Steroid Receptors and Vertebrate Evolution

Considering that life on earth evolved about 3.7 billion years ago, vertebrates are young, appearing in the fossil record during the Cambrian explosion about 542 to 515 million years ago. Results from sequence analyses of genomes from bacteria, yeast, plants, invertebrates and vertebrates indicate that receptors for adrenal steroids (aldosterone, cortisol), and sex steroids (estrogen, progesterone, testosterone) also are young, with receptors for estrogens and 3-ketosteroids first appearing in basal chordates (cephalochordates: amphioxus), which are close ancestors of vertebrates. An ancestral progesterone receptor and an ancestral corticoid receptor, the common ancestor of the glucocorticoid and mineralocorticoid receptors, evolved in jawless vertebrates (cyclostomes: lampreys, hagfish). This was followed by evolution of an androgen receptor and distinct glucocorticoid and mineralocorticoid receptors in cartilaginous fishes (gnathostomes: sharks). Adrenal and sex steroid receptors are not found in echinoderms: and hemichordates, which are ancestors in the lineage of cephalochordates and vertebrates. The presence of steroid receptors in vertebrates, in which these steroid receptors act as master switches to regulate differentiation, development, reproduction, immune responses, electrolyte homeostasis and stress responses, argues for an important role for steroid receptors in the evolutionary success of vertebrates, considering that the human genome contains about 22,000 genes, which is not much larger than genomes of invertebrates, such as Caenorhabditis elegans (~18,000 genes) and Drosophila (~14,000 genes).Comment: 18 pages, 5 figure

Insights from the Structure of Estrogen Receptor into the Evolution of Estrogens: Implications for Endocrine Disruption

In the last decade, there has been important progress in understanding the origins and evolution of receptors for adrenal steroids (aldosterone, cortisol) and sex steroids (estradiol, progesterone, testosterone) due to the sequencing of genomes from animals that are at key sites in vertebrate evolution. Although the estrogen receptor [ER] appears to be the ancestral vertebrate steroid receptor and estradiol [E2] is the physiological ligand for vertebrate ERs, the identity of the ancestral ligand(s) for the ER remains unknown. Here, using an analysis of crystal structures of human ER[alpha] with E2 and other chemicals and 3D models of human ER[alpha] with 27-hydroxycholesterol and 5-androsten-3[beta],17[beta]-diol, we propose that one or more [DELTA]5 steroids were the ancestral ligands for the ER, with E2 evolving later as the canonical estrogen. The evidence that chemicals with a [beta]-hydroxy at C3 in a saturated A ring can act as estrogens and the conformational flexibility of the vertebrate ER can explain the diversity of synthetic chemicals that disrupt estrogen responses by binding to vertebrate ERs

Trichoplax, the simplest known animal, contains an estrogen-related receptor: Implications for the evolution of vertebrate and invertebrate estrogen receptors

Although, as their names imply, vertebrate and invertebrate estrogen receptors [ERs] and estrogen-related receptors [ERRs] are related transcription factors, their evolutionary relationships to each other are not fully understood. We searched recently sequenced genome of _Trichoplax_, the simplest known animal, and genomes from three lophotrochozoans: _Capitella_, a worm, _Helobdella robusta_, a leech, and _Lottia gigantea_, a snail, to elucidate the origins and evolution of ERs and ERRs. BLAST found an ERR in _Trichoplax_, but no ER. BLAST searches of the lophotrochozaons found ERRs in all three and invertebrate ERs in _Capitella_ and _Lottia_, but not in _Helobdella_. These database searches and a phylogenetic analyses indicate that invertebrate ERs arose in a protostome, and vertebrate ERs arose later in deuterostome

Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors

Recent sequencing of amphioxus and sea urchin genomes has provided important data for understanding the origins of enzymes that synthesize adrenal and sex steroids and the receptors that mediate physiological response to these vertebrate steroids. Phylogenetic analyses reveal that CYP11A and CYP19, which are involved in the synthesis of adrenal and sex steroids, first appear in the common ancestor of amphioxus and vertebrates. This correlates with recent evidence for the first appearance in amphioxus of receptors with close similarity to vertebrate steroid receptors. Other CYP450 enzymes involved in steroid synthesis can be traced back to invertebrates, in which they have at least two functions: detoxifying xenobiotics and catalyzing the synthesis of sterols that activate nuclear receptors. CYP450 metabolism of hydrophobic xenobiotics may have been a key event in the origin of ligand-activated steroid receptors from constitutively active nuclear receptors

Measuring the Delivery Costs of Prepurchase Homeownership Education and Counseling

In order to understand the roles that public policy and the business and consumer sectors play in paying for homeownership education and counseling, the costs, benefits and beneficiaries of the education and training must be fully accounted for. This paper estimates the total costs of delivering homeownership education and counseling and discusses proven and implied benefits to stakeholders. Based on one set of assumptions, and depending on the level of activities offered, homeownership education and counseling costs range from $500 to$1,500. Empirical and anecdotal evidence suggest that homeownership education and counseling offer important benefits to borrowers, lenders, real estate professionals and communities. Many nonprofit organizations providing such services, however, remain underfunded. Providers, financial institutions and policy makers must increase their knowledge of what works, what costs are incurred, who benefits, and what value is created by homeownership education and counseling activities in order to develop a sustainable delivery system.This paper uses information from NeighborWorks organizations that offer homeownership education and counseling programs as illustration of the cost structure of the homeownership education and counseling industry. Part 2 provides background information on the homeownership education and counseling industry. Part 3 explains the methodology and assumptions used for this analysis. Part 4 reviews cost accounting and presents a framework for the cost analysis. Part 5 discusses the value proposition for homeownership education and counseling while Part 6 offers conclusions and implications

Motif analysis of amphioxus, lamprey and invertebrate estrogen receptors and amphioxus and human estrogen-related receptors: Towards a better understanding of estrogen receptor evolution

*Background.* The origins of steroid-dependent regulation of the vertebrate estrogen receptor (ER) are poorly understood. Genes with statistically significant sequence similarity to vertebrate ERs have been found in lamprey, a basal vertebrate, and amphioxus, a basal chordate. Motif analysis of these sequences provides an opportunity to investigate early events in the evolution of the ER.
*Results.* We used artificial intelligence-based software to construct twelve motifs specific to the estrogen-binding domain of ER[alpha] and ER[beta] in land vertebrates and teleosts. We mapped these ER-specific motifs onto the sequences of lamprey, amphioxus, invertebrate and selected vertebrate ERs and amphioxus, Ciona and human estrogen-related receptor (ERR). We find that lamprey ER contains eleven motifs common to ERs in the training set. In contrast, amphioxus ER contains only six motifs. Various invertebrate ERs contain either six or seven motifs. Unexpectedly, human and amphioxus ERRs contain nine of the twelve motifs, despite extensive sequence divergence during the descent of chordate ERs and ERRs from a common ancestor. We mapped the twelve motifs onto a multiple alignment of human, lamprey and amphioxus ERs, which depicted residues in human ER[alpha] that are known to bind estradiol. There is excellent conservation of these key residues in lamprey ER and poor conservation in amphioxus ER. Out of seventeen residues on human ER[alpha] that bind estradiol, sixteen and six are identical in lamprey and amphioxus ER, respectively. A phylogenetic tree of ERs and ERRs reveals a long branch for amphioxus ER, which is in agreement with the low sequence and motif similarity between amphioxus ER and other ERs.
*Conclusions.* There are significant differences between _B. floridae_ ER and vertebrate ERs in the steroid-binding domain as measured by motif analysis and percent of amino acids that are known to stabilize estradiol in human ER[alpha]. The absence in lamprey ER of motif 10, which maps to the C-terminus half of [alpha]-helix 9, may be important in recognition of novel estrogens, such as 15[alpha]-hydroxy-estradiol. 
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Variations on the Vev Flip-Flop: Instantaneous Freeze-out and Decaying Dark Matter

In this work we consider a simple model for dark matter and identify regions of parameter space where the relic abundance is set via kinematic thresholds, which open and close due to thermal effects. We discuss instantaneous freeze-out, where dark matter suddenly freezes-out when the channel connecting dark matter to the thermal bath closes, and decaying dark matter, where dark matter freezes-out while relativistic and later decays when a kinematic threshold temporarily opens. These mechanisms can occur in the vicinity of a one-step or a two-step phase transition. In all cases thermal effects provide this dynamic behaviour, while ensuring that dark matter remains stable until the present day.Comment: 23 pages, 13 figures; v2: version matched to journal (JHEP), added a detailed discussion of further two-to-two processe

Duration Dependence and Nonparametric Heterogeneity: A Monte Carlo Study

We examine the behaviour of the nonparametric maximum likelihood estimator (NPMLE) for a discrete duration model with unobserved heterogeneity and unknown duration dependence. We find that a nonparametric specification of either the duration dependence or unobserved heterogeneity, when the other feature of the hazard is known to be absent, leads to estimators that are well behaved even in modestly sized samples. In contrast, there is a large and systematic bias in the parameters of these components when both are specified nonparametrically, as well as a complementary bias in the coefficients on observed heterogeneity. Furthermore, these biases diminish very gradually as sample size increases. We find that a minor modification of the quasilikelihood that penalizes specifications with many points of support leads to a dramatic improvement.Duration model, unobserved heterogeneity, NPMLE

Earnings Dynamics and Inequality among Canadian Men, 1976-1992: Evidence from Longitudinal Income Tax Records

Several recent studies have found that earnings inequality in Canada has grown considerably since the late 1970's. Using an extraordinary data base drawn from longitudinal income tax records, we decompose this growth in earnings inequality into its persistent and transitory components. We find that the growth in earnings inequality reflects both an increase in long-run inequality and an increase in earnings instability. The large size of our earnings panel allows us to estimate and test richer models of earnings dynamics than could be supported by the relatively small panel surveys used in U.S. research. The Canadian data strongly reject several restrictions commonly imposed in the U.S. literature, and they also suggest that imposing these evidently false restrictions may lead to distorted inferences about earnings dynamics and inequality trends.