PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2112)
2081. Modeling the Excess Cell Surface Stored in a Complex Morphology of Bleb-Like Protrusions
- Title Tesim:
- Modeling the Excess Cell Surface Stored in a Complex Morphology of Bleb-Like Protrusions
- Creator:
- Wessler, Timothy, Chen, Alex, Wang, Qi, Zhao, Jia, Forest, M. Gregory, Roach, Nathan, Elston, Timothy C., Kapustina, Maryna, Jacobson, Ken, Tsygankov, Denis, and Yang, Xiaofeng
- Date of publication:
- 2016
- Abstract Tesim:
- Cells transition from spread to rounded morphologies in diverse physiological contexts including mitosis and mesenchymal-to-amoeboid transitions. When these drastic shape changes occur rapidly, cell volume and surface area are approximately conserved. Consequently, the rounded cells are suddenly presented with a several-fold excess of cell surface whose area far exceeds that of a smooth sphere enclosing the cell volume. This excess is stored in a population of bleb-like protrusions (BLiPs), whose size distribution is shown by electron micrographs to be skewed. We introduce three complementary models of rounded cell morphologies with a prescribed excess surface area. A 2D Hamiltonian model provides a mechanistic description of how discrete attachment points between the cell surface and cortex together with surface bending energy can generate a morphology that satisfies a prescribed excess area and BLiP number density. A 3D random seed-and-growth model simulates efficient packing of BLiPs over a primary rounded shape, demonstrating a pathway for skewed BLiP size distributions that recapitulate 3D morphologies. Finally, a phase field model (2D and 3D) posits energy-based constitutive laws for the cell membrane, nematic F-actin cortex, interior cytosol, and external aqueous medium. The cell surface is equipped with a spontaneous curvature function, a proxy for the cell surface-cortex couple, that is a priori unknown, which the model “learns” from the thin section transmission electron micrograph image (2D) or the “seed and growth” model image (3D). Converged phase field simulations predict self-consistent amplitudes and spatial localization of pressure and stress throughout the cell for any posited stationary morphology target and cell compartment constitutive properties. The models form a general framework for future studies of cell morphological dynamics in a variety of biological contexts.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Mathematics, Department of Cell Biology and Physiology, and Department of Pharmacology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/73fd-sb43
- Identifier:
- PMID: 27015526, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1004841, PMCID: PMC4807848, and Onescience id: b8647e9ce665683ff5d9f9f3e215a8942d74b557
- ISSN:
- 1553-734X and 1553-7358
- Journal Issue:
- 3
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 12
- Keyword:
- Animals, Cricetulus, CHO Cells, Membrane Fluidity, Cell Surface Extensions, Cell Size, Computer Simulation, Models, Chemical, and Models, Molecular
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Risk Analytics Laboratory; GE Global Research Center, Department of Mathematics; University of South Carolina, Department of Applied Physical Sciences, Department of Biology; Program in Cellular; Molecular; and Developmental Biology and Biophysics; Johns Hopkins University, School of Medicine, and Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University
- Page Start:
- e1004841
- Person:
- Wessler, Timothy, Chen, Alex, Wang, Qi, Zhao, Jia, Forest, M. Gregory, Roach, Nathan, Elston, Timothy C., Kapustina, Maryna, Jacobson, Ken, Tsygankov, Denis, and Yang, Xiaofeng
- Rights Statement Label:
- In Copyright
- Source:
- jh343z631
2082. Modeling and Simulation of Mucus Flow in Human Bronchial Epithelial Cell Cultures – Part I: Idealized Axisymmetric Swirling Flow
- Title Tesim:
- Modeling and Simulation of Mucus Flow in Human Bronchial Epithelial Cell Cultures – Part I: Idealized Axisymmetric Swirling Flow
- Creator:
- Jin, Yuan, Vasquez, Paula A., Hill, David, Forest, M. Gregory, and Palmer, Erik
- Date of publication:
- 2016
- Abstract Tesim:
- A multi-mode nonlinear constitutive model for mucus is constructed directly from micro- and macro-rheology experimental data on cell culture mucus, and a numerical algorithm is developed for the culture geometry and idealized cilia driving conditions. This study investigates the roles that mucus rheology, wall effects, and HBE culture geometry play in the development of flow profiles and the shape of the air-mucus interface. Simulations show that viscoelasticity captures normal stress generation in shear leading to a peak in the air-mucus interface at the middle of the culture and a depression at the walls. Linear and nonlinear viscoelastic regimes can be observed in cultures by varying the hurricane radius and mean rotational velocity. The advection-diffusion of a drug concentration dropped at the surface of the mucus flow is simulated as a function of Peclet number.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Mathematics and School of Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/23hr-r408
- Identifier:
- Onescience id: 07b146d494b9ae3fdbbae088bb445b547b25b76f, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1004872, PMCID: PMC4975472, and PMID: 27494700
- ISSN:
- 1553-734X and 1553-7358
- Journal Issue:
- 8
- Journal Title:
- PLoS Computational Biology
- Journal Volume:
- 12
- Keyword:
- Viscosity, Cells, Cultured, Mucus, Algorithms, Models, Biological, Nonlinear Dynamics, Humans, Cilia, Computer Simulation, Epithelial Cells, Bronchi, Elasticity, and Computational Biology
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Mathematics; University of South Carolina, Department of Physics and Astronomy, and Department of Biomedical Engineering - Biomedical Engineering
- Page Start:
- e1004872
- Person:
- Jin, Yuan, Vasquez, Paula A., Hill, David, Forest, M. Gregory, and Palmer, Erik
- Rights Statement Label:
- In Copyright
- Source:
- b5644x977
2083. Fidelity to a behavioral intervention to improve goals of care decisions for nursing home residents with advanced dementia
- Title Tesim:
- Fidelity to a behavioral intervention to improve goals of care decisions for nursing home residents with advanced dementia
- Creator:
- Song, Mi-Kyung, Gilliam, Robin, Rosemond, Cherie, Lin, Feng-Chang, Hanson, Laura C., Zimmerman, Sheryl, and Chisholm, Latarsha
- Date of publication:
- 2016
- Abstract Tesim:
- Ensuring fidelity to a behavioral intervention implemented in nursing homes requires awareness of the unique considerations of this setting for research. The purpose of this manuscript is to describe the Goals of Care (GOC) cluster-randomized trial and the methods used to monitor and promote fidelity to a GOC decision aid intervention delivered in nursing homes.
- Resource type:
- Article
- Affiliation Label Tesim:
- University of North Carolina at Chapel Hill, Cecil G. Sheps Center for Health Services Research, UNC Center for Health Promotion and Disease Prevention, North Carolina Translational and Clinical Sciences Institute, and Division of Geriatric Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/hzm3-n257
- Identifier:
- Onescience id: c76617d4c94b03b897ec1b42e4115a015bdf6502, Publisher DOI: https://doi.org/10.1177/1740774516650863, PMCID: PMC5133163, and PMID: 27271683
- ISSN:
- 1555-5887
- Journal Issue:
- 6
- Journal Title:
- PLoS Clinical Trials
- Journal Volume:
- 13
- Keyword:
- Process Assessment (Health Care), dementia, Dementia, Communication, Fidelity, Patient Care Planning, Decision Support Techniques, Decision Making, Proxy, Randomized Controlled Trials as Topic, Humans, Nursing Homes, nursing home, Family, behavioral intervention, and Palliative Care
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Health Management and Informatics; University of Central Florida
- Page End:
- 604
- Page Start:
- 599
- Person:
- Song, Mi-Kyung, Gilliam, Robin, Rosemond, Cherie, Lin, Feng-Chang, Hanson, Laura C., Zimmerman, Sheryl, and Chisholm, Latarsha
- Rights Statement Label:
- In Copyright
- Source:
- hq37vt596
2084. Research priorities for harnessing plant microbiomes in sustainable agriculture
- Title Tesim:
- Research priorities for harnessing plant microbiomes in sustainable agriculture
- Creator:
- Kremer, James, Bennett, Alison, Soman, Chinmay, Morsy, Mustafa, Busby, Posy E., Friesen, Maren L., Eisen, Jonathan A., Leach, Jan E., Wagner, Maggie R., and Dangl, Jeffery L.
- Date of publication:
- 2017
- Abstract Tesim:
- Feeding a growing world population amidst climate change requires optimizing the reliability, resource use, and environmental impacts of food production. One way to assist in achieving these goals is to integrate beneficial plant microbiomes—i.e., those enhancing plant growth, nutrient use efficiency, abiotic stress tolerance, and disease resistance—into agricultural production. This integration will require a large-scale effort among academic researchers, industry researchers, and farmers to understand and manage plant-microbiome interactions in the context of modern agricultural systems. Here, we identify priorities for research in this area: (1) develop model host–microbiome systems for crop plants and non-crop plants with associated microbial culture collections and reference genomes, (2) define core microbiomes and metagenomes in these model systems, (3) elucidate the rules of synthetic, functionally programmable microbiome assembly, (4) determine functional mechanisms of plant-microbiome interactions, and (5) characterize and refine plant genotype-by-environment-by-microbiome-by-management interactions. Meeting these goals should accelerate our ability to design and implement effective agricultural microbiome manipulations and management strategies, which, in turn, will pay dividends for both the consumers and producers of the world food supply.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/bt3a-tr35
- Identifier:
- PMCID: PMC5370116, Publisher DOI: https://doi.org/10.1371/journal.pbio.2001793, Onescience id: 2949633fa2f683acf1d4c0018927a27c91d67bc8, and PMID: 28350798
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 3
- Journal Title:
- PLoS Biology
- Journal Volume:
- 15
- Keyword:
- Agricultural workers, Microbiome, Agriculture, Host-pathogen interactions, Microbial ecology, Flowering plants, Plant-microbial interactions, and Community ecology
- Language Label:
- English
- ORCID:
- and 0000-0002-2837-9820
- Other Affiliation:
- MSU-DOE Plant Research Laboratory; Michigan State University, The James Hutton Institute, Department of Natural Resources and Environmental Sciences; University of Illinois at Urbana Champaign, College of Natural Sciences and Mathematics; University of West Alabama, Department of Botany and Plant Pathology; Oregon State University, Department of Plant Biology; Michigan State University, Program in Ecology; Evolutionary Biology and Behavior; Michigan State University, Genome Center; University of California, Bioagricultural Sciences and Pest Management; Colorado State University, and Department of Plant Pathology; North Carolina State University
- Page Start:
- e2001793
- Person:
- Kremer, James, Bennett, Alison, Soman, Chinmay, Morsy, Mustafa, Busby, Posy E., Friesen, Maren L., Eisen, Jonathan A., Leach, Jan E., Wagner, Maggie R., and Dangl, Jeffery L.
- Rights Statement Label:
- In Copyright
- Source:
- 2r36v3892
2085. Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus
- Title Tesim:
- Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus
- Creator:
- Maile, Robert, Lachiewicz, Anne M., Cairns, Bruce A., Wolfgang, Matthew C., Vitko, Nicholas P., Conlon, Brian P., Rowe, Sarah E., Kartchner, Laurel B., Gode, Cindy J., and Radlinski, Lauren
- Date of publication:
- 2017
- Abstract Tesim:
- Chronic coinfections of Staphylococcus aureus and Pseudomonas aeruginosa frequently fail to respond to antibiotic treatment, leading to significant patient morbidity and mortality. Currently, the impact of interspecies interaction on S. aureus antibiotic susceptibility remains poorly understood. In this study, we utilize a panel of P. aeruginosa burn wound and cystic fibrosis (CF) lung isolates to demonstrate that P. aeruginosa alters S. aureus susceptibility to bactericidal antibiotics in a variable, strain-dependent manner and further identify 3 independent interactions responsible for antagonizing or potentiating antibiotic activity against S. aureus. We find that P. aeruginosa LasA endopeptidase potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent tobramycin uptake, and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We find that the production of each of these factors varies between clinical isolates and corresponds to the capacity of each isolate to alter S. aureus antibiotic susceptibility. Furthermore, we demonstrate that vancomycin treatment of a S. aureus mouse burn infection is potentiated by the presence of a LasA-producing P. aeruginosa population. These findings demonstrate that antibiotic susceptibility is complex and dependent not only upon the genotype of the pathogen being targeted, but also on interactions with other microorganisms in the infection environment. Consideration of these interactions will improve the treatment of polymicrobial infections.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Microbiology and Immunology, Department of Surgery, and School of Medicine
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/jacm-s175
- Identifier:
- Onescience id: 7b1aa6c7da4d4469abf7674b885254d97e05ace7, PMCID: PMC5720819, Publisher DOI: https://doi.org/10.1371/journal.pbio.2003981, and PMID: 29176757
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 11
- Journal Title:
- PLoS Biology
- Journal Volume:
- 15
- Keyword:
- Mouse models, Cystic fibrosis, Antibiotics, Co-infections, Respiratory infections, Vancomycin, Staphylococcus aureus, and Pseudomonas aeruginosa
- Language Label:
- English
- ORCID:
- and 0000-0003-1863-5525
- Other Affiliation:
- Department of Surgery, Division of Infectious Diseases, and School of Medicine
- Page Start:
- e2003981
- Person:
- Maile, Robert, Lachiewicz, Anne M., Cairns, Bruce A., Wolfgang, Matthew C., Vitko, Nicholas P., Conlon, Brian P., Rowe, Sarah E., Kartchner, Laurel B., Gode, Cindy J., and Radlinski, Lauren
- Rights Statement Label:
- In Copyright
- Source:
- dr26z335h
2086. Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells
- Title Tesim:
- Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells
- Creator:
- Cocchiaro, Jordan L., Sheikh, Shehzad Z., Camp, J. Gray, Furey, Terrence S., Weiser, Matthew, Lickwar, Colin R., Rawls, John F., and Kingsley, David M.
- Date of publication:
- 2017
- Abstract Tesim:
- The intestinal epithelium serves critical physiologic functions that are shared among all vertebrates. However, it is unknown how the transcriptional regulatory mechanisms underlying these functions have changed over the course of vertebrate evolution. We generated genome-wide mRNA and accessible chromatin data from adult intestinal epithelial cells (IECs) in zebrafish, stickleback, mouse, and human species to determine if conserved IEC functions are achieved through common transcriptional regulation. We found evidence for substantial common regulation and conservation of gene expression regionally along the length of the intestine from fish to mammals and identified a core set of genes comprising a vertebrate IEC signature. We also identified transcriptional start sites and other putative regulatory regions that are differentially accessible in IECs in all 4 species. Although these sites rarely showed sequence conservation from fish to mammals, surprisingly, they drove highly conserved IEC expression in a zebrafish reporter assay. Common putative transcription factor binding sites (TFBS) found at these sites in multiple species indicate that sequence conservation alone is insufficient to identify much of the functionally conserved IEC regulatory information. Among the rare, highly sequence-conserved, IEC-specific regulatory regions, we discovered an ancient enhancer upstream from her6/HES1 that is active in a distinct population of Notch-positive cells in the intestinal epithelium. Together, these results show how combining accessible chromatin and mRNA datasets with TFBS prediction and in vivo reporter assays can reveal tissue-specific regulatory information conserved across 420 million years of vertebrate evolution. We define an IEC transcriptional regulatory network that is shared between fish and mammals and establish an experimental platform for studying how evolutionarily distilled regulatory information commonly controls IEC development and physiology.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Cell Biology and Physiology, Department of Medicine, and Department of Genetics
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/pbfq-qa19
- Identifier:
- PMID: 28850571, Onescience id: a1f2c244db9b465bd68bcf4eb0f6753c4a32073c, Publisher DOI: https://doi.org/10.1371/journal.pbio.2002054, and PMCID: PMC5574553
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 8
- Journal Title:
- PLoS Biology
- Journal Volume:
- 15
- Keyword:
- Female, Fish Proteins, Gene Expression Regulation, Genomics, Humans, Duodenum, Animals, Ileum, Gene Expression Profiling, Intestinal Mucosa, California, and Colon
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Molecular Genetics and Microbiology; Center for the Genomics of Microbial Systems; Duke University and Department of Developmental Biology; Stanford University
- Page Start:
- e2002054
- Person:
- Cocchiaro, Jordan L., Sheikh, Shehzad Z., Camp, J. Gray, Furey, Terrence S., Weiser, Matthew, Lickwar, Colin R., Rawls, John F., and Kingsley, David M.
- Rights Statement Label:
- In Copyright
- Source:
- 6969z6207
2087. Genome-wide identification of bacterial plant colonization genes
- Title Tesim:
- Genome-wide identification of bacterial plant colonization genes
- Creator:
- Malmstrom, Rex R., Deutschbauer, Adam M., McDonald, Meredith, Waters, Robert J., Visel, Axel, Wetmore, Kelly M., Yoshikuni, Yasuo, Ryan, Elizabeth M., Mucyn, Tatiana S., Wang, Gaoyan, Feltcher, Meghan E., Dangl, Jeffery L., Ul-Hasan, Sabah, and Cole, Benjamin J.
- Date of publication:
- 2017
- Abstract Tesim:
- Diverse soil-resident bacteria can contribute to plant growth and health, but the molecular mechanisms enabling them to effectively colonize their plant hosts remain poorly understood. We used randomly barcoded transposon mutagenesis sequencing (RB-TnSeq) in Pseudomonas simiae, a model root-colonizing bacterium, to establish a genome-wide map of bacterial genes required for colonization of the Arabidopsis thaliana root system. We identified 115 genes (2% of all P. simiae genes) with functions that are required for maximal competitive colonization of the root system. Among the genes we identified were some with obvious colonization-related roles in motility and carbon metabolism, as well as 44 other genes that had no or vague functional predictions. Independent validation assays of individual genes confirmed colonization functions for 20 of 22 (91%) cases tested. To further characterize genes identified by our screen, we compared the functional contributions of P. simiae genes to growth in 90 distinct in vitro conditions by RB-TnSeq, highlighting specific metabolic functions associated with root colonization genes. Our analysis of bacterial genes by sequence-driven saturation mutagenesis revealed a genome-wide map of the genetic determinants of plant root colonization and offers a starting point for targeted improvement of the colonization capabilities of plant-beneficial microbes.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Biology
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/hkht-ws09
- Identifier:
- PMCID: PMC5627942, PMID: 28938018, Onescience id: f1540a394a71fb75f9ed278ee4aac65e0d606327, and Publisher DOI: https://doi.org/10.1371/journal.pbio.2002860
- ISSN:
- 1544-9173 and 1545-7885
- Journal Issue:
- 9
- Journal Title:
- PLoS Biology
- Journal Volume:
- 15
- Keyword:
- Plant Roots, Mutation, DNA, Bacterial, Genes, Bacterial, Pseudomonas, Arabidopsis, Chromosomes, Bacterial, Chromosome Mapping, DNA Transposable Elements, and DNA Barcoding, Taxonomic
- Language Label:
- English
- ORCID:
- and 0000-0001-9652-624X
- Other Affiliation:
- US Department of Energy Joint Genome Institute, Environmental Genomics and Systems Biology Division; Lawrence Berkeley National Laboratory, and School of Natural Sciences; University of California Merced
- Page Start:
- e2002860
- Person:
- Malmstrom, Rex R., Deutschbauer, Adam M., McDonald, Meredith, Waters, Robert J., Visel, Axel, Wetmore, Kelly M., Yoshikuni, Yasuo, Ryan, Elizabeth M., Mucyn, Tatiana S., Wang, Gaoyan, Feltcher, Meghan E., Dangl, Jeffery L., Ul-Hasan, Sabah, and Cole, Benjamin J.
- Rights Statement Label:
- In Copyright
- Source:
- zs25xf322
2088. Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent
- Title Tesim:
- Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent
- Creator:
- Shin, Hae Won, Hadar, Eldad, Lefebvre, Jérémie, Alagapan, Sankaraleengam, Frӧhlich, Flavio, and Schmidt, Stephen L.
- Date of publication:
- 2016
- Abstract Tesim:
- Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Neurosurgery and Department of Psychiatry
- Deposit Record:
- http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/80kv-re78
- Identifier:
- Publisher DOI: https://doi.org/10.1371/journal.pbio.1002424, PMCID: PMC4811434, Onescience id: 773676000e8270964478615f5b41aad84d855693, and PMID: 27023427
- ISSN:
- 1545-7885 and 1544-9173
- Journal Issue:
- 3
- Journal Title:
- PLoS Biology
- Journal Volume:
- 14
- Keyword:
- Neurons, Frontal lobe, Transcranial alternating current stimulation, Functional electrical stimulation, Electrode recording, Modulation, Eyes, and Parietal lobe
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Department of Neurology, Krembil Research Institute; University Health Network, Department of Mathematics; University of Toronto, Neuroscience Curriculum, UNC Neuroscience Center, University of North Carolina at Chapel Hill, and Department of Cell Biology and Physiology
- Page Start:
- e1002424
- Person:
- Shin, Hae Won, Hadar, Eldad, Lefebvre, Jérémie, Alagapan, Sankaraleengam, Frӧhlich, Flavio, and Schmidt, Stephen L.
- Rights Statement Label:
- In Copyright
- Source:
- rx913v93c
2089. SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism
- Title Tesim:
- SARS-CoV Pathogenesis Is Regulated by a STAT1 Dependent but a Type I, II and III Interferon Receptor Independent Mechanism
- Creator:
- Morrison, Thomas E., Roberts, Anjeanette, Lamirande, Elaine W., Baric, Ralph S., Heise, Mark, Funkhouser, William, Chen, Jun, Subbarao, Kanta, Whitmore, Alan, Frieman, Matthew, and Ward, Jerrold M.
- Date of publication:
- 2010
- Abstract Tesim:
- Severe acute respiratory syndrome coronavirus (SARS-CoV) infection often caused severe end stage lung disease and organizing phase diffuse alveolar damage, especially in the elderly. The virus-host interactions that governed development of these acute end stage lung diseases and death are unknown. To address this question, we evaluated the role of innate immune signaling in protection from human (Urbani) and a recombinant mouse adapted SARS-CoV, designated rMA15. In contrast to most models of viral pathogenesis, infection of type I, type II or type III interferon knockout mice (129 background) with either Urbani or MA15 viruses resulted in clinical disease outcomes, including transient weight loss, denuding bronchiolitis and alveolar inflammation and recovery, identical to that seen in infection of wildtype mice. This suggests that type I, II and III interferon signaling play minor roles in regulating SARS pathogenesis in mouse models. In contrast, infection of STAT1−/− mice resulted in severe disease, high virus titer, extensive pulmonary lesions and 100% mortality by day 9 and 30 post-infection with rMA15 or Urbani viruses, respectively. Non-lethal in BALB/c mice, Urbani SARS-CoV infection in STAT1−/− mice caused disseminated infection involving the liver, spleen and other tissues after day 9. These findings demonstrated that SARS-CoV pathogenesis is regulated by a STAT1 dependent but type I, II and III interferon receptor independent, mechanism. In contrast to a well documented role in innate immunity, we propose that STAT1 also protects mice via its role as an antagonist of unrestrained cell proliferation.
- Resource type:
- Article
- Admin Note:
- deposited as part of the 1Science batch
- Affiliation Label Tesim:
- Department of Microbiology and Immunology, Department of Epidemiology, and Department of Pathology and Laboratory Medicine
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/qnkn-hk61
- Identifier:
- https://dx.doi.org/10.1371/journal.ppat.1000849
- ISSN:
- 1553-7366
- Journal Issue:
- 4
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 6
- Keyword:
- Flow Cytometry, Mice, Knockout, Interferon Type I, Cytokines, Mice, Reverse Transcriptase Polymerase Chain Reaction, In Situ Hybridization, SARS Virus, Receptors, Interferon, Female, Interferon-gamma, Animals, and Gene Expression Profiling
- Language Label:
- English
- ORCID:
- Other Affiliation:
- and National Institutes of Health
- Person:
- Morrison, Thomas E., Roberts, Anjeanette, Lamirande, Elaine W., Baric, Ralph S., Heise, Mark, Funkhouser, William, Chen, Jun, Subbarao, Kanta, Whitmore, Alan, Frieman, Matthew, and Ward, Jerrold M.
- Rights Statement Label:
- In Copyright
- Source:
- j098zg88f
2090. Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing
- Title Tesim:
- Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing
- Creator:
- Lu, Xiaotao, Scherbakova, Sana, Denison, Mark R., Baric, Ralph S., Li, Kelvin, Stockwell, Timothy B., Graham, Rachel L., Becker, Michelle M., Venter, Eli, Halpin, Rebecca A., Eckerle, Lance D., and Spiro, David J.
- Date of publication:
- 2010
- Abstract Tesim:
- Most RNA viruses lack the mechanisms to recognize and correct mutations that arise during genome replication, resulting in quasispecies diversity that is required for pathogenesis and adaptation. However, it is not known how viruses encoding large viral RNA genomes such as the Coronaviridae (26 to 32 kb) balance the requirements for genome stability and quasispecies diversity. Further, the limits of replication infidelity during replication of large RNA genomes and how decreased fidelity impacts virus fitness over time are not known. Our previous work demonstrated that genetic inactivation of the coronavirus exoribonuclease (ExoN) in nonstructural protein 14 (nsp14) of murine hepatitis virus results in a 15-fold decrease in replication fidelity. However, it is not known whether nsp14-ExoN is required for replication fidelity of all coronaviruses, nor the impact of decreased fidelity on genome diversity and fitness during replication and passage. We report here the engineering and recovery of nsp14-ExoN mutant viruses of severe acute respiratory syndrome coronavirus (SARS-CoV) that have stable growth defects and demonstrate a 21-fold increase in mutation frequency during replication in culture. Analysis of complete genome sequences from SARS-ExoN mutant viral clones revealed unique mutation sets in every genome examined from the same round of replication and a total of 100 unique mutations across the genome. Using novel bioinformatic tools and deep sequencing across the full-length genome following 10 population passages in vitro, we demonstrate retention of ExoN mutations and continued increased diversity and mutational load compared to wild-type SARS-CoV. The results define a novel genetic and bioinformatics model for introduction and identification of multi-allelic mutations in replication competent viruses that will be powerful tools for testing the effects of decreased fidelity and increased quasispecies diversity on viral replication, pathogenesis, and evolution.
- Resource type:
- Article
- Admin Note:
- deposited as part of the 1Science batch
- Affiliation Label Tesim:
- Department of Epidemiology
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/65nc-nw44
- Identifier:
- https://dx.doi.org/10.1371/journal.ppat.1000896
- ISSN:
- 1553-7366
- Journal Issue:
- 5
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 6
- Keyword:
- Models, Genetic, Cercopithecus aethiops, Phenotype, Molecular Sequence Data, Genetic Variation, Polymorphism, Single Nucleotide, Amino Acid Sequence, Genome, Viral, Mutation, Animals, SARS Virus, Severe Acute Respiratory Syndrome, Evolution, Molecular, Exoribonucleases, and Genetic Engineering
- Language Label:
- English
- ORCID:
- Other Affiliation:
- Vanderbilt University Medical Center, The J. Craig Venter Institute, and
- Person:
- Lu, Xiaotao, Scherbakova, Sana, Denison, Mark R., Baric, Ralph S., Li, Kelvin, Stockwell, Timothy B., Graham, Rachel L., Becker, Michelle M., Venter, Eli, Halpin, Rebecca A., Eckerle, Lance D., and Spiro, David J.
- Rights Statement Label:
- In Copyright
- Source:
- 9k41zk125
Collection Details
- Total items
-
2112
- Size
-
unknown
- Date created
-
February 2, 2022