Drosophila mitoferrin is essential for male fertility: evidence for a role of mitochondrial iron metabolism during spermatogenesis

<p>Abstract</p> <p>Background</p> <p>Mammals and <it>Drosophila melanogaster </it>share some striking similarities in spermatogenesis. Mitochondria in spermatids undergo dramatic morphological changes and syncytial spermatids are stripped from their cytoplasm and then individually wrapped by single membranes in an individualization process. In mammalian and fruit fly testis, components of the mitochondrial iron metabolism are expressed, but so far their function during spermatogenesis is unknown. Here we investigate the role of <it>Drosophila </it>mitoferrin (dmfrn), which is a mitochondrial carrier protein with an established role in the mitochondrial iron metabolism, during spermatogenesis.</p> <p>Results</p> <p>We found that P-element insertions into the 5'-untranslated region of the <it>dmfrn </it>gene cause recessive male sterility, which was rescued by a fluorescently tagged transgenic <it>dmfrn </it>genomic construct (<it>dmfrn^venus</it>). Testes of mutant homozygous <it>dmfrn^SH115</it>flies were either small with unorganized content or contained some partially elongated spermatids, or testes were of normal size but lacked mature sperm. Testis squashes indicated that spermatid elongation was defective and electron micrographs showed mitochondrial defects in elongated spermatids and indicated failed individualization. Using a <it>LacZ </it>reporter and the <it>dmfrn^venus</it>transgene, we found that dmfrn expression in testes was highest in spermatids, coinciding with the stages that showed defects in the mutants. Dmfrn-venus protein accumulated in mitochondrial derivatives of spermatids, where it remained until most of it was stripped off during individualization and disposed of in waste bags. Male sterility in flies with the hypomorph alleles <it>dmfrn^BG00456</it>and <it>dmfrn^EY01302</it>over the deletion <it>Df(3R)ED6277 </it>was increased by dietary iron chelation and suppressed by iron supplementation of the food, while male sterility of <it>dmfrn^SH115/Df(3R)ED6277 </it>flies was not affected by food iron levels.</p> <p>Conclusions</p> <p>In this work, we show that mutations in the <it>Drosophila </it>mitoferrin gene result in male sterility caused by developmental defects. From the sensitivity of the hypomorph mutants to low food iron levels we conclude that mitochondrial iron is essential for spermatogenesis. This is the first time that a link between the mitochondrial iron metabolism and spermatogenesis has been shown. Furthermore, due to the similar expression patterns of some mitochondrial iron metabolism genes in <it>Drosophila </it>and mammals, it is likely that our results are applicable for mammals as well.</p

LTE or non-LTE, that is the question

Strontium has proven itself to be one of the most important neutron-capture elements in the study of metal-poor stars. Thanks to the strong absorption lines of Sr, they can be detected even in the most metal-poor stars and also in low-resolution spectra. However, we still cannot explain the large star-to-star abundance scatter we derive for metal-poor stars. Here we contrast Galactic chemical evolution (GCE) with improved abundances for SrI+II including updated atomic data, to evaluate possible explanations for the large star-to-star scatter at low metallicities. We derive abundances under both local thermodynamic equilibrium (LTE) and non-LTE (NLTE) for stars spanning a large interval of stellar parameters. Gravities and metallicities are also determined in NLTE. We confirm that the ionisation equilibrium between SrI and SrII is satisfied under NLTE but not LTE, where the difference between SrI and SrII is on average ~0.3dex. We show that the NLTE corrections are of increasing importance as the metallicity decreases. For the stars with [Fe/H]>-3 the SrI NLTE correction is ~0.35/0.55dex in dwarfs/giants, while the Sr II NLTE correction is +/-0.05dex. On the basis of the large NLTE corrections, SrI should not be applied as a chemical tracer under LTE, while it is a good tracer under NLTE. SrII is a good tracer under both LTE and NLTE (down to [Fe/H]\sim -3), and LTE is a safe assumption for this majority species. However, the Sr abundance from SrII lines is dependent on an accurate surface gravity determination, which can be obtained from NLTE spectroscopy of Fe lines or from parallax measurements. We could not explain the star-to-star scatter (which remains under both LTE and NLTE) by the use of the GCE model, since the Sr yields to date are too uncertain to draw firm conclusions. At least two production sites seem necessary in order to account for this large scatter (abridged).Comment: 14 pages, 12 figures and one online table (accepted by A&A

The Gaia-ESO survey: A quiescent milky way with no significant dark/stellar accreted disc

According to our current cosmological model, galaxies like the Milky Way are expected to experience many mergers over their lifetimes. The most massive of the merging galaxies will be dragged towards the disc plane, depositing stars and dark matter into an accreted disc structure. In this work, we utilize the chemodynamical template developed in Ruchti et al. to hunt for accreted stars. We apply the template to a sample of 4675 stars in the third internal data release from the Gaia-ESO Spectroscopic Survey. We find a significant component of accreted halo stars, but find no evidence of an accreted disc component. This suggests that the Milky Way has had a rather quiescent merger history since its disc formed some 8-10 billion years ago and therefore possesses no significant dark matter disc

Этно-педагогические аспекты формирования интереса у девочек к физической культуре

The evolution of learning can be constrained by trade-offs. As male and female life-histories often diverge, the relationship between learning and fitness may differ between the sexes. However, because sexes share much of their genome, intersexual genetic correlations can prevent males and females from reaching their sex-specific optima resulting in intralocus sexual conflict (IaSC). To investigate if IaSC constraints sex-specific evolution of learning we selected Caenorhabditis remanei nematode females for increased or decreased olfactory learning performance and measured learning, lifespan (in mated and virgin worms), reproduction and locomotory activity in both sexes. Males from downward-selected female lines had higher locomotory activity and longer virgin lifespan but sired fewer progeny than males from upward-selected female lines. In contrast, we found no effect of selection on female reproduction and downward-selected females showed higher locomotory activity but lived shorter as virgins than upward-selected females. Strikingly, selection on learning performance led to the reversal of sexual dimorphism in virgin lifespan. We thus show sex-specific trade-offs between learning, reproduction and lifespan. Our results support the hypothesis that selection on learning performance can shape the evolution of sexually dimorphic life-histories via sex-specific genetic correlations

High precision abundances of the old solar twin HIP 102152: Insights on Li depletion from the oldest sun

We present the first detailed chemical abundance analysis of the old 8.2 Gyr solar twin, HIP 102152. We derive differential abundances of 21 elements relative to the Sun with precisions as high as 0.004 dex (≲1%), using ultra high-resolution (R = 110,0

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

The Expression of BAFF, APRIL and TWEAK Is Altered in Eczema Skin but Not in the Circulation of Atopic and Seborrheic Eczema Patients

The TNF family cytokines BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand) are crucial survival factors for B-cell development and activation. B-cell directed treatments have been shown to improve atopic eczema (AE), suggesting the involvement of these cytokines in the pathogenesis of AE. We therefore analyzed the expression of these TNF cytokines in AE, seborrheic eczema (SE) and healthy controls (HC). The serum/plasma concentration of BAFF, APRIL and a close TNF member TWEAK (TNF-like weak inducer of apoptosis) was measured by ELISA. The expression of these cytokines and their receptors in skin was analyzed by quantitative RT-PCR and immunofluorescence. Unlike other inflammatory diseases including autoimmune diseases and asthma, the circulating levels of BAFF, APRIL and TWEAK were not elevated in AE or SE patients compared with HCs and did not correlate with the disease severity or systemic IgE levels in AE patients. Interestingly, we found that the expression of these cytokines and their receptors was altered in positive atopy patch test reactions in AE patients (APT-AE) and in lesional skin of AE and SE patients. The expression of APRIL was decreased and the expression of BAFF was increased in eczema skin of AE and SE, which could contribute to a reduced negative regulatory input on B-cells. This was found to be more pronounced in APT-AE, the initiating acute stage of AE, which may result in dysregulation of over-activated B-cells. Furthermore, the expression levels of TWEAK and its receptor positively correlated to each other in SE lesions, but inversely correlated in AE lesions. These results shed light on potential pathogenic roles of these TNF factors in AE and SE, and pinpoint a potential of tailored treatments towards these factors in AE and SE

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci

Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention