An Emerging Role for the Mammalian Target of Rapamycin in “Pathological” Protein Translation: Relevance to Cocaine Addiction

Complex neuroadaptations within key nodes of the brain’s “reward circuitry” are thought to underpin long-term vulnerability to relapse. A more comprehensive understanding of the molecular and cellular signaling events that subserve relapse vulnerability may lead to pharmacological treatments that could improve treatment outcomes for psychostimulant-addicted individuals. Recent advances in this regard include findings that drug-induced perturbations to neurotrophin, metabotropic glutamate receptor, and dopamine receptor signaling pathways perpetuate plasticity impairments at excitatory glutamatergic synapses on ventral tegmental area and nucleus accumbens neurons. In the context of addiction, much previous work, in terms of downstream effectors to these receptor systems, has centered on the extracellular-regulated MAP kinase signaling pathway. The purpose of the present review is to highlight the evidence of an emerging role for another downstream effector of these addiction-relevant receptor systems – the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 functions to regulate synaptic protein translation and is a potential critical link in our understanding of the neurobiological processes that drive addiction and relapse behavior. The precise cellular and molecular changes that are regulated by mTORC1 and contribute to relapse vulnerability are only just coming to light. Therefore, we aim to highlight evidence that mTORC1 signaling may be dysregulated by drug exposure and that these changes may contribute to aberrant translation of synaptic proteins that appear critical to increased relapse vulnerability, including AMPARs. The importance of understanding the role of this signaling pathway in the development of addiction vulnerability is underscored by the fact that the mTORC1 inhibitor rapamycin reduces drug-seeking in pre-clinical models and preliminary evidence indicating that rapamycin suppresses drug craving in humans

Mineral ages for multi isotope system in phlogopite-bearing pyroxene granulite and felsic gneiss, the Howard Hills, Enderby Land, East Antarctica: Possible Proterozoic tectonothermal events in the Napier Complex

Large mafic to ultramafic blocks in felsic gneisses on the northern part of the Howard Hills, Napier Complex, East Antarctica are accompanied by phlogopite-bearing pyroxene granulite occurring in the margins of the block. In order to understand the crustal evolution of the Napier Complex, especially regarding the thermal history after peak metamorphism, Rb-Sr, Sm-Nd and U-Pb isotopic analyses have been carried out on different minerals from the phlogopite-bearing pyroxene granulite and adjacent orthopyroxene felsic gneiss. Zircon grains from the orthopyroxene felsic gneiss yielded near concordant U-Pb isotopic ages of about 2.5Ga by conventional isotope dilution methods and defined a discordia with 2.44±0.02Ga lower intercept age. This age shows the waning stage of UHT granulite facies metamorphism in the Howard Hills. Rutile fractions from pyroxene granulite yielded a near concordant U-Pb isotopic age of about 1.5Ga. This age is interpreted as the final thermal episode, excepting local igneous intrusions, in the Howard Hills region. Fluorophlogopite fractions from pyroxene granulite yielded Rb-Sr model ages of about 1.85Ga, although evidence of retrograde metamorphism with fluid activity or deformation were poor in the pyroxene granulite. An internal Sm-Nd isochron of whole rock and orthopyroxene and feldspar separated from the same sample shows 1.85±0.15Ga. The Rb-Sr phlogopite model age, along with the Sm-Nd internal isochron age, records the time when the rocks of the Howard Hills underwent medium to high grade metamorphism at temperatures well above the currently accepted closure temperature of biotite (about 300-350°C )

Occurrences of metamorphosed ultramafic rock and associating rocks in Howard Hills, Enderby Land, East Antarctica: Evidence of partial melting from geochemical and isotopic characteristics

Large blocks of metamorphic rocks with mafic to ultramafic compositions were discovered in felsic gneiss at the central part of northern Howard Hills in Enderby Land. The ultramafic core is separated from the felsic gneiss by a mantle of pyroxene granulite. We can recognize from mineral assemblages and chemical compositions that the metamorphic rocks experienced ultrahigh temperature (UHT) metamorphism. Rubidium-strontium and samarium neodymium analytical data from the metamorphic rocks yield apparent ages of about 2.65 Ga within analytical error on isochron diagrams. Metamorphic rocks with mafic to ultramafic compositions are enriched in incompatible elements and have high Sr isotope ratios, resulting in some samples in improbable Nd model ages. This is attributed to enrichment of compatible elements and/or depletion of incompatible elements during metamorphism. We conclude that these metamorphic rocks experienced partial melting during UHT metamorphism. Pyroxene granulite was produced as a residual material after partial melting of LILE-enriched protoliths with high Sr isotope ratios

Changes in zircon chemistry during archean UHT metamorphism in the Napier complex, Antarctica

Zircons from two paragneisses (from Mount Sones and Dallwitz Nunatak) and one orthogneiss (from Gage Ridge) in the Tula Mountains, Napier Complex (East Antarctica) were analyzed for U-Pb age, oxygen isotopes, REEs and by scanning ion imaging. A large number of zircons from all samples are reversely discordant. Mount Sones zircons show an age range from 3.0 Ga to 2.5 Ga and underwent high-grade metamorphism at both ~2.8 Ga and 2.5 Ga. Zircons from Dallwitz Nunatak record detrital ages between 3.5 Ga and 2.5 Ga. Zircons from Gage Ridge record multiple age groups, with concordant data between 3.6 Ga and 3.3 Ga and reversely discordant data that form a discrete ~3.8 Ga population. All of the grains show evidence of Pb mobility during metamorphism. Ion imaging of zircons reveals Y and U zonation, characteristic of magmatic zircon, together with a micro-scale patchy distribution of 206Pb and 207Pb that does not correspond to either growth zonation or crystal imperfections. Some of these patches yield 207Pb/206Pb ages >4 Ga, whereas others yield ages younger than the magmatic crystallization age. Reversely discordant data are the result of ancient Pb mobilization, which is independent of the degree of metamictisation, oxygen isotope and REE content of the zircons. This mobilization can result in spurious ages and was most likely caused by polymetamorphism under anhydrous conditions; that is two high-grade events; one poorly defined at ~2.8 Ga and the other ultra-high temperature (UHT) metamorphism at 2.5 Ga

High-grade metamorphic rocks from Skallevikshalsen in the Lutzow-Holm Complex, East Antarctica: metamorphic conditions and possibility of partial melting

The high-grade metamorphic rocks of Skallevikshalsen, Lutzow-Holm Complex, East Antarctica predominantly comprise garnet-sillimanite gneiss, garnet-spinel-sillimanite gneiss, garnet-biotite gneiss and garnet-two pyroxene-mafic granulite. The metamorphic conditions were estimated using various geothermometers and geobarometers for garnet-biotite gneiss and mafic gneiss. The results were 770-940℃and 0.65-1.2 GPa for garnet-biotite gneiss and 780-960℃ and 0.6-1.1 GPa for mafic gneiss. Garnet-biotite gneiss is widespread in this area and displays a well-developed migmatitic structure. Garnet porphyroblasts in the leucosome and the boundaries between leucosome and melanosome in garnet-biotite gneiss commonly have a poikiloblastic texture with euhedral feldspar and quartz inclusions. High Y concentrations in garnet cores, high An values for plagioclase inclusions, and high Ba contents in K-feldspar from garnet-biotite gneiss are inferred to reflect growth in the presence of partial melt. Garnet in garnet-sillimanite gneiss also has high Y and P contents and chemical zoning that implies changes in trace element distribution coefficients. It is suggested that hydrous melt in garnet-sillimanite gneiss was generated during prograde metamorphism while anhydrous restite underwent continuous high-temperature metamorphism. Garnet-sillimanite gneiss is likely to be the restitic product of partial melting and shows evidence for melt segregation and movement

Core Health Outcomes In Childhood Epilepsy (CHOICE):Protocol for the selection of a core outcome set

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: There is increasing recognition that establishing a core set of outcomes to be evaluated and reported in trials of interventions for particular conditions will improve the usefulness of health research. There is no established core outcome set for childhood epilepsy. The aim of this work is to select a core outcome set to be used in evaluative research of interventions for children with rolandic epilepsy, as an exemplar of common childhood epilepsy syndromes. METHODS: First we will identify what outcomes should be measured; then we will decide how to measure those outcomes. We will engage relevant UK charities and health professional societies as partners, and convene advisory panels for young people with epilepsy and parents of children with epilepsy. We will identify candidate outcomes from a search for trials of interventions for childhood epilepsy, statutory guidance and consultation with our advisory panels. Families, charities and health, education and neuropsychology professionals will be invited to participate in a Delphi survey following recommended practices in the development of core outcome sets. Participants will be able to recommend additional outcome domains. Over three rounds of Delphi survey participants will rate the importance of candidate outcome domains and state the rationale for their decisions. Over the three rounds we will seek consensus across and between families and health professionals on the more important outcomes. A face-to-face meeting will be convened to ratify the core outcome set. We will then review and recommend ways to measure the shortlisted outcomes using clinical assessment and/or patient-reported outcome measures. DISCUSSION: Our methodology is a proportionate and pragmatic approach to expediently produce a core outcome set for evaluative research of interventions aiming to improve the health of children with epilepsy. A number of decisions have to be made when designing a study to develop a core outcome set including defining the scope, choosing which stakeholders to engage, most effective ways to elicit their views, especially children and a potential role for qualitative research.This study is part of Changing Agendas on Sleep, Treatment and Learning in Childhood Epilepsy (CASTLE), which is funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research RP-PG-0615-20007

Anti-glycoprotein VI mediated immune thrombocytopenia: An under-recognized and significant entity?

Idiopathic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by relapsing/remitting thrombocytopenia. Bleeding complications are infrequent with platelet counts above 30x10(9)/L, and this level is commonly used as a threshold for treatment. The question of another/co-existent diagnosis or an alternate mechanism of platelet destruction arises when bleeding is experienced with platelet counts above this threshold. We report a case of anti-GPVI mediated ITP that was diagnosed following investigations performed to address this key clinical question. A patient with ITP experienced exaggerated bruising symptoms despite a platelet count of 91x10(9)/L. Platelet functional testing showed an isolated platelet defect of collagen-induced aggregation. Next generation sequencing excluded a pathogenic variant of GP6, and anti-GPVI antibodies that curtailed GPVI function were confirmed by extended platelet phenotyping. We propose that anti-GPVI mediated ITP may be under-recognized, and that inclusion of GPVI in antibody detection assays may improve their diagnostic utility and in turn, facilitate a better understanding of ITP pathophysiology and aid individualized treatment approaches

The Acquisition of Human B Cell Memory in Response to Plasmodium Falciparum Malaria

Immunity to Plasmodium falciparum (Pf), the most deadly agent of malaria, is only acquired after years of repeated infections and appears to wane rapidly without ongoing exposure. Antibodies (Abs) are central to malaria immunity, yet little is known about the B‐cell biology that underlies Pf‐specific humoral immunity. To address this gap in our knowledge we carried out a year‐long prospective study of the acquisition and maintenance of long‐lived plasma cells (LLPCs) and memory B cells (MBCs) in 225 individuals aged two to twenty‐five years in Mali, in an area of intense seasonal transmission. Using protein microarrays containing approximately 25% of the Pf proteome we determined that Pf‐specific Abs were acquired only gradually, in a stepwise fashion over years of Pf exposure. Pf‐specific Ab levels were significantly boosted each year during the transmission season but the majority of these Abs were short lived and were lost over the subsequent six month period of no transmission. Thus, we observed only a small incremental increase in stable Ab levels each year, presumably reflecting the slow acquisition LLPCs. The acquisition Pf‐specific MBCs mirrored the slow step‐wise acquisition of LLPCs. This slow acquisition of Pf‐specific LLPCs and MBCs was in sharp contrast to that of tetanus toxoid (TT)‐specific LLPCs and MBCs that were vi vi rapidly acquired and stably maintained following a single vaccination in individuals in this cohort. In addition to the development of normal MBCs we observed an expansion of atypical MBCs that are phenotypically similar to hyporesponsive FCRL4+ cells described in HIV‐infected individuals. Atypical MBC expansion correlated with cumulative exposure to Pf, and with persistent asymptomatic Pf‐infection in children, suggesting that the parasite may play a role in driving the expansion of atypical MBCs. Collectively, these observations provide a rare glimpse into the process of the acquisition of human B cell memory in response to infection and provide evidence for a selective deficit in the generation of Pf‐specific LLPCs and MBCs during malaria. Future studies will address the mechanisms underlying the slow acquisition of LLPCs and MBCs and the generation and function of atypical MBCs

CMBPol Mission Concept Study: Foreground Science Knowledge and Prospects

We report on our knowledge of Galactic foregrounds, as well as on how a CMB satellite mission aiming at detecting a primordial B-mode signal (CMBPol) will contribute to improving it. We review the observational and analysis techniques used to constrain the structure of the Galactic magnetic field, whose presence is responsible for the polarization of Galactic emissions. Although our current understanding of the magnetized interstellar medium is somewhat limited, dramatic improvements in our knowledge of its properties are expected by the time CMBPol flies. Thanks to high resolution and high sensitivity instruments observing the whole sky at frequencies between 30 GHz and 850 GHz, CMBPol will not only improve this picture by observing the synchrotron emission from our galaxy, but also help constrain dust models. Polarized emission from interstellar dust indeed dominates over any other signal in CMBPol's highest frequency channels. Observations at these wavelengths, combined with ground-based studies of starlight polarization, will therefore enable us to improve our understanding of dust properties and of the mechanism(s) responsible for the alignment of dust grains with the Galactic magnetic field. CMBPol will also shed new light on observations that are presently not well understood. Morphological studies of anomalous dust and synchrotron emissions will indeed constrain their natures and properties, while searching for fluctuations in the emission from heliospheric dust will test our understanding of the circumheliospheric interstellar medium. Finally, acquiring more information on the properties of extra-Galactic sources will be necessary in order to maximize the cosmological constraints extracted from CMBPol's observations of CMB lensing. (abridged)Comment: 43 pages, 7 figures, 2 table

The GMRT EoR Experiment: Limits on Polarized Sky Brightness at 150 MHz

The GMRT reionization effort aims to map out the large scale structure of the Universe during the epoch of reionization (EoR). Removal of polarized Galactic emission is a difficult part of any 21 cm EoR program, and we present new upper limits to diffuse polarized foregrounds at 150 MHz. We find no high significance evidence of polarized emission in our observed field at mid galactic latitude (J2000 08h26m+26). We find an upper limit on the 2-dimensional angular power spectrum of diffuse polarized foregrounds of [l^2 C_l/(2 PI)]^{1/2}< 3K in frequency bins of width 1 MHz at 300<l<1000. The 3-dimensional power spectrum of polarized emission, which is most directly relevant to EoR observations, is [k^3 P_p(k)/(2 PI^2)]^{1/2} 0.03 h/Mpc, k < 0.1 h/Mpc. This can be compared to the expected EoR signal in total intensity of [k^3 P(k)/ (2 PI^2) ]^{1/2} ~ 10 mK. We find polarized structure is substantially weaker than suggested by extrapolation from higher frequency observations, so the new low upper limits reported here reduce the anticipated impact of these foregrounds on EoR experiments. We discuss Faraday beam and depth depolarization models and compare predictions of these models to our data. We report on a new technique for polarization calibration using pulsars, as well as a new technique to remove broadband radio frequency interference. Our data indicate that, on the edges of the main beam at GMRT, polarization squint creates ~ 3% leakage of unpolarized power into polarized maps at zero rotation measure. Ionospheric rotation was largely stable during these solar minimum night time observations.Comment: 17 pages, 6 figures, 2 tables; changed figures, added appendices. To appear in MNRA