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81.
An Activin A/BMP2 Chimera,AB204, Displays Bone‐Healing Properties Superior to Those of BMP2
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Byung‐Hak Yoon Luis Esquivies Chihoon Ahn Peter C Gray Sang‐kyu Ye Witek Kwiatkowski Senyon Choe 《Journal of bone and mineral research》2014,29(9):1950-1959
Recombinant bone morphogenetic protein 2 (rhBMP2) has been used clinically to treat bone fractures in human patients. However, the high doses of rhBMP2 required for a therapeutic response can cause undesirable side effects. Here, we demonstrate that a novel Activin A/BMP2 (AB2) chimera, AB204, promotes osteogenesis and bone healing much more potently and effectively than rhBMP2. Remarkably, 1 month of AB204 treatment completely heals tibial and calvarial defects of critical size in mice at a concentration 10‐fold lower than a dose of rhBMP2 that only partially heals the defect. We determine the structure of AB204 to 2.3 Å that reveals a distinct BMP2‐like fold in which the Activin A sequence segments confer insensitivity to the BMP2 antagonist Noggin and an affinity for the Activin/BMP type II receptor ActRII that is 100‐fold greater than that of BMP2. The structure also led to our identification of a single Activin A‐derived amino acid residue, which, when mutated to the corresponding BMP2 residue, resulted in a significant increase in the affinity of AB204 for its type I receptor BMPRIa and a further enhancement in AB204's osteogenic potency. Together, these findings demonstrate that rationally designed AB2 chimeras can provide BMP2 substitutes with enhanced potency for treating non‐union bone fractures. © 2014 American Society for Bone and Mineral Research. 相似文献
82.
Sara Kim Seoyun Choe Junseong Kim Sanga Nam Yeon Shin Sunmi Lee 《Osong Public Health and Research Perspectives》2014,5(1):40-45
Objectives
According to the Korea Centers for Disease Control and Prevention, new active tuberculosis (TB) cases have increased since 2001. Some key factors explain and characterize the transmission dynamics of Korean TB infection, such as a higher ratio of latent individuals and a new reporting system implemented in 2001, among others.Methods
We propose a mathematical TB model that includes exogenous reinfection to gain a better understanding of the recent trend for TB incidence. We divide the simulation time window into two periods, 1970–2000 and 2001–2012, according to the implementation date of a new TB detection system.Results
Two sets of parameters, including the transmission rate, the latent period, the recovery rate, and the proportion of exogenous reinfection, are estimated using the least-squares method and calibrated to data on the incidence of active TB.Conclusion
Among some key parameters in the model, the case finding effort turned out to be the most significant impacting component on the reduction in the active TB cases. 相似文献83.
Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid 总被引:4,自引:0,他引:4
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Nanao MH Green T Stern-Bach Y Heinemann SF Choe S 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(5):1708-1713
We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the kainate receptor subunit GluR6, in complex with the agonist domoate. The structure shows the expected overall homology with AMPA and NMDA receptor subunit structures but reveals an unexpected binding mode for the side chain of domoate, in which contact is made to the larger lobe only (lobe I). In common with the AMPA receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved. Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not. The structure incorporates native glycosylation, which has not previously been described for ionotropic glutamate receptors. The position of the sugars near the subunit interface rules out their direct involvement in subunit association but leaves open the possibility of indirect modulation. Finally, we observed several tetrameric assemblies that satisfy topological constraints with respect to connection to the receptor pore, and which are therefore candidates for the native quaternary structure. 相似文献
84.
Choe R Durduran T Yu G Nijland MJ Chance B Yodh AG Ramanujam N 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(22):12950-12954
The feasibility of transabdominal near-infrared (NIR) spectroscopy for detecting and quantifying fetal hypoxia in utero is demonstrated in a pregnant ewe model. A frequency domain NIR spectroscopy probe, consisting of two detectors and six sources operating at three wavelengths (675, 786, and 830 nm), was placed on the maternal abdomen directly above the fetal head. Fetal hypoxia was indirectly induced through occlusion of uterine blood flow for approximately 3 min. NIR photon diffusion measurements were made during a baseline period, during hypoxia of the fetus, and during recovery. Fetal blood samples were drawn from the fetal brachial artery and jugular veins at several time points during the cycle. Seven hypoxic cycles were induced in a total of five pregnant ewes. The NIR measurements were analyzed by using a two-layer diffusion model to deconvolve the fetal blood saturation from that of the pregnant ewe. Fetal hypoxia was detected. Good agreement was found between fetal blood saturation determined by the transabdominal NIR method and arterial and venous fetal blood saturation quantified from fetal blood samples by using a hemoximeter. 相似文献
85.
Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association 总被引:46,自引:0,他引:46
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Sui J Li W Murakami A Tamin A Matthews LJ Wong SK Moore MJ Tallarico AS Olurinde M Choe H Anderson LJ Bellini WJ Farzan M Marasco WA 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(8):2536-2541
Effective prophylaxis and antiviral therapies are urgently needed in the event of reemergence of the highly contagious and often fatal severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) infection. We have identified eight recombinant human single-chain variable region fragments (scFvs) against the S1 domain of spike (S) protein of the SARS-CoV from two nonimmune human antibody libraries. One scFv 80R efficiently neutralized SARS-CoV and inhibited syncytia formation between cells expressing the S protein and those expressing the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2). Mapping of the 80R epitope showed it is located within the N-terminal 261-672 amino acids of S protein and is not glycosylation-dependent. 80R scFv competed with soluble ACE2 for association with the S1 domain and bound S1 with high affinity (equilibrium dissociation constant, Kd=32.3 nM). A human IgG1 form of 80R bound S1 with a 20-fold higher affinity of 1.59 nM comparable to that of ACE2 (Kd=1.70 nM), and neutralized virus 20-fold more efficiently than the 80R scFv. These data suggest that the 80R human monoclonal antibody may be a useful viral entry inhibitor for the emergency prophylaxis and treatment of SARS, and that the ACE2-binding site of S1 could be an attractive target for subunit vaccine and drug development. 相似文献
86.
Jung Yeon Heo Ji Eun Lee Hye Kang Kim Kang-Won Choe 《Emerging infectious diseases》2014,20(5):875-877
During April 2011–March 2012, we retrospectively reviewed medical records for South Korea soldiers to assess the etiology and epidemiology of acute viral lower respiratory tract infections. Adenovirus was the most commonly identified virus (63.2%) and the most common cause of pneumonia (79.3%) and hospitalization (76.6%); 3 soldiers died of adenovirus-related illness. 相似文献
87.
Chul Han Se-woon Choe Yong Hwan Kim Abhinav P. Acharya Benjamin G. Keselowsky Brian S. Sorg Young-Jae Lee S. Paul Oh 《Angiogenesis》2014,17(4):823-830
Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings. 相似文献
88.
Cho Soo Hyun Choe Yeong Sim Kim Hee Jin Jang Hyemin Kim Yeshin Kim Si Eun Kim Seung Joo Kim Jun Pyo Jung Young Hee Kim Byeong C. Baker Suzanne L. Lockhart Samuel N. Na Duk L. Park Seongbeom Seo Sang Won 《European journal of nuclear medicine and molecular imaging》2020,47(8):1938-1948
European Journal of Nuclear Medicine and Molecular Imaging - We developed a new method to directly calculate Centiloid (CL) units of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) without... 相似文献
89.
90.
Pyoeng Gyun Choe Hyung Jin Choi Nak-Hyun Kim Wan Beom Park Kyoung-Ho Song Ji Hwan Bang Eu Suk Kim Sang Won Park Hong Bin Kim Myoung-don Oh Nam Joong Kim 《Journal of the International AIDS Society》2014,17(1)