The Ever-Changing Social Perception of Autism Spectrum Disorder in the United States

Danielle Martin is the winner of the 2012 Michael F. Bassman Honors Thesis Award.This paper aims to examine the comprehensive social perception of autism spectrum disorders (ASDs) within the United States today. In order to study the broad public view of those with ASDs, this study investigates the evolution of the syndrome in both sociological and scientificrealms. By drawing on the scientific progression of the syndrome and the mixture of this research with concurrent social issues and media representations, this study infers why such a significant amount of stigmatization has become attached to those with ASDs and how these stigmatizations have varied throughout history. After studying this evolving social perception of ASDs in the United States, the writer details suggestions for the betterment of this awareness, including boosted and specified research efforts, increased collaboration within those experts in autism, and positive visibility of those with ASDs and their families. Overall, the writer suggests that public awareness has increased and thus negative stigmatization has decreased in recent years; however, there remains much to be done to increase general social understanding of ASDs

Multiple Kinase Involvement in the Regulation of Vascular Growth

The initial discovery of protein phosphorylation as a regulatory mechanism for the control of glycogen metabolism has led to intense interest of protein phosphorylation in regulating protein function (Cohen et al., 2001). Kinases play a variety of roles in many physiological processes within cells and represent one of the largest families in the human genome with over 500 members comprising protein serine/threonine, tyrosine, and dual-specificity kinases (Manning et al., 2002). Phosphorylation of proteins is one of the most significant signal transduction mechanisms which regulate intracellular processes such as transport, growth, metabolism, apoptosis, cystoskeletal arrangement and hormone responses (Bononi et al., 2011; Heidenreich et al., 1991; Manning et al., 2002; Pawson et al., 2000). As such, abnormal phosphorylation of proteins can be either a cause or a consequence of disease. Kinases are regulated by activator and inhibitor proteins, ligand binding, and phosphorylation by other proteins or via autophosphorylation (Hanks et al., 1991; Hug et al., 1993; Scott, 1991; Taylor et al., 1990; Taylor et al., 1992). Since kinases play key functions in many cellular processes, they represent an attractive target for therapeutic interventions in many disease states such as cancer, inflammation, diabetes and arthritis (Cohen et al., 2010; Fry et al., 1994; Karin, 2005; Mayers et al., 2005). In particular, the serine/threonine family of kinases comprises approximately 125 of the 500 family of kinases and includes the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), and protein kinase C (PKC). These kinases are implicated in the regulation of cell growth and are the focus of this current study.We would like to acknowledge Jonathan C. Fox and Patti Shaver for assistance with isolation and culture of rat primary vascular smooth muscle cells. This project was supported by Award Number R01HL081720 from the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI), by ARRA Award Number R01HL081720-03S2, and by Post-doctoral Research Supplement Award Number R01HL081720-05S1 from the NHLBI

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders

Germ Cell Recovery, Cryopreservation and Transplantation in the California white sturgeon, Acipenser transmontanus

The white sturgeon (Acipenser transmontanus) is the largest freshwater fish in North America. Because of the unique life history characteristics of sturgeon, including longevity, late maturation and long spawning intervals, their aquaculture can be a significant investment of resources. As a result of habitat loss and overharvesting, natural populations of white sturgeon are threatened and there is a growing effort to improve conservation aquaculture programs. Germ cell transplantation is an innovative technology previously demonstrated in a variety of fish species to be able to produce a surrogate broodstock. The technique relies upon optimal donor germ cell recovery and transplantation into a recipient fish. In this study, we developed and optimized the harvest of donor cells for germline transplantation and evaluated methods for ovary cryopreservation for the first time in the white sturgeon. We found that harvesting gonads from juveniles between the ages of 1.5 and 2.5-years resulted in reliably high proportions of pre-meiotic cells regardless of sex, a critical feature for using white sturgeon for transplantation studies since the species shows no distinguishing external sex characteristics. From the viable cells, we identified germline cells using immunolabeling with the antibody DDX4, a marker specific to the germline. For in vivo tracking of donor cells during transplantations, gonadal cells were stained with a long half-life non-toxic cell membrane dye, PKH26, and microinjected into the peritoneal cavity of newly hatched white sturgeon larvae. Larvae were reared until 3 months post-transplantation to monitor for colonization and proliferation of PKH26-labeled cells within the recipient larval gonads. Furthermore, viable cell detection, assessment of germline-specificity, and transplantation was determined for cells recovered from cryopreserved ovarian tissue from sexually immature females. Transplantations using cells cryopreserved with media supplemented with dimethyl sulfoxide (DMSO) rather than ethylene glycol (EG) demonstrated the highest number of PKH26-labeled cells distributed along the gonadal ridges of the larval recipient. Determining optimal methods of tissue cryopreservation, and germ cell recovery and transplantation are foundational to the future development of germ cell transplantation as a strategy to improve the aquaculture and conservation of this species. Our study demonstrates that conservation actions, such as surrogate breeding, could be utilized by hatcheries to retain or improve natural gamete production without genetic modification, and provide an encouraging approach to the management of threatened sturgeon species

Control of Vascular Smooth Muscle Cell Growth by Connexin 43

Connexin 43 (Cx43), the principal gap junction protein in vascular smooth muscle cells (VSMCs), regulates movement of ions and other signaling molecules through gap junction intercellular communication (GJIC) and plays important roles in maintaining normal vessel function; however, many of the signaling mechanisms controlling Cx43 in VSMCs are not clearly described. The goal of this study was to investigate mechanisms of Cx43 regulation with respect to VSMC proliferation. Treatment of rat primary VSMCs with the cAMP analog 8Br-cAMP, the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 (BAY), or the Cx inducer diallyl disulfide (DADS) significantly reduced proliferation after 72 h compared with vehicle controls. Bromodeoxyuridine uptake revealed reduction (p < 0.05) in DNA synthesis after 6 h and flow cytometry showed reduced (40%) S-phase cell numbers after 16 h in DADS-treated cells compared with vehicle controls. Cx43 expression significantly increased after 270 min treatment with 8Br-cAMP, 8Br-cGMP, BAY or DADS. Inhibition of PKA, PKG or PKC reversed 8Br-cAMP-stimulated increases in Cx43 expression, whereas only PKG or PKC inhibition reversed 8Br-cGMP- and BAY-stimulated increases in total Cx43. Interestingly, stimulation of Cx43 expression by DADS was not dependent on PKA, PKG or PKC. Using fluorescence recovery after photobleaching, only 8Br-cAMP or DADS increased GJIC with 8Br-cAMP mediated by PKC and DADS mediated by PKG. Further, DADS significantly increased phosphorylation at MAPK-sensitive Serine (Ser)255 and Ser279, the cell cycle regulatory kinase-sensitive Ser262 and PKC-sensitive Ser368 after 30 min while 8Br-cAMP significantly increased phosphorylation only at Ser279 compared with controls. This study demonstrates that 8Br-cAMP- and DADS-enhanced GJIC rather than Cx43 expression and/or phosphorylation plays important roles in the regulation of VSMC proliferation and provides new insights into the growth-regulatory capacities of Cx43 in VSM

MW151 Inhibited IL-1β Levels After Traumatic Brain Injury with No Effect on Microglia Physiological Responses

A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI). In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5–5.0 mg/kg) administration of MW151 suppresses interleukin-1 beta (IL-1β) levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1β increases while sparing other glial responses to injury

The C. elegans ephrin EFN-4 functions non-cell autonomously with heparan sulfate proteoglycans to promote axon outgrowth and branching

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body wall muscle, and in parallel with HS biosynthesis genes and HSPG core proteins, which function cell autonomously in the AIY neurons. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system

More than clean air and tranquillity: residential green is independently associated with decreasing mortality

Green space may improve health by enabling physical activity and recovery from stress or by decreased pollution levels. We investigated the association between residential green (greenness or green space) and mortality in adults using the Swiss National Cohort (SNC) by mutually considering air pollution and transportation noise exposure. To reflect residential green at the address level, two different metrics were derived: normalised difference vegetation index (NDVI) for greenness, and high resolution land use classification data to identify green spaces (LU-green). We used stratified Cox proportional hazard models (stratified by sex) to study the association between exposure and all natural cause mortality, respiratory and cardiovascular disease (CVD), including ischemic heart disease, stroke and hypertension related mortality. Models were adjusted for civil status, job position, education, neighbourhood socio-economic position (SEP), geographic region, area type, altitude, air pollution (PM10), and transportation noise. From the nation-wide SNC, 4.2 million adults were included providing 7.8years of follow-up and respectively 363,553, 85,314 and 232,322 natural cause, respiratory and CVD deaths. Hazard ratios (and 95%-confidence intervals) for NDVI [and LU-green] per interquartile range within 500m of residence were highly comparable: 0.94 (0.93-0.95) [0.94 (0.93-0.95)] for natural causes; 0.92 (0.91-0.94) [0.92 (0.90-0.95)] for respiratory; and 0.95 (0.94-0.96) [0.96 (0.95-0.98)] for CVD mortality. Protective effects were stronger in younger individuals and in women and, for most outcomes, in urban (vs. rural) and in the highest (vs. lowest) SEP quartile. Estimates remained virtually unchanged after incremental adjustment for air pollution and transportation noise, and mediation by these environmental factors was found to be small. We found consistent evidence that residential green reduced the risk of mortality independently from other environmental exposures. This suggests the protective effect goes beyond the absence of pollution sources. Environmental public health measures should not only aim at reducing pollutant exposure, but additionally maintain existing and increase residential green in areas where lacking