Determinants of Bone and Blood Lead Levels among Minorities Living in the Boston Area

We measured blood and bone lead levels among minority individuals who live in some of Boston’s neighborhoods with high minority representation. Compared with samples of predominantly white subjects we had studied before, the 84 volunteers in this study (33:67 male:female ratio; 31–72 years of age) had similar educational, occupational, and smoking profiles and mean blood, tibia, and patella lead levels (3 μg/dL, 11.9 μg/g, and 14.2 μg/g, respectively) that were also similar. The slopes of the univariate regressions of blood, tibia, and patella lead versus age were 0.10 μg/dL/year (p < 0.001), 0.45 μg/g/year (p < 0.001), and 0.73 μg/g/year (p < 0.001), respectively. Analyses of smoothing curves and regression lines for tibia and patella lead suggested an inflection point at 55 years of age, with slopes for subjects ≥ 55 years of age that were not only steeper than those of younger subjects but also substantially steeper than those observed for individuals > 55 years of age in studies of predominantly white participants. This apparent racial disparity at older ages may be related to differences in historic occupational and/or environmental exposures, or possibly the lower rates of bone turnover that are known to occur in postmenopausal black women. The higher levels of lead accumulation seen in this age group are of concern because such levels have been shown in other studies to predict elevated risks of chronic disease such as hypertension and cognitive dysfunction. Additional research on bone lead levels in minorities and their socioeconomic and racial determinants is needed

Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells

Natural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as Mirc11 (which includes miRNA-23a, miRNA-24a, and miRNA-27a) in NK cell–mediated proinflammatory responses. Absence of Mirc11 did not alter the development or the antitumor cytotoxicity of NK cells. However, loss of Mirc11 reduced generation of proinflammatory factors in vitro and interferon-γ–dependent clearance of Listeria monocytogenes or B16F10 melanoma in vivo by NK cells. These functional changes resulted from Mirc11 silencing ubiquitin modifiers A20, Cbl-b, and Itch, allowing TRAF6-dependent activation of NF-κB and AP-1. Lack of Mirc11 caused increased translation of A20, Cbl-b, and Itch proteins, resulting in deubiquitylation of scaffolding K63 and addition of degradative K48 moieties on TRAF6. Collectively, our results describe a function of Mirc11 that regulates generation of proinflammatory cytokines from effector lymphocytes

Practical Applications of the Bioinformatics Toolbox for Narrowing Quantitative Trait Loci

Dissecting the genes involved in complex traits can be confounded by multiple factors, including extensive epistatic interactions among genes, the involvement of epigenetic regulators, and the variable expressivity of traits. Although quantitative trait locus (QTL) analysis has been a powerful tool for localizing the chromosomal regions underlying complex traits, systematically identifying the causal genes remains challenging. Here, through its application to plasma levels of high-density lipoprotein cholesterol (HDL) in mice, we demonstrate a strategy for narrowing QTL that utilizes comparative genomics and bioinformatics techniques. We show how QTL detected in multiple crosses are subjected to both combined cross analysis and haplotype block analysis; how QTL from one species are mapped to the concordant regions in another species; and how genomewide scans associating haplotype groups with their phenotypes can be used to prioritize the narrowed regions. Then we illustrate how these individual methods for narrowing QTL can be systematically integrated for mouse chromosomes 12 and 15, resulting in a significantly reduced number of candidate genes, often from hundreds to <10. Finally, we give an example of how additional bioinformatics resources can be combined with experiments to determine the most likely quantitative trait genes

NNAT is a novel mediator of oxidative stress that suppresses ER + breast cancer

Abstract Background Neuronatin (NNAT) was recently identified as a novel mediator of estrogen receptor-positive (ER+) breast cancer cell proliferation and migration, which correlated with decreased tumorigenic potential and prolonged patient survival. However, despite these observations, the molecular and pathophysiological role(s) of NNAT in ER + breast cancer remains unclear. Based on high protein homology with phospholamban, we hypothesized that NNAT mediates the homeostasis of intracellular calcium [Ca2+]i levels and endoplasmic reticulum (EndoR) function, which is frequently disrupted in ER + breast cancer and other malignancies. Methods To evaluate the role of NNAT on [Ca2+]i homeostasis, we used a combination of bioinformatics, gene expression and promoter activity assays, CRISPR gene manipulation, pharmacological tools and confocal imaging to characterize the association between ROS, NNAT and calcium signaling. Results Our data indicate that NNAT localizes predominantly to EndoR and lysosome, and genetic manipulation of NNAT levels demonstrated that NNAT modulates [Ca2+]i influx and maintains Ca2+ homeostasis. Pharmacological inhibition of calcium channels revealed that NNAT regulates [Ca2+]i levels in breast cancer cells through the interaction with ORAI but not the TRPC signaling cascade. Furthermore, NNAT is transcriptionally regulated by NRF1, PPARα, and PPARγ and is strongly upregulated by oxidative stress via the ROS and PPAR signaling cascades. Conclusion Collectively, these data suggest that NNAT expression is mediated by oxidative stress and acts as a regulator of Ca2+ homeostasis to impact ER + breast cancer proliferation, thus providing a molecular link between the longstanding observation that is accumulating ROS and altered Ca2+ signaling are key oncogenic drivers of cancer