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Articles by D Hu
Total Records ( 6 ) for D Hu
  D Hu , H Barajas Martinez , E Burashnikov , M Springer , Y Wu , A Varro , R Pfeiffer , T. T Koopmann , J. M Cordeiro , A Guerchicoff , G. D Pollevick and C. Antzelevitch

Background— Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.

Methods and Results— A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a –9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium.

Conclusions— Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

  Z Xing , C Lu , D Hu , Y. y Yu , X Wang , C Colnot , M Nakamura , Y Wu , T Miclau and R. S. Marcucio
  Zhiqing Xing, Chuanyong Lu, Diane Hu, Yan-yiu Yu, Xiaodong Wang, Celine Colnot, Mary Nakamura, Yalei Wu, Theodore Miclau, and Ralph S. Marcucio

Bone injury induces an inflammatory response that involves neutrophils, macrophages and other inflammatory cells. The recruitment of inflammatory cells to sites of injury occurs in response to specific signaling pathways. The CC chemokine receptor type 2 (CCR2) is crucial for recruiting macrophages, as well as regulating osteoclast function. In this study, we examined fracture healing in Ccr2–/– mice. We first demonstrated that the expression of Ccr2 transcripts and the filtration of macrophages into fracture calluses were most robust during the early phases of fracture healing. We then determined that the number of macrophages at the fracture site was significantly lower in Ccr2–/– mice compared with wild-type controls at 3 days after injury. As a result, impaired vascularization, decreased formation of callus, and delayed maturation of cartilage were observed at 7 days after injury in mutant mice. At day 14, Ccr2–/– mice had less bone in their calluses. At day 21, Ccr2–/– mice had larger calluses and more bone compared with wild-type mice, suggesting a delayed remodeling. In addition, we examined the effect of Ccr2 mutation on osteoclasts. We found that a lack of Ccr2 did not affect the number of osteoclasts within fracture calluses at 21 days after injury. However, Ccr2–/– osteoclasts exhibited a decreased ability to resorb bone compared with wild-type cells, which could contribute to the delayed remodeling of fracture calluses observed in Ccr2–/– mice. Collectively, these results indicate that a deficiency of Ccr2 reduces the infiltration of macrophages and impairs the function of osteoclasts, leading to delayed fracture healing.

  D Hu , Y Kamiya , K Totani , D Kamiya , N Kawasaki , D Yamaguchi , I Matsuo , N Matsumoto , Y Ito , K Kato and K. Yamamoto

Glucosidase II (GII) is a glycan-processing enzyme that trims two 1,3-linked glucose residues from N-glycan on newly synthesized glycoproteins. Trimming of the first 1,3-linked glucose from Glc2Man9GlcNAc2 (G2M9) is important for a glycoprotein to interact with calnexin/calreticulin (CNX/CRT), and cleavage of the innermost glucose from Glc1Man9GlcNAc2 (G1M9) sets glycoproteins free from the CNX/CRT cycle and allows them to proceed to the Golgi apparatus. GII is a heterodimeric complex consisting of a catalytic subunit (GII) and a tightly associated β subunit (GIIβ) that contains a mannose 6-phosphate receptor homology (MRH) domain. A recent study has suggested a possible involvement of the MRH domain of GIIβ (GIIβ-MRH) in the glucose trimming process via its putative sugar-binding activity. However, it remains unknown whether GIIβ-MRH possesses sugar-binding activity and, if so, what role this activity plays in the function of GII. Here, we demonstrate that human GIIβ-MRH binds to high-mannose-type glycans. Frontal affinity chromatography revealed that GIIβ-MRH binds most strongly to the glycans with the 1,2-linked mannobiose structure. GII with the mutant GIIβ that lost the sugar-binding activity of GIIβ-MRH hydrolyzes p-nitrophenyl--glucopyranoside, but the capacity to remove glucose residues from G1M9 and G2M9 is significantly decreased. Our results clearly demonstrate the capacity of the GIIβ-MRH to bind high-mannose-type glycans and its importance in efficient glucose trimming of N-glycans.

  K Mikami , D Yamaguchi , H Tateno , D Hu , S. Y Qin , N Kawasaki , M Yamada , N Matsumoto , J Hirabayashi , Y Ito and K. Yamamoto

Misfolded glycoproteins are translocated from the endoplasmic reticulum (ER) into the cytoplasm for proteasome-mediated degradation. OS-9 protein is thought to participate in ER-associated glycoprotein degradation (ERAD). The recombinant biotinylated mannose 6-phosphate receptor homology (MRH) domain of human OS-9 (OS-9MRH) together with six kinds of mutated OS-9MRH were prepared and mixed with R-phycoerythrin (PE)-labeled streptavidin to form tetramers (OS-9MRH-SA). The PE-labeled OS-9MRH-SA bound to HeLaS3 cells in a metal ion-independent manner through amino acid residues homologous to those participating in sugar binding of the cation-dependent mannose 6-phosphate receptor, and this binding was greatly increased by swainsonine, deoxymannojirimycin, or kifunensine treatment. N-Acetylglucosaminyltransferase I-deficient Lec1 cells, but not Lec2 or Lec8 cells, were also strongly bound by the tetramer. OS-9MRH-SA binding to the cells was strongly inhibited by Man1,6(Man1,3)Man1,6(Man1,3)Man and Man1,6Man. To further determine the specificity of native ligands for OS-9MRH, frontal affinity chromatography was performed using a wide variety of 92 different oligosaccharides. We found that several N-glycans containing terminal 1,6-linked mannose in the Man1,6(Man1,3)Man1,6(Man1,3)Man structure were good ligands for OS-9MRH, having Ka values of approximately 104 M–1 and that trimming of either an 1,6-linked mannose from the C-arm or an 1,3-linked mannose from the B-arm abrogated binding to OS-9MRH. An immunoprecipitation experiment demonstrated that the 1-antitrypsin variant nullHong Kong, but not wild-type 1-antitrypsin, selectively interacted with OS-9 in the cells in a sugar-dependent manner. These results suggest that trimming of the outermost 1,2-linked mannose on the C-arm is a critical process for misfolded proteins to enter ERAD.

  D Yamaguchi , D Hu , N Matsumoto and K. Yamamoto

XTP3-B is a soluble endoplasmic reticulum (ER)-resident protein containing two mannose-6-phosphate receptor homology (MRH) domains in its sequence. XTP3-B interacts with a membrane-associated ubiquitin ligase complex, and, therefore, is thought to participate in ER-associated degradation (ERAD). In this study, the recombinant human XTP3-B fused with IgG-Fc (XTP3-B-Fc), XTP3-B without an N-terminal MRH domain fused with IgG-Fc (XTP3-B1-Fc), or XTP3-B without a C-terminal MRH domain fused with IgG-Fc (XTP3-B2-Fc) were prepared. XTP3-B-Fc and XTP3-B1-Fc bound to Lec1 cells but not to CHO, Lec2, or Lec8 cells, while XTP3-B2-Fc did not bind to any of these cells. The binding of XTP3-B-Fc and XTP3-B1-Fc to Lec1 cells was abrogated by treatment of the cells with endo-β-N-acetylglucosaminidase H, Man1,6Man or Man1,6(Man1,3)Man1,6(Man1,3)Man, or by substitution of Arg428 or Tyr457 in the C-terminal MRH domain with alanine. Arg428 and Tyr457 are homologous to amino acids that mediate glycan binding by the cation-dependent mannose-6-phosphate receptor. An immunoprecipitation experiment using lysates of cells co-expressing wild-type 1-antitrypsin (AT), 1-antitrypsin variant nullHong Kong (ATNHK), and FLAG-tagged XTP3-B, or its mutants, demonstrated that ATNHK, but not AT, specifically co-precipitated with XTP3-B and XTP3-B1. The glycan-binding-deficient XTP3-B2 did not bind either AT or ATNHK. These results suggest that XTP3-B specifically binds to ATNHK, which is a well-known substrate of ERAD, via a C-terminal MRH domain in a glycan-dependent manner.

  E Liu , S Cheng , X Wang , D Hu , T Zhang and C. Chu

Contact investigation is a logical approach to intensified case finding in China. However, currently there are no written national guidelines. The aim of this study is to review the published literature that describes the procedures followed by local level and report the yield for active tuberculosis (TB) cases.


Studies conducted in China and published between 1997 and 2007 on contact investigation were searched.


Twelve studies were included in the review. There was no standard definition of contact and no study provided details on how to prioritize contacts. Investigation methods vary between each study. The number of contacts investigated per index case ranged from 22.7 to 658 in congregate settings and from 1.5 to 5.8 in household. The yields for active TB ranged from 0 to 11.765% in congregate settings and from 0 to 6.897% in household. The weighted yields for smear-positive index and smear-negative index were 1 and 0.2% respectively in household and 0.5% for pulmonary case index in congregate settings.


There is considerable heterogeneity amongst the methods used and the cases yielded in these studies, and in general the quality of contact investigation is low; therefore, there is a need for China to develop national guidelines on contact investigation.

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