The Empower Action Model: A Framework for Preventing Adverse Childhood Experiences by Promoting Health, Equity, and Well-Being Across the Life Span.

The empower action model addresses childhood adversity as a root cause of disease by building resilience across multiple levels of influence to promote health, equity, and well-being. The model builds on the current evidence around adverse childhood experiences and merges important frameworks within key areas of public health-the socio-ecological model, protective factors, race equity and inclusion, and the life course perspective. The socio-ecological model is used as the foundation for this model to highlight the multilevel approach needed for improvement in public health.

Pulmonary particulate matter and systemic microvascular dysfunction.

Pulmonary particulate matter (PM) exposure has been epidemiologically associated with an increased risk of cardiovascular morbidity and mortality, but the mechanistic foundations for this association are unclear. Exposure to certain types of PM causes changes in the vascular reactivity of several macrovascular segments. However, no studies have focused upon the systemic microcirculation, which is the primary site for the development of peripheral resistance and, typically, the site of origin for numerous pathologies.

Targeted mutations in the Na,K-ATPase α 2 isoform confer ouabain resistance and result in abnormal behavior in mice.

Sodium and potassium-activated adenosine triphosphatases (Na,K-ATPase) are ubiquitous, participate in osmotic balance and membrane potential, and are composed of α, β, and γ subunits. The α subunit is required for the catalytic and transport properties of the enzyme and contains binding sites for cations, ATP, and digitalis-like compounds including ouabain. There are four known α isoforms; three that are expressed in the CNS in a regional and cell-specific manner.

Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous alpha2 Na+ -K+ -ATPase knockout mice.

Intracerebroventricular (ICV) infusion of NaCl mimics the effects of a high-salt diet in salt-sensitive hypertension, raising the sodium concentration in the cerebrospinal fluid (CSF [Na]) and subsequently increasing the concentration of an endogenous ouabain-like substance (OLS) in the brain. The OLS, in turn, inhibits the brain Na(+)-K(+)-ATPase, causing increases in the activity of the brain renin-angiotensin system (RAS) and blood pressure. The Na(+)-K(+)-ATPase alpha (catalytic)-isoform(s) that mediates the pressor response to increased CSF [Na] is unknown, but it is likely that one or more isoforms that bind ouabain with high affinity are involved (e.

Na,K-ATPase and the role of alpha isoforms in behavior.

The Na,K-ATPase is composed of multiple isoforms and the isoform distribution varies with the tissue and during development. The alpha1 isoform for example, is the major isoform in the kidney and many other tissues, while the alpha2 isoform is the predominate one in skeletal muscle. All three isoforms are found in the brain although in adult rodent brain, the alpha 3 isoform is located essentially in neurons while the alpha2 isoform is found in astrocytes and some limited neuronal populations.

Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice.

Several disorders have been associated with mutations in Na,K-ATPase alpha isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the alpha1 isoform is found in many cell types, the alpha2 isoform is predominantly expressed in astrocytes, and the alpha3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the alpha2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze.

Phylogenetic preservation of alpha3 Na+,K+-ATPase distribution in vertebrate peripheral nervous systems.

The alpha(3) isoform of Na(+),K(+)-ATPase is uniquely expressed in afferent and efferent neurons innervating muscle spindles in the peripheral nervous system (PNS) of adult rats, but the distribution pattern of this isoform in other species has not been investigated. We compared expression of alpha(3) Na(+),K(+)-ATPase in lumbar dorsal root ganglia (DRG), spinal roots, and skeletal muscle samples of amphibian (frog), reptilian (turtle), avian (pigeon and chicken), and mammalian (mouse and human) species. In all species studied, the alpha(3) Na(+),K(+)-ATPase isoform was nonuniformly expressed in peripheral ganglia and nerves.

Physiological role of the alpha1- and alpha2-isoforms of the Na+-K+-ATPase and biological significance of their cardiac glycoside binding site.

An interesting feature of Na+-K+-ATPase is that it contains four isoforms of the catalytic alpha-subunit, each with a tissue-specific distribution. Our laboratory has used gene targeting to define the functional role of the alpha1- and alpha2-isoforms. While knockout mice demonstrated the importance of the alpha1- and alpha2-isoforms for survival, the knockin mice, in which each isoform can be individually inhibited by ouabain and its function determined, demonstrated that both isoforms are regulators of cardiac muscle contractility.

Relative abundance of alpha2 Na(+) pump isoform influences Na(+)-Ca(2+) exchanger currents and Ca(2+) transients in mouse ventricular myocytes.

In the mouse, genetic reduction in the Na(+), K(+)-ATPase alpha1 or alpha2 isoforms results in different functional phenotypes: heterozygous alpha2 isolated hearts are hypercontractile, whereas heterozygous alpha1 hearts are hypocontractile. We examined Na(+)/Ca(2+) exchange (NCX) currents in voltage clamped myocytes (pipette [Na(+)]=15 mM) induced by abrupt removal of extracellular Na(+). In wild-type (WT) myocytes, peak exchanger currents were 0.

Genetic profiling reveals global changes in multiple biological pathways in the hearts of Na, K-ATPase alpha 1 isoform haploinsufficient mice.

The Na,K-ATPase transports three sodium ions out of the cell and two potassium ions into the cell using ATP hydrolysis for energy. The ion gradient formed by the Na,K-ATPase contributes to the resting membrane potential, maintains cellular excitability and is important for glucose and amino acid uptake in the cell. The alpha1 catalytic isoform is expressed in virtually all cell types.

Attenuation of cardiac contractility in Na,K-ATPase alpha1 isoform-deficient hearts under reduced calcium conditions.

We have previously reported that genetic reduction of the Na,K-ATPase alpha1 isoform (alpha1(+/-)) results in a hypocontractile cardiac phenotype. This observation was surprising and unexpected. In order to determine if calcium overload contributes to the depressed phenotype, cardiac performance was examined by perfusing the hearts with buffer containing 2 or 1.

The Na(+)-K(+)-ATPase alpha2-subunit isoform modulates contractility in the perinatal mouse diaphragm.

This study uses genetically altered mice to examine the contribution of the Na(+)-K(+)-ATPase alpha2 catalytic subunit to resting potential, excitability, and contractility of the perinatal diaphragm. The alpha2 protein is reduced by 38% in alpha2-heterozygous and absent in alpha2-knockout mice, and alpha1-isoform is upregulated 1.9-fold in alpha2-knockout.

Developmental induction of DHPR alpha 1s and RYR1 gene expression does not require neural or mechanical signals.

This study compares dihydropyridine receptor (DHPR) and ryanodine receptor (RyR1) gene expression in the diaphragm and hindlimb skeletal muscles of neonatal mice, and examines the contribution of neural and mechanical signals to their developmental induction in vivo. DHPR alpha 1s subunit and RyR1 protein are expressed concurrently, while their respective mRNAs are induced sequentially, with DHPR mRNA ahead of RyR1 mRNA. Both DHPR and RyR1 are more abundant in the diaphragm at birth, and become more abundant in the hindlimb at maturity.

Neural system-enriched gene expression: relationship to biological pathways and neurological diseases.

To understand the commitment of the genome to nervous system differentiation and function, we sought to compare nervous system gene expression to that of a wide variety of other tissues by gene expression database construction and mining. Gene expression profiles of 10 different adult nervous tissues were compared with that of 72 other tissues. Using ANOVA, we identified 1,361 genes whose expression was higher in the nervous system than other organs and, separately, 600 genes whose expression was at least threefold higher in one or more regions of the nervous system compared with their median expression across all organs.

Na,K-ATPase alpha 2 inhibition alters calcium responses in optic nerve astrocytes.

Experiments were conducted to test the effect of 1 microM ouabain, an Na,K-ATPase inhibitor, on capacitative calcium entry (CCE) and calcium responses elicited by ATP in rat optic nerve astrocytes. In the rat, 1 microM ouabain is sufficient to inhibit the alpha2 Na,K-ATPase, but not the alpha1. Immortalized astrocytes derived from Na,K-ATPase alpha2 homozygous knockout (KO) mice and wild-type (WT) littermates were also used.

Na(+) pump alpha 2-isoform specifically couples to contractility in vascular smooth muscle: evidence from gene-targeted neonatal mice.

The relative expression of alpha(1)- and alpha(2)-Na(+)/K(+)-ATPase isoforms found in vascular smooth muscle is developmentally regulated and under hormonal and neurogenic control. The physiological roles of these isoforms in vascular function are not known. It has been postulated that the alpha(1)-isoform serves a "housekeeping" role, whereas the alpha(2)-isoform localizes to a subsarcolemmal compartment and modulates contractility.

Urinary benzo[a]pyrene and its metabolites as molecular biomarkers of asphalt fume exposure characterized by microflow LC coupled to hybrid quadrupole time-of-flight mass spectrometry.

As a step to study the health effects of asphalt fume exposure, an analytical method was developed to characterize benzo[a]pyrene and its hydroxy metabolites in the urine of asphalt fume-exposed rats. This method is based on microflow liquid chromatography (LC) coupled to hybrid quadrupole orthogonal acceleration time-of-flight mass spectrometry (Q-TOFMS). Twenty-four female Sprague-Dawley rats were used in the experiment, with 8 as controls and 16 exposed to asphalt fumes in a whole-body inhalation chamber for 10 days (4 h/day).

Effect of asphalt fume inhalation exposure at simulated road paving conditions prior to bacterial infection on lung defense responses in rats.

Asphalt fume inhalation has been suspected of affecting immune function in exposed workers. The objective of this study was to evaluate the effect of asphalt exposure on lung immune responses in rats using a bacterial infectivity model. Pathogen-free male Sprague-Dawley rats were exposed by inhalation to asphalt fumes (72.

Functional roles of the alpha isoforms of the Na,K-ATPase.

The Na,K-ATPase is composed of two subunits, alpha and beta, and each subunit consists of multiple isoforms. In the case of alpha, four isoforms, alpha1, alpha2, alpha3, and alpha4 are present in mammalian cells. The distribution of these isoforms is tissue- and developmental-specific, suggesting that they may play specific roles, either during development or coupled to specific physiological processes.

The Na,K-ATPase alpha 2 isoform is expressed in neurons, and its absence disrupts neuronal activity in newborn mice.

Na,K-ATPase is an ion transporter that impacts neural and glial physiology by direct electrogenic activity and the modulation of ion gradients. Its three isoforms in brain have cell-type and development-specific expression patterns. Interestingly, our studies demonstrate that in late gestation, the alpha2 isoform is widely expressed in neurons, unlike in the adult brain, in which alpha2 has been shown to be expressed primarily in astrocytes.

Na,K-ATPase alpha- and beta-isoform expression in developing skeletal muscles: alpha(2) correlates with t-tubule formation.

This study examined the developmental expression of Na,K-ATPase alpha- and beta-subunit isoforms in different skeletal muscles of the mouse, and the relationship of Na,K-ATPase alpha(2) isoform expression to the developing transverse tubules (t-tubules). We measured Na,K-ATPase and dihydropyridine receptor (DHPR) mRNA and protein in the diaphragm and hindlimb muscles from embryonic day 18.5 (E18.

Altered Na,K-ATPase pattern in gamma-crystallin mutant mice.

Purpose: Na,K-adenosine triphosphatase (ATPase) activity is elevated in the lenses of murine cataract Cryge(t) and Cryge(ns) mutant mice. In the present study, the expression of Na,K-ATPase alpha1, alpha2, and alpha3 catalytic subunit polypeptides was examined in the lenses of these mutant mice.

Methods: Membrane material was isolated from lenses and brain of 3-week-old wild-type mice, as well as heterozygous and homozygous mutant mice.