Abstract:
:Hereditary hemochromatosis (HH) is a common genetic disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. The vast majority of individuals with HH are homozygous for mutations in the HFE gene. Recently a second transferrin receptor (TFR2) was discovered, and a previously uncharacterized type of hemochromatosis (HH type 3) was identified in humans carrying mutations in the TFR2 gene. To characterize the role for TFR2 in iron homeostasis, we generated mice in which a premature stop codon (Y245X) was introduced by targeted mutagenesis in the murine Tfr2 coding sequence. This mutation is orthologous to the Y250X mutation identified in some patients with HH type 3. The homozygous Tfr2(Y245X) mutant mice showed profound abnormalities in parameters of iron homeostasis. Even on a standard diet, hepatic iron concentration was several-fold higher in the homozygous Tfr2(Y245X) mutant mice than in wild-type littermates by 4 weeks of age. The iron deposition in the mutant mice was predominantly hepatocellular and periportal. The mean splenic iron concentration in the homozygous Tfr2(Y245X) mutant mice was significantly less than that observed in the wild-type mice. The homozygous Tfr2(Y245X) mutant mice also demonstrated elevated transferrin saturations. There were no significant differences in parameters of erythrocyte production including hemoglobin levels, hematocrits, erythrocyte indices, and reticulocyte counts. Heterozygous Tfr2(Y245X) mice did not differ in any measured parameter from wild-type mice. This study confirms the important role for TFR2 in iron homeostasis and provides a tool for investigating the excess iron absorption and abnormal iron distribution in iron-overload disorders.
journal_name
Proc Natl Acad Sci U S Aauthors
Fleming RE,Ahmann JR,Migas MC,Waheed A,Koeffler HP,Kawabata H,Britton RS,Bacon BR,Sly WSdoi
10.1073/pnas.162360699keywords:
subject
Has Abstractpub_date
2002-08-06 00:00:00pages
10653-8issue
16eissn
0027-8424issn
1091-6490pii
162360699journal_volume
99pub_type
杂志文章abstract::We have developed an efficient, versatile, and user-friendly viral engineering and expression system that is based on in planta assembly of functional viral vectors from separate pro-vector modules. With this new system, instead of supplying a plant cell with a complete viral vector as a mature viral particle, an RNA ...
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.0400149101
更新日期:2004-05-04 00:00:00
abstract::When histones in chromatin core particles were crosslinked with dimethylsuberimidate, the resulting particles had properties closely similar to those of native core particles. A crosslinked octameric histone complex was isolated from these particles under nondenaturing conditions. Upon reaction with DNA, this octameri...
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.74.7.2780
更新日期:1977-07-01 00:00:00
abstract::Small molecules of biological origin continue to yield the most promising leads for drug design, but systematic approaches for exploring nature's cache of structural diversity are lacking. Here, we demonstrate the use of 2D NMR spectroscopy to screen a library of biorationally selected insect metabolite samples for pa...
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.1107020108
更新日期:2011-06-14 00:00:00
abstract::Involution of the thymus is accompanied by a decline in the number of thymic epithelial cells (TECs) and a severely restricted peripheral repertoire of T-cell specificities. TECs are essential for T-cell differentiation; they originate from a bipotent progenitor that gives rise to cells of cortical (cTEC) and medullar...
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.1118823109
更新日期:2012-02-28 00:00:00
abstract::The size of virus-specific RNA synthesized in cultured mouse kidney cells infected with polyoma virus was estimated by electrophoresis and sedimentation analysis of RNA extracts from whole cells. Newly synthesized "late" polyoma-specific RNA appears as "giant" molecules of heterogeneous size, up to several times large...
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.68.9.2231
更新日期:1971-09-01 00:00:00
abstract::Periodical cicadas are well known for their prime-numbered life cycles (17 and 13 years) and their mass periodical emergences. The origination and persistence of prime-numbered cycles are explained by the hybridization hypothesis on the basis of their lower likelihood of hybridization with other cycles. Recently, we 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.0900215106
更新日期:2009-06-02 00:00:00
abstract::Adult-born granule cells in the dentate gyrus of the rodent hippocampus are important for memory formation and mood regulation, but the cellular mechanism underlying their polarized development, a process critical for their incorporation into functional circuits, remains unknown. We found that deletion of the serine-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.1321454111
更新日期:2014-01-07 00:00:00
abstract::A posttranslational protein O-mannosylation process resembling that found in fungi and animals has been reported in the major human pathogen Mycobacterium tuberculosis (Mtb) and related actinobacteria. However, the role and incidence of this process, which is essential in eukaryotes, have never been explored in Mtb. W...
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.1219704110
更新日期:2013-04-16 00:00:00
abstract::Bacteriophage Mu was inserted into the unc genes of Escherichia coli. The resulting mutation AS12 had a polar effect on the unc operon: membranes of the mutant AS12 contained the dicyclohexylcarbodiimide-binding protein c and the protein a as sole subunits of the ATP synthase. It was shown by peptide mapping and amino...
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.78.11.6643
更新日期:1981-11-01 00:00:00
abstract::Human epidermal stem cells express higher levels of beta1 integrins and are more adhesive than keratinocytes that are destined to differentiate. To investigate whether high beta1 integrin expression and adhesiveness are essential for maintaining keratinocytes in the stem cell compartment, we introduced a dominant-nega...
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.96.12.6728
更新日期:1999-06-08 00:00:00
abstract::We provide evidence for an interaction between mouse class I major histocompatibility complex antigens and insulin receptors. Antibodies against class I but not class II major histocompatibility complex antigens immunoprecipitate photoaffinity-labeled hepatic insulin receptors. Haplotype specificity is demonstrated by...
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.83.10.3474
更新日期:1986-05-01 00:00:00
abstract::Comparison of about 50 pairs of homologous nucleotide sequences for different genes revealed that the substitutions between synonymous codons occurred at much higher rates than did amino acid substitutions. Furthermore, five pairs of mRNA sequences for different genes were compared in species that had diverged at 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.77.12.7328
更新日期:1980-12-01 00:00:00
abstract::mtDNA mutations occur in a wide variety of degenerative diseases and cancer. mtDNA seems to be more susceptible to DNA damage and consequently sustains higher rates of mutation than does nuclear DNA (nDNA). Many of the somatic mtDNA mutations in human cancers are located in the displacement loop (D-loop) and in partic...
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.0437910100
更新日期:2003-02-18 00:00:00
abstract::In order to study the mutagenic effects of site-specific, covalent modifications of biologically active DNA, we need host cells that are permissive for any type of mutation that might be produced in vivo from the modified DNA. Specifically, we require a general, in vivo complementation system for the bacteriophage phi...
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.75.2.774
更新日期:1978-02-01 00:00:00
abstract::Previous studies have identified lipid-poor high density lipoproteins with electrophoretic pre-beta mobility as the initial acceptors of cell-derived cholesterol in human plasma. These lipoproteins contain apolipoprotein A-I (apo A-I) as their sole apolipoprotein. In the present study, incubation of human plasma with ...
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.91.5.1834
更新日期:1994-03-01 00:00:00
abstract::The nit-2 major nitrogen regulatory gene of Neurospora crassa turns on the expression of various unlinked structural genes that specify nitrogen-catabolic enzymes under nitrogen-limitation conditions. The nit-2 gene encodes a protein of 1036 amino acid residues with a single zinc finger and a downstream basic region 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.87.14.5331
更新日期:1990-07-01 00:00:00
abstract::The overall structure of the transition-state and intermediate ensembles observed experimentally for dihydrofolate reductase and interleukin-1beta can be obtained by using simplified models that have almost no energetic frustration. The predictive power of these models suggests that, even for these very large proteins...
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.100547897
更新日期:2000-05-23 00:00:00
abstract::Infection is a major complication of implantable medical devices, which provide a scaffold for biofilm formation, thereby reducing susceptibility to antibiotics and complicating treatment. Hematogenous implant-related infections following bacteremia are particularly problematic because they can occur at any time in a ...
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.1703427114
更新日期:2017-06-27 00:00:00
abstract::Single crystal diamond produced by chemical vapor deposition (CVD) at very high growth rates (up to 150 microm/h) has been successfully annealed without graphitization at temperatures up to 2200 degrees C and pressures <300 torr. Crystals were annealed in a hydrogen environment by using microwave plasma techniques for...
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.0808230105
更新日期:2008-11-18 00:00:00
abstract::Unit electrical activity was recorded from single neurons in the isolated lumbo-sacral spinal cord of 14- to 19-day chick embryos, in situ. Spinal cord transection was combined with transection of all lumbo-sacral dorsal roots. The spontaneous discharge of cells is confined, for the most part, to the lower two thirds ...
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.66.1.40
更新日期:1970-05-01 00:00:00
abstract::The bactericidal effects of antibiotics are undoubtedly triggered by target-specific interactions, but there is growing evidence that an important aspect of cytotoxicity results from treatment-induced metabolic perturbations. In this study, we characterized molecular mechanisms whereby trimethoprim treatment results i...
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.1706236114
更新日期:2017-10-24 00:00:00
abstract::Therapeutics for cerebral ischemia/hypoxia, which often results in ischemic stroke in humans, are a global unmet medical need. Here, we report that bryostatin-1, a highly potent protein kinase C (PKC) activator, interrupts pathophysiological molecular cascades and apoptosis triggered by cerebral ischemia/hypoxia, enha...
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.0907842106
更新日期:2009-08-25 00:00:00
abstract::Studies of perception usually emphasize processes that are largely universal across observers and--except for short-term fluctuations--stationary over time. Here we test the universality and stationarity assumptions with two families of ambiguous visual stimuli. Each stimulus can be perceived in two different ways, pa...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,随机对照试验
doi:10.1073/pnas.1508847112
更新日期:2015-12-01 00:00:00
abstract::Protein O-mannosylation represents an evolutionarily conserved, essential posttranslational modification with immense impact on a variety of cellular processes. In humans, O-mannosylation defects result in Walker-Warburg syndrome, a severe recessive congenital muscular dystrophy associated with defects in neuronal mig...
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.0700374104
更新日期:2007-05-08 00:00:00
abstract::We have developed a color complementation assay that allows rapid screening of specific genomic DNA sequences. It is based on the simultaneous amplification of two or more DNA segments with fluorescent oligonucleotide primers such that the generation of a color, or combination of colors, can be visualized and used for...
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.86.23.9178
更新日期:1989-12-01 00:00:00
abstract::Diversity in 39 HLA-A, -B, and -C molecules is derived from 20 amino acid positions of high variability and 71 positions of low variability. Variation in the structurally homologous alpha 1 and alpha 2 domains is distinct and may correlate with partial segregation of peptide and T-cell receptor binding functions. Comp...
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.85.11.4005
更新日期:1988-06-01 00:00:00
abstract::Many methods have been developed to search for homologous members of a protein family in databases, and the reliability of results and conclusions may be compromised if only one method is used, neglecting the others. Here we introduce a general scheme for combining such methods. Based on this scheme, we implemented a ...
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.0405612101
更新日期:2004-09-21 00:00:00
abstract::Sublethal insults can induce tolerance to subsequent stressors in neurons. As cell death activators such as ROS generation and decreased ATP can initiate tolerance, we tested whether other cellular elements normally associated with neuronal injury could add to this process. In an in vivo model of ischemic tolerance, w...
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.0232966100
更新日期:2003-01-21 00:00:00
abstract::We used electron cryotomography and subtomogram averaging to determine the in situ structures of mitochondrial ATP synthase dimers from two organisms belonging to the phylum euglenozoa: Trypanosoma brucei, a lethal human parasite, and Euglena gracilis, a photosynthetic protist. At a resolution of 32.5 Å and 27.5 Å, re...
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.1612386114
更新日期:2017-01-31 00:00:00
abstract::GB virus B (GBV-B), which infects tamarins, is the virus most closely related to hepatitis C virus (HCV). HCV has a protein (p7) that is believed to form an ion channel. It is critical for viability. In vitro studies suggest that GBV-B has an analogous but larger protein (p13). We found that substitutions of the -1 an...
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.0511297103
更新日期:2006-02-28 00:00:00