Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study.

Background2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant that can bioaccumulate in humans, cross the placenta, and cause immunological effects in children, including altering their risk of developing allergies. On July 10, 1976, a chemical explosion in Seveso, Italy, exposed nearby residents to a high amount of TCDD. In 1996, the Seveso Women's Health Study (SWHS) was established to study the effects of TCDD on women's health. Using data from the Seveso Second Generation Health Study, we aim to examine the effect of prenatal exposure to TCDD on the risk of atopic conditions in SWHS children born after the explosion.MethodsIndividual-level TCDD was measured in maternal serum collected soon after the accident. In 2014, we initiated the Seveso Second Generation Health Study to follow-up the children of the SWHS cohort who were born after the explosion or who were exposed in utero to TCDD. We enrolled 677 children, and cases of atopic conditions, including eczema, asthma, and hay fever, were identified by self-report during personal interviews with the mothers and children. Log-binomial and Poisson regressions were used to determine the association between prenatal TCDD and atopic conditions.ResultsA 10-fold increase in 1976 maternal serum TCDD (log10TCDD) was not significantly associated with asthma (adjusted relative risk (RR) = 0.93; 95% CI: 0.61, 1.40) or hay fever (adjusted RR = 0.99; 95% CI: 0.76, 1.27), but was significantly inversely associated with eczema (adjusted RR = 0.63; 95% CI: 0.40, 0.99). Maternal TCDD estimated at pregnancy was not significantly associated with eczema, asthma, or hay fever. There was no strong evidence of effect modification by child sex.ConclusionsOur results suggest that maternal serum TCDD near the time of explosion is associated with lower risk of eczema, which supports other evidence pointing to the dysregulated immune effects of TCDD

Insulin direct pancreatic progenitor cell differentiation via Pdx1 regulation

poster abstractDifferentiation of early foregut endoderm into pancreatic endocrine and exocrine cells depends on a sequence of gene expression directed by various signals secreted from nearby tissue. Prior studies have shown that the pancreas is derived from Pdx1+ progenitor cells; however Pdx1 is turned off in pancreatic exocrine cells and α cells while maintained in β cells. Here, using zebrafish genetic knockdown, we showed that insulin secreted by early β cells can repress Pdx1 expression in pancreatic progenitor cells allowing them to differentiate to different pancreatic cell types. Knockdown of insulin gene severely impairs exocrine pancreas development. My results further demonstrate that inhibition of insulin signaling can induce pre-differentiation of Pdx1+ progenitor cells to β cells and Pdx1+ α cells. These Pdx1+ α cells can transdifferentiate to β cells following β cell ablation. Overall, these data represent the first in vivo evidence of local insulin signaling on pancreas development via regulation of Pdx1 expression

Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12

AbstractActivation of the type I TGF β receptor (T β R-I) requires phosphorylation of a regulatory segment known as the GS region, located upstream of the serine/threonine kinase domain in the cytoplasmic portion of the receptor. The crystal structure of a fragment of unphosphorylated T β R-I, containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12. T β R-I adopts an inactive conformation that is maintained by the unphosphorylated GS region. FKBP12 binds to the GS region of the receptor, capping the T β R-II phosphorylation sites and further stabilizing the inactive conformation of T β R-I. Certain structural features at the catalytic center of T β R-I are characteristic of tyrosine kinases rather than Ser/Thr kinases

An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation

Differences in Periodic Magnetic Helicity Injection Behavior between Flaring and Non-flaring Active Regions:Case Study

The evolution of magnetic helicity has a close relationship with solar eruptions and is of interest as a predictive diagnostic. In this case study, we analyse the evolution of the normalised emergence, shearing and total magnetic helicity components in the case of three flaring and three non-flaring active regions (ARs) using SHARPs (Spaceweather Helioseismic Magnetic Imager Active Region Patches) vector magnetic field data. The evolution of the three magnetic helicity components is analysed with wavelet transforms, revealing significant common periodicities of the normalised emergence, shearing and total helicity fluxes before flares in the flaring ARs. The three non-flaring ARs do not show such common periodic behaviour. This case study suggests that the presence of significant periodicities in the power spectrum of magnetic helicity components could serve as a valuable precursor for flares

Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

The interconversion of cell lineages via transdifferentiation is an adaptive mode of tissue regeneration and an appealing therapeutic target. However, its clinical exploitation is contingent upon the discovery of contextual regulators of cell fate acquisition and maintenance. In murine models of diabetes, glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet. However, the molecular triggers of this mode of regeneration are unknown. Here, using lineage-tracing assays in a transgenic zebrafish model of beta cell ablation, we demonstrate conserved plasticity of alpha cells during islet regeneration. In addition, we show that glucagon expression is upregulated after injury. Through gene knockdown and rescue approaches, we also find that peptides derived from the glucagon gene are necessary for alpha-to-beta cell fate switching. Importantly, whereas beta cell neogenesis was stimulated by glucose, alpha-to-beta cell conversion was not, suggesting that transdifferentiation is not mediated by glucagon/GLP-1 control of hepatic glucose production. Overall, this study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells. It further reveals that glucagon plays an important role in maintaining endocrine cell homeostasis through feedback mechanisms that govern cell fate stability

Three-dimensional checkerboard spin structure on a breathing pyrochlore lattice

The standard approach to realize a spin liquid state is through magnetically frustrated states, relying on ingredients such as the lattice geometry, dimensionality, and magnetic interaction type of the spins. While Heisenberg spins on a pyrochlore lattice with only antiferromagnetic nearest neighbors interactions are theoretically proven disordered, spins in real systems generally include longer-range interactions. The spatial correlations at longer distances typically stabilize a long-range order rather than enhancing a spin liquid state. Both states can, however, be destroyed by short-range static correlations introduced by chemical disorder. Here, using disorder-free specimens with a clear long-range antiferromagnetic order, we refine the spin structure of the Heisenberg spinel ZnFe2O4 through neutron magnetic diffraction. The unique wave vector (1, 0, 1/2) leads to a spin structure that can be viewed as alternatively stacked ferromagnetic and antiferromagnetic tetrahedra in a three-dimensional checkerboard form. Stable coexistence of these opposing types of clusters is enabled by the bipartite breathing-pyrochlore crystal structure, leading to a second order phase transition at 10 K. The diffraction intensity of ZnFe2O4 is an exact complement to the inelastic scattering intensity of several chromate spinel systems which are regarded as model classical spin liquids. Our results challenge this attribution, and suggest instead of the six-spin ring-mode, spin excitations in chromate spinels are closely related to the (1, 0, 1/2) type of spin order and the four-spin ferromagnetic cluster locally at one tetrahedron.Comment: Submitted to Phys. Rev.

Structural Changes Induced by Flash in a Single Crystal of Pr2CuO4

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Synthesis and evaluation of phosphopeptides containing iminodiacetate groups as binding ligands of the Src SH2 domain

Phosphopeptide pTyr-Glu-Glu-Ile (pYEEI) has been introduced as an optimal Src SH2 domain ligand. Peptides, Ac-K(IDA)pYEEIEK(IDA) (1), Ac-KpYEEIEK (2), Ac-K(IDA)pYEEIEK (3), and Ac-KpYEEIEK(IDA) (4), containing 0–2 iminodiacetate (IDA) groups at the N- and C-terminal lysine residues were synthesized and evaluated as the Src SH2 domain binding ligands. Fluorescence polarization assays showed that peptide 1 had a higher binding affinity (Kd = 0.6 μM) to the Src SH2 domain when compared with Ac-pYEEI (Kd = 1.7 μM), an optimal Src SH2 domain ligand, and peptides 2–4 (Kd = 2.9–52.7 μM). The binding affinity of peptide 1 to the SH2 domain was reduced by more than 2-fold (Kd = 1.6 μM) upon addition of Ni2+ (300 μM), possibly due to modest structural effect of Ni2+ on the protein as shown by circular dichroism experimental results. The binding affinity of 1 was restored in the presence of EDTA (300 μM) (Kd = 0.79 μM). These studies suggest that peptides containing IDA groups may be used for designing novel SH2 domain binding ligands. [Refer to PDF for graphical abstract

Time delays in PG1115+080: new estimates

We report new estimates of the time delays in the quadruple gravitationally lensed quasar PG1115+080, obtained from the monitoring data in filter R with the 1.5-m telescope at the Maidanak Mountain (Uzbekistan, Central Asia) in 2004-2006. The time delays are 16.4 days between images C and B, and 12 days between C and A1+A2, with image C being leading for both pairs. The only known estimates of the time delays in PG1115 are those based on observations by Schechter et al. (1997) -- 23.7 and 9.4 days between images C and B, C and A1+A2, respectively, as calculated by Schechter et al., and 25 and 13.3 days as revised by Barkana (1997) for the same image components with the use of another method. The new values of time delays in PG 1115+080 may be expected to provide larger estimates of the Hubble constant thus decreasing a diversity between the H_0 estimates taken from gravitationally lensed quasars and with other methods.Comment: 5 pages, 2 figures, Accepted for publication in MNRAS Letter