Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

<p>Abstract</p> <p>Background</p> <p>Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.</p> <p>Methods</p> <p>Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: <it>HFE </it>[hemochromatosis], <it>TF </it>[transferrin], and <it>ALAD </it>[δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.</p> <p>Results</p> <p>Percentage of participants carrying at least one copy of <it>HFE C282Y</it>, <it>HFE H63D</it>, <it>TF P570S</it>, and <it>ALAD K59N </it>variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either <it>C282Y </it>or <it>H63D </it>allele in <it>HFE </it>gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any <it>HFE </it>variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). <it>TF </it>and <it>ALAD </it>variants were not significant predictors of blood manganese. In animal models, <it>Hfe</it>^-/-mice displayed a significant reduction in blood manganese compared with <it>Hfe</it>^+/+mice, replicating the altered manganese metabolism found in our human research.</p> <p>Conclusions</p> <p>Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.</p

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

British India and British Scotland, 1780-1830: Career-Building, Empire-Building, and a Scottish School of Thought on Indian Governance

“This [book] holds significance for scholars of intellectual history in the fields of both Britain and British colonial India. It shows well how the Scottish educational system, based on the Scottish Enlightenment, shaped the thinking and promotion rate of three important officials in the East India Company throughout their influential careers.” —Michael Fisher, Oberlin College “This is a valuable contribution to the field of British imperialism in South Asia. Scholars interested in the English-Scottish relations during this period, especially as they pertain to the empire, will also likely read this with profit.” —Lynn Zastoupil, Rhodes Collegehttps://ideaexchange.uakron.edu/uapress_publications/1063/thumbnail.jp

Does Family Planning Increase Children's Opportunities? Evidence from the War on Poverty and the Title X

This paper examines the relationship between parents’ access to family planning and the economic resources of the average child. Using the county-level introduction of U.S. family planning programs between 1964 and 1973, we find that children born after programs began had 2.5% higher household incomes. They werealso 7% less likely to live in poverty and 11% less likely to live in households receiving public assistance.Even with extreme assumptions about selection, these estimates are large enough to imply that familyplanning programs directly increased children’s resources, including increases in mothers’ paid work andincreased childbearing within marriage

Does Access to Family Planning Increase Children’s Opportunities?

This paper examines the relationship between parents' access to family planning and the economic resources of their children. Using the county-level introduction of U.S. family planning programs between 1964 and 1973, we find that children born after programs began had 2.8% higher household incomes. They were also 7% less likely to live in poverty and 12% less likely to live in households receiving public assistance. A bounding exercise suggests that the direct effects of family planning programs on parents' resources account for roughly two-thirds of these gains

Reduced spermatogonial proliferation and decreased fertility in mice overexpressing cyclin E in spermatogonia

Cyclin E is a key component of the cell cycle regulatory machinery, contributing to the activation of Cdk2 and the control of cell cycle progression at several stages. Cyclin E expression is tightly regulated, by periodic transcription and ubiquitin-mediated degradation. Overexpression of cyclin E has been associated with tumor development and poor prognosis in several tumor types, including germ cell tumors and both cyclin E and its partner Cdk2 are required for normal spermatogenesis. Here we have generated and characterized transgenic mice overexpressing a cyclin E mutant protein, resistant to ubiquitin-mediated proteolysis, in testicular germ cells, under the control of the human EF-1alpha promoter. The transgenic mice develop normally and live a normal life span, with no signs of testicular tumor development. The transgenic mice display however reduced fertility and testicular atrophy, due to reduced spermatogonial proliferation as a consequence of deregulated cyclin E levels. Overall our results show that deregulation of cyclin E expression contribute to infertility, due to inability of the spermatogonial cells to start the mitotic cycles prior to entering meiosis