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 Articles by B Li Total Records ( 12 ) for B Li
Y Wang , S Mao , B Li , P Tan , D Feng and J. Wen

Hepatitis C virus (HCV) infection is a leading cause of liver-related morbidity and mortality throughout the world. There is no vaccine available and current therapy is only partially effective. Since HCV infects only a minority of hepatocytes, we hypothesized that induction of apoptosis might be a promising approach for the treatment of hepatitis C. In the present study, recombinant caspase-3 gene (re-caspase-3) was used because it has the ability to induce apoptosis that is independent of the initiator caspases. An HCV-specific promoter is required to regulate the cytotoxic caspase-3 expression in HCV-infected cells. It has been reported that HCV core protein can specifically activate the 2',5'-oligoadenylate synthetase (OAS) gene promoter in human hepatocytes. Therefore, we constructed an expression vector consisting of the re-caspase-3 under the OAS gene promoter (pGL3-OAS-re-caspase-3) and then investigated its effect on HCV core-positive liver cells. It was found that the pGL3-OAS-re-caspase-3 construct induced apoptosis in HCV core-positive liver cells, but not in normal liver cells. These results strongly suggested that the transfer of the re-caspase-3 gene under the OAS promoter was a novel targeting approach for the treatment of HCV infection.

B Li , X Chu , M Gao and W. Li

The aim of this study was to investigate the pro-apoptotic mechanism of C-phycocyanin (C-PC)-mediated photodynamic therapy (PDT) in a murine tumor model and cultured MCF-7 cells. The mice were divided into four groups: control, He–Ne laser radiation, C-PC treatment, and C-PC treatment + He–Ne laser radiation. The effects of C-PC and/or laser on immune organs, immunocyte proliferation, tumor genesis, and apoptosis-related proteins expressions were investigated by immunohistochemistry, in situ hybridization, MTT, electron microscope, western blot, and immunofluorescence assay. The results showed that He–Ne laser treatment alone showed marginal effects. In C-PC-treated mice, the weight of immune organs, proliferation of immunocytes, and expression of pro-apoptotic Fas protein were increased, whereas the tumor weight and the expressions of anti-apoptotic proteins (NF-B and P53) and CD44 mRNA were comparatively decreased. In vitro, C-PC was able to inhibit MCF-7 cell proliferation and cause ultrastructural changes including microvilli loss, formation of membrane blebs, and chromatin condensation. Moreover, C-PC treatment could activate caspase-9 expression, induce cytochrome c release, and downregulate Bcl-2 expression. When combined with He–Ne laser irradiation, the effects of C-PC treatment were further enhanced. Facilitating the apoptosis signals transduction and finally leading to the apoptosis of MCF-7 cells may be the mechanism of the anti-tumor activities of C-PC-mediated PDT.

H Miao , W Jiang , L Ge , B Li and B. Song

Sterol-regulated degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a rapid feedback regulatory mechanism by which cells employ to control the cholesterol biosynthesis. This process is initiated by the sterol-induced interaction between HMGCR and Insig-1/gp78, a membrane-bound ubiquitin ligase complex. There are two Lys residues (Lys89 and Lys248) facing cytosol in the membrane domain of HMGCR, and Lys248 is the major ubiquitination site. In this study, we investigated the mechanism of ubiquitination site selection in HMGCR. We find that the distance of Lys248 to membrane is dispensable for its ubiquitination. However, the conserved tetra-glutamic acid residues adjacent to Lys248 in HMGCR are essential. Replacement of these negatively charged residues with tetra-arginine causes the resistance of HMGCR to sterol-induced ubiquitination and degradation, albeit this mutant HMGCR can still binds to Insig-1. We further find that the tetra-glutamic acid residues are necessary but not sufficient for the modification on their adjacent Lys, since they are not functional on Lys89 of HMGCR or in SCAP. UBE2G2, a previously known E2 of gp78, is demonstrated to be involved in the sterol-regulated ubiquitination and degradation of HMGCR. In summary, these results identify the tetra-glutamic acid residues as a critical motif in HMGCR for the ubiquitination reaction mediated by gp78 and UBE2G2.

C Bian , F Zhang , F Wang , Z Ling , M Luo , H Wu , Y Sun , J Li , B Li , J Zhu , L Tang , Y Zhou , Q Shi , Y Ji , L Tian , G Lin , Y Fan , N Wang and B. Sun

DNA immunization is an efficient method for high-affinity monoclonal antibody generation. Here, we describe the generation of several high-quality monoclonal antibodies (mAbs) against retinol-binding protein 4 (RBP4), an important marker for kidney abnormality and dysfunction, with a combination method of DNA priming and protein boost. The mAbs generated could bind to RBP4 with high sensitivity and using these mAbs, an immunocolloidal gold fast test strip was constructed. The strip can give a result in <5 min and is very sensitive with a detection limit of about 1 ng/ml. A small-scale clinical test revealed that the result of this strip was well in accordance with that of an enzyme-labeled immunosorbent assay kit currently available on the market. Consequently, it could be useful for more convenient and faster RBP4 determination in the clinic.

D. B Ennis , G. R Rudd Barnard , B Li , C. G Fonseca , A. A Young , B. R Cowan and R. A. H. Stewart
Background—

Remodeling of the mitral annulus contributes to progression of mitral regurgitation (MR). In patients with moderate-to-severe MR, short-term treatment with β-blockers has been shown to increase left ventricular (LV) end-diastolic and end-systolic volume, and this could deleteriously increase mitral valve annular dimensions. The objective of this study was to quantify the effects of a short duration of β-blocker treatment on mitral annular dimensions and dynamics in patients with MR due to primary degenerative valve disease.

Methods and Results—

Twenty-five patients with moderate-to-severe degenerative MR and normal LV systolic function were studied in a double-blind crossover experiment using a β1-selective adrenergic blocker and placebo administered for 14±3 days. Cardiac MRI images were acquired after each treatment period to quantify mitral annular dimensions. At end diastole, there was no change in annular area (1659±331 versus 1632±299 mm2; P<0.19), annular perimeter (154.3±16.4 versus 152±13.9 mm; P<0.13), septal-lateral (SL) dimension (38.0±5 versus 39.0±4.5 mm; P<0.15), or annular height (9.8±3.8 versus 9.5±2.5 mm; P<0.53). β-blockade resulted in significant end-diastole decreases in commissure-commissure dimension (48.9±4.6 versus 47.2±4.0 mm; P<0.01) and eccentricity (1.3±0.2 versus 1.2±0.1; P<0.01). At end systole (ES), β-blockade conferred a small, but significant decrease in annular perimeter (161.0±19.3 versus 156.8±16.9 mm; P<0.04) and eccentricity (1.2±0.1 versus 1.1±0.1; P<0.02), and the SL dimension significantly increased (41.5±5.7 versus 43.0±5.3 mm; P<0.03). Commissure-commissure dimension, annular area, and annular height at ES were not significantly different.

Conclusions—

Despite significant increases in LV end-diastolic and end-systolic volume, short-term β-blocker treatment of patients with moderate-to-severe MR reduced or preserved all mitral annular dimensions except SL at ES.

C De Coster , H Quan , R Elford , B Li , L Mazzei and S. Zimmer

Background. Nurse telephone advice (NTA) lines, a major initiative in primary health care reform, provide symptom triage and health information. Compliance studies utilizing database analysis are frequently limited to a defined population, such as children or Emergency Department (ED) users.

Objectives. To explore caller characteristics associated with following NTA advice to go to the ED, see a health care professional or self-care for Calgary, Canada (population 1 million).

Methods. NTA data were linked with utilization data to assess ED and physician visits following a call. Four nurse advice categories were defined: go to ED, health care provider in 24 hours, health care provider in 72 hours if symptoms persist and self-care. Follow-through was defined based on health care utilization within specified time periods following the call. Logistic regression identified characteristics associated with follow-through of NTA nurse advice; characteristics included age, sex, neighbourhood income, health status, time of call and type of care protocol.

Conclusions. Understanding characteristics associated with lower follow-through may help the NTA service to refine its approaches to clients.

N Nadif Kasri , A Nakano Kobayashi , R Malinow , B Li and L. Van Aelst

Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.

K. J McKernan , H. E Peckham , G. L Costa , S. F McLaughlin , Y Fu , E. F Tsung , C. R Clouser , C Duncan , J. K Ichikawa , C. C Lee , Z Zhang , S. S Ranade , E. T Dimalanta , F. C Hyland , T. D Sokolsky , L Zhang , A Sheridan , H Fu , C. L Hendrickson , B Li , L Kotler , J. R Stuart , J. A Malek , J. M Manning , A. A Antipova , D. S Perez , M. P Moore , K. C Hayashibara , M. R Lyons , R. E Beaudoin , B. E Coleman , M. W Laptewicz , A. E Sannicandro , M. D Rhodes , R. K Gottimukkala , S Yang , V Bafna , A Bashir , A MacBride , C Alkan , J. M Kidd , E. E Eichler , M. G Reese , F. M De La Vega and A. P. Blanchard

We describe the genome sequencing of an anonymous individual of African origin using a novel ligation-based sequencing assay that enables a unique form of error correction that improves the raw accuracy of the aligned reads to >99.9%, allowing us to accurately call SNPs with as few as two reads per allele. We collected several billion mate-paired reads yielding ~18x haploid coverage of aligned sequence and close to 300x clone coverage. Over 98% of the reference genome is covered with at least one uniquely placed read, and 99.65% is spanned by at least one uniquely placed mate-paired clone. We identify over 3.8 million SNPs, 19% of which are novel. Mate-paired data are used to physically resolve haplotype phases of nearly two-thirds of the genotypes obtained and produce phased segments of up to 215 kb. We detect 226,529 intra-read indels, 5590 indels between mate-paired reads, 91 inversions, and four gene fusions. We use a novel approach for detecting indels between mate-paired reads that are smaller than the standard deviation of the insert size of the library and discover deletions in common with those detected with our intra-read approach. Dozens of mutations previously described in OMIM and hundreds of nonsynonymous single-nucleotide and structural variants in genes previously implicated in disease are identified in this individual. There is more genetic variation in the human genome still to be uncovered, and we provide guidance for future surveys in populations and cancer biopsies.

B Li and W. Sun

The general (composite) Newton–Cotes rules are studied for Hadamard finite-part integrals. We prove that the error of the kth-order Newton–Cotes rule is O$$\left({h}^{k}\right|\mathrm{ln}h\left|\right)$$ for odd k and O$$\left({h}^{k+1}\right|\mathrm{ln}h\left|\right)$$ for even k when the singular point coincides with an element junction point. Two modified Newton–Cotes rules are proposed to remove the factor ln h from the error bound. The convergence rate (accuracy) of even-order Newton–Cotes rules at element junction points is the same as the superconvergence rate at certain Gaussian points as presented in Wu & Lü (2005, IMA J. Numer. Anal., 25, 253–263) and Wu & Sun (2008, Numer. Math., 109, 143–165). Based on the analysis, a class of collocation-type methods are proposed for solving integral equations with Hadamard finite-part kernels. The accuracy of the collocation method is the same as the accuracy of the proposed even-order Newton–Cotes rules. Several numerical examples are provided to illustrate the theoretical analysis.

N. C Henney , B Li , C Elford , P Reviriego , A. K Campbell , K. T Wann and B. A. J. Evans

The pharmacology of the large-conductance K+ (BK) channel in human osteoblasts is not well defined, and its role in bone is speculative. Here we assess BK channel properties in MG63 cells and primary human osteoblasts and determine whether pharmacological modulation affects cell function. We used RT-PCR and patch-clamp methods to determine the expression of BK channel subunits and cell number assays in the absence and presence of BK channel modulators. RT-PCR showed the presence of KCNMA1, KCNMB1, KCNMB2, KCNMB3, and KCNMB4 subunits. The BK channel was voltage dependent, with a mean unitary conductance of 228.8 pS (n = 10) in cell-attached patches (140 mM K+/140 mM K+) and a conductance of 142.5 pS (n = 16) in excised outside-out and 155 pS (n = 6) in inside-out patches in 3 mM K+/140 mM K+. The selectivity ratio (ratio of K+ to Na+ permeability) was 15:1. The channel was blocked by tetraethylammonium (TEA, 0.3 mM), iberiotoxin (5–60 nM), tetrandrine (5–30 µM), and paxilline (10 µM) and activated by isopimaric acid (20 µM). BK channel modulators affected MG63 cell numbers: TEA and tetrandrine significantly increased cell numbers at low concentrations (3 mM and 3 µM, respectively) and reduced cell numbers at higher concentrations (>10 mM and >10 µM, respectively). Neither iberiotoxin (20–300 nM) nor slotoxin (300 nM) affected cell numbers. The increase in cell numbers by TEA was blocked by isopimaric acid. TEA (0.1–3.0 mM) significantly increased mineralization in primary osteoblasts. In conclusion, the BK channel has a distinctive pharmacology and is thus a target for therapeutic strategies aimed at modulating osteoblast proliferation and function.

W Lu , P Ran , D Zhang , G Peng , B Li , N Zhong and J. Wang

In pulmonary arterial smooth muscle cells (PASMCs), Ca2+ influx through store-operated Ca2+ channels thought to be composed of canonical transient receptor potential (TRPC) proteins is an important determinant of intracellular free calcium concentration ([Ca2+]i) and pulmonary vascular tone. Sildenafil, a type V phosphodiesterase inhibitor that increases cellular cGMP, is recently identified as a promising agent for treatment of pulmonary hypertension. We previously demonstrated that chronic hypoxia elevated basal [Ca2+]i in PASMCs due in large part to enhanced store-operated Ca2+ entry (SOCE); moreover, ex vivo exposure to prolonged hypoxia (4% O2 for 60 h) upregulated TRPC1 and TRPC6 expression in PASMCs. We examined the effect of sildenafil on basal [Ca2+]i, SOCE, and the expression of TRPC in PASMCs under prolonged hypoxia exposure. We also examined the effect of sildenafil on TRPC1 and TRPC6 expression in pulmonary arterial smooth muscle (PA) from rats that developed chronically hypoxic pulmonary hypertension (CHPH). Compared with vehicle control, treatment with sildenafil (300 nM) inhibited prolonged hypoxia induced increases of 1) basal [Ca2+]i, 2) SOCE, and 3) mRNA and protein expression of TRPC in PASMCs. Moreover, sildenafil (50 mg · kg–1 · day–1) inhibited mRNA and protein expression of TRPC1 and TRPC6 in PA from chronically hypoxic (10% O2 for 21 days) rats, which was associated with decreased right ventricular pressure and right ventricular hypertrophy. Furthermore, we found, in PASMCs exposed to prolonged hypoxia, that knockdown of TRPC1 or TRPC6 by their specific small interference RNA attenuated the hypoxic increases of SOCE and basal [Ca2+]i, suggesting a cause and effect link between increases of TRPC1 and TRPC6 expression and the hypoxic increases of SOCE and basal [Ca2+]i. These results suggest that sildenafil may alter basal [Ca2+]i in PASMCs by decreasing SOCE through downregulation of TRPC1 and TRPC6 expression, thereby contributing to decreased vascular tone of pulmonary arteries during the development of CHPH.

B Gu , P Sun , Y Yuan , R. C Moraes , A Li , A Teng , A Agrawal , C Rheaume , V Bilanchone , J. M Veltmaat , K. I Takemaru , S Millar , E. Y. H.P Lee , M. T Lewis , B Li and X. Dai

Recent studies have unequivocally identified multipotent stem/progenitor cells in mammary glands, offering a tractable model system to unravel genetic and epigenetic regulation of epithelial stem/progenitor cell development and homeostasis. In this study, we show that Pygo2, a member of an evolutionarily conserved family of plant homeo domain–containing proteins, is expressed in embryonic and postnatal mammary progenitor cells. Pygo2 deficiency, which is achieved by complete or epithelia-specific gene ablation in mice, results in defective mammary morphogenesis and regeneration accompanied by severely compromised expansive self-renewal of epithelial progenitor cells. Pygo2 converges with Wnt/β-catenin signaling on progenitor cell regulation and cell cycle gene expression, and loss of epithelial Pygo2 completely rescues β-catenin–induced mammary outgrowth. We further describe a novel molecular function of Pygo2 that is required for mammary progenitor cell expansion, which is to facilitate K4 trimethylation of histone H3, both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes.