Membrane-Localized Estrogen Receptor α Is Required for Normal Organ Development and Function

SummarySteroid receptors are found in discrete cellular locations, but it is unknown whether extranuclear pools are necessary for normal organ development. To assess this, we developed a point mutant estrogen receptor α (ERα) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ERα [NOER]) show loss of rapid signaling that occurs from membrane ERα in wild-type mice. Multiple developmental abnormalities were found, including infertility, relatively hypoplastic uteri, abnormal ovaries, stunted mammary gland ductal development, and abnormal pituitary hormone regulation in NOER mice. These abnormalities were rescued in heterozygous NOER mice that were comparable to wild-type mice. mRNAs implicated in organ development were often poorly stimulated by estrogen only in homozygous NOER mice. We conclude that many organs require membrane ERα and resulting signal transduction to collaborate with nuclear ERα for normal development and function

Well-proportioned universes suppress CMB quadrupole

A widespread myth asserts that all small universe models suppress the CMB quadrupole. In actual fact, some models suppress the quadrupole while others elevate it, according to whether their low-order modes are weak or strong relative to their high-order modes. Elementary geometrical reasoning shows that a model's largest dimension determines the rough value ell_min at which the CMB power spectrum ell(ell + 1)C_ell/(2pi) effectively begins; for cosmologically relevant models, ell_min < 4. More surprisingly, elementary geometrical reasoning shows that further reduction of a model's smaller dimensions -- with its largest dimension held fixed -- serves to elevate modes in the neighborhood of ell_min relative to the high-ell portion of the spectrum, rather than suppressing them as one might naively expect. Thus among the models whose largest dimension is comparable to or less than the horizon diameter, the low-order C_ell tend to be relatively weak in well-proportioned spaces (spaces whose dimensions are approximately equal in all directions) but relatively strong in oddly-proportioned spaces (spaces that are significantly longer in some directions and shorter in others). We illustrate this principle in detail for the special cases of rectangular 3-tori and spherical spaces. We conclude that well-proportioned spaces make the best candidates for a topological explanation of the low CMB quadrupole observed by COBE and WMAP.Comment: v1: 10 pages, 1 figure. v2: improved exposition of competing mode-suppression and mode-enhancement effects, coincides with published version, 12 pages, 1 figur

Estrogen receptor-beta prevents cardiac fibrosis.

Development of cardiac fibrosis portends the transition and deterioration from hypertrophy to dilation and heart failure. Here we examined how estrogen blocks this important development. Angiotensin II (AngII) and endothelin-1 induce cardiac hypertrophy and fibrosis in humans. and we find that these agents directly stimulate the transition of the cardiac fibroblast to a myofibroblast. AngII and endothelin-1 stimulated TGFβ1 synthesis in the fibroblast, an inducer of fibrosis that signaled via c-jun kinase to Sma- and Mad-related protein 3 phosphorylation and nuclear translocation in myofibroblasts. As a result, mesenchymal proteins fibronectin and vimentin were produced, as were collagens I and III, the major forms found in fibrotic hearts. 17β-Estradiol (E2) or dipropylnitrile, an estrogen receptor (ER)β agonist, comparably blocked all these events, reversed by estrogen receptor (ER)β small interfering RNA. E2 and dipropylnitrile signaling through cAMP and protein kinase A prevented myofibroblast formation and blocked activation of c-jun kinase and important events of fibrosis. In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents. Our results establish the cardiac fibroblast as an important target for hypertrophic/fibrosis-inducing peptides the actions of which were mitigated by E2/ERβ acting in these stromal cells

Statistical isotropy of the Cosmic Microwave Background

The breakdown of statistical homogeneity and isotropy of cosmic perturbations is a generic feature of ultra large scale structure of the cosmos, in particular, of non trivial cosmic topology. The statistical isotropy (SI) of the Cosmic Microwave Background temperature fluctuations (CMB anisotropy) is sensitive to this breakdown on the largest scales comparable to, and even beyond the cosmic horizon. We propose a set of measures, $\kappa_\ell$ ($\ell=1,2,3, ...$) which for non-zero values indicate and quantify statistical isotropy violations in a CMB map. We numerically compute the predicted $\kappa_\ell$ spectra for CMB anisotropy in flat torus universe models. Characteristic signature of different models in the $\kappa_\ell$ spectrum are noted.Comment: Presented at PASCOS'03, January 3-8, 2003, in TIFR, Mumbai; to be published in a special issue of 'Pramana' (4 pages, 1 figure, style files included

Endogenous opioid modulation of pancreatic hormone secretion: Studies in dogs

The role of endogenous opioid peptides in the modulation of secretion of hormones from the endocrine pancreas was studied in dogs. In response to insulin-induced hypoglycemia, plasma glucagon secretion significantly increased, followed by an increase in plasma somatostatin immunoreactivity. Pretreatment with the opiate antagonist, naloxone, prevented the somatostatin response but had no effect on the augmented glucagon secretion. Neither the degree of hypoglycemia nor recovery from the induced glucose nadir were affected by naloxone. Arginine Hcl administration resulted in prompt increases in immunoreactive glucagon and insulin secretion, as well as a rise in serum glucose. Pretreatment with naloxone failed to affect any of these responses. Our results suggest that endogenous opioid peptides mediate the somatostatin response following hypoglycemia-induced glucagon secretion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26333/1/0000420.pd

Estrogen signaling in the cardiovascular system

Estrogen exerts complex biological effects through the two isoforms of estrogen receptors (ERs): ERα and ERβ. Whether through alteration of gene expression or rapid, plasma membrane-localized signaling to non-transcriptional actions, estrogen-activated ERs have significant implications in cardiovascular physiology. 17-β-estradiol (E2) generally has a protective property on the vasculature. Estrogen treatment is anti-atherogenic, protecting injured endothelial surfaces and lowering LDL oxidation in animal models. Increased NO production stimulated by E2 results in vasodilation of the coronary vascular bed, and involves rapid activation of phosphotidylinositol-3 kinase (PI3K)/Akt signaling to eNOS in carotid and femoral arteries. Both isoforms of ERs impact various vascular functions, modulating ion channel integrity, mitigating the response to arterial injury, inducing vasodilation, and preventing development of hypertension in animal models. In addition to reducing afterload by vasodilation, ERs have a direct antihypertrophic effect on the myocardium. E2-activated ERs (E2/ER) antagonize the hypertrophic pathway induced by vasoactive peptides such as angiotensin II by activating PI3K, subsequent MICIP gene expression, leading to the inhibition of calcineurin activity and the induction of hypertrophic genes. In models of ischemia-reperfusion, E2/ER is antiapoptotic for cardiomyocytes, exerting the protective actions via PI3K and p38 MAP kinases and suppressing the generation of reactive oxygen species. In sum, E2-activated ERs consistently and positively modulate multiple aspects of the cardiovascular system

The description of F2 at small x incorporating angular ordering

We study the perturbative QCD description of the HERA measurements of $F_2 (x, Q^2)$ using a gluon distribution that is obtained from an evolution incorporating angular ordering of the gluon emissions, and which embodies both GLAP and BFKL dynamics. We compare the predictions with recent HERA data for $F_2$. We present estimates of the charm component $F_2^c (x, Q^2)$ and of $F_L (x, Q^2)$.Comment: 8 LaTeX pages + 4 uuencoded figure

Estrogens promote misfolded proinsulin degradation to protect insulin production and delay diabetes

Summary: Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and β cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-α (ERα), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERα modulator bazedoxifene mimics CE protection of β cells in females but not in males. : Estrogens prevent diabetes in women, but the mechanism is poorly understood. Xu et al. report that estrogens activate the endoplasmic-reticulum-associated protein degradation pathway, which promotes misfolded proinsulin degradation, suppresses endoplasmic reticulum stress, and protects insulin secretion in mice and in human pancreatic β cells. Keywords: estrogens, beta cell, islet, endoplasmic reticulum stress, proinsulin misfolding, diabetes, bazedoxifene, sex dimorphism, ERAD, SER

How large is our universe?

We reexamine constraints on the spatial size of closed toroidal models with cold dark matter and the cosmological constant from cosmic microwave background. We carry out Bayesian analyses using the Cosmic Background Explorer (COBE) data properly taking into account the statistically anisotropic correlation, i.e., off-diagonal elements in the covariance. We find that the COBE constraint becomes more stringent in comparison with that using only the angular power spectrum, if the likelihood is marginalized over the orientation of the observer. For some limited choices of orientations, the fit to the COBE data is considerably better than that of the infinite counterpart. The best-fit matter normalization is increased because of large-angle suppression in the power and the global anisotropy of the temperature fluctuations. We also study several deformed closed toroidal models in which the fundamental cell is described by a rectangular box. In contrast to the cubic models, the large-angle power can be enhanced in comparison with the infinite counterparts if the cell is sufficiently squashed in a certain direction. It turns out that constraints on some slightly deformed models are less stringent. We comment on how these results affect our understanding of the global topology of our universe.Comment: 19 pages, 9 figures, version accepted for PRD. More elaborate discussion on the best-fit orientation has been adde