Abstract:
:Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable and dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe the appearance of transgene-specific T-cell responses in two subjects that were part of the phase II trial. The patient with the more robust T-cell response, which was associated with a reduction in transgene expression, was characterized more thoroughly in this study. We learned that the AAT-specific T cells in this patient were cytolytic in phenotype, mapped to a peptide in the endogenous mutant AAT protein that contained a common polymorphism not incorporated into the transgene, and were restricted by a rare HLA class I C alleles present only in this patient. These human studies illustrate the genetic influence of the endogenous gene and HLA haplotype on the outcome of gene therapy.
journal_name
Proc Natl Acad Sci U S Aauthors
Calcedo R,Somanathan S,Qin Q,Betts MR,Rech AJ,Vonderheide RH,Mueller C,Flotte TR,Wilson JMdoi
10.1073/pnas.1617726114subject
Has Abstractpub_date
2017-02-14 00:00:00pages
1655-1659issue
7eissn
0027-8424issn
1091-6490pii
1617726114journal_volume
114pub_type
杂志文章,多中心研究abstract::The formation of a fracture network is a key process for many geophysical and industrial practices from energy resource recovery to induced seismic management. We focus on the initial stage of a fracture network formation using experiments on the symmetric coalescence of two equal coplanar, fluid-driven, penny-shaped ...
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.1809233115
更新日期:2018-10-09 00:00:00
abstract::Past research found that the ingestion of glucose can enhance self-control. It has been widely assumed that basic physiological processes underlie this effect. We hypothesized that the effect of glucose also depends on people's theories about willpower. Three experiments, both measuring (experiment 1) and manipulating...
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.1313475110
更新日期:2013-09-10 00:00:00
abstract::Bacteriophage lambda encodes a number of genes involved in the recombinational repair of DNA double-strand breaks. The product of one of these genes, rap, has been purified. Truncated Rap proteins that copurify with the full-length form are derived, at least in part, from a rho-dependent transcription terminator locat...
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.95.23.13507
更新日期:1998-11-10 00:00:00
abstract::Evolutionary thinking can be applied to both cultural microevolution and macroevolution. However, much of the current literature focuses on cultural microevolution. In this article, we argue that the growing availability of large cross-cultural datasets facilitates the use of computational methods derived from evoluti...
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.1620746114
更新日期:2017-07-25 00:00:00
abstract::The regulation of glycogen metabolism is critical for the maintenance of glucose and energy homeostasis in mammals. Glycogen synthase, the enzyme responsible for glycogen production, is regulated by multisite phosphorylation in yeast and mammals. We have previously identified PAS kinase as a physiological regulator of...
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.0508481102
更新日期:2005-11-15 00:00:00
abstract::WOPR-domain proteins are found throughout the fungal kingdom where they function as master regulators of cell morphology and pathogenesis. Genetic and biochemical experiments previously demonstrated that these proteins bind to specific DNA sequences and thereby regulate transcription. However, their primary sequence s...
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.1410110111
更新日期:2014-07-22 00:00:00
abstract::A spherical harmonic analysis is made of the hydrodynamic equation governing the flow of an incompressible liquid in a rotating sphere in the presence of the magnetic Lorentz force. Nonlinear partial differential equations are derived for the functions S(n)(r,t) and T(n)(r,t) entering the spherical harmonic representa...
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.72.4.1496
更新日期:1975-04-01 00:00:00
abstract::The vascular endothelial growth factor (VEGF) family has recently expanded by the identification and cloning of three additional members, namely VEGF-B, VEGF-C, and VEGF-D. In this study we demonstrate that VEGF-B binds selectively to VEGF receptor-1/Flt-1. This binding can be blocked by excess VEGF, indicating that t...
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.95.20.11709
更新日期:1998-09-29 00:00:00
abstract::Clostridium ljungdahlii is an anaerobic homoacetogen, able to ferment sugars, other organic compounds, or CO(2)/H(2) and synthesis gas (CO/H(2)). The latter feature makes it an interesting microbe for the biotech industry, as important bulk chemicals and proteins can be produced at the expense of CO(2), thus combining...
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.1004716107
更新日期:2010-07-20 00:00:00
abstract::We have found the two-dimensional electrophoretic technique of O'Farrell to be highly efficient in the detection of charge-change substitutions in a large number of proteins. We have applied this method to determine the level of heterozygosity of the most abundant proteins in Drosophila melanogaster adults from a natu...
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.76.5.2381
更新日期:1979-05-01 00:00:00
abstract::Heterogeneous nucleation is vital to a wide range of areas as diverse as ice nucleation on atmospheric aerosols and the fabrication of high-performance thin films. There is excellent evidence that surface topography is a key factor in directing crystallization in real systems; however, the mechanisms by which nanoscal...
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.1617717114
更新日期:2017-01-31 00:00:00
abstract::This paper reports that there are major differences between mammalian cell lines in the propensity to progress into subsequent cell cycles when mitosis is inhibited with agents that disrupt the assembly of the mitotic spindle apparatus (Colcemid, nocodazole, and taxol). Human HeLa S3 cells, which represent one extreme...
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.87.24.9553
更新日期:1990-12-01 00:00:00
abstract::Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effecti...
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.1203789109
更新日期:2012-07-17 00:00:00
abstract::Skin fibroblasts from two patients who had symptoms of the Sanfilippo syndrome (mucopolysaccharidosis III) accumulated excessive amounts of heparan sulfate and were unable to release sulfate from N-acetylglucosamine-6-sulfate linkages in heparan sulfate-derived oligosaccharides. Keratan sulfate-derived oligosaccharide...
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.77.11.6822
更新日期:1980-11-01 00:00:00
abstract::It has often been suggested that the frequently observed Watson-Crick base-pair compensatory substitutions in RNA helical structures occur mainly through a slightly deleterious G.U intermediate state. We have scored base substitutions in a set of 82 related Drosophila species for the D1 and D2 variable domains of the ...
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.88.22.10032
更新日期:1991-11-15 00:00:00
abstract::The Hairy-related transcription-factor (HRT) genes encode three related basic helix-loop-helix transcription factors that show sequence similarity to the Hairy and Enhancer of split family of transcriptional repressors. HRT proteins are expressed in specific regions of the developing heart, vasculature, pharyngeal arc...
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.250485597
更新日期:2000-12-05 00:00:00
abstract::In eukaryotes, RNA polymerase I transcription is controlled by DNA elements located within the spacers that separate the tandemly arranged rRNA genes. Unlike rRNA coding sequences, the intergenic spacers evolve rapidly and have little sequence similarity even among closely related species. Nonetheless, the arrangement...
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.90.16.7528
更新日期:1993-08-15 00:00:00
abstract::Agrobacterium tumefaciens transfers the T-DNA portion of its Ti plasmid to the nuclear genome of plant cells. Upon cocultivation of A. tumefaciens strain A348 with regenerating tobacco leaf protoplasts, restriction endonuclease fragments of the T-DNA were generated that are consistent with double-stranded cleavage of ...
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.84.7.1881
更新日期:1987-04-01 00:00:00
abstract::Modern functional imaging techniques of the brain measure local hemodynamic responses evoked by neuronal activity. Capillary pericytes recently were suggested to mediate neurovascular coupling in brain slices, but their role in vivo remains unexplored. We used two-photon microscopy to study in real time pericytes and ...
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.1011321108
更新日期:2010-12-21 00:00:00
abstract::Polyadenylation, the process of eukaryotic mRNA 3' end formation, is essential for gene expression and cell viability. Polyadenylation of male germ cell mRNAs is unusual, exhibiting increased alternative polyadenylation, decreased AAUAAA polyadenylation signal use, and reduced downstream sequence element dependence. C...
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.0707589104
更新日期:2007-12-18 00:00:00
abstract::Helping and sharing among humans is often motivated by empathy and accompanied by a sense of satisfaction. To determine whether similar self-rewarding mechanisms may underpin assistance among nonhuman primates, eight female brown capuchin monkeys (Cebus apella) underwent testing in a simple choice paradigm. Paired wit...
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.0807060105
更新日期:2008-09-09 00:00:00
abstract::The spatiotemporal regulation of neurotransmitter transporters involves proteins that interact with their intracellular domains. Using a proteomic approach, we identified several proteins that interact with the C terminus of the serotonin transporter (SERT). These included neuronal nitric oxide synthase (nNOS), a PSD-...
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.0610964104
更新日期:2007-05-08 00:00:00
abstract::Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications ...
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.1111628109
更新日期:2012-01-17 00:00:00
abstract::Genes encoding thymidylate synthetase from Bacillus subtilis bacteriophages were cloned in Escherichia coli. Chimeric plasmids pCD1 and pCD3 were constructed from site-specific endonuclease digests of bacteriophage phi3T DNA cloned in pMB9 in E. coli. Similar cloning techniques with bacteriophage beta22 DNA yielded ch...
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.75.8.3664
更新日期:1978-08-01 00:00:00
abstract::Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression....
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.1307100110
更新日期:2013-07-09 00:00:00
abstract::Little is known about genetic regulation of the development of white matter. This knowledge is critical in understanding the pathophysiology of neurodevelopmental syndromes associated with altered cognition as well as in elucidating the genetics of normal human cognition. The hemideletion of approximately 25 genes on ...
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.0704311104
更新日期:2007-09-18 00:00:00
abstract::Although proteins generally fold to their thermodynamically most stable state, some metastable proteins populate higher free energy states. Conformational changes from metastable higher free energy states to lower free energy states with greater stability can then generate the work required to perform physiologically ...
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.1603386113
更新日期:2016-06-07 00:00:00
abstract::We have investigated the minimum extent of DNA sequence required for the attachment site of bacteriophage lambda to function in integrative recombination. A DNA fragment carrying the phage attachment site (attP) of bacteriophage lambda was trimmed, recloned, and tested for recombination proficiency. In order to recomb...
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.77.6.3220
更新日期:1980-06-01 00:00:00
abstract::Most class I MHC ligands are generated from the vast majority of cellular proteins by proteolysis within the ubiquitin-proteasome pathway and are presented on the cell surface by MHC class I molecules. Here, we present the crystallographic analysis of yeast 20S proteasome in complex with the inhibitor homobelactosin C...
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.0600647103
更新日期:2006-03-21 00:00:00
abstract::We have investigated the biochemical basis for negative regulation of interleukin 2 receptor alpha-chain (IL-2R alpha) gene expression. Transient transfection studies employing internally deleted forms of the IL-2R alpha promoter localized a negative regulatory element (NRE) between nucleotides -400 and -368 relative ...
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.86.21.8526
更新日期:1989-11-01 00:00:00