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Search Results: 1 - 10 of 2204 matches for " Heather Mottaz-Brewer "
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Global Systems-Level Analysis of Hfq and SmpB Deletion Mutants in Salmonella: Implications for Virulence and Global Protein Translation
Charles Ansong, Hyunjin Yoon, Steffen Porwollik, Heather Mottaz-Brewer, Brianne O. Petritis, Navdeep Jaitly, Joshua N. Adkins, Michael McClelland, Fred Heffron, Richard D. Smith
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004809
Abstract: Using sample-matched transcriptomics and proteomics measurements it is now possible to begin to understand the impact of post-transcriptional regulatory programs in Enterobacteria. In bacteria post-transcriptional regulation is mediated by relatively few identified RNA-binding protein factors including CsrA, Hfq and SmpB. A mutation in any one of these three genes, csrA, hfq, and smpB, in Salmonella is attenuated for mouse virulence and unable to survive in macrophages. CsrA has a clearly defined specificity based on binding to a specific mRNA sequence to inhibit translation. However, the proteins regulated by Hfq and SmpB are not as clearly defined. Previous work identified proteins regulated by hfq using purification of the RNA-protein complex with direct sequencing of the bound RNAs and found binding to a surprisingly large number of transcripts. In this report we have used global proteomics to directly identify proteins regulated by Hfq or SmpB by comparing protein abundance in the parent and isogenic hfq or smpB mutant. From these same samples we also prepared RNA for microarray analysis to determine if alteration of protein expression was mediated post-transcriptionally. Samples were analyzed from bacteria grown under four different conditions; two laboratory conditions and two that are thought to mimic the intracellular environment. We show that mutants of hfq and smpB directly or indirectly modulate at least 20% and 4% of all possible Salmonella proteins, respectively, with limited correlation between transcription and protein expression. These proteins represent a broad spectrum of Salmonella proteins required for many biological processes including host cell invasion, motility, central metabolism, LPS biosynthesis, two-component regulatory systems, and fatty acid metabolism. Our results represent one of the first global analyses of post-transcriptional regulons in any organism and suggest that regulation at the translational level is widespread and plays an important role in virulence regulation and environmental adaptation for Salmonella.
B16 melanoma tumor growth is delayed in mice in an age-dependent manner
Christina Pettan-Brewer,John Morton,Rebecca Coil,Heather Hopkins
Pathobiology of Aging & Age-related Diseases , 2012, DOI: 10.3402/pba.v2i0.19182
Abstract: A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×105 tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6) and C57BL/6×BALB/c F1 (CB6 F1) mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm3. The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm3, respectively (p≤0.001). The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm3. The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm3, respectively (p≤0.01). The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm3 for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm3, respectively (p≤0.05). The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm3 for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm3 (p≤0.01). In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average tumor volumes of 417.62 and 216.34 mm3 in the 16- and 24-month age groups, respectively (p≤0.005). Histologically, implanted tumors in young mice exhibited characteristics of aggressive, rapidly growing tumor cells including high vascularity, mitosis, and invasiveness compared to tumors in old mice. We contend that the decrease in B16 melanoma tumor growth seen with increasing age in B6 and CB6 F1 mice represents a biological process, which we are calling age-dependent cancer resistance (ADCR). Our data provide a detailed description of conditions necessary to use the model to investigate the mechanisms of ADCR and deter
Mitochondrial targeted catalase suppresses invasive breast cancer in mice
Jorming Goh, Linda Enns, Soroosh Fatemie, Heather Hopkins, John Morton, Christina Pettan-Brewer, Warren Ladiges
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-191
Abstract: Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined.PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p ≤ 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p ≤ 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects.Targeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer.Please see related commentary article: http://www.biomedcentral.com/1741-7015/9
Timing and Awareness of Movement Decisions: Does Consciousness Really Come Too Late?
Adrian G. Guggisberg,Ana?s Mottaz
Frontiers in Human Neuroscience , 2013, DOI: 10.3389/fnhum.2013.00385
Abstract: Since Libet's seminal observation that a brain potential related to movement preparation occurs before participants report to be aware of their movement intention, it has been debated whether consciousness has causal influence on movement decisions. Here we review recent advances that provide new insights into the dynamics of human decision-making and question the validity of different markers used for determining the onset of neural and conscious events. Motor decisions involve multiple stages of goal evaluation, intention formation, and action execution. While the validity of the Bereitschaftspotential (BP) as index of neural movement preparation is controversial, improved neural markers are able to predict decision outcome even at early stages. Participants report being conscious of their decisions only at the time of final intention formation, just before the primary motor cortex starts executing the chosen action. However, accumulating evidence suggests that this is an artifact of Libet's clock method used for assessing consciousness. More refined methods suggest that intention consciousness does not appear instantaneously but builds up progressively. In this view, early neural markers of decision outcome are not unconscious but simply reflect conscious goal evaluation stages which are not final yet and therefore not reported with the clock method. Alternatives to the Libet clock are discussed that might allow for assessment of consciousness during decision making with improved sensitivity to early decision stages and with less influence from meta-conscious and perceptual inferences.
Effects of healthy aging on human primary visual cortex  [PDF]
Alyssa A. Brewer, Brian Barton
Health (Health) , 2012, DOI: 10.4236/health.2012.429109
Abstract: Aging often results in reduced visual acuity from changes in both the eye and neural circuits [1-4]. In normally aging subjects, primary visual cortex has been shown to have reduced responses to visual stimulation [5]. It is not known, however, to what extent aging affects visual field repre-sentations and population receptive sizes in human primary visual cortex. Here we use func-tional MRI (fMRI) and population receptive field (pRF) modeling [6] to measure angular and ec-centric retinotopic representations and population receptive fields in primary visual cortex in healthy aging subjects ages 57 - 70 and in healthy young volunteers ages 24 - 36 (n = 9). Retinotopic stimuli consisted of black and white, drifting checkerboards comprising moving bars 11 deg in radius. Primary visual cortex (V1) was clearly identifiable along the calcarine sulcus in all hemispheres. There was a significant decrease in the surface area of V1 from 0 to 3 deg eccentricity in the aging subjects with respect to the young subjects (p = 0.039). The coherence of the fMRI% BOLD modulation was significantly decreased in the aging subjects compared to the young subjects in the more peripheral eccentricity band from 7 to 10 deg (p = 0.029). Finally, pRF sizes were significantly increased within the 0 to 3 deg foveal representation of V1 in the aging subjects compared to the young subjects (p = 0.019). Understanding the extent of changes that occur in primary visual cortex during normal aging is essential both for understanding the normal aging process and for comparisons of healthy, aging subjects with aging patients suffering from age-related visual and cortical disorders.
Visual Working Memory in Human Cortex  [PDF]
Brian Barton, Alyssa A. Brewer
Psychology (PSYCH) , 2013, DOI: 10.4236/psych.2013.48093
Abstract:

Visual working memory (VWM) is the ability to maintain visual information in a readily available and easily updated state. Converging evidence has revealed that VWM capacity is limited by the number of maintained objects, which is about 3 - 4 for the average human. Recent work suggests that VWM capacity is also limited by the resolution required to maintain objects, which is tied to the objects’ inherent complexity. Electroencephalogram (EEG) studies using the Contralateral Delay Activity (CDA) paradigm have revealed that cortical representations of VWM are at a minimum loosely organized like the primary visual system, such that the left side of space is represented in the right hemisphere, and vice versa. Recent functional magnetic resonance imaging (fMRI) work shows that the number of objects is maintained by representations in the inferior intraparietal sulcus (IPS) along dorsal parietal cortex, whereas the resolution of these maintained objects is subserved by the superior IPS and the lateral occipital complex (LOC). These areas overlap with recently-discovered, retinotopically-organized visual field maps (VFMs) spanning the IPS (IPS-0/1/2/3/4/5), and potentially maps in lateral occipital cortex, such as LO-1/2, and/or TO-1/2 (hMT+). Other fMRI studies have implicated early VFMs in posterior occipital cortex, suggesting that visual areas V1-hV4 are recruited to represent information in VWM. Insight into whether and how these VFMs subserve VWM may illuminate the nature of VWM. In addition, understanding the nature of these maps may allow a greater investigation into individual differences among subjects and even between hemispheres within subjects.

HIV Prevention in Papua New Guinea: Is It Working or Not?  [PDF]
Heather Worth
World Journal of AIDS (WJA) , 2012, DOI: 10.4236/wja.2012.23016
Abstract: Introduction: There is a global call for structural approaches to HIV that go beyond awareness and HIV testing to approach prevention work via the social and economic drivers of the epidemic. Papua New Guinea is the epicentre of the HIV epidemic in the Pacific, with an adult prevalence rate of 0.9%. Since 2004, there has been a concerted response to HIV, with vastly increased rates of HIV testing and roll-out of antiretroviral therapy, and considerable funding for HIV prevention. Objectives: While incidence is slowing there are still a considerable number of new infections each year and many commentators are worried that HIV prevention is not working in that country. This article aims to critically examine HIV prevention programs in Papua New Guinea to show whether HIV prevention is effectiveness in reaching those most vulnerable to infection. Methods: Using data from HIV prevention programs and behavioural surveys this article will assess how HIV prevention has been carried out and the effectiveness of those programs. Results: There is little evidence to indicate that HIV prevention in Papua New Guinea, particularly among those most at risk of HIV has been successful. Conclusion: there is a dearth of HIV prevention interventions in Papua New Guinea that go beyond awareness-raising to deal with the structural drivers of the epidemic.
Integrative Analysis of the Mitochondrial Proteome in Yeast
Holger Prokisch,Curt Scharfe,David G. Camp II,Wenzhong Xiao,Lior David,Christophe Andreoli,Matthew E. Monroe,Ronald J. Moore,Marina A. Gritsenko,Christian Kozany,Kim K. Hixson,Heather M. Mottaz,Hans Zischka,Marius Ueffing,Zelek S. Herman,Ronald W. Davis,Thomas Meitinger,Peter J. Oefner,Richard D. Smith,Lars M. Steinmetz
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020160
Abstract: In this study yeast mitochondria were used as a model system to apply, evaluate, and integrate different genomic approaches to define the proteins of an organelle. Liquid chromatography mass spectrometry applied to purified mitochondria identified 546 proteins. By expression analysis and comparison to other proteome studies, we demonstrate that the proteomic approach identifies primarily highly abundant proteins. By expanding our evaluation to other types of genomic approaches, including systematic deletion phenotype screening, expression profiling, subcellular localization studies, protein interaction analyses, and computational predictions, we show that an integration of approaches moves beyond the limitations of any single approach. We report the success of each approach by benchmarking it against a reference set of known mitochondrial proteins, and predict approximately 700 proteins associated with the mitochondrial organelle from the integration of 22 datasets. We show that a combination of complementary approaches like deletion phenotype screening and mass spectrometry can identify over 75% of the known mitochondrial proteome. These findings have implications for choosing optimal genome-wide approaches for the study of other cellular systems, including organelles and pathways in various species. Furthermore, our systematic identification of genes involved in mitochondrial function and biogenesis in yeast expands the candidate genes available for mapping Mendelian and complex mitochondrial disorders in humans.
Integrative Analysis of the Mitochondrial Proteome in Yeast
Holger Prokisch equal contributor,Curt Scharfe equal contributor,David G Camp II equal contributor,Wenzhong Xiao equal contributor,Lior David,Christophe Andreoli,Matthew E Monroe,Ronald J Moore,Marina A Gritsenko,Christian Kozany,Kim K Hixson,Heather M Mottaz,Hans Zischka,Marius Ueffing,Zelek S Herman,Ronald W Davis,Thomas Meitinger,Peter J Oefner,Richard D Smith,Lars M Steinmetz
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020160
Abstract: In this study yeast mitochondria were used as a model system to apply, evaluate, and integrate different genomic approaches to define the proteins of an organelle. Liquid chromatography mass spectrometry applied to purified mitochondria identified 546 proteins. By expression analysis and comparison to other proteome studies, we demonstrate that the proteomic approach identifies primarily highly abundant proteins. By expanding our evaluation to other types of genomic approaches, including systematic deletion phenotype screening, expression profiling, subcellular localization studies, protein interaction analyses, and computational predictions, we show that an integration of approaches moves beyond the limitations of any single approach. We report the success of each approach by benchmarking it against a reference set of known mitochondrial proteins, and predict approximately 700 proteins associated with the mitochondrial organelle from the integration of 22 datasets. We show that a combination of complementary approaches like deletion phenotype screening and mass spectrometry can identify over 75% of the known mitochondrial proteome. These findings have implications for choosing optimal genome-wide approaches for the study of other cellular systems, including organelles and pathways in various species. Furthermore, our systematic identification of genes involved in mitochondrial function and biogenesis in yeast expands the candidate genes available for mapping Mendelian and complex mitochondrial disorders in humans.
Genes for the Major Structural Components of Thermotogales Species’ Togas Revealed by Proteomic and Evolutionary Analyses of OmpA and OmpB Homologs
Amanda K. Petrus, Kristen S. Swithers, Chaman Ranjit, Si Wu, Heather M. Brewer, J. Peter Gogarten, Ljiljana Pasa-Tolic, Kenneth M. Noll
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040236
Abstract: The unifying structural characteristic of members of the bacterial order Thermotogales is their toga, an unusual cell envelope that includes a loose-fitting sheath around each cell. Only two toga-associated structural proteins have been purified and characterized in Thermotoga maritima: the anchor protein OmpA1 (or Ompα) and the porin OmpB (or Ompβ). The gene encoding OmpA1 (ompA1) was cloned and sequenced and later assigned to TM0477 in the genome sequence, but because no peptide sequence was available for OmpB, its gene (ompB) was not annotated. We identified six porin candidates in the genome sequence of T. maritima. Of these candidates, only one, encoded by TM0476, has all the characteristics reported for OmpB and characteristics expected of a porin including predominant β-sheet structure, a carboxy terminus porin anchoring motif, and a porin-specific amino acid composition. We highly enriched a toga fraction of cells for OmpB by sucrose gradient centrifugation and hydroxyapatite chromatography and analyzed it by LC/MS/MS. We found that the only porin candidate that it contained was the TM0476 product. This cell fraction also had β-sheet character as determined by circular dichroism, consistent with its enrichment for OmpB. We conclude that TM0476 encodes OmpB. A phylogenetic analysis of OmpB found orthologs encoded in syntenic locations in the genomes of all but two Thermotogales species. Those without orthologs have putative isofunctional genes in their place. Phylogenetic analyses of OmpA1 revealed that each species of the Thermotogales has one or two OmpA homologs. T. maritima has two OmpA homologs, encoded by ompA1 (TM0477) and ompA2 (TM1729), both of which were found in the toga protein-enriched cell extracts. These annotations of the genes encoding toga structural proteins will guide future examinations of the structure and function of this unusual lineage-defining cell sheath.
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