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Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling.
Blundon JA, Roy NC, Teubner BJW, Yu J, Eom TY, Sample KJ, Pani A, Smeyne RJ, Han SB, Kerekes RA, Rose DC, Hackett TA, Vuppala PK, Freeman BB, Zakharenko SS
(2017) Science 356: 1352-1356
MeSH Terms: 5'-Nucleotidase, Adenosine, Adenosine A1 Receptor Agonists, Adenosine A1 Receptor Antagonists, Animals, Auditory Cortex, Auditory Perception, GPI-Linked Proteins, Mice, Neuronal Plasticity, Piperidines, Pyridazines, Receptor, Adenosine A1, Signal Transduction, Thalamus
Show Abstract · Added April 3, 2018
Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. Here we show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase-dependent adenosine production or A-adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement of tone-discrimination abilities. We conclude that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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MeSH Terms
Characterization of the Domain Orientations of E. coli 5'-Nucleotidase by Fitting an Ensemble of Conformers to DEER Distance Distributions.
Krug U, Alexander NS, Stein RA, Keim A, Mchaourab HS, Sträter N, Meiler J
(2016) Structure 24: 43-56
MeSH Terms: 5'-Nucleotidase, Amino Acid Sequence, Escherichia coli, Escherichia coli Proteins, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Structure, Tertiary
Show Abstract · Added February 5, 2016
Escherichia coli 5'-nucleotidase is a two-domain enzyme exhibiting a unique 96° domain motion that is required for catalysis. Here we present an integrated structural biology study that combines DEER distance distributions with structural information from X-ray crystallography and computational biology to describe the population of presumably almost isoenergetic open and closed states in solution. Ensembles of models that best represent the experimental distance distributions are determined by a Monte Carlo search algorithm. As a result, predominantly open conformations are observed in the unliganded state indicating that the majority of enzyme molecules await substrate binding for the catalytic cycle. The addition of a substrate analog yields ensembles with an almost equal mixture of open and closed states. Thus, in the presence of substrate, efficient catalysis is provided by the simultaneous appearance of open conformers (binding substrate or releasing product) and closed conformers (enabling the turnover of the substrate).
Copyright © 2016 Elsevier Ltd. All rights reserved.
1 Communities
2 Members
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7 MeSH Terms
Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors.
Ryzhov SV, Pickup MW, Chytil A, Gorska AE, Zhang Q, Owens P, Feoktistov I, Moses HL, Novitskiy SV
(2014) J Immunol 193: 3155-64
MeSH Terms: 5'-Nucleotidase, Animals, Antigens, CD, Apyrase, Bone Marrow Cells, Carcinoma, Lewis Lung, Cell Differentiation, Cell Line, Tumor, Cell Movement, Female, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, T-Lymphocytes, Transforming Growth Factor beta, Tumor Microenvironment, Vascular Endothelial Growth Factor A
Show Abstract · Added December 3, 2014
There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and proangiogenic properties of myeloid cells. We have previously shown that the deletion of the TGF-β type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth, suggesting protumorigenic effect of TGF-β signaling. In this study, we tested the hypothesis that TGF-β drives differentiation of myeloid-derived suppressor cells into protumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell-surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from mice with spontaneous tumor formation of mammary gland and conditional deletion of the type II TGF-β receptor in mammary epithelium, an increased level of TGF-β protein was associated with further increase in number of CD39(+)CD73(+) TDMMCs compared with MMTV-PyMT/TGFβRII(WT) control tumors with intact TGF-β signaling. Using genetic and pharmacological approaches, we demonstrated that the TGF-β signaling mediates maturation of myeloid-derived suppressor cells into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGF-β signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels, and diminished progression of both Lewis lung carcinoma and spontaneous mammary carcinomas. We propose that TGF-β signaling can directly induce the generation of CD39(+)CD73(+) TDMMCs, thus contributing to the immunosuppressive, proangiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.
Copyright © 2014 by The American Association of Immunologists, Inc.
2 Communities
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24 MeSH Terms
Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.
Wen W, Zheng W, Okada Y, Takeuchi F, Tabara Y, Hwang JY, Dorajoo R, Li H, Tsai FJ, Yang X, He J, Wu Y, He M, Zhang Y, Liang J, Guo X, Sheu WH, Delahanty R, Guo X, Kubo M, Yamamoto K, Ohkubo T, Go MJ, Liu JJ, Gan W, Chen CC, Gao Y, Li S, Lee NR, Wu C, Zhou X, Song H, Yao J, Lee IT, Long J, Tsunoda T, Akiyama K, Takashima N, Cho YS, Ong RT, Lu L, Chen CH, Tan A, Rice TK, Adair LS, Gui L, Allison M, Lee WJ, Cai Q, Isomura M, Umemura S, Kim YJ, Seielstad M, Hixson J, Xiang YB, Isono M, Kim BJ, Sim X, Lu W, Nabika T, Lee J, Lim WY, Gao YT, Takayanagi R, Kang DH, Wong TY, Hsiung CA, Wu IC, Juang JM, Shi J, Choi BY, Aung T, Hu F, Kim MK, Lim WY, Wang TD, Shin MH, Lee J, Ji BT, Lee YH, Young TL, Shin DH, Chun BY, Cho MC, Han BG, Hwu CM, Assimes TL, Absher D, Yan X, Kim E, Kuo JZ, Kwon S, Taylor KD, Chen YD, Rotter JI, Qi L, Zhu D, Wu T, Mohlke KL, Gu D, Mo Z, Wu JY, Lin X, Miki T, Tai ES, Lee JY, Kato N, Shu XO, Tanaka T
(2014) Hum Mol Genet 23: 5492-504
MeSH Terms: 5'-Nucleotidase, Aldehyde Dehydrogenase, Aldehyde Dehydrogenase, Mitochondrial, Asian Continental Ancestry Group, Blood Proteins, Body Mass Index, Cardiac Myosins, Far East, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glycoproteins, Humans, KCNQ1 Potassium Channel, Male, Myosin Light Chains, Obesity, Polymorphism, Single Nucleotide, Proteinase Inhibitory Proteins, Secretory
Show Abstract · Added June 26, 2014
Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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19 MeSH Terms
CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy.
Tak E, Ridyard D, Kim JH, Zimmerman M, Werner T, Wang XX, Shabeka U, Seo SW, Christians U, Klawitter J, Moldovan R, Garcia G, Levi M, Haase V, Ravid K, Eltzschig HK, Grenz A
(2014) J Am Soc Nephrol 25: 547-63
MeSH Terms: 5'-Nucleotidase, Adenosine, Animals, Diabetic Nephropathies, Endothelium, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Adenosine A2B
Show Abstract · Added February 25, 2014
Nucleotide phosphohydrolysis by the ecto-5'-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b(-/-) mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.
0 Communities
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11 MeSH Terms
Skeletal trauma generates systemic BMP2 activation that is temporally related to the mobilization of CD73+ cells.
Marsell R, Steen B, Bais MV, Mortlock DP, Einhorn TA, Gerstenfeld LC
(2014) J Orthop Res 32: 17-23
MeSH Terms: 5'-Nucleotidase, Animals, Bone Marrow Cells, Bone Morphogenetic Protein 2, Cells, Cultured, Chemokine CXCL12, Disease Models, Animal, Flow Cytometry, Hematopoietic Stem Cell Mobilization, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteogenesis, Receptors, CXCR4, Stromal Cells, Tibia
Show Abstract · Added May 27, 2014
The relationship between BMP2 expression and the recruitment of skeletogenic stem cells was assessed following bone marrow reaming. BMP2 expression was examined using transgenic mice in which β-galactosidase had been inserted into the coding region of BMP2. Stem cell mobilization was analyzed by FACS analysis using CD73, a marker associated with bone marrow stromal stem cells. BMP2 expression was induced in endosteal lining cells, cortical osteocytes and periosteal cells in both the reamed and in contralateral bones. BMP2 mRNA expression in the reamed bone showed an early peak within the first 24 h of reaming followed by a later peak at 7 days, while contralateral bones only showed the 7 days peak of expression. FACS analysis sorting on CD73 positive cells showed a 50% increase of these cells at 3 and 14 days in the marrow of the injured bone and a single peak at 14 days of the marrow cell population of the contralateral bone. A ∼20% increase of CD73 positive cells was seen in the peripheral blood 2 days after reaming. These data showed that traumatic bone injury caused a systemic induction of BMP2 expression and that this increase is correlated with the mobilization of CD73 positive cells.
© 2013 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society.
1 Communities
1 Members
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17 MeSH Terms
Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells.
Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I
(2011) J Immunol 187: 6120-9
MeSH Terms: 5'-Nucleotidase, Adenosine, Animals, CD11b Antigen, Carcinoma, Lewis Lung, Cell Differentiation, Cell Proliferation, Cell Separation, Female, Flow Cytometry, Granulocytes, Male, Mice, Mice, Inbred C57BL, Myeloid Cells, Real-Time Polymerase Chain Reaction, Receptors, Purinergic P1
Show Abstract · Added May 29, 2014
Extracellular adenosine and purine nucleotides are elevated in many pathological situations associated with the expansion of CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs). Therefore, we tested whether adenosinergic pathways play a role in MDSC expansion and functions. We found that A(2B) adenosine receptors on hematopoietic cells play an important role in accumulation of intratumoral CD11b(+)Gr1(high) cells in a mouse Lewis lung carcinoma model in vivo and demonstrated that these receptors promote preferential expansion of the granulocytic CD11b(+)Gr1(high) subset of MDSCs in vitro. Flow cytometry analysis of MDSCs generated from mouse hematopoietic progenitor cells revealed that the CD11b(+)Gr-1(high) subset had the highest levels of CD73 (ecto-5'-nucleotidase) expression (Δmean fluorescence intensity [MFI] of 118.5 ± 16.8), followed by CD11b(+)Gr-1(int) (ΔMFI of 57.9 ± 6.8) and CD11b(+)Gr-1(-/low) (ΔMFI of 12.4 ± 1.0) subsets. Even lower levels of CD73 expression were found on Lewis lung carcinoma tumor cells (ΔMFI of 3.2 ± 0.2). The high levels of CD73 expression in granulocytic CD11b(+)Gr-1(high) cells correlated with high levels of ecto-5'-nucleotidase enzymatic activity. We further demonstrated that the ability of granulocytic MDSCs to suppress CD3/CD28-induced T cell proliferation was significantly facilitated in the presence of the ecto-5'-nucleotidase substrate 5'-AMP. We propose that generation of adenosine by CD73 expressed at high levels on granulocytic MDSCs may promote their expansion and facilitate their immunosuppressive activity.
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17 MeSH Terms