Phospholipid environment alters hormone-sensitivity of the purified insulin receptor kinase

Insulin receptor kinase, affinity-purified by adsorption and elution from immobilized insulin, is stimulated 2-3-fold by insulin in detergent solution. Reconstitution of the receptor kinase into leaky vesicles containing phosphatidylcholine and phosphatidylethanolamine (1:1, w/w) by detergent removal on Sephadex G-50 results in the complete loss of receptor kinase sensitivity to activation by insulin. Insulin receptors in these vesicles also exhibit an increase in their apparent affinity for 125I-insulin (Kd = 0.12 nM versus 0.76 nM). Inclusion of 8.3-16.7% phosphatidylserine into the reconstituted vesicles restores 40-50% of the insulin-sensitivity to the receptor kinase. An elevated apparent affinity for 125I-insulin of insulin receptors in vesicles containing phosphatidylcholine and phosphatidylethanolamine is also restored to the value observed in detergent solution by the inclusion of phosphatidylserine in the reconstituted system. The effect of phosphatidylserine on insulin receptor kinase appears specific, because cholesterol, phosphatidylinositol and phosphatidic acid are all unable to restore insulin-sensitivity to the receptor kinase. Autophosphorylation sites on the insulin receptor as analysed by h.p.l.c. of tryptic 32P-labelled receptor phosphopeptides are not different for insulin receptors autophosphorylated in detergent solution or for the reconstituted vesicles in the presence or absence of phosphatidylserine. These data indicate that the phospholipid environment of insulin receptors can modulate its binding and kinase activity, and phosphatidylserine acts to restore insulin-sensitivity to the receptor kinase incorporated into phosphatidylcholine/phosphatidylethanolamine vesicles

Growth and form of the mound in Gale Crater, Mars: Slope wind enhanced erosion and transport

Ancient sediments provide archives of climate and habitability on Mars. Gale Crater, the landing site for the Mars Science Laboratory (MSL), hosts a 5-km-high sedimentary mound (Mount Sharp/Aeolis Mons). Hypotheses for mound formation include evaporitic, lacustrine, fluviodeltaic, and aeolian processes, but the origin and original extent of Gale’s mound is unknown. Here we show new measurements of sedimentary strata within the mound that indicate ∼3° outward dips oriented radially away from the mound center, inconsistent with the first three hypotheses. Moreover, although mounds are widely considered to be erosional remnants of a once crater-filling unit, we find that the Gale mound’s current form is close to its maximal extent. Instead we propose that the mound’s structure, stratigraphy, and current shape can be explained by growth in place near the center of the crater mediated by wind-topography feedbacks. Our model shows how sediment can initially accrete near the crater center far from crater-wall katabatic winds, until the increasing relief of the resulting mound generates mound-flank slope winds strong enough to erode the mound. The slope wind enhanced erosion and transport (SWEET) hypothesis indicates mound formation dominantly by aeolian deposition with limited organic carbon preservation potential, and a relatively limited role for lacustrine and fluvial activity. Morphodynamic feedbacks between wind and topography are widely applicable to a range of sedimentary and ice mounds across the Martian surface, and possibly other planets

The ASD Living Biology: from cell proliferation to clinical phenotype.

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child's development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD

Asking people in each state who they think will win suggests that the presidential election may be very close.

In new survey research, Andreas E. Murr and Michael S. Lewis-Beck asked people in each of the 50 states and Washington DC who they thought would win their state in the presidential election. Adding up their raw data, their survey suggests that President Trump will win re-election next week with 320 electoral votes to 218 for former Vice President, Democrat Joe Biden

Citizen forecasting 2020 : a state-by-state experiment

The leading approaches to scientific election forecasting in the United States consist of structural models, prediction markets and opinion polling. With respect to the last, by far the dominant mode relies on vote intention polling, e.g., “If the election were held tomorrow, who would you vote for?” However, there exists an abiding opinion polling strategy that shows a good deal of promise—citizen forecasting. That is, rather than query on vote intention, query on vote expectation, e.g., “Who do you think will win the upcoming election?” This approach has been pursued most extensively in the United Kingdom (Murr 2016) and the United States (LewisBeck and Tien 1999). Recent performance evaluations have shown that in the United Kingdom vote expectations clearly offer more predictive accuracy than vote intentions (Murr et al. forthcoming) and that in the United States vote expectations appear to be superior to an array of rival forecasting tools (Graefe 2014). However, the timing of the data collection has forced most of the studies using citizen forecasts to forecast elections ex post, i.e., after they occurred. Indeed, to date, there are only two ex ante citizen forecasting papers to have appeared before a national election (Lewis-Beck and Stegmaier 2011; Murr 2016). Both these efforts forecasted British General Elections, with Murr (2016) relatively most accurate among 12 academic forecasts (Fisher and Lewis-Beck 2016). With respect to the United States, the case at hand, none of the work has been ex ante and all studies have focused on the national level, with the exception of a lone study carried out at the state level (Murr, 2015). The latter point seems critical, since the final selection of the president takes place in the Electoral College. The citizen forecasting research here stands unique, being ex ante and focusing on the states. Utilizing survey questions on Amazon.com’s Mechanical Turk (MTurk), administered in July, we render forecasts for the November 2020 presidential contest. This experiment, which has been conducted before-the-fact and looks at the states, provides a strong test of the quality of citizen forecasting in this American election

Enkephalin systems in diencephalon and brainstem of the rat

The immunocytochemical distribution of [Leu]enkephalin and an adrenal enkephalin precursor fragment (BAM-22P) immunoreactivity was investigated in the diencephalon and brainstem of rats pretreated with relatively high doses of colchicine (300–400 Μg/10 Μl intracerebroventricularly). The higher ranges of colchicine pretreatment allowed the visualization of extensive enkephalin-containing systems in these brain regions, some of which are reported for the first time. Immunoreactive perikarya were found in many hypothalamic and thalamic nuclei, interpeduncular nucleus, substan-tia nigra, the colliculi, periaqueductal gray, parabrachial nuclei, trigeminal motor and spinal nuclei, nucleus raphe magnus and other raphe nuclei, nucleus reticularis paragigantocellularis, vestibular nuclei, several nor-adrenergic cell groups, nucleus tractus solitarius, as well as in the spinal cord dorsal horn. In addition to the above regions, immunoreactive fibers were also noted in the habenular nuclei, trigeminal sensory nuclei, locus coeruleus, motor facial nucleus, cochlear nuclei, dorsal motor nucleus of the vagus, and hypoglossal nucleus. When adjacent sections to those stained for [Leu]enkephalin were processed for BAM-22P immunoreactivity, it was found that these two immunoreactivities were distributed identically at almost all anatomical locations. B AM-22P immunoreactivity was generally less pronounced and was preferentially localized to neuronal perikarya. The results of the present as well as the preceding studies (Khachaturian et ai., '83) strongly suggest substantial structural similarity between the adrenal proenkephalin precursor and that which occurs in the brain. Also discussed are some differences and parallels between the distribution of [Leu]enkeph-alin and dynorphin immunoreactivities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50020/1/902200305_ftp.pd

Vol. 27, No. 2

Contents: Labor Relations in Hard Times, by Michael J. Duggan, Julie E. Lewis, and Mallory Milluzzi Recent Developmentshttps://scholarship.kentlaw.iit.edu/iperr/1050/thumbnail.jp

Regional Stratigraphic Framework of Surficial Sediments and Bedrock Beneath Lake Ontario

Approximately 2550 km of single-channel high-resolution seismic reflection profiles have been interpreted and calibrated with lithological and geochronological information from four representative piston cores and one grab sample to provide a regional stratigraphie framework for the subbottom deposits of Lake Ontario. Five units overlying Paleozoic bedrock were identified and mapped. These are classified as informal units and represent, from oldest to youngest: (A) subglacial till (?) deposited by the Port Huron ice at the end of the Wisconsin glaciation; (B) an ice-marginal (?) unit confined to the western part of the lake that was probably deposited during retreat of the Port Huron ice shortly after 13 ka; (C) a regionally extensive unit of laminated glacio-lacustrine clay that accumulated until about 11 ka; (D) a weakly laminated to more massive lake clay deposited during a period of reduced water supply and rising water levels after the drawdown of the high-level glacial lakes (Iroquois and successors); and (E) modern lake clay less than 10 m thick that began accumulating around 6-8 ka with the subsequent return of upper Great Lakes drainage through the Ontario basin. Seismic reflections also define the configuration of the bedrock surface and pre-glacial stream valleys incised in the bedrock surface. Several anomalous bottom and subbottom features in the surficial sediments are mapped, such as discontinuous and offset reflections, furrows, gas pockets, and areas of large subbottom relief. None of these features appear to be spatially correlative with the diffuse seismicity that characterizes the lake area or with deeper structures such as Paleozoic bedrock faults or crustal-penetrating faults in the Precambrian basement.On a interprété et étalonné environ 2550 km de profils de sismique réflexion monocanal à haute résolution selon les données lithologiques et géochronologique de quatre sondages représentatifs faits par carottier à piston et un échantillon prélevé avec une benne afin d'établir le cadre stratigraphique des dépôts accumulés sous le fond du lac Ontario. Cinq unités recouvrant le substratum paiéozoïque ont été identifées et cartographiées. Ces unités informelles, de la plus ancienne à la plus jeune, sont : (A) un till sous-glaciaire (?) déposé par les glaces de Port Huron à la fin de la glaciation wisconsienne; (B) une unité de limite glaciaire (?) confinée à la partie ouest du lac et qui a probablement été déposée pendant le retrait des glaces de Port Huron, peu après 13 ka; (C) une unité d'étendue régionale d'argile glaciolacustre feuilletée qui s'est accumulée jusqu'à environ 11 ka; (D) une argile lacustre, de faiblement feuilletée à massive, mise en place au cours d'une période où il y eut approvisionnement en eau réduit et hausse du niveau de l'eau après l'abaissement des lacs glaciaires (Iroquois et ultérieurs); et (E) une argile lacustre moderne de moins de 10 m d'épaisseur qui a commencé à s'accumuler à partir de 6-8 ka après la reprise du drainage des Grands Lacs par le bassin Ontario. La sismique réflexion a aussi permis de délimiter la configuration de la surface du socle et des vallées pré-glaciaires qui y sont entaillées. Plusieurs éléments des sédiments de surface du fond du lac et sous le fond ont été cartographies, comme des réflexions de discontinuités et de décalages, des rainures, des poches de gaz et des zones de grandes formes enfouies. Aucun de ces éléments ne semble correspondre spatialement à la sis-micité diffuse qui caractérise la région du lac ou aux structures profondes comme les failles de substratum paiéozoïque ou celle du socle précambrien.Ungefàhr 2550 km seismischer Reflexionsprofile wurden interpretiert und kalibiriert mit lithologischen und geochronologischen Informationen von vier repràsentativen Kolbenbohrkernen und einer ausges-chùrften Probe, um den regionalen stratigraphischen Rahmen fur die unter dem Bett des Ontariosees gelegenen Ablagerungen zu erhalten. Man hat fùnf Einheiten, die das anstehende Gestein aus dem Palàozoikum ùberlagern, identifiziert und kartographiert: (A) eine subglaziale Grundmoràne (?), die durch das Eis von Port Huron am Ende der Wisconsin-Vereisung abgelagert wurde; (B) eine auf den westlichen Teil des Sees begrenzte Eisrand (?)-Einheit, die wahrs-cheinlich wàhrend des Rùckzugs des Port Huron-Eises kurz nach 13ka abgelagert wurde; (C) eine regional ausgedehnte Einheit von blâttrigem glaziallimnischem Lehm, die sien bis etwa 11 ka ansammelte, (D) ein schwachbis massivblàttriger Seelehm, der wàhrend einer Période verminderter Wasserzufuhr und steigenden Wasserspiegeln sich ansammelte; und (E) moderner Seelehm von weniger als 10 m Dicke, der sich um etwa 6-8 ka anzusammeln begann, mit der Rùckkehr der Drainage der oberen GroRen Seen durch das Ontariobecken. Seismische Reflexionen las-sen auch die Konfiguration der Sockeloberflàche und der pràglazialen in die Sockeloberflàche eingeschnittenen FluBtàler erkennen. Mehrere unregelmàfîige Grundund Untergrunderscheinungen der Oberflàchensedimente wurden kartographiert, wie Diskontinuitàt und Hôhenunschiede der Reflexionen, Mulden, Gastaschen und Gebiete mit breitem Untergrundrelief. Keine dieser Erscheinungen scheint ràumlich mit der fur das Seen-Gebiet charakteristischen Seismik zu korrelieren oder mit tieferen Strukturen, wie die Verwerfungen des anstehenden Gestems aus dem Palàozoikum order durch die Kruste dringende Verwergungen im pràkambrischen Untergrund