Estrogen induces rapid translocation of estrogen receptor beta, but not estrogen receptor alpha, to the neuronal plasma membrane.

Estrogen receptors can activate transcription in the nucleus, and activate rapid signal transduction cascades in the cytosol. Multiple reports identify estrogen receptors at the plasma membrane, while others document the dynamic responses of estrogen receptor to ligand binding. However, the function and identity of membrane estrogen receptors remain controversial.

Estrogen replacement regimen and brain infusion of lipopolysaccharide differentially alter steroid receptor expression in the uterus and hypothalamus.

The regimen of estrogen replacement can alter the consequences of estrogen therapy and stressors. To determine the long-term effects and interaction of these systems on the brain and periphery, adult female rats were infused with lipopolysaccharide (LPS) into the fourth ventricle of the brain for 4 weeks, and ovariectomized rats were administered either constant or pulsed regimens of estrogen replacement (17beta-estradiol) until sacrifice at 8 weeks. Constant, but not pulsed, estrogen replacement reduced ERalpha and increased HSP90, HSP70, and PR(B) uterine protein levels.

Neuroprotective effects of estrogen and selective estrogen receptor modulators begin at the plasma membrane.

Estrogen is neuroprotective in a large number of models in vivo and in vitro. Its application in hormone replacement therapy has proven to be more complicated, necessitating better understanding of how estrogen signals in the brain. Estrogen binds to estrogen receptors to regulate gene transcription, and activates a number of rapid signaling cascades from the plasma membrane.

Brain infusion of lipopolysaccharide increases uterine growth as a function of estrogen replacement regimen: suppression of uterine estrogen receptor-alpha by constant, but not pulsed, estrogen replacement.

The effects of estrogen therapy can differ depending on the regimen of estrogen administration. In addition, estrogen can modulate the effects of stressors. To examine the interaction between these systems, we infused adult female rats with lipopolysaccharide (LPS) into the fourth ventricle of the brain for 6 d and compared the effects of constant and pulsed estrogen replacement.

Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection.

Estrogen reduces brain injury after experimental cerebral ischemia in part through a genomic mechanism of action. Using DNA microarrays, we analyzed the genomic response of the brain to estradiol, and we identified a transcript, cocaine- and amphetamine-regulated transcript (CART), that is highly induced in the cerebral cortex by estradiol under ischemic conditions. Using in vitro and in vivo models of neural injury, we confirmed and characterized CART mRNA and protein up-regulation by estradiol in surviving neurons, and we demonstrated that i.

Multiple pathways transmit neuroprotective effects of gonadal steroids.

Numerous preclinical studies suggest that gonadal steroids, particularly estrogen, may be neuroprotective against insult or disease progression. This paper reviews the mechanisms contributing to estrogen-mediated neuroprotection. Rapid signaling pathways, such as MAPK, PI3K, Akt, and PKC, are required for estrogen's ability to provide neuroprotection.

Nuclear-mitochondrial epistasis and drosophila aging: introgression of Drosophila simulans mtDNA modifies longevity in D. melanogaster nuclear backgrounds.

Under the mitochondrial theory of aging, physiological decline with age results from the accumulated cellular damage produced by reactive oxygen species generated during electron transport in the mitochondrion. A large body of literature has documented age-specific declines in mitochondrial function that are consistent with this theory, but relatively few studies have been able to distinguish cause from consequence in the association between mitochondrial function and aging. Since mitochondrial function is jointly encoded by mitochondrial (mtDNA) and nuclear genes, the mitochondrial genetics of aging should be controlled by variation in (1) mtDNA, (2) nuclear genes, or (3) nuclear-mtDNA interactions.

Recombination, dominance and selection on amino acid polymorphism in the Drosophila genome: contrasting patterns on the X and fourth chromosomes.

Surveys of nucleotide polymorphism and divergence indicate that the average selection coefficient on Drosophila proteins is weakly positive. Similar surveys in mitochondrial genomes and in the selfing plant Arabidopsis show that weak negative selection has operated. These differences have been attributed to the low recombination environment of mtDNA and Arabidopsis that has hindered adaptive evolution through the interference effects of linkage.

Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos.

Wnt ligands and Frizzled (Fz) receptors have been shown to activate multiple intracellular signaling pathways. Activation of the Wnt-beta-catenin pathway has been described in greatest detail, but it has been reported that Wnts and Fzs also activate vertebrate planar cell polarity (PCP) and Wnt-Ca2+ pathways. Although the intracellular protein Dishevelled (Dsh) plays a dual role in both the Wnt-beta-catenin and the PCP pathways, its potential involvement in the Wnt-Ca2+ pathway has not been investigated.

Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.

Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation.

Dapper was isolated in a screen for proteins interacting with Dishevelled, a key factor in Wnt signaling. Dapper and Dishevelled colocalize intracellularly and form a complex with Axin, GSK-3, CKI, and beta-catenin. Overexpression of Dapper increases Axin and GSK-3 in this complex, resulting in decreased soluble beta-catenin and decreased activation of beta-catenin-responsive genes.

A transgenic Lef1/beta-catenin-dependent reporter is expressed in spatially restricted domains throughout zebrafish development.

The Wnt/beta-catenin signaling pathway plays multiple roles during embryonic development, only a few of which have been extensively characterized. Although domains of Wnt expression have been identified throughout embryogenesis, anatomical and molecular characterization of responding cells has been mostly unexplored. We have generated a transgenic zebrafish line that expresses a destabilized green fluorescent protein (GFP) variant under the control of a beta-catenin responsive promoter.

Antagonistic regulation of convergent extension movements in Xenopus by Wnt/beta-catenin and Wnt/Ca2+ signaling.

Convergent extension movements are the main driving force of Xenopus gastrulation. A fine-tuned regulation of cadherin-mediated cell-cell adhesion is thought to be required for this process. Members of the Wnt family of extracellular glycoproteins have been shown to modulate cadherin-mediated cell-cell adhesion, convergent extension movements, and cell differentiation.

The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape.

Members of the vertebrate Wnt family have been subdivided into two functional classes according to their biological activities. Some Wnts signal through the canonical Wnt-1/wingless pathway by stabilizing cytoplasmic beta-catenin. By contrast other Wnts stimulate intracellular Ca2+ release and activate two kinases, CamKII and PKC, in a G-protein-dependent manner.

Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus.

Wnt ligands working through Frizzled receptors have a differential ability to stimulate release of intracellular calcium (Ca(2+)) and activation of protein kinase C (PKC). Since targets of this Ca(2+) release could play a role in Wnt signaling, we first tested the hypothesis that Ca(2+)/calmodulin-dependent protein kinase II (CamKII) is activated by some Wnt and Frizzled homologs. We report that Wnt and Frizzled homologs that activate Ca(2+) release and PKC also activate CamKII activity in Xenopus embryos, while Wnt and Frizzled homologs that activate beta-catenin function do not.

Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner.

In studies of developmental signaling pathways stimulated by the Wnt proteins and their receptors, Xenopus Wnt-5A (Xwnt-5A) and a prospective Wnt receptor, rat Frizzled 2 (Rfz2), have been shown to stimulate inositol signaling and Ca2+ fluxes in zebrafish [1] [2] [3]. As protein kinase C (PKC) isoforms can respond to Ca2+ signals [4], we asked whether expression of different Wnt and Frizzled homologs modulates PKC. Expression of Rfz2 and Xwnt-5A resulted in translocation of PKC to the plasma membrane, whereas expression of rat Frizzled 1 (Rfz1), which activates a Wnt pathway using beta-catenin but not Ca2+ fluxes [5], did not.

Predictors of lean body mass and total adipose mass in community-dwelling elderly men and women.

As part of an ongoing longitudinal study, we analyzed cross-sectional data to identify the predictors of lean body mass (LBM) and total adipose mass (TAM) in community-dwelling elderly men and women. Body composition analysis was done using dual energy x-ray absorptiometry. A total 262 subjects (118 women and 144 men), 60 to 80 years of age, from the urban and suburban communities of southeastern Wisconsin were studied.

Association of dehydroepiandrosterone sulfate, body composition, and physical fitness in independent community-dwelling older men and women.

Objectives: To determine the association of dehydroepiandrosterone sulfate (DHEAS), body composition, and physical fitness in independent community-dwelling men and women aged 60 to 80 years.

Design: Cross sectional analysis.

Participants: Independent men and women, 60 years of age and older, living in urban and suburban communities of Southeastern Wisconsin.

Physiological comparison of walking among bilateral above-knee amputee and able-bodied subjects, and a model to account for the differences in metabolic cost.

Objective: To compare the metabolic cost for prosthetic ambulation among persons with bilateral above-knee amputation with that for able-bodied ambulation, and to test a model that differentiates the metabolic cost of walking into three components.

Design: Cross-sectional comparison.

Setting: Community-dwelling subjects studied at an academic medical center.

Responses of people with coronary artery disease to common lawn-care tasks.

The primary purpose of the present study was to determine oxygen uptake (VO2) and heart rate (HR) responses of patients with coronary artery disease (CAD) to common lawn-care activities. The study was conducted in three phases. In phase I, 8 men with CAD performed 30 min of push motorized lawn mowing at a self-paced rate.

Energy expenditure during household tasks in women with coronary artery disease.

The energy expenditure for and heart rate responses to common household tasks were determined in 26 older (mean age 62 +/- 2 years) women with coronary artery disease (CAD). Each activity was performed at a self-determined pace for 6 or 8 minutes. The average oxygen uptake (ml/kg/min) for each task evaluated was 6.

Snow blowing and shoveling in normal and asymptomatic coronary artery diseased men.

We evaluated the oxygen uptake and heart-rate responses to self-paced snow blowing and snow shoveling in 10 men with asymptomatic coronary artery disease, 10 older normal men, and six younger normal men. Mean peak treadmill oxygen uptake in the three groups ranged from 26.4 +/- 1.

Effect of aerobic training on baroreflex regulation of cardiac and sympathetic function.

To investigate the effect of aerobic exercise training on baroreflex regulation of muscle sympathetic nerve activity (MSNA) and cardiac R-R intervals in a middle-aged to older population, 10 healthy men > 40 yr of age underwent tests of autonomic function before and after 12 wk of high-intensity training. Cardiac and peripheral baroslopes were determined from the R-R interval vs. mean arterial pressure (MAP) and peroneal MSNA vs.

Comparison of adaptations and compliance to exercise training between middle-aged and older men.

Objective: To compare the rate and magnitude of physiologic and psychologic adaptations to aerobic training between middle-age and older men, to assess their interest in continued participation (> 6 months) in a supervised high-intensity training program, and to evaluate the safety of high-intensity training for older people.

Design: Before-after intervention trial.

Setting: Medical center in a Midwestern metropolitan city.

Physiologic responses to shoveling and thermal stress in men with cardiac disease.

To investigate the effect of temperature stress on responses to static-dynamic work in patients with ischemic heart disease (IHD), 10 men with IHD shoveled gravel for 30 min in a warm (29 degrees C), neutral (24 degrees C), and cold (-8 degrees C) environment (on separate days). A pace of 15 lifts.min-1 was set, and the load per lift approximated 5.