The use of random projections for the analysis of mass spectrometry imaging data

The ‘curse of dimensionality’ imposes fundamental limits on the analysis of the large, information rich datasets that are produced by mass spectrometry imaging. Additionally, such datasets are often too large to be analyzed as a whole and so dimensionality reduction is required before further analysis can be performed. We investigate the use of simple random projections for the dimensionality reduction of mass spectrometry imaging data and examine how they enable efficient and fast segmentation using k-means clustering. The method is computationally efficient and can be implemented such that only one spectrum is needed in memory at any time. We use this technique to reveal histologically significant regions within MALDI images of diseased human liver. Segmentation results achieved following a reduction in the dimensionality of the data by more than 99% (without peak picking) showed that histologic changes due to disease can be automatically visualized from molecular images. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-014-1024-7) contains supplementary material, which is available to authorized users

Extensive loss of translational genes in the structurally dynamic mitochondrial genome of the angiosperm Silene latifolia

<p>Abstract</p> <p>Background</p> <p>Mitochondrial gene loss and functional transfer to the nucleus is an ongoing process in many lineages of plants, resulting in substantial variation across species in mitochondrial gene content. The Caryophyllaceae represents one lineage that has experienced a particularly high rate of mitochondrial gene loss relative to other angiosperms.</p> <p>Results</p> <p>In this study, we report the first complete mitochondrial genome sequence from a member of this family, <it>Silene latifolia</it>. The genome can be mapped as a 253,413 bp circle, but its structure is complicated by a large repeated region that is present in 6 copies. Active recombination among these copies produces a suite of alternative genome configurations that appear to be at or near "recombinational equilibrium". The genome contains the fewest genes of any angiosperm mitochondrial genome sequenced to date, with intact copies of only 25 of the 41 protein genes inferred to be present in the common ancestor of angiosperms. As observed more broadly in angiosperms, ribosomal proteins have been especially prone to gene loss in the <it>S. latifolia </it>lineage. The genome has also experienced a major reduction in tRNA gene content, including loss of functional tRNAs of both native and chloroplast origin. Even assuming expanded wobble-pairing rules, the mitochondrial genome can support translation of only 17 of the 61 sense codons, which code for only 9 of the 20 amino acids. In addition, genes encoding 18S and, especially, 5S rRNA exhibit exceptional sequence divergence relative to other plants. Divergence in one region of 18S rRNA appears to be the result of a gene conversion event, in which recombination with a homologous gene of chloroplast origin led to the complete replacement of a helix in this ribosomal RNA.</p> <p>Conclusions</p> <p>These findings suggest a markedly expanded role for nuclear gene products in the translation of mitochondrial genes in <it>S. latifolia </it>and raise the possibility of altered selective constraints operating on the mitochondrial translational apparatus in this lineage.</p

A collaborative study of the etiology of breast cancer subtypes in African American women: the AMBER consortium

Breast cancer is a heterogeneous disease, with at least five intrinsic subtypes defined by molecular characteristics. Tumors that express the estrogen receptor (ER+) have better outcomes than ER− tumors, due in part to the success of hormonal therapies that target ER+ tumors. The incidence of ER− breast cancer, and the subset of ER− cancers that are basal-like, is about twice as high among African American (AA) women as among U.S. women of European descent (EA). This disparity appears to explain, in part, the disproportionately high mortality from breast cancer that occurs in AA women. Epidemiologic research on breast cancer in AA women lags behind research in EA women. Here, we review differences in the etiology of breast cancer subtypes among AA women and describe a new consortium of ongoing studies of breast cancer in AA women

Biofilm Formation by Listeria monocytogenes 15G01, a Persistent Isolate from a Seafood-Processing Plant, Is Influenced by Inactivation of Multiple Genes Belonging to Different Functional Groups

Listeria monocytogenes is a ubiquitous foodborne pathogen that results in a high rate of mortality in sensitive and immunocompromised people. Contamination of food with L. monocytogenes is thought to occur during food processing, most often as a result of the pathogen producing a biofilm that persists in the environment and acting as the source for subsequent dispersal of cells onto food. A survey of seafoodprocessing plants in New Zealand identified the persistent strain 15G01, which has a high capacity to form biofilms. In this study, a transposon library of L. monocytogenes 15G01 was screened for mutants with altered biofilm formation, assessed by a crystal violet assay, to identify genes involved in biofilm formation. This screen identified 36 transposants that showed a significant change in biofilm formation compared to the wild type. The insertion sites were in 27 genes, 20 of which led to decreased biofilm formation and seven to an increase. Two insertions were in intergenic regions. Annotation of the genes suggested that they are involved in diverse cellular processes, including stress response, autolysis, transporter systems, and cell wall/membrane synthesis. Analysis of the biofilms produced by the transposants using scanning electron microscopy and fluorescence microscopy showed notable differences in the structure of the biofilms compared to the wild type. In particular, inactivation of uvrB and mltD produced coccoid-shaped cells and elongated cells in long chains, respectively, and the mgtB mutant produced a unique biofilm with a sandwich structure which was reversed to the wild-type level upon magnesium addition. The mltD transposant was successfully complemented with the wild-type gene, whereas the phenotypes were not or only partially restored for the remaining mutants. IMPORTANCE The major source of contamination of food with Listeria monocytogenes is thought to be due to biofilm formation and/or persistence in food-processing plants. By establishing as a biofilm, L. monocytogenes cells become harder to eradicate due to their increased resistance to environmental threats. Understanding the genes involved in biofilm formation and their influence on biofilm structure will help identify new ways to eliminate harmful biofilms in food processing environments. To date, multiple genes have been identified as being involved in biofilm formation by L. monocytogenes; however, the exact mechanism remains unclear. This study identified four genes associated with biofilm formation by a persistent strain. Extensive microscopic analysis illustrated the effect of the disruption of mgtB, clsA, uvrB, and mltD and the influence of magnesium on the biofilm structure. The results strongly suggest an involvement in biofilm formation for the four genes and provide a basis for further studies to analyze gene regulation to assess the specific role of these biofilm-associated genes.Peer reviewe

Deep Hubble Space Telescope Imaging of IC 1613 II. The Star Formation History

We present deep HST WFPC2 imaging of the Local Group dwarf irregular galaxy IC 1613. The photometry is the deepest to date for an isolated dwarf irregular galaxy. The resulting color-magnitude diagram (CMD) is analyzed using three different methods to derive a star formation history (SFH). All three find an enhanced star formation rate (SFR), from 3 to 6 Gyr ago, and similar age-metallicity relationships (AMR). A comparison of the newly observed outer field with an earlier studied central field of IC 1613 shows that the SFR in the outer field has been significantly depressed during the last Gyr. This implies that the optical scale length of the galaxy has been decreasing with time and that comparison of galaxies at intermediate redshift with present day galaxies should take this effect into account. We find strong similarities between IC 1613 and the more distant Milky Way dSph companions in that all are dominated by star formation at intermediate ages. In particular, the SFH and AMR for IC 1613 and Leo I are indistinguishable. This implies that dIrr galaxies cannot be distinguished from dSphs by their intermediate age stellar populations. This type of a SFH may also be evidence for slower or suppressed early star formation in dwarf galaxies due to photoionization after the reionization of the universe by background radiation. Assuming that IC 1613 is typical of a dIrr evolving in isolation, since most of the star formation occurs at intermediate ages, these dwarf systems cannot be responsible for the fast chemical enrichment of the IGM which is seen at high redshift. There is no evidence for any large amplitude bursts of star formation in IC 1613, and we find it highly unlikely that analogs of IC 1613 have contributed to the excess of faint blue galaxies in existing galaxy redshift surveys.Comment: 32 pages, including 1 table and 17 figures, accepted for publication in the Astrophysical Journal October 10, 2003 issu

The jellification of north temperate lakes.

Calcium (Ca) concentrations are decreasing in softwater lakes across eastern North America and western Europe. Using long-term contemporary and palaeo-environmental field data, we show that this is precipitating a dramatic change in Canadian lakes: the replacement of previously dominant pelagic herbivores (Ca-rich Daphnia species) by Holopedium glacialis, a jelly-clad, Ca-poor competitor. In some lakes, this transformation is being facilitated by increases in macro-invertebrate predation, both from native (Chaoborus spp.) and introduced (Bythotrephes longimanus) zooplanktivores, to which Holopedium, with its jelly coat, is relatively invulnerable. Greater representation by Holopedium within cladoceran zooplankton communities will reduce nutrient transfer through food webs, given their lower phosphorus content relative to daphniids, and greater absolute abundances may pose long-term problems to water users. The dominance of jelly-clad zooplankton will likely persist while lakewater Ca levels remain low.This work was primarily supported by grants from the Natural Sciences and Engineering Research Council of Canada and funding from the Ontario Ministry of the Environment.This is the accepted manuscript. The final version is available at http://rspb.royalsocietypublishing.org/content/282/1798/20142449

Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis.

Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non-OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression. Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice. We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-κB signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice. This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-κB signaling pathways, skeletal muscle-related genes, and induction and/or progression of OA. Copyright © 2012 by the American College of Rheumatology

Observational Constraints on Red and Blue Helium Burning Sequences

We derive the optical luminosity, colors, and ratios of the blue and red helium burning (HeB) stellar populations from archival Hubble Space Telescope observations of nineteen starburst dwarf galaxies and compare them with theoretical isochrones from Padova stellar evolution models across metallicities from Z=0.001 to 0.009. We find that the observational data and the theoretical isochrones for both blue and red HeB populations overlap in optical luminosities and colors and the observed and predicted blue to red HeB ratios agree for stars older than 50 Myr over the time bins studied. These findings confirm the usefulness of applying isochrones to interpret observations of HeB populations. However, there are significant differences, especially for the red HeB population. Specifically we find: (1) offsets in color between the observations and theoretical isochrones of order 0.15 mag (0.5 mag) for the blue (red) HeB populations brighter than M_V ~ -4 mag, which cannot be solely due to differential extinction; (2) blue HeB stars fainter than M_V ~ -3 mag are bluer than predicted; (3) the slope of the red HeB sequence is shallower than predicted by a factor of ~3; and (4) the models overpredict the ratio of the most luminous blue to red HeB stars corresponding to ages <50 Myr. Additionally, we find that for the more metal-rich galaxies in our sample (Z> 0.5 Zsolar) the red HeB stars overlap with the red giant branch stars in the color magnitude diagrams, thus reducing their usefulness as indicators of star formation for ages >100 Myr.Comment: 18 pages, 11 figures, 3 table