Abstract:
:We previously developed a biological containment system using recombinant Salmonella Typhimurium strains that are attenuated yet capable of synthesizing protective antigens. The regulated delayed attenuation and programmed self-destructing features designed into these S. Typhimurium strains enable them to efficiently colonize host tissues and allow release of the bacterial cell contents after lysis. To turn such a recombinant attenuated Salmonella vaccine (RASV) strain into a universal DNA vaccine-delivery vehicle, our approach was to genetically modify RASV strains to display a hyperinvasive phenotype to maximize Salmonella host entry and host cell internalization, to enable Salmonella endosomal escape to release a DNA vaccine into the cytosol, and to decrease Salmonella-induced pyroptosis/apoptosis that allows the DNA vaccine time to traffic to the nucleus for efficient synthesis of encoded protective antigens. A DNA vaccine vector that encodes a domain that contributes to the arabinose-regulated lysis phenotype but has a eukaryotic promoter was constructed. The vector was then improved by insertion of multiple DNA nuclear-targeting sequences for efficient nuclear trafficking and gene expression, and by increasing nuclease resistance to protect the plasmid from host degradation. A DNA vaccine encoding influenza WSN virus HA antigen delivered by the RASV strain with the best genetic attributes induced complete protection to mice against a lethal influenza virus challenge. Adoption of these technological improvements will revolutionize means for effective delivery of DNA vaccines to stimulate mucosal, systemic, and cellular protective immunities, and lead to a paradigm shift in cost-effective control and prevention of a diversity of diseases.
journal_name
Proc Natl Acad Sci U S Aauthors
Kong W,Brovold M,Koeneman BA,Clark-Curtiss J,Curtiss R 3rddoi
10.1073/pnas.1217554109subject
Has Abstractpub_date
2012-11-20 00:00:00pages
19414-9issue
47eissn
0027-8424issn
1091-6490pii
1217554109journal_volume
109pub_type
杂志文章abstract::3.L2 T cell receptor transgenic T cells are activated by the 64-76 peptide of the mouse hemoglobin d beta chain [Hb(64-76)], and their response is antagonized by the position 72 alanine substitution of this peptide (A72). To test the effect of this altered peptide ligand (APL) on 3.L2 T cell function in vivo, a transg...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.95.24.14332
更新日期:1998-11-24 00:00:00
abstract::Protein 2.1 is a 210-kilodalton protein that connects erythrocyte spectrin to the NH2-terminal cytoplasmic domain of band 3 and thereby functions as the essential linkage between the membrane skeleton and the bilayer. We cleaved this protein into specific chemical domains by limited digestion with trypsin and alpha-ch...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.81.13.4095
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abstract::A method is proposed for rapidly, quantitatively comparing protein structures of arbitrary sizes, based on the differential geometric representation. The method is applied to a group of 22 protein x-ray structures, and the resulting network of closest relationships is delineated. Several well-known fold types are auto...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.85.3.777
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abstract::Prokaryotic genomes are substantially diverse, even when from closely related species, with the resulting phenotypic diversity representing a repertoire of adaptations to specific constraints. Within the microbial population, genome content may not be fixed, as changing selective forces favor particular phenotypes; ho...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Identifying potentially unique features of the human cerebral cortex is a first step to understanding how evolution has shaped the brain in our species. By analyzing MR images obtained from 177 humans and 73 chimpanzees, we observed a human-specific asymmetry in the superior temporal sulcus at the heart of the communi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Transgenic pigs were generated that produced human protein C in their milk at up to 1 g/liter. The gene construct was a fusion gene consisting of the cDNA for human protein C inserted into the first exon of the mouse whey acidic protein gene. These results demonstrate that the mouse whey acidic protein gene contains r...
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abstract::The vertical occipital fasciculus (VOF) is the only major fiber bundle connecting dorsolateral and ventrolateral visual cortex. Only a handful of studies have examined the anatomy of the VOF or its role in cognition in the living human brain. Here, we trace the contentious history of the VOF, beginning with its origin...
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abstract::Animal movements result from a complex balance of many different forces. Muscles produce force to move the body; the body has inertial, elastic, and damping properties that may aid or oppose the muscle force; and the environment produces reaction forces back on the body. The actual motion is an emergent property of th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::A 1,942-base-pair DNA segment encoding the structural gene for diphtheria toxin was sequenced, and the primary structure of the toxin was deduced. Restriction enzyme fragments corresponding to nontoxic or hypotoxic peptides of the toxin were isolated from corynebacteriophage beta and cloned into Escherichia coli on pl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::As root symbionts of cycad trees, cyanobacteria of the genus Nostoc produce beta-methylamino-l-alanine (BMAA), a neurotoxic nonprotein amino acid. The biomagnification of BMAA through the Guam ecosystem fits a classic triangle of increasing concentrations of toxic compounds up the food chain. However, because BMAA is ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation. We used array comparative genomic hybridization to analyze a ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.1017137108
更新日期:2011-06-07 00:00:00
abstract::The mechanism of the inotropic effect of cardiac glycosides on the heart has long been controversial. Inotropic effects at low concentrations of cardiac glycosides indicate more than one class of receptor or more than one cellular mechanism. In the brain of the rat, high- and low-affinity cardiac glycoside receptors h...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.23.8404
更新日期:1987-12-01 00:00:00
abstract::The primary product of biological nitrogen fixation, ammonia, reversibly regulates nitrogenase activity in a variety of diazotrophs by a process called "NH4(+)-switch-off/on." Strong correlative evidence from work in Azospirillum lipoferum and Rhodospirillum rubrum indicates that this regulation involves both the inac...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.87.5.1720
更新日期:1990-03-01 00:00:00
abstract::We outline a theory to quantify the interplay of entropic and selective forces on nucleotide organization and apply it to the genomes of single-stranded RNA viruses. We quantify these forces as intensive variables that can easily be compared between sequences, outline a computationally efficient transfer-matrix method...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1402285111
更新日期:2014-04-01 00:00:00
abstract::The C terminus of transcription factor NusA from Escherichia coli comprises two repeat units, which bind during antitermination to protein N from phage lambda. To delineate the structural basis of the NusA-lambdaN interaction, we attempted to crystallize the NusA C-terminal repeats in complex with a lambdaN peptide (r...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2004-09-21 00:00:00
abstract::More than a thousand proteins are thought to contribute to mammalian chromatin and its regulation, but our understanding of the genomic occupancy and function of most of these proteins is limited. Here we describe an approach, which we call "chromatin proteomic profiling," to identify proteins associated with genomic ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1502971112
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abstract::The sodium/iodide symporter (NIS) mediates active I(-) transport in the thyroid-the first step in thyroid hormone biosynthesis-with a 2 Na(+): 1 I(-) stoichiometry. The two Na(+) binding sites (Na1 and Na2) and the I(-) binding site interact allosterically: when Na(+) binds to a Na(+) site, the affinity of NIS for the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2016-09-13 00:00:00
abstract::A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Oxidative stress plays a central role in many human diseases and in aging. In Caenorhabditis elegans the SKN-1 protein induces phase II detoxification gene transcription, a conserved oxidative stress response, and is required for oxidative stress resistance and longevity. Oxidative stress induces SKN-1 to accumulate i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1977-03-01 00:00:00
abstract::Experiments were designed with the aim of understanding the mechanism whereby the lambda repressor inhibits messenger RNA synthesis. Complexes containing lambda DNA and RNA polymerase were isolated from repressed and derepressed lysogens and analyzed for the relative amounts of RNA polymerase per phage genome. The dat...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::The het-s locus of Podospora anserina is a heterokaryon incompatibility locus. The coexpression of the antagonistic het-s and het-S alleles triggers a lethal reaction that prevents the formation of viable heterokaryons. Strains that contain the het-s allele can display two different phenotypes, [Het-s] or [Het-s*], ac...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Global activation of the embryonic genome is the most critical event in early mammalian development. After fertilization, a rich supply of maternal proteins and RNAs support development whereas a number of zygotic and embryonic genes are expressed in a stage-specific manner leading to embryonic genome activation (EGA)...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2006-12-12 00:00:00
abstract::Clinical data showing correlations between low thyroid-stimulating hormone (TSH) levels and high bone turnover markers, low bone mineral density, and an increased risk of osteoporosis-related fractures are buttressed by mouse genetic and pharmacological studies identifying a direct action of TSH on the skeleton. Here ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2013-06-11 00:00:00
abstract::Breast tumors lacking expression of human epidermal growth factor receptor 2 (HER2) and the estrogen and the progesterone receptors (triple negative; TNBC) are more aggressive than other disease subtypes, and no molecular targeted agents are currently available for their treatment. Because TNBC commonly displays EGF r...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2013-01-29 00:00:00
abstract::Regulation of cardiac contraction by neurotransmitters and hormones is often correlated with regulation of the L-type Ca2(+)-channel current (ICa) through the opposite actions of two second messengers, cyclic AMP and cyclic GMP. While cyclic AMP stimulation of ICa is mediated by the activation of cyclic AMP-dependent ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.4.1197
更新日期:1991-02-15 00:00:00