Abstract:
:The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRbetaIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.
journal_name
Proc Natl Acad Sci U S Aauthors
Louvet C,Szot GL,Lang J,Lee MR,Martinier N,Bollag G,Zhu S,Weiss A,Bluestone JAdoi
10.1073/pnas.0810246105subject
Has Abstractpub_date
2008-12-02 00:00:00pages
18895-900issue
48eissn
0027-8424issn
1091-6490pii
0810246105journal_volume
105pub_type
杂志文章abstract::Supported metal catalysts are extensively used in industrial and environmental applications. To improve their performance, it is crucial to identify the most active sites. This identification is, however, made challenging by the presence of a large number of potential surface structures that complicate such an assignm...
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.2002342117
更新日期:2020-06-30 00:00:00
abstract::Recoverin, a recently discovered member of the EF-hand superfamily of Ca(2+)-binding proteins, serves as a Ca2+ sensor in vision. The amino terminus of the protein from retinal rod cells contains a covalently attached myristoyl or related N-acyl group. We report here studies of unmyristoylated and myristoylated 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.89.23.11569
更新日期:1992-12-01 00:00:00
abstract::Mutations in the DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome; NR0B1] gene cause X-linked AHC associated with hypogonadotropic hypogonadism. DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily, acting as a transcriptional rep...
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.122044099
更新日期:2002-06-11 00:00:00
abstract::Immediately after focal retinal lesions, receptive fields (RFs) in primary visual cortex expand considerably, even when the retinal damage is limited to the photoreceptor layer. The time course of these changes suggests that mere lack of stimulation in the vicinity of the RF accompanied by stimulation in the surroundi...
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.89.17.8366
更新日期:1992-09-01 00:00:00
abstract::Treatment of Madin-Darby bovine kidney (MDBK) cells with human interferon (IFN)-alpha 2 at 37 degrees C results in a dose-dependent inhibition of cell growth and a reduction of the subsequent binding of 125I-labeled epidermal growth factor (EGF) at 4 degrees C. Human IFN-beta and -gamma, which exhibit little antiviral...
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.83.21.8226
更新日期:1986-11-01 00:00:00
abstract::Colonization of land by plants was a major transition on Earth, but the developmental and genetic innovations required for this transition remain unknown. Physiological studies and the fossil record strongly suggest that the ability of the first land plants to form symbiotic associations with beneficial fungi was one ...
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.1515426112
更新日期:2015-10-27 00:00:00
abstract::The BCL2 protooncogene encodes an inner mitochondrial membrane protein that blocks programmed cell death. BCL2 was isolated from the chromosomal breakpoint of follicular B-cell lymphoma. Transgenic mice that overexpress BCL2 display extended survival of resting B cells. In this study we use a monospecific anti-human B...
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.88.16.6961
更新日期:1991-08-15 00:00:00
abstract::Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS...
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.0807298105
更新日期:2008-09-23 00:00:00
abstract::Stability of the long noncoding-polyadenylated nuclear (PAN) RNA from Kaposi's sarcoma-associated herpesvirus is conferred by an expression and nuclear retention element (ENE). The ENE protects PAN RNA from a rapid deadenylation-dependent decay pathway via formation of a triple helix between the U-rich internal loop o...
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.1217338109
更新日期:2012-11-20 00:00:00
abstract::Using an antibody highly specific for D-serine conjugated to glutaraldehyde, we have localized endogenous D-serine in rat brain. Highest levels of D-serine immunoreactivity occur in the gray matter of the cerebral cortex, hippocampus, anterior olfactory nucleus, olfactory tubercle, and amygdala. Localizations of D-ser...
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.92.9.3948
更新日期:1995-04-25 00:00:00
abstract::Cumulative distributions of the number of doublings undergone by mixed megakaryocytic/erythroblastic colonies and by pure megakaryocytic colonies were determined from plasma clot cultures of bone marrow (from C57BL/6 mice) supplemented with erythropoietin. Analysis of these distributions suggests that these colonies 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.79.14.4410
更新日期:1982-07-01 00:00:00
abstract::Markov chain Monte Carlo (MCMC) or the Metropolis-Hastings algorithm is a simulation algorithm that has made modern Bayesian statistical inference possible. Nevertheless, the efficiency of different Metropolis-Hastings proposal kernels has rarely been studied except for the Gaussian proposal. Here we propose a unique ...
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.1311790110
更新日期:2013-11-26 00:00:00
abstract::Infection of mice with sporozoites of Plasmodium berghei or Plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. Unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. Thus, mi...
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.0805452105
更新日期:2008-09-16 00:00:00
abstract::Legionella pneumophila, the causal agent of Legionnaires' disease, is an intracellular parasite and invades and proliferates within different eukaryotic cells, including human alveolar macrophages. After several 100-fold multiplication within host cells, the pathogens are released for new invasion by induction of apop...
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.0601562103
更新日期:2006-11-07 00:00:00
abstract::We construct a C*-algebra that has only one irreducible representation up to unitary equivalence but is not isomorphic to the algebra of compact operators on any Hilbert space. This answers an old question of Naimark. Our construction uses a combinatorial statement called the diamond principle, which is known to be co...
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.0401489101
更新日期:2004-05-18 00:00:00
abstract::Hematopoietic stem/progenitor cells (HSPCs) possess the potentials of self-renewal, proliferation, and differentiation toward different lineages of blood cells. These cells not only play a primordial role in hematopoietic development but also have important clinical application. Characterization of the gene expression...
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.95.14.8175
更新日期:1998-07-07 00:00:00
abstract::The reversible binding of the haptens 2,4-dinitrophenyllysine (DNP-lysine) and 2,4,6-trinitrophenyllysine (TNP-lysine) to either the nitrophenyl-binding myeloma protein MOPC-315 or to pooled mouse anti-DNP or anti-TNP antibodies produces large and characteristic extrinsic Cotton effects (in the circular dichroic spect...
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.68.10.2477
更新日期:1971-10-01 00:00:00
abstract::When encountering unexpected event changes, memories of relevant past experiences must be updated to form new representations. Current models of memory updating propose that people must first generate memory-based predictions to detect and register that features of the environment have changed, then encode the new eve...
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.1918063117
更新日期:2020-11-24 00:00:00
abstract::Cyclic electron flow (CEF) around photosystem I is thought to balance the ATP/NADPH energy budget of photosynthesis, requiring that its rate be finely regulated. The mechanisms of this regulation are not well understood. We observed that mutants that exhibited constitutively high rates of CEF also showed elevated prod...
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.1418223112
更新日期:2015-04-28 00:00:00
abstract::Gecko and many insects have adopted nanoscale fibrillar structures on their feet as adhesion devices. Here, we consider adhesion between a single fiber and a substrate by van der Waals or electrostatic interactions. For a given contact area A, the theoretical pull-off force of the fiber is sigma(th)A where sigma(th) 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.0400757101
更新日期:2004-05-25 00:00:00
abstract::In the Burmese python (Python molurus), the rapid up-regulation of gastrointestinal (GI) function and morphology after feeding, and subsequent down-regulation on completing digestion, are expected to be mediated by GI hormones and neuropeptides. Hence, we examined postfeeding changes in plasma and tissue concentration...
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.241524698
更新日期:2001-11-20 00:00:00
abstract::The ribonucleotide reductase system of Escherichia coli B participates in the biosynthesis of DNA by reducing ribonucleoside diphosphates to the corresponding deoxyribonucleotides. The enzyme is regulated in a complicated way by allosteric modifiers. We now find that infection of E. coli with the bacteriophage T4 resu...
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.62.3.829
更新日期:1969-03-01 00:00:00
abstract::Mitochondrial cytochrome c oxidase plays an essential role in aerobic cellular respiration, reducing dioxygen to water in a process coupled with the pumping of protons across the mitochondrial inner membrane. An aspartate residue, Asp-51, located near the enzyme surface, undergoes a redox-coupled x-ray structural chan...
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.2635097100
更新日期:2003-12-23 00:00:00
abstract::Visual crowding is a breakdown in object identification that occurs in cluttered scenes, a process that represents the principle restriction on visual performance in the periphery. When crowded objects are presented experimentally, a key finding is that observers frequently report nearby flanking items instead 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.0901352106
更新日期:2009-08-04 00:00:00
abstract::Canavan's disease (CD) is a fatal, hereditary disorder of CNS development that has been linked to mutations in the gene for the enzyme aspartoacylase (ASPA) (EC 3.5.1.15). ASPA acts to hydrolyze N-acetylaspartate (NAA) into l-aspartate and acetate, but the connection between ASPA deficiency and the failure of proper 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.0409184102
更新日期:2005-04-05 00:00:00
abstract::Biological membranes are highly dynamic and complex lipid bilayers, responsible for the fate of living cells. To achieve this function, the hydrating environment is crucial. However, membrane imaging typically neglects water, focusing on the insertion of probes, resonant responses of lipids, or the hydrophobic core. O...
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.1719347115
更新日期:2018-04-17 00:00:00
abstract::The crystal structure of the decapeptide Boc-Aib-Glu(OBzl)-Leu-Aib-Ala-Leu-Aib-Ala-Lys(Z)-Aib-OMe (where Aib is alpha-aminoisobutyryl, Boc is t-butoxycarbonyl, OBzl is benzyl ester, and Z is benzyloxycarbonyl) illustrates a parallel zipper arrangement of interacting helical peptide columns. Head-to-tail NH...OC hydrog...
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.87.20.7921
更新日期:1990-10-01 00:00:00
abstract::Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) protein interactions at the synaptic vesicle/plasma membrane interface play an essential role in neurotransmitter release. The membrane-proximal region (amino acids 77-90) of the v-SNARE vesicle-associated membrane protein 2 (VAMP 2,...
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.0303274101
更新日期:2004-02-10 00:00:00
abstract::Social interactions are fundamental for human behavior, but the quantification of their neural underpinnings remains challenging. Here, we used hyperscanning functional MRI (fMRI) to study information flow between brains of human dyads during real-time social interaction in a joint attention paradigm. In a hardware se...
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.1421831112
更新日期:2015-04-21 00:00:00
abstract::For decades, scientists have debated whether supercooled liquids stop flowing below a glass transition temperature [Formula: see text] or whether motion continues to slow gradually down to zero temperature. Answering this question is challenging because human time scales set a limit on the largest measurable viscosity...
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.1705978114
更新日期:2017-07-25 00:00:00