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Search Results: 1 - 10 of 342008 matches for " Trevor R. F. Smith "
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Elucidating the Kinetics of Expression and Immune Cell Infiltration Resulting from Plasmid Gene Delivery Enhanced by Surface Dermal Electroporation
Janess M. Mendoza,Dinah H. Amante,Gleb Kichaev,Christine L. Knott,William B. Kiosses,Trevor R. F. Smith,Niranjan Y. Sardesai,Kate E. Broderick
Vaccines , 2013, DOI: 10.3390/vaccines1030384
Abstract: The skin is an attractive tissue for vaccination in a clinical setting due to the accessibility of the target, the ease of monitoring and most importantly the immune competent nature of the dermal tissue. While skin electroporation offers an exciting and novel future methodology for the delivery of DNA vaccines in the clinic, little is known about the actual mechanism of the approach and the elucidation of the resulting immune responses. To further understand the mechanism of this platform, the expression kinetics and localization of a reporter plasmid delivered via a surface dermal electroporation (SEP) device as well as the effect that this treatment would have on the resident immune cells in that tissue was investigated. Initially a time course (day 0 to day 21) of enhanced gene delivery with electroporation (EP) was performed to observe the localization of green fluorescent protein (GFP) expression and the kinetics of its appearance as well as clearance. Using gross imaging, GFP expression was not detected on the surface of the skin until 8 h post treatment. However, histological analysis by fluorescent microscopy revealed GFP positive cells as early as 1 h after plasmid delivery and electroporation. Peak GFP expression was observed at 24 h and the expression was maintained in skin for up to seven days. Using an antibody specific for a keratinocyte cell surface marker, reporter gene positive keratinocytes in the epidermis were identified. H&E staining of treated skin sections demonstrated an influx of monocytes and granulocytes at the EP site starting at 4 h and persisting up to day 14 post treatment. Immunological staining revealed a significant migration of lymphocytic cells to the EP site, congregating around cells expressing the delivered antigen. In conclusion, this study provides insights into the expression kinetics following EP enhanced DNA delivery targeting the dermal space. These findings may have implications in the future to design efficient DNA vaccination strategies for the clinic.
Student Understanding of Taylor Series Expansions in Statistical Mechanics
Trevor I. Smith,John R. Thompson,Donald B. Mountcastle
Physics , 2011, DOI: 10.1103/PhysRevSTPER.9.020110
Abstract: One goal of physics instruction is to have students learn to make physical meaning of specific mathematical ideas, concepts, and procedures in different physical settings. As part of research investigating student learning in statistical physics, we are developing curriculum materials that guide students through a derivation of the Boltzmann factor, using a Taylor series expansion of entropy. Using results from written surveys, classroom observations, and both individual think-aloud and teaching interviews, we present evidence that many students can recognize and interpret series expansions, but they often lack fluency with the Taylor series despite previous exposures in both calculus and physics courses. We present students' successes and failures both using and interpreting Taylor series expansions in a variety of contexts.
Student understanding of the Boltzmann factor
Trevor I. Smith,Donald B. Mountcastle,John R. Thompson
Physics , 2015, DOI: 10.1103/PhysRevSTPER.11.020123
Abstract: We present results of our investigation into student understanding of the physical significance and utility of the Boltzmann factor in several simple models. We identify various justifications, both correct and incorrect, that students use when answering written questions that require application of the Boltzmann factor. Results from written data as well as teaching interviews suggest that many students can neither recognize situations in which the Boltzmann factor is applicable, nor articulate the physical significance of the Boltzmann factor as an expression for multiplicity, a fundamental quantity of statistical mechanics. The specific student difficulties seen in the written data led us to develop a guided-inquiry tutorial activity, centered around the derivation of the Boltzmann factor, for use in undergraduate statistical mechanics courses. We report on the development process of our tutorial, including data from teaching interviews and classroom observations on student discussions about the Boltzmann factor and its derivation during the tutorial development process. This additional information informed modifications that improved students' abilities to complete the tutorial during the allowed class time without sacrificing the effectiveness as we have measured it. These data also show an increase in students' appreciation of the origin and significance of the Boltzmann factor during the student discussions. Our findings provide evidence that working in groups to better understand the physical origins of the canonical probability distribution helps students gain a better understanding of when the Boltzmann factor is applicable and how to use it appropriately in answering relevant questions.
DNA Damage–Induced Bcl-xL Deamidation Is Mediated by NHE-1 Antiport Regulated Intracellular pH
Rui Zhao,David Oxley,Trevor S. Smith,George A. Follows,Anthony R. Green,Denis R. Alexander
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050001
Abstract: The pro-survival protein Bcl-xL is critical for the resistance of tumour cells to DNA damage. We have previously demonstrated, using a mouse cancer model, that oncogenic tyrosine kinase inhibition of DNA damage–induced Bcl-xL deamidation tightly correlates with T cell transformation in vivo, although the pathway to Bcl-xL deamidation remains unknown and its functional consequences unclear. We show here that rBcl-xL deamidation generates an iso-Asp52/iso-Asp66 species that is unable to sequester pro-apoptotic BH3-only proteins such as Bim and Puma. DNA damage in thymocytes results in increased expression of the NHE-1 Na/H antiport, an event both necessary and sufficient for subsequent intracellular alkalinisation, Bcl-xL deamidation, and apoptosis. In murine thymocytes and tumour cells expressing an oncogenic tyrosine kinase, this DNA damage–induced cascade is blocked. Enforced intracellular alkalinisation mimics the effects of DNA damage in murine tumour cells and human B-lineage chronic lymphocytic leukaemia cells, thereby causing Bcl-xL deamidation and increased apoptosis. Our results define a signalling pathway leading from DNA damage to up-regulation of the NHE-1 antiport, to intracellular alkalanisation to Bcl-xL deamidation, to apoptosis, representing the first example, to our knowledge, of how deamidation of internal asparagine residues can be regulated in a protein in vivo. Our findings also suggest novel approaches to cancer therapy.
DNA Damage–Induced Bcl-xL Deamidation Is Mediated by NHE-1 Antiport Regulated Intracellular pH
Rui Zhao,David Oxley,Trevor S Smith,George A Follows,Anthony R Green,Denis R Alexander
PLOS Biology , 2007, DOI: 10.1371/journal.pbio.0050001
Abstract: The pro-survival protein Bcl-xL is critical for the resistance of tumour cells to DNA damage. We have previously demonstrated, using a mouse cancer model, that oncogenic tyrosine kinase inhibition of DNA damage–induced Bcl-xL deamidation tightly correlates with T cell transformation in vivo, although the pathway to Bcl-xL deamidation remains unknown and its functional consequences unclear. We show here that rBcl-xL deamidation generates an iso-Asp52/iso-Asp66 species that is unable to sequester pro-apoptotic BH3-only proteins such as Bim and Puma. DNA damage in thymocytes results in increased expression of the NHE-1 Na/H antiport, an event both necessary and sufficient for subsequent intracellular alkalinisation, Bcl-xL deamidation, and apoptosis. In murine thymocytes and tumour cells expressing an oncogenic tyrosine kinase, this DNA damage–induced cascade is blocked. Enforced intracellular alkalinisation mimics the effects of DNA damage in murine tumour cells and human B-lineage chronic lymphocytic leukaemia cells, thereby causing Bcl-xL deamidation and increased apoptosis. Our results define a signalling pathway leading from DNA damage to up-regulation of the NHE-1 antiport, to intracellular alkalanisation to Bcl-xL deamidation, to apoptosis, representing the first example, to our knowledge, of how deamidation of internal asparagine residues can be regulated in a protein in vivo. Our findings also suggest novel approaches to cancer therapy.
Inhibition of Translation Initiation by Protein 169: A Vaccinia Virus Strategy to Suppress Innate and Adaptive Immunity and Alter Virus Virulence
Pavla Strnadova?,Hongwei Ren?,Robert Valentine?,Michela Mazzon?,Trevor R. Sweeney?,Ian Brierley?,Geoffrey L. Smith
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1005151
Abstract: Vaccinia virus (VACV) is the prototypic orthopoxvirus and the vaccine used to eradicate smallpox. Here we show that VACV strain Western Reserve protein 169 is a cytoplasmic polypeptide expressed early during infection that is excluded from virus factories and inhibits the initiation of cap-dependent and cap-independent translation. Ectopic expression of protein 169 causes the accumulation of 80S ribosomes, a reduction of polysomes, and inhibition of protein expression deriving from activation of multiple innate immune signaling pathways. A virus lacking 169 (vΔ169) replicates and spreads normally in cell culture but is more virulent than parental and revertant control viruses in intranasal and intradermal murine models of infection. Intranasal infection by vΔ169 caused increased pro-inflammatory cytokines and chemokines, infiltration of pulmonary leukocytes, and lung weight. These alterations in innate immunity resulted in a stronger CD8+ T-cell memory response and better protection against virus challenge. This work illustrates how inhibition of host protein synthesis can be a strategy for virus suppression of innate and adaptive immunity.
Identifying Student Difficulties with Entropy, Heat Engines, and the Carnot Cycle
Trevor I. Smith,Warren M. Christensen,Donald B. Mountcastle,John R. Thompson
Physics , 2015, DOI: 10.1103/PhysRevSTPER.11.020116
Abstract: We report on several specific student difficulties regarding the Second Law of Thermodynamics in the context of heat engines within upper-division undergraduates thermal physics courses. Data come from ungraded written surveys, graded homework assignments, and videotaped classroom observations of tutorial activities. Written data show that students in these courses do not clearly articulate the connection between the Carnot cycle and the Second Law after lecture instruction. This result is consistent both within and across student populations. Observation data provide evidence for myriad difficulties related to entropy and heat engines, including students' struggles in reasoning about situations that are physically impossible and failures to differentiate between differential and net changes of state properties of a system. Results herein may be seen as the application of previously documented difficulties in the context of heat engines, but others are novel and emphasize the subtle and complex nature of cyclic processes and heat engines, which are central to the teaching and learning of thermodynamics and its applications. Moreover, the sophistication of these difficulties is indicative of the more advanced thinking required of students at the upper division, whose developing knowledge and understanding give rise to questions and struggles that are inaccessible to novices.
The Sorcerer II Global Ocean Sampling Expedition: Northwest Atlantic through Eastern Tropical Pacific
Douglas B. Rusch,Aaron L. Halpern,Granger Sutton,Karla B. Heidelberg,Shannon Williamson,Shibu Yooseph,Dongying Wu,Jonathan A. Eisen,Jeff M. Hoffman,Karin Remington,Karen Beeson,Bao Tran,Hamilton Smith,Holly Baden-Tillson,Clare Stewart,Joyce Thorpe,Jason Freeman,Cynthia Andrews-Pfannkoch,Joseph E. Venter,Kelvin Li,Saul Kravitz,John F. Heidelberg,Terry Utterback,Yu-Hui Rogers,Luisa I. Falcón,Valeria Souza,Germán Bonilla-Rosso,Luis E. Eguiarte,David M. Karl,Shubha Sathyendranath,Trevor Platt,Eldredge Bermingham,Victor Gallardo,Giselle Tamayo-Castillo,Michael R. Ferrari,Robert L. Strausberg,Kenneth Nealson,Robert Friedman,Marvin Frazier,J. Craig Venter
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050077
Abstract: The world's oceans contain a complex mixture of micro-organisms that are for the most part, uncharacterized both genetically and biochemically. We report here a metagenomic study of the marine planktonic microbiota in which surface (mostly marine) water samples were analyzed as part of the Sorcerer II Global Ocean Sampling expedition. These samples, collected across a several-thousand km transect from the North Atlantic through the Panama Canal and ending in the South Pacific yielded an extensive dataset consisting of 7.7 million sequencing reads (6.3 billion bp). Though a few major microbial clades dominate the planktonic marine niche, the dataset contains great diversity with 85% of the assembled sequence and 57% of the unassembled data being unique at a 98% sequence identity cutoff. Using the metadata associated with each sample and sequencing library, we developed new comparative genomic and assembly methods. One comparative genomic method, termed “fragment recruitment,” addressed questions of genome structure, evolution, and taxonomic or phylogenetic diversity, as well as the biochemical diversity of genes and gene families. A second method, termed “extreme assembly,” made possible the assembly and reconstruction of large segments of abundant but clearly nonclonal organisms. Within all abundant populations analyzed, we found extensive intra-ribotype diversity in several forms: (1) extensive sequence variation within orthologous regions throughout a given genome; despite coverage of individual ribotypes approaching 500-fold, most individual sequencing reads are unique; (2) numerous changes in gene content some with direct adaptive implications; and (3) hypervariable genomic islands that are too variable to assemble. The intra-ribotype diversity is organized into genetically isolated populations that have overlapping but independent distributions, implying distinct environmental preference. We present novel methods for measuring the genomic similarity between metagenomic samples and show how they may be grouped into several community types. Specific functional adaptations can be identified both within individual ribotypes and across the entire community, including proteorhodopsin spectral tuning and the presence or absence of the phosphate-binding gene PstS.
The Sorcerer II Global Ocean Sampling Expedition: Northwest Atlantic through Eastern Tropical Pacific
Douglas B Rusch ,Aaron L Halpern,Granger Sutton,Karla B Heidelberg,Shannon Williamson,Shibu Yooseph,Dongying Wu,Jonathan A Eisen,Jeff M Hoffman,Karin Remington,Karen Beeson,Bao Tran,Hamilton Smith,Holly Baden-Tillson,Clare Stewart,Joyce Thorpe,Jason Freeman,Cynthia Andrews-Pfannkoch,Joseph E Venter,Kelvin Li,Saul Kravitz,John F Heidelberg,Terry Utterback,Yu-Hui Rogers,Luisa I Falcón,Valeria Souza,Germán Bonilla-Rosso,Luis E Eguiarte,David M Karl,Shubha Sathyendranath,Trevor Platt,Eldredge Bermingham,Victor Gallardo,Giselle Tamayo-Castillo,Michael R Ferrari,Robert L Strausberg,Kenneth Nealson,Robert Friedman,Marvin Frazier,J. Craig Venter
PLOS Biology , 2007, DOI: 10.1371/journal.pbio.0050077
Abstract: The world's oceans contain a complex mixture of micro-organisms that are for the most part, uncharacterized both genetically and biochemically. We report here a metagenomic study of the marine planktonic microbiota in which surface (mostly marine) water samples were analyzed as part of the Sorcerer II Global Ocean Sampling expedition. These samples, collected across a several-thousand km transect from the North Atlantic through the Panama Canal and ending in the South Pacific yielded an extensive dataset consisting of 7.7 million sequencing reads (6.3 billion bp). Though a few major microbial clades dominate the planktonic marine niche, the dataset contains great diversity with 85% of the assembled sequence and 57% of the unassembled data being unique at a 98% sequence identity cutoff. Using the metadata associated with each sample and sequencing library, we developed new comparative genomic and assembly methods. One comparative genomic method, termed “fragment recruitment,” addressed questions of genome structure, evolution, and taxonomic or phylogenetic diversity, as well as the biochemical diversity of genes and gene families. A second method, termed “extreme assembly,” made possible the assembly and reconstruction of large segments of abundant but clearly nonclonal organisms. Within all abundant populations analyzed, we found extensive intra-ribotype diversity in several forms: (1) extensive sequence variation within orthologous regions throughout a given genome; despite coverage of individual ribotypes approaching 500-fold, most individual sequencing reads are unique; (2) numerous changes in gene content some with direct adaptive implications; and (3) hypervariable genomic islands that are too variable to assemble. The intra-ribotype diversity is organized into genetically isolated populations that have overlapping but independent distributions, implying distinct environmental preference. We present novel methods for measuring the genomic similarity between metagenomic samples and show how they may be grouped into several community types. Specific functional adaptations can be identified both within individual ribotypes and across the entire community, including proteorhodopsin spectral tuning and the presence or absence of the phosphate-binding gene PstS.
The Arecibo Galaxy Environment Survey VIII : Discovery of an Isolated Dwarf Galaxy in the Local Volume
R. Taylor,R. F. Minchin,H. Herbst,R. Smith
Physics , 2014, DOI: 10.1093/mnrasl/slu054
Abstract: The Arecibo Galaxy Environment Survey (AGES) has detected a nearby HI source at a heliocentric velocity of +363 km/s . The object was detected through its neutral hydrogen emission and has an obvious possible optical counterpart in Sloan Digital Sky Survey (SDSS) data (though it does not have an optical redshift measurement). We discuss three possible scenarios for the object : 1) It is within the Local Group, in which case its HI properties are comparable with recently discovered ultra-compact high velocity clouds; 2) It is just behind the Local Group, in which case its optical characteristics are similar to the newly discovered Leo P galaxy; 3) It is a blue compact dwarf galaxy within the local volume but not associated with the Local Group. We find the third possibility to be the most likely, based on distance estimates from the Tully-Fisher relation and its velocity relative to the Local Group.
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