Rock \u27 n\u27 Roll in the 1950s: Rockin\u27 for Civil Rights

This thesis has three parts, a historiography and original research into the impact of rock and roll on civil rights in history, original research, and ending with publishable teaching materials on Rock \u27n\u27 Roll and the Civil Rights Movement that will take seven class periods to complete. Five of these class periods are set aside for the students to complete a pod cast for the summative assessment portion of the unit. The lessons are planned for seventy-two minute block classes but can easily be adapted to any class period length

Identification de nouveaux substrats de la voie Ras-MAP Kinase

ERK1 et ERK2 (ERK1/2) sont des kinases membres de la voie de signalisation Ras-MAP Kinase impliquées dans la régulation de la croissance, de la division ainsi que de la différenciation des cellules. Bien que le rôle crucial de la voie MAP Kinase dans ces fonctions soit bien documenté, les mécanismes à son origine le sont moins. Ainsi, de nombreux effecteurs en aval de ces kinases continuent à ce jour d’être identifiés et caractérisés. Dans un effort pour identifier de nouveaux substrats des kinases ERK1/2, deux études phosphoprotéomiques à grande échelle furent effectuées par notre laboratoire et ont permis d’identifier plus d’une centaine de nouveaux substrats potentiels. Parmi ceux-ci se retrouvent notamment des régulateurs de l’épissage alternatif de l’ARN messager. Les mécanismes de régulation de ce processus par les voies de signalisation ne sont cependant toujours pas bien caractérisés. La première étude de cette thèse s’intéresse ainsi à la validation de ces nouveaux substrats de ERK1/2. Nous avons notamment identifié et validé les régulateurs de l’épissage CDK12, RNPS1, MBNL2 et SRPK2 comme de nouveaux substrats de ERK1/2 par essai kinase in vitro. En regard au rôle potentiel qu’une régulation de ces substrats par la voie MAP Kinase pourrait avoir, nous avons étudié les étapes précoces de la différenciation telle qu’entraînée par l’expression de la kinase ERK1 dans un modèle de cellules souches embryonnaires murines déficientes en ERK1/2. Nous avons identifié une soixantaine de transcrits épissés de manière différentielle suivant l’expression de ERK1, dont notamment ceux de DNMT3b et de la delta-caténine. Nous avons ainsi observé une diminution de l’épissage du transcrit de DNMT3b en réponse à l’activité ERK1, menant à une augmentation de l’expression de l’enzyme avec l’exon encodant le domaine catalytique. La dernière étude de cette thèse porte finalement sur l’identification de la beta-caténine comme nouveau substrat de MEK1/2. Nos expériences suggèrent que cette phosphorylation survient de manière prédominante sur la thréonine 472 et que ce site a un rôle important dans la stabilité de la protéine. Ainsi, cette thèse édifie, d’une part, les bases d’une régulation à grande échelle de l’épissage alternatif par les MAP Kinases ERK1/2, et d’autre part révèle un nouvel élément de régulation entre la voie Wnt/beta-caténine et la voie MAP Kinase par l’identification de la beta-caténine comme nouveau substrat de MEK1/2.ERK1 and ERK2 (ERK1/2) are members of the Ras-dependent MAP Kinase pathway involved in the regulation of cell proliferation, differentiation and survival. While the roles of these MAP Kinases in the control of these functions are now well documented, the mechanisms behind them are often poorly described. Therefore, many effectors downstream of these kinases are still being identified and characterized. To identify new substrates of the ERK1/2 kinases, two large-scale phosphoproteomic studies were performed by our laboratory and allowed us to identify over a hundred new putative substrates. Among these are some alternative splicing regulators. The mechanisms governing the regulation of this process by upstream signaling pathways aren’t quite well understood yet. The first study within this thesis focuses on the validation of these new substrates of ERK1/2. Namely, we identified and validated that the splicing factors CDK12, RNPS1, MBNL2 and SRPK2 are novel substrates of ERK1/2 by in vitro kinase assay. Regarding the potential role that a regulation of these factors by the MAP Kinase pathway might have, we studied the early stages of differentiation as driven by the expression of the ERK1 kinase in a ERK1/2 DKO embryonic stem cells murine model. We identified 60 alternatively spliced transcripts following ERK1 expression, including those from DNMT3b and delta-catenin expression. We notably observed a decrease in the splicing of the DNMT3b transcript in response to ERK1 activity, leading to an increase in the expression of the enzyme with the exon coding the catalytic domain. The last part of this thesis revolves around the identification and characterization of beta-catenin as a novel substrate of MEK1/2. Our research suggest that this phosphorylation occurs predominantly on threonine 472 and that this site is important in maintaining the stability of the protein. This thesis lays the ground work for a global understanding on how the MAP Kinases ERK1/2 regulates alternative splicing on one hand, and also defines a novel element of regulation between the Wnt/beta-catenin and the MAP Kinase pathway by identifying beta-catenin as a new substrate of MEK1/2

Origins of the 1/4 keV Soft X-Ray Background

Snowden and coworkers have presented a model for the 1/4 keV soft X-ray diffuse background in which the observed flux is dominated by a ~ 10^6 K thermal plasma located in a 100-300 pc diameter bubble surrounding the Sun, but has significant contributions from a very patchy Galactic halo. Halo emission provides about 11% of the total observed flux and is responsible for half of the H I anticorrelation. The remainder of the anticorrelation is presumably produced by displacement of disk H I by the varying extent of the local hot bubble (LHB). The ROSAT R1 and R2 bands used for this work had the unique spatial resolution and statistical precision required for separating the halo and local components, but provide little spectral information. Some consistency checks had been made with older observations at lower X-ray energies, but we have made a careful investigation of the extent to which the model is supported by existing sounding rocket data in the Be (73-111 eV) and B bands (115-188 eV) where the sensitivities to the model are qualitatively different from the ROSAT bands. We conclude that the two-component model is well supported by the low-energy data. We find that these combined observations of the local component may be consistent with single-temperature thermal emission models in collisional ionization equilibrium if depleted abundances are assumed. However, different model implementations give significantly different results, offering little support for the conclusion that the astrophysical situation is so simple.Comment: 17 pages, 6 figures, accepted by the Astrophysical Journa

Pharmacological targeting of β-adrenergic receptor functions abrogates NF-κB signaling and MMP-9 secretion in medulloblastoma cells

Targeting of the vascular endothelium compartment explains, in part, the therapeutic efficacy of the nonselective β-adrenergic antagonist propranolol against common endothelial tumors such as hemangiomas. In vitro, the antiangiogenic biological activity of propranolol was shown to inhibit human brain microvascular endothelial cell tubulogenesis. However, possible interference of propranolol with cell signaling associated with the tumoral compartment remains unexplored. We therefore assessed the potency of propranolol against a pediatric brain tumor- derived DAOY medulloblastoma cell model. Gene expression of β1-, β2-, and β3-adrenergic receptors was confirmed in DAOY cells by semiquantitative RT-PCR. We next found that propranolol dose-dependently inhibited induction of the key extracellular matrix-degrading and blood–brain barrier disrupting enzyme matrix metalloproteinase- 9 (MMP-9) by phorbol 12-myristate 13-acetate (PMA). Propranolol not only inhibited PMA- induced phosphorylation of the extracellular signal-regulated kinase (Erk), but also that of IkappaB (IκB), preventing the IκB phosphorylation which is a prerequisite for IκB degradation. Propranolol inhibition of IκB phosphorylation was shown to occur with optimal efficacy at 30 μM. Although propranolol, at up to 100 μM, did not affect cell viability, it potentiated PMA- mediated signaling that ultimately led to diminished phosphorylation of Akt. The anti-Erk and anti-Akt phosphorylation effects are both suggestive of antiproliferative and antisurvival signaling, respectively. Our data are therefore indicative of a pharmacological role for propranolol against β-adrenergic receptor signaling functions involving the nuclear factor-kappaB-mediated regulation of MMP-9

Probing Interstellar Grain Growth through Polarimetry in the Taurus Cloud Complex

The optical and near-infrared (OIR) polarization of starlight is typically understood to arise from the dichroicextinction of that light by dust grains whose axes are aligned with respect to a local magnetic field. The sizedistribution of the aligned grain population can be constrained by measurements of the wavelength dependence of the polarization. The leading physical model for producing the alignment is that of radiative alignment torques (RAT), which predicts that the most efficiently aligned grains are those with sizes larger than the wavelengths of light composing the local radiation field. Therefore, for a given grain size distribution, the wavelength at which the polarization reaches a maximum (max) should correlate with the characteristic reddening along the line of sight between the dust grains and the illumination source. A correlation between max and reddening has been previously established for extinctions up to AV 4 mag. We extend the study of this relationship to a larger sample of stars in the Taurus cloud complex, including extinctions AV > 10 mag. We confirm the earlier results for AV </p

Functional Identification of Valerena-1,10-diene Synthase, a Terpene Synthase Catalyzing a Unique Chemical Cascade in the Biosynthesis of Biologically Active Sesquiterpenes in Valeriana officinalis

Valerian is an herbal preparation from the roots of Valeriana officinalis used as an anxiolytic and sedative and in the treatment of insomnia. The biological activities of valerian are attributed to valerenic acid and its putative biosynthetic precursor valerenadiene, sesquiterpenes, found in V. officinalis roots. These sesquiterpenes retain an isobutenyl side chain whose origin has been long recognized as enigmatic because a chemical rationalization for their biosynthesis has not been obvious. Using recently developed metabolomic and transcriptomic resources, we identified seven V. officinalis terpene synthase genes (VoTPSs), two that were functionally characterized as monoterpene synthases and three that preferred farnesyl diphosphate, the substrate for sesquiterpene synthases. The reaction products for two of the sesquiterpene synthases exhibiting root-specific expression were characterized by a combination of GC-MS and NMR in comparison to the terpenes accumulating in planta. VoTPS7 encodes for a synthase that biosynthesizes predominately germacrene C, whereas VoTPS1 catalyzes the conversion of farnesyl diphosphate to valerena-1,10-diene. Using a yeast expression system, specific labeled [13C]acetate, and NMR, we investigated the catalytic mechanism for VoTPS1 and provide evidence for the involvement of a caryophyllenyl carbocation, a cyclobutyl intermediate, in the biosynthesis of valerena-1,10-diene. We suggest a similar mechanism for the biosynthesis of several other biologically related isobutenyl-containing sesquiterpenes

Memory-guided force output is associated with self-reported ADHD symptoms in young adults

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental health disorder in childhood and persists into adulthood in up to 65 % of cases. ADHD is associated with adverse outcomes such as the ability to gain and maintain employment and is associated with an increased risk for substance abuse obesity workplace injuries and traffic accidents A majority of diagnosed children have motor deficits; however, few studies have examined motor deficits in young adults. This study provides a novel examination of visuomotor control of grip force in young adults with and without ADHD. Participants were instructed to maintain force production over a 20-second trial with and without real-time visual feedback about their performance. The results demonstrated that when visual feedback was available, adults with ADHD produced slightly higher grip force than controls. However, when visual feedback was removed, adults with ADHD had a faster rate of decay of force, which was associated with ADHD symptom severity and trait impulsivity. These findings suggest that there may be important differences in the way that adults with ADHD integrate visual feedback during continuous motor tasks. These may account for some of the motor impairments reported in children with ADHD. These deficits could result from (1) dysfunctional sensory motor integration and/or (2) deficits in short-term visuomotor memory

Exposure to family stressful life events in autistic children: Longitudinal associations with mental health and the moderating role of cognitive flexibility

Mental health problems are prevalent in autistic youth, but the underpinning mechanisms are not well explored. In neurotypical youth, stressful life events are an established risk factor for mental health problems. This study tested longitudinal bidirectional associations between family-level stressful life events and mental health problems and whether these were moderated by cognitive flexibility, in a cohort of autistic children (N = 247). Family-stressful life events, assessed using the parent-reported Family Inventory of Life Events and Changes, and mental health problems, assessed using the teacher-reported Child Behavior Checklist Internalizing and Externalizing Symptoms subscales, were measured at multiple points between 7 and 11 years. Analyses showed no significant pathways from internalizing or externalizing symptoms to family-stressful life events or from family-stressful life events to internalizing or externalizing symptoms. There was some evidence of moderation by cognitive flexibility; the family-stressful life events to internalizing symptoms pathway was non-significant in the group with typical shifting ability but significant in the group with clinically significant shifting problems. Information about family-level stressful life event exposure and cognitive flexibility may be helpful in identifying autistic youth who may be at higher risk of developing mental health problems. Established risk factors for mental health problems in neurotypical populations are relevant for understanding mental health in autistic youth

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed