Anticipation or ascertainment bias in schizophrenia? Penrose's familial mental illness sample.

Several studies have observed anticipation (earlier age at onset [AAO] in successive generations) in familial schizophrenia. However, whether true anticipation or ascertainment bias is the principal originating mechanism remains unclear. In 1944 L. S. Penrose collected AAO data on a large, representative sample of familial mental illness, using a broad ascertainment strategy. These data allowed examination of anticipation and ascertainment biases in five two-generation samples of affected relative pairs. The median intergenerational difference (MID) in AAO was used to assess anticipation. Results showed significant anticipation in parent-offspring pairs with schizophrenia (n = 137 pairs; MID 15 years; P = .0001) and in a positive control sample with Huntington disease (n = 11; P = .01). Broadening the diagnosis of the schizophrenia sample suggested anticipation of severity of illness. However, other analyses provided evidence for ascertainment bias, especially in later-AAO parents, in parent-offspring pairs. Aunt/uncle-niece/nephew schizophrenia pairs showed anticipation (n = 111; P = .0001), but the MID was 8 years and aunts/uncles had earlier median AAO than parents. Anticipation effects were greatest in pairs with late-AAO parents but remained significant in a subgroup of schizophrenia pairs with early parental AAO (n = 31; P = .03). A small control sample of other diseases had MID of 5 years but no significant anticipation (n = 9; P = .38). These results suggest that, although ascertainment-bias effects were observed in parent-offspring pairs, true anticipation appears to be inherent in the transmission of familial schizophrenia. The findings support investigations of unstable mutations and other mechanisms that may contribute to true anticipation in schizophrenia.     

The mitogenome of Onchocerca volvulus from the Brazilian Amazonia focus

We report here the first complete mitochondria genome of Onchocerca volvulus from a focus outside of Africa. An O. volvulus mitogenome from the Brazilian Amazonia focus was obtained using a combination of high-throughput and Sanger sequencing technologies. Comparisons made between this mitochondrial genome and publicly available mitochondrial sequences identified 46 variant nucleotide positions and suggested that our Brazilian mitogenome is more closely related to Cameroon-origin mitochondria than West African-origin mitochondria. As well as providing insights into the origins of Latin American onchocerciasis, the Brazilian Amazonia focus mitogenome may also have value as an epidemiological resource.     

Long-term landscape changes in vegetation structure: fire management in the wetlands of KwaMbonambi,South Africa

In wetlands the effects of fire on vegetation dynamics are somewhat uncertain. A change detection analysis in the herbaceous wetlands of KwaMbonambi, South Africa, which were subject to frequent fires, revealed that in 1937 the study area comprised grassland (69%), herbaceous wetland (25%), indigenous swamp forest (4%) and tree plantations (1%). However, by 1970, tree plantations occupied 78% of the landscape and grasslands and herbaceous wetlands had declined to 9% and 6%, respectively, whereas indigenous swamp forest had increased to 6%. By 2009 tree plantations had been removed from the wetland areas. Despite this opportunity for herbaceous wetlands to recover their historical extent, they decreased to only 2%, mostly changing to indigenous swamp forest or to an herbaceous/fern (Stenochlaena tenuifolia)/woodland mosaic. Fire records showed suppression of fire to be an important contributing factor, particularly in wetlands that had been disturbed by tree plantations, although subsequently removed. A pilot burning experiment revealed that S. tenuifolia did not inhibit fire. It is therefore practicable to increase fire frequency to prevent the mosaic developing into forest. A conceptual model of the influence of fire regime on wetland vegetation type is presented and priorities for further research on wetlands and fire are recommended.     

Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.     

Metabolomic and elemental profiling of melon fruit quality as affected by genotype and environment

Melon (Cucumis melo L.) is a global crop in terms of economic importance and nutritional quality. The aim of this study was to explore the variability in metabolite and elemental composition of several commercial varieties of melon in various environmental conditions. Volatile and non-volatile metabolites as well as mineral elements were profiled in the flesh of mature fruit, employing a range of complementary analytical technologies. More than 1,000 metabolite signatures and 19 mineral elements were determined. Data analyses revealed variations related to factors such as variety, growing season, contrasting agricultural management practices (greenhouse vs. field with or without fruit thinning) and planting date. Two hundred and ninety-one analytes discriminated two contrasting varieties, one from the var. inodorous group and the other from the var. cantaloupensis group. Two hundred and eighty analytes discriminated a short shelf-life from a mid-shelf-life variety within the var. cantaloupensis group. Three hundred and twenty-seven analytes discriminated two seasons, and two hundred and fifty-two analytes discriminated two contrasting agricultural management practices. The affected compound families greatly depended on the factor studied. The compositional variability of identified or partially identified compounds was used to study metabolite and mineral element co-regulation using correlation networks. The results confirm that metabolome and mineral element profiling are useful diagnostic tools to characterize the quality of fruits cultivated under commercial conditions. They can also provide knowledge on fruit metabolism and the mechanisms of plant response to environmental modifications, thereby paving the way for metabolomics-guided improvement of cultural practices for better fruit quality.     

Bio-available zinc in rice seeds is increased by activation tagging of nicotianamine synthase

We generated rice lines with increased content of nicotianamine (NA), a key ligand for metal transport and homeostasis. This was accomplished by activation tagging of rice nicotianamine synthase 2 (OsNAS2). Enhanced expression of the gene resulted in elevated NA levels, greater Zn accumulations and improved plant tolerance to a Zn deficiency. Expression of Zn-uptake genes and those for the biosynthesis of phytosiderophores (PS) were increased in transgenic plants. This suggests that the higher amount of NA led to greater exudation of PS from the roots, as well as stimulated Zn uptake, translocation and seed-loading. In the endosperm, the OsNAS2 activation-tagged line contained up to 20-fold more NA and 2.7-fold more zinc. Liquid chromatography combined with inductively coupled plasma mass spectrometry revealed that the total content of zinc complexed with NA and 2'-deoxymugineic acid was increased 16-fold. Mice fed with OsNAS2-D1 seeds recovered more rapidly from a zinc deficiency than did control mice receiving WT seeds. These results demonstrate that the level of bio-available zinc in rice grains can be enhanced significantly by activation tagging of OsNAS2.     

Elevated nicotianamine levels in Arabidopsis halleri roots play a key role in zinc hyperaccumulation

Zn deficiency is among the leading health risk factors in developing countries. Breeding of Zn-enriched crops is expected to be facilitated by molecular dissection of plant Zn hyperaccumulation (i.e., the ability of certain plants to accumulate Zn to levels >100-fold higher than normal plants). The model hyperaccumulators Arabidopsis halleri and Noccaea caerulescens share elevated nicotianamine synthase (NAS) expression relative to nonaccumulators among a core of alterations in metal homeostasis. Suppression of Ah-NAS2 by RNA interference (RNAi) resulted in strongly reduced root nicotianamine (NA) accumulation and a concomitant decrease in root-to-shoot translocation of Zn. Speciation analysis by size-exclusion chromatography coupled to inductively coupled plasma mass spectrometry showed that the dominating Zn ligands in roots were NA and thiols. In NAS2-RNAi plants, a marked increase in Zn-thiol species was observed. Wild-type A. halleri plants cultivated on their native soil showed elemental profiles very similar to those found in field samples. Leaf Zn concentrations in NAS2-RNAi lines, however, did not reach the Zn hyperaccumulation threshold. Leaf Cd accumulation was also significantly reduced. These results demonstrate a role for NAS2 in Zn hyperaccumulation also under near-natural conditions. We propose that NA forms complexes with Zn(II) in root cells and facilitates symplastic passage of Zn(II) toward the xylem.     

Zinc transport mediated by barley ZIP proteins are induced by low pH

It is estimated that nearly 50% of the world''s population is at risk of zinc (Zn) deficiency. The challenge is therefore to increase the Zn content in edible plant parts in order to improve the nutritional value of staple foods. We recently reported the identification and characterization of three barley genes encoding zinc transport proteins belonging to the ZIP protein family. These proteins are believed to be involved in cellular uptake of Zn²⁺. In this addendum, the Zn²⁺ transport capacity of ZIP proteins isolated from barley roots was investigated in response to various pH levels. We show that a lowering of pH induces a better growth at low Zn²⁺ concentrations of yeast cells expressing ZIP proteins. However, no significant change in transport capacity (V_max) could be observed for HvIRT1, whereas lowering of pH from 5.5 to 4.2 increased the V_max value with 64% for HvZIP5. These results indicate that proton activity has an important role in regulating the Zn²⁺ transport capacity of Zn²⁺ specific ZIP transport proteins. This information will increase the understanding of ZIP proteins and facilitate engineering of genotypes able to grow efficiently on marginal soils.Key words: ZIP proteins, barley, zinc transport, pH     

Biosphere-atmosphere interactions of ammonia with grasslands: Experimental strategy and results from a new European initiative

A new study to address the biosphere-atmosphere exchange of ammonia (NH₃) with grasslands is applying a European transect to interpret NH₃ fluxes in relation to atmospheric conditions, grassland management and soil chemistry. Micrometeorological measurements using the aerodynamic gradient method (AGM) with continuous NH₃ detectors are supported by bioassays of the NH₃ `stomatal compensation point' (<sub>s</sub>). Relaxed eddy accumulation (REA) is also applied to enable flux measurements at one height; this is relevant to help address flux divergence due to gas-particle inter-conversion or the presence of local sources in a landscape.Continuous measurements that contrast intensively managed grasslands with semi-natural grasslands allow a scaling up from 15 min values to seasonal means. The measurements demonstrate the bi-directional nature of NH<sub>3</sub> fluxes, with typically daytime emission and small nocturnal deposition. They confirm the existence of enhanced NH<sub>3</sub> emissions (e.g. 30 g N ha<sup>–1</sup> d<sup>–1</sup>) following cutting of intensively managed swards. Further increased emissions follow fertilization with NH<sub>4</sub>NO<sub>3</sub> (typically 70 g N ha<sup>–1</sup> d<sup>–1</sup>). Measurements using REA support these patterns, but require a greater analytical precision than with the AGM.The results are being used to develop models of NH<sub>3</sub> exchange. `Canopy compensation point' resistance models reproduce bi-directional diurnal patterns, but currently lack a mechanistic basis to predict changes in relation to grassland phenology. An advance proposal here is the coupling of _s to dynamic models of grassland C–N cycling, and a relationship with modelled plant substrate-N is shown. Applications of the work include incorporation of the resistance models in NH₃ dispersion modelling and assessment of global change scenarios.