101 research outputs found

    Leigh syndrome: One disorder, more than 75 monogenic causes

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    Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137543/1/ana24551_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137543/2/ana24551.pd

    ‘Street-level’ agents operating beyond ‘remote control’: how overseas liaison officers and foreign state officials shape UK extraterritorial migration management

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    Extraterritorial migration management perspectives on how states try to enforce immigration controls beyond their juridical borders are strongly influenced by ‘remote control’ metaphors. This is conceptually limited and outdated. Most research fails to sufficiently acknowledge agency by a destination state's officials acting abroad, foreign states and their officials, when evaluating extraterritorial measures and ‘outcomes’. We study UK liaison officers abroad, specifically, how they see their efforts to implement extraterritorial immigration control through interactions with foreign state officials. Our approach links inter-state relations to the social world of on-the-ground ‘street-level’ interactions between officers abroad and their foreign counterparts. The empirical analysis draws from original interviews and official sources. We compare factors accounting for the UK's activities and perceived ‘outcomes’ across USA, France, Thailand, Egypt and Ghana. Findings show the UK's extraterritorial migration management results from a very long chain of decisions and actions, by foreign and UK state actors, operating at different institutional-levels, with uncontrollable local circumstances abroad. Realising extraterritorial goals depends strongly on liaison officers’ agency, ‘soft power’ over foreign officials and foreign officials’ willingness to cooperate. Meanwhile liaison officers’ ‘feedbacks’ importantly influence Home Office decision-making. Against the simplistic one-way causality of ‘remote control’, this is ‘street-level’ agency beyond ‘remote control’

    K-Band Spectroscopy of (Pre-)Cataclysmic Variables: Are Some Donor Stars Really Carbon Poor?

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    We present a new sample of KK-band spectral observations for CVs: non-magnetic and magnetic as well as present day and pre CVs. The purpose of this diverse sample is to address the recent claim that the secondary stars in dwarf novae are carbon deficient, having become so through a far more evolved evolution than the current paradigm predicts. Our new observations, along with previous literature results, span a wide range of orbital period and CV type. In general, dwarf novae in which the secondary star is seen show weak to no CO absorption while polar and pre-CV donor stars appear to have normal CO absorption for their spectral type. However, this is not universal. The presence of normal looking CO absorption in the dwarf nova SS Aur and the hibernating CV QS Vir and a complete lack of CO absorption in the long period polar V1309 Ori cloud the issue. A summary of the literature pointing to non-solar abundances including enhanced NV/CIV ratios is presented. It appears that some CVs have non-solar abundance material accreting onto the white dwarf suggesting an evolved secondary star while for others CO emission in the accretion disk may play a role. However, the exact mechanism or combination of factors causing the CO absorption anomaly in CVs is not yet clear.Comment: Accepted in A

    A novel SARS-CoV-2 (T Cell) vaccine candidate designed using the iVAX platform

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    EpiVax, Inc., a Rhode Island-based Biotechnology company, develops vaccines that exploit T cell immunity using the innovative iVAX vaccine antigen design platform. The premise of our strategy is the crucial role T cells play in development of protective antibody and cell-mediated immunity in natural infection. Because vaccines aim to recapitulate protective immune responses in infection, a vaccine should effectively harness T cell immunity to be protective. The significance of T cell immunity is underscored by COVID-19. Efficacy trial and real-world COVID-19 vaccine data for different vaccine modalities show a single vaccine dose is as much as 90% effective starting 14 days post-administration, when 100% of vaccinees have functional CD4 and CD8 T cells but no detectable neutralizing antibodies. As T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission, we set out to develop a vaccine designed by iVAX to enhance T cell immunity and provide long lasting protection. Please click Download on the upper right corner to see the full abstract

    Recon 2.2: from reconstruction to model of human metabolism.

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    IntroductionThe human genome-scale metabolic reconstruction details all known metabolic reactions occurring in humans, and thereby holds substantial promise for studying complex diseases and phenotypes. Capturing the whole human metabolic reconstruction is an on-going task and since the last community effort generated a consensus reconstruction, several updates have been developed.ObjectivesWe report a new consensus version, Recon 2.2, which integrates various alternative versions with significant additional updates. In addition to re-establishing a consensus reconstruction, further key objectives included providing more comprehensive annotation of metabolites and genes, ensuring full mass and charge balance in all reactions, and developing a model that correctly predicts ATP production on a range of carbon sources.MethodsRecon 2.2 has been developed through a combination of manual curation and automated error checking. Specific and significant manual updates include a respecification of fatty acid metabolism, oxidative phosphorylation and a coupling of the electron transport chain to ATP synthase activity. All metabolites have definitive chemical formulae and charges specified, and these are used to ensure full mass and charge reaction balancing through an automated linear programming approach. Additionally, improved integration with transcriptomics and proteomics data has been facilitated with the updated curation of relationships between genes, proteins and reactions.ResultsRecon 2.2 now represents the most predictive model of human metabolism to date as demonstrated here. Extensive manual curation has increased the reconstruction size to 5324 metabolites, 7785 reactions and 1675 associated genes, which now are mapped to a single standard. The focus upon mass and charge balancing of all reactions, along with better representation of energy generation, has produced a flux model that correctly predicts ATP yield on different carbon sources.ConclusionThrough these updates we have achieved the most complete and best annotated consensus human metabolic reconstruction available, thereby increasing the ability of this resource to provide novel insights into normal and disease states in human. The model is freely available from the Biomodels database (http://identifiers.org/biomodels.db/MODEL1603150001)

    TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis

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    Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies

    The Vehicle, Fall 1997

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    Vol 39, No. 1 Table of Contents dancingDavid Moutraypage 1 UntitledMaria Nelsonpage 2 Braver Shades of FireEric Footepage 3 A CoverAmanda Davispage 4 Soup KitchenBlanca Delgadopage 5 Shades of TruthChad P. Elliotpage 5 UntitledNicole Guzaldopage 6 The FogJoe Howardpage 7 Horse-spitMichael Kawapage 8 A Red Coffee MugJoe Howardpage 9 Morning AfterRafael Gomezpage 10 Watching BoysKim Hunterpage 11 UntitledNatalie Macellaiopage 12 Synesthesia in Mood of JulyDoug Strahanpage 13 picasso heartRyan Reevespage 14 Spanish ClassBlanca Delgadopage 15 UntitledElizabeth Hollandpage 16 ApocalypseBlanca Delgadopage 17 CHRISTIANITY IN CALIFORNIAMichael H. Lakepage 18 To Love a MannequinSylvia L. Whippopage 19 UntitledGwen Griffinpage 20 cardboard wolverinesRyan Reevespage 21 NeilKelly Flohrpage 22-25https://thekeep.eiu.edu/vehicle/1068/thumbnail.jp

    Deleterious Heteroplasmic Mitochondrial Mutations are associated With an increased Risk of Overall and Cancer-Specific Mortality

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    Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia
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