When Goods Become Gods: Fractured Identities and the Call for Safe Spaces in Sports

What is the relationship between identity, idolatry, wholeness, and community? What are the ways in which sports culture bolsters or misdirects God-given identity? How can leaders in sports cultivate authentic, loving community that provides athletes safe spaces to explore and discern messages from the world and truth from God? In this paper, we will explore existential questions such as these. First, we will describe how identity is inherently physiological, psychological, social, and spiritual, developing subconsciously through explicit and implicit messaging. Then, we will explore the ways in which sports – organized play, human creation, and a good gift from God – can become an idol, and how idolatry both stems from and perpetuates fragmented identity. Next, we will explain what a life of wholeness means for sportspeople. Lastly, we will conclude with recommendations for leaders in sports to provide authentic and safe communities driven by love and faithfulness

Non-genomic Effects of Glucocorticoids: An Updated View

Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs ‘rapidly’ enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss (i) the non-genomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and (ii) the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index

Budesonide Enhances Agonist-Induced Bronchodilation in Human Small Airways by Increasing cAMP Production in Airway Smooth Muscle

The non-genomic mechanisms by which glucocorticoids modulate β2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX) or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation, and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease

Glucocorticoids Rapidly Activate cAMP Production via G\u3csub\u3eαs\u3c/sub\u3e to Initiate Non-Genomic Signaling That Contributes to One-Third of Their Canonical Genomic Effects

Glucocorticoids are widely used for the suppression of inflammation, but evidence is growing that they can have rapid, non-genomic actions that have been unappreciated. Diverse cell signaling effects have been reported for glucocorticoids, leading us to hypothesize that glucocorticoids alone can swiftly increase the 3′,5′-cyclic adenosine monophosphate (cAMP) production. We found that prednisone, fluticasone, budesonide, and progesterone each increased cAMP levels within 3 minutes without phosphodiesterase inhibitors by measuring real-time cAMP dynamics using the cAMP difference detector in situ assay in a variety of immortalized cell lines and primary human airway smooth muscle (HASM) cells. A membrane- impermeable glucocorticoid showed similarly rapid stimulation of cAMP, implying that responses are initiated at the cell surface. siRNA knockdown of Gαs virtually eliminated glucocorticoidstimulated cAMP responses, suggesting that these drugs activate the cAMP production via a G protein-coupled receptor. Estradiol had small effects on cAMP levels but G protein estrogen receptor antagonists had little effect on responses to any of the glucocorticoids tested. The genomic and non-genomic actions of budesonide were analyzed by RNA-Seq analysis of 24 hours treated HASM, with and without knockdown of Gαs. A 140-gene budesonide signature was identified, of which 48 genes represent a non-genomic signature that requires Gαs signaling. Collectively, this non-genomic cAMP signaling modality contributes to one-third of the gene expression changes induced by glucocorticoid treatment and shifts the view of how this important class of drugs exerts its effect

NESC Peer-Review of the Flight Rationale for Expected Debris Report

Since the loss of Columbia on February 1, 2003, the Space Shuttle Program (SSP) has significantly improved the understanding of launch and ascent debris, implemented hardware modifications to reduce debris, and conducted tests and analyses to understand the risks associated with expected debris. The STS-114 flight rationale for expected debris relies on a combination of all three of these factors. A number of design improvements have been implemented to reduce debris at the source. The External Tank (ET) thermal protection system (TPS) foam has been redesigned and/or process improvements have been implemented in the following locations: the bipod closeout, the first ten feet of the liquid hydrogen (LH2) tank protuberance air load (PAL) ramp, and the LH2 tank-to-intertank flange closeout. In addition, the forward bipod ramp has been eliminated and heaters have been installed on the bipod fittings and the liquid oxygen (LO2) feedline forward bellows to prevent ice formation. The Solid Rocket Booster (SRB) bolt catcher has been redesigned. The Orbiter reaction control system (RCS) thruster cover "butcher paper" has been replaced with a material that sheds at a low velocity. Finally, the pad area has been cleaned to reduce debris during lift-off

Lrp1 is essential for lethal Rift Valley fever hepatic disease in mice

Rift Valley fever virus (RVFV) is an emerging arbovirus found in Africa. While RVFV is pantropic and infects many cells and tissues, viral replication and necrosis within the liver play a critical role in mediating severe disease. The low-density lipoprotein receptor-related protein 1 (Lrp1) is a recently identified host factor for cellular entry and infection by RVFV. The biological significance of Lrp1, including its role in hepatic disease in vivo, however, remains to be determined. Because Lrp1 has a high expression level in hepatocytes, we developed a mouse model in which Lrp1 is specifically deleted in hepatocytes to test how the absence of liver Lrp1 expression affects RVF pathogenesis. Mice lacking Lrp1 expression in hepatocytes showed minimal RVFV replication in the liver, longer time to death, and altered clinical signs toward neurological disease. In contrast, RVFV infection levels in other tissues showed no difference between the two genotypes. Therefore, Lrp1 is essential for RVF hepatic disease in mice

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

Depression and HIV Infection are Risk Factors for Incident Heart Failure Among Veterans: Veterans Aging Cohort Study.

Background: Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among HIV+ adults. We assessed the association between HIV, depression and incident HF. Methods and Results: Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (N = 81,427; 26,908 HIV+, 54,51

Vocalization deficits in mice over-expressing alpha-synuclein, a model of pre-manifest Parkinson’s disease.

Communication and swallowing deficits are common in Parkinson’s disease (PD). Evidence indicates that voice and speech dysfunction manifest early, prior to motor deficits typically associated with striatal dopamine loss. Unlike deficits in the extremities, cranial sensorimotor deficits are refractory to standard dopamine-related pharmacological and surgical interventions, thus the mechanisms underlying vocal deficits are unclear. While neurotoxin models have provided some insight, they typically model nigrostriatal dopamine depletion and are therefore limited. Widespread alpha-synuclein (aSyn) pathology is common to familial and sporadic PD, and transgenic mouse models based on aSyn over-expression present a unique opportunity to explore vocalization deficits in relation to extra-striatal, non-dopaminergic pathologies. Specifically, mice over-expressing human wild-type aSyn under a broad neuronal promoter (Thy1-aSyn) present early, progressive motor and non-motor deficits starting at 2–3 months, followed by parkinsonism with dopamine loss at 14 months. We recorded ultrasonic vocalizations from Thy1-aSyn mice and wild-type (WT) controls at 2–3, 6–7 and 9 months. Thy1- aSyn mice demonstrated early, progressive vocalization deficits compared to WT. Duration and intensity of calls were significantly reduced and call profile was altered in the Thy1-aSyn mice, particularly at 2–3 months. Call rate trended towards a more drastic decrease with age in the Thy1-aSyn mice compared to WT. Alpha-synuclein pathology is present in the periaqueductal gray and may underlie the manifestation of vocalization deficits. These results indicate that aSyn over-expression can induce vocalization deficits at an early age in mice and provides a new model for studying the mechanisms underlying cranial sensorimotor deficits and treatment interventions for PD