Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism.

Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of beta-cell function and peripheral insulin sensitivity. Among these, upregulation of Ppargamma and Tcf4 impairs insulin-secretion and beta-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate beta-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and beta-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in beta-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general

Lorentz invariance of entanglement classes in multipartite systems

We analyze multipartite entanglement in systems of spin-1/2 particles from a relativistic perspective. General conditions which have to be met for any classification of multipartite entanglement to be Lorentz invariant are derived, which contributes to a physical understanding of entanglement classification. We show that quantum information in a relativistic setting requires the partition of the Hilbert space into particles to be taken seriously. Furthermore, we study exemplary cases and show how the spin and momentum entanglement transforms relativistically in a multipartite setting.Comment: v2: 5 pages, 4 figures, minor changes to main body, journal references update

Assessing Metal Exposures in a Community near a Cement Plant in the Northeast U.S.

Abstract Cement production is a major source of metals and metalloids in the environment, while exposures to metals and metalloids may impact human health in the surrounding communities. We recruited 185 participants living in the vicinity of a cement plant in the northeast U.S., and measured the levels of aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), mercury (Hg), and selenium (Se) in blood and Hg in hair samples from them. A questionnaire was used to assess potential sources of Hg exposure. Multivariate regressions and spatial analyses were performed to evaluate the relative importance of different routes of exposures. The metal concentrations in blood or hair samples of our study participants were comparable to the U.S. general or regional population. Smoking contributed significantly to Cd and Pb exposures, and seafood consumption contributed significantly to Hg and As exposures, while variables related to the cement plant were not significantly associated with metal concentrations. Our results suggest that our study population was not at elevated health risk due to metal exposures, and that the contribution of the cement plant to metal exposures in the surrounding community was minimal

Within- and Between-Child Variation in Repeated Urinary Pesticide Metabolite Measurements over a 1-Year Period

Background: Children are exposed to pesticides from many sources and routes, including dietary and incidental ingestion, dermal absorption, and inhalation. Linking health outcomes to these exposures using urinary metabolites requires understanding temporal variability within subjects to avoid exposure misclassification. Objectives: We characterized the within- and between-child variability of urinary organophosphorus and pyrethroid metabolites in 23 participants of the Children’s Pesticide Exposure Study–Washington over 1 year and examined the ability of one to four spot urine samples to categorize mean exposures. Methods: Each child provided urine samples twice daily over 7- to 16-day sessions in four seasons in 2003 and 2004. Samples were analyzed for five pyrethroid and five organophosphorus (OP) metabolites. After adjusting for specific gravity, we used a customized maximum likelihood estimation linear mixed-effects model that accounted for values below the limit of detection to calculate intraclass correlation coefficients (ICC) and conducted surrogate category analyses. Results: Within-child variability was 2–11 times greater than between-child variability. When restricted to samples collected during a single season, ICCs were higher in the fall, winter, and spring than in summer for OPs, and higher in summer and winter for pyrethroids, indicating an increase in between-person variability relative to within-person variability during these seasons. Surrogate category analyses demonstrated that a single spot urine sample did not categorize metabolite concentrations well, and that four or more samples would be needed to categorize children into quartiles consistently. Conclusions: Urinary biomarkers of these short half-life pesticides exhibited substantial within-person variability in children observed over four seasons. Researchers investigating pesticides and health outcomes in children may need repeated biomarker measurements to derive accurate estimates of exposure and relative risks. Citation: Attfield KR, Hughes MD, Spengler JD, Lu C. 2014. Within- and between-child variation in repeated urinary pesticide metabolite measurements over a 1-year period. Environ Health Perspect 122:201–206; http://dx.doi.org/10.1289/ehp.130673

Imprinted Zac1 in neural stem cells.

Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging