equally effective. In an additional pot experiment, P application in combination with red mud or lime decreased the Pb concentration, but not total uptake of Pb in
Festuca rubra compared to red mud alone. The results show that both red mud and lime can be used to remediate a heavily contaminated acid soil to allow re-vegetation.
Red mud was effective in immobilising heavy metals in soil.
We have used high-resolution, Hubble Space Telescope, near-infrared imaging to conduct a detailed analysis of the morphological properties of the most massive galaxies at high redshift, modelling the ...WFC3/IR H
160-band images of the ≃200 galaxies in the CANDELS-UDS field with photometric redshifts 1 < z < 3, and stellar masses M
* > 1011 M⊙. We have explored the results of fitting single-Sérsic and bulge+disc models, and have investigated the additional errors and potential biases introduced by uncertainties in the background and the on-image point spread function. This approach has enabled us to obtain formally acceptable model fits to the WFC3/IR images of >90 per cent of the galaxies. Our results indicate that these massive galaxies at 1 < z < 3 lie both on and below the local size-mass relation, with a median effective radius of ∼2.6 kpc, a factor of ≃2.3 smaller than comparably massive local galaxies. Moreover, we find that bulge-dominated objects in particular show evidence for a growing bimodality in the size-mass relation with increasing redshift, and by z > 2 the compact bulges display effective radii a factor of ≃4 smaller than local ellipticals of comparable mass. These trends also appear to extend to the bulge components of disc-dominated galaxies. In addition, we find that, while such massive galaxies at low redshift are generally bulge-dominated, at redshifts 1 < z < 2 they are predominantly mixed bulge+disc systems, and by z > 2 they are mostly disc-dominated. The majority of the disc-dominated galaxies are actively forming stars, although this is also true for many of the bulge-dominated systems. Interestingly, however, while most of the quiescent galaxies are bulge-dominated, we find that a significant fraction (25-40 per cent) of the most quiescent galaxies, with specific star formation rates sSFR < 10−10 yr−1, have disc-dominated morphologies. Thus, while our results show that the massive galaxy population is undergoing dramatic changes at this crucial epoch, they also suggest that the physical mechanisms which quench star formation activity are not simply connected to those responsible for the morphological transformation of massive galaxies into present-day giant ellipticals.
Anaerobic bacteria are increasingly regarded as important in cystic fibrosis (CF) pulmonary infection. The aim of this study was to determine the effect of antibiotic treatment on aerobic and ...anaerobic microbial community diversity and abundance during exacerbations in patients with CF.
Sputum was collected at the start and completion of antibiotic treatment of exacerbations and when clinically stable. Bacteria were quantified and identified following culture, and community composition was also examined using culture-independent methods.
Pseudomonas aeruginosa or Burkholderia cepacia complex were detected by culture in 24/26 samples at the start of treatment, 22/26 samples at completion of treatment and 11/13 stable samples. Anaerobic bacteria were detected in all start of treatment and stable samples and in 23/26 completion of treatment samples. Molecular analysis showed greater bacterial diversity within sputum samples than was detected by culture; there was reasonably good agreement between the methods for the presence or absence of aerobic bacteria such as P aeruginosa (κ=0.74) and B cepacia complex (κ=0.92), but agreement was poorer for anaerobes. Both methods showed that the composition of the bacterial community varied between patients but remained relatively stable in most individuals despite treatment. Bacterial abundance decreased transiently following treatment, with this effect more evident for aerobes (median decrease in total viable count 2.3×10(7) cfu/g, p=0.005) than for anaerobes (median decrease in total viable count 3×10(6) cfu/g, p=0.046).
Antibiotic treatment targeted against aerobes had a minimal effect on abundance of anaerobes and community composition, with both culture and molecular detection methods required for comprehensive characterisation of the microbial community in the CF lung. Further studies are required to determine the clinical significance of and optimal treatment for these newly identified bacteria.
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