Dietary Sodium Restriction Reverses Vascular Endothelial Dysfunction in Middle-Aged/Older Adults With Moderately Elevated Systolic Blood Pressure

ObjectivesThis study sought to determine the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP) (130–159 mm Hg) and the associated physiological mechanisms.BackgroundVascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown.MethodsSeventeen subjects (11 men and 6 women; mean age, 62 ± 7 years) completed a, randomized crossover study of 4 weeks of both low (DSR) and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4) bioavailability, and oxidative stress-associated mechanisms were assessed following each condition.ResultsUrinary sodium excretion was reduced by ∼50% (to 70 ± 30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMDBA]) and resistance (forearm blood flow responses to acetylcholine [FBFACh]) artery EDD were 68% and 42% (peak FBFACh) higher following DSR (p < 0.005). Low sodium markedly enhanced NO-mediated EDD (greater ΔFBFACh with endothelial NO synthase inhibition) without changing endothelial NO synthase expression/activation (Ser 1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (all p < 0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged.ConclusionsDSR largely reversed both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects

The Meis homeoprotein regulates the axolotl Prod 1 promoter during limb regeneration

During limb regeneration in salamanders the blastemal cells give rise only to structures distal to the level of amputation. This proximodistal identity can be regulated by ectopic expression of Meis homeoproteins or the three finger protein Prod 1 which acts at the cell surface. It has been suggested that Meis acts by regulating the transcription of Prod 1. We have sequenced the axolotl Prod 1 promoter and selected two candidate sites for binding Meis homeoproteins. The sites were mutated in various combinations in promoters expressing a luciferase reporter gene. The promoter activity was assayed by nucleofecting AL1 cells, a cultured axolotl limb cell line that expresses both Prod 1 and Meis 1 and 2. The activity of the promoter was inhibited by 60% after mutation at Meis site 1, but not at Meis site 2. The promoter constructs were electroporated into axolotl limb blastemas and the wild type promoter was more active in a proximal blastema than in a contralateral distal blastema. The wild type promoter was significantly more active than a (site 1+site 2) mutant promoter in contralateral proximal blastemas, but the promoters were equivalent in contralateral distal blastemas. The separate site 1 or site 2 mutants were not significantly different from wild type in contralateral proximal blastemas, thus contrasting with the site 1 results in AL1 cells. These data provide strong support for the hypotheses that the Prod 1 promoter is regulated on the proximodistal axis, and that Meis homeoproteins directly regulate the promoter on this axis during limb regeneration in addition to cultured cells

Solution Structure and Phylogenetics of Prod1, a Member of the Three-Finger Protein Superfamily Implicated in Salamander Limb Regeneration

Prod1 is a cell-surface molecule of the three-finger protein (TFP) superfamily involved in the specification of newt limb PD identity. The TFP superfamily is a highly diverse group of metazoan proteins that includes snake venom toxins, mammalian transmembrane receptors and miscellaneous signaling molecules..The available data suggest that Prod1, and thereby its role in encoding PD identity, is restricted to salamanders. The lack of comparable limb-regenerative capability in other adult vertebrates could be correlated with the absence of the Prod1 gene

SDSS-III: Massive Spectroscopic Surveys of the Distant Universe, the Milky Way Galaxy, and Extra-Solar Planetary Systems

Building on the legacy of the Sloan Digital Sky Survey (SDSS-I and II), SDSS-III is a program of four spectroscopic surveys on three scientific themes: dark energy and cosmological parameters, the history and structure of the Milky Way, and the population of giant planets around other stars. In keeping with SDSS tradition, SDSS-III will provide regular public releases of all its data, beginning with SDSS DR8 (which occurred in Jan 2011). This paper presents an overview of the four SDSS-III surveys. BOSS will measure redshifts of 1.5 million massive galaxies and Lya forest spectra of 150,000 quasars, using the BAO feature of large scale structure to obtain percent-level determinations of the distance scale and Hubble expansion rate at z<0.7 and at z~2.5. SEGUE-2, which is now completed, measured medium-resolution (R=1800) optical spectra of 118,000 stars in a variety of target categories, probing chemical evolution, stellar kinematics and substructure, and the mass profile of the dark matter halo from the solar neighborhood to distances of 100 kpc. APOGEE will obtain high-resolution (R~30,000), high signal-to-noise (S/N>100 per resolution element), H-band (1.51-1.70 micron) spectra of 10^5 evolved, late-type stars, measuring separate abundances for ~15 elements per star and creating the first high-precision spectroscopic survey of all Galactic stellar populations (bulge, bar, disks, halo) with a uniform set of stellar tracers and spectral diagnostics. MARVELS will monitor radial velocities of more than 8000 FGK stars with the sensitivity and cadence (10-40 m/s, ~24 visits per star) needed to detect giant planets with periods up to two years, providing an unprecedented data set for understanding the formation and dynamical evolution of giant planet systems. (Abridged)Comment: Revised to version published in The Astronomical Journa

Bone Mineral Density in Postmenopausal Women Heterozygous for the C282Y HFE Mutation

Mutations in the HFE gene may be associated with increased tissue iron stores reflected in an elevated serum ferritin. With homozygous mutation C282Y, the increase in serum ferritin may be associated with tissue damage in the liver, pancreas, and pituitary and with a reduced bone mineral density. With heterozygous mutation C282Y, the degree of iron retention is less but information relating to how a heterozygous C282Y mutation might impact bone mineral density is uncertain. The present study was undertaken to study the relationships between bone mineral density measured by dual energy X-ray absorptiometry and the serum ferritin and serum iron in postmenopausal women heterozygous for the C282Y mutation. The spinal bone mineral density, L2–4, was significantly less than age matched community controls (P=0.016). There was no significant change in the femoral neck bone mineral density compared to age matched community controls. The correlation between the spinal bone mineral density, L2–4, the femoral neck bone mineral density, and the serum ferritin was not significant. The serum iron correlated significantly inversely with the femoral neck bone mineral density (P=0.048). The heterozygous C282Y mutation may be associated with impairment of bone cell function in postmenopausal women when only small increases in the serum iron or serum ferritin have occurred

Receptor isoform specificity in a cellular-response to retinoic.

The effects of retinoic acid on cell proliferation, differentiation and patterning are thought to be mediated by the various retinoic acid receptors. Different receptor types are encoded by distinct genes (a, b, and g), whereas various isoforms within each type are encoded by splicing variants resulting from the use of alternative promoters. The only region that differs between isoforms is the N-terminal A region containing a transcriptional activating domain. It has been proposed that these alternative A regions confer distinct activities on the receptors, thus allowing each to mediate specific effects of retinoic acid, but it has been difficult to demonstrate such isoform specificity as most cells express a number of different retinoic acid receptors. In an attempt to test whether different isoforms can mediate distinct biological effects we are focusing on retinoic-acid-dependent growth inhibition of newt limb cells. We have constructed chimaeric receptors in which the retinoic acid binding domain of each of five newt retinoic acid receptors has been replaced with a thyroid hormone (T3) binding domain. These constructs were introduced individually into cells whose growth rate was then measured in the presence of T3. The chimaeric a1 receptor mediated T3-dependent inhibition of proliferation that was comparable to that given by retinoic acid, whereas the a2 isoform had no activity in this assay, nor did the d1A, d1B and d2 receptors. When the A region was deleted from the a1 chimaera it remained a potent T3-dependent transcriptional activator, but no longer mediated T3-dependent growth inhibition. In contrast, when the A region of a1 was transferred to a d chimaeric receptor, the resulting molecule was fully active in T3-dependent growth inhibition. This is the first direct evidence for isoform specificity in a biological response to retinoic acid, and demonstrates that the specificity of this response is confined to the A region