Lipidomic QTL in Diversity Outbred mice identifies a novel function for α/β hydrolase domain 2 (Abhd2) as an enzyme that metabolizes phosphatidylcholine and cardiolipin.

We and others have previously shown that genetic association can be used to make causal connections between gene loci and small molecules measured by mass spectrometry in the bloodstream and in tissues. We identified a locus on mouse chromosome 7 where several phospholipids in liver showed strong genetic association to distinct gene loci. In this study, we integrated gene expression data with genetic association data to identify a single gene at the chromosome 7 locus as the driver of the phospholipid phenotypes. The gene encodes α/β-hydrolase domain 2 (Abhd2), one of 23 members of the ABHD gene family. We validated this observation by measuring lipids in a mouse with a whole-body deletion of Abhd2. The Abhd2KO mice had a significant increase in liver levels of phosphatidylcholine and phosphatidylethanolamine. Unexpectedly, we also found a decrease in two key mitochondrial lipids, cardiolipin and phosphatidylglycerol, in male Abhd2KO mice. These data suggest that Abhd2 plays a role in the synthesis, turnover, or remodeling of liver phospholipids

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Testing LMC Microlensing Scenarios: The Discrimination Power of the SuperMACHO Microlensing Survey

Characterizing the nature and spatial distribution of the lensing objects that produce the previously measured microlensing optical depth toward the Large Magellanic Cloud (LMC) remains an open problem. We present an appraisal of the ability of the SuperMACHO Project, a next-generation microlensing survey directed toward the LMC, to discriminate between various proposed lensing populations. We consider two scenarios: lensing by a uniform foreground screen of objects and self-lensing by LMC stars. We have carried out extensive simulations, based upon data obtained during the first year of the project, to assess the SuperMACHO survey's ability to discriminate between these two scenarios. We find that the event rate itself shows significant sensitivity to the choice of the LMC luminosity function, limiting the conclusions which can be drawn from the absolute rate. If instead we determine the differential event rate across the LMC, we will decrease the impact of these systematic biases and render our conclusions more robust. With this approach the SuperMACHO Project should be able to distinguish between the two categories of lens populations. This will provide important constraints on the nature of the lensing objects and their contributions to the Galactic dark matter halo.Comment: 40 pages, 9 figures, to appear in ApJ 634 (2005

Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria. METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms). RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm. CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians

Keck HIRES spectroscopy of SkyMapper commissioning survey candidate extremely metal-poor stars

We present results from the analysis of high-resolution spectra obtained with the Keck HIRES spectrograph for a sample of 17 candidate extremely metal-poor (EMP) stars originally selected from commissioning data obtained with the SkyMapper telescope. Fourteen of the stars have not been observed previously at high dispersion. Three have [Fe/H] ≤ −3.0, while the remainder, with two more metal-rich exceptions, have −3.0 ≤ [Fe/H] ≤ −2.0 dex. Apart from Fe, we also derive abundances for the elements C, N, Na, Mg, Al, Si, Ca, Sc, Ti, Cr, Mn, Co, Ni, and Zn, and for n-capture elements Sr, Ba, and Eu. None of the current sample of stars is found to be carbon-rich. In general, our chemical abundances follow previous trends found in the literature, although we note that two of the most metal-poor stars show very low [Ba/Fe] (∼−1.7) coupled with low [Sr/Ba] (∼−0.3). Such stars are relatively rare in the Galactic halo. One further star, and possibly two others, meet the criteria for classification as a r-I star. This study, together with that of Jacobson et al. (2015), completes the outcomes of the SkyMapper commissioning data survey for EMP stars.SkyMapper research on EMP stars has been supported in part through the Australian Research Council (ARC) Discovery Grant programs DP120101237 and DP150103294 (Lead-CI Da Costa). A. F. M., A. R. C., and A. D. M. have been in part supported by ARC through the Discovery Early Career Researcher Award DE160100851, the Discovery Project DP160100637, and the Future Fellowship FT160100206, respectively. M. A. gratefully acknowledges generous funding from an ARC Laureate Fellowship (grant FL110100012). Parts of this research were conducted under the auspices of the Australian Research Council Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), which is supported through project number CE170100013. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie SkłodowskaCurie Grant Agreement No. (797100; Beneficiary: A. F. M.). The national facility capability for SkyMapper has been funded through ARC LIEF grant LE130100104 from the Australian Research Council, awarded to the University of Sydney, the Australian National University, Swinburne University of Technology, the University of Queensland, the University of Western Australia, the University of Melbourne, Curtin University of Technology, Monash University, and the Australian Astronomical Observator

Additive genetic variation in schizophrenia risk is shared by populations of African and European descent

Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

A Mighty Small Heart: The Cardiac Proteome of Adult Drosophila melanogaster

Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca2+-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease