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941.
Lili Hao Xiaomeng Ge Haolei Wan Songnian Hu Martin J Lercher Jun Yu Wei-Hua Chen 《BMC evolutionary biology》2010,10(1):316
Background
Many functional, structural and evolutionary features of human genes have been observed to correlate with expression breadth and/or gene age. Here, we systematically explore these correlations. 相似文献942.
Williams TM Stump CA Nguyen DN Quigley AG Bell IM Gallicchio SN Zartman CB Wan BL Penna KD Kunapuli P Kane SA Koblan KS Mosser SD Rutledge RZ Salvatore C Fay JF Vacca JP Graham SL 《Bioorganic & medicinal chemistry letters》2006,16(10):2595-2598
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine. 相似文献
943.
Purandare AV Wan H Gao A Somerville J Burke C Vaccaro W Yang X McIntyre KW Poss MA 《Bioorganic & medicinal chemistry letters》2006,16(1):204-207
The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED(50) 30 mg/kg). 相似文献
944.
Moretto AF Kirincich SJ Xu WX Smith MJ Wan ZK Wilson DP Follows BC Binnun E Joseph-McCarthy D Foreman K Erbe DV Zhang YL Tam SK Tam SY Lee J 《Bioorganic & medicinal chemistry》2006,14(7):2162-2177
A novel pyridothiophene inhibitor of PTP1B was discovered by rational screening of phosphotyrosine mimics at high micromolar concentrations. The potency of this lead compound has been improved significantly by medicinal chemistry guided by X-ray crystallography and molecular modeling. Excellent consistency has been observed between structure-activity relationships and structural information from PTP1B-inhibitor complexes. 相似文献
945.
Zhang YH Bhunia A Wan KF Lee MC Chan SL Yu VC Mok YK 《Journal of molecular biology》2006,364(3):536-549
The ratio of the levels of pro-survival and pro-apoptotic members of the Bcl-2 protein family is thought to be an important regulatory factor for determining the sensitivity of the mammalian cells to apoptotic stimuli. High levels of expression of pro-survival members such as Bcl(XL) in human cancers were frequently found to be a good prognostic indicator predicting poor response to chemotherapy. The pro-survival members of the Bcl-2 family mediate their effects through heterodimerization with the BH3 region of the pro-apoptotic members. Structural analyses of the binding complex of the BH3 peptide and Bcl(XL) showed that a hydrophobic groove termed the BH3 binding cleft is the docking site for the BH3 region. Chemical mimetics of the BH3 region such as BH3I-1 that target the BH3 binding cleft indeed exhibit pro-apoptotic activities. Chelerythrine (CHE) and sanguinarine (SAN) are natural benzophenanthridine alkaloids that are structurally homologous to each other. CHE was previously identified as an inhibitor of Bcl(XL) function from a high-throughput screen of natural products, but its mode of interaction with Bcl(XL) is not known. By determining the effect of site-directed mutagenesis on ligand binding and using saturation transfer difference (STD) NMR experiments, we have verified locations of these docked ligands. Surprisingly, CHE and SAN bind separately at the BH groove and BH1 region of Bcl(XL) respectively, different from the BH3 binding cleft where other known inhibitors of Bcl(XL) target. Interestingly, certain residues on the flexible loop between helices alpha1 and alpha2 of Bcl(XL) are also perturbed upon CHE, but not SAN or BH3I-1 binding. Although CHE and SAN are similarly effective as BH3I-1 in displacing bound BH3 peptide, they are much more effective in inducing apoptosis, raising the possibility that CHE and SAN might be able to antagonize other pro-survival mechanisms in addition to the one that involves BH3 region binding. 相似文献
946.
Marsano A Maidhof R Wan LQ Wang Y Gao J Tandon N Vunjak-Novakovic G 《Biotechnology progress》2010,26(5):1382-1390
We investigated the effects of the initial stiffness of a three-dimensional elastomer scaffold--highly porous poly(glycerol sebacate)--on functional assembly of cardiomyocytes cultured with perfusion for 8 days. The polymer elasticity varied with the extent of polymer cross-links, resulting in three different stiffness groups, with compressive modulus of 2.35 ± 0.03 (low), 5.28 ± 0.36 (medium), and 5.99 ± 0.40 (high) kPa. Laminin coating improved the efficiency of cell seeding (from 59 ± 15 to 90 ± 21%), resulting in markedly increased final cell density, construct contractility, and matrix deposition, likely because of enhanced cell interaction and spreading on scaffold surfaces. Compact tissue was formed in the low and medium stiffness groups, but not in the high stiffness group. In particular, the low stiffness group exhibited the greatest contraction amplitude in response to electric field pacing, and had the highest compressive modulus at the end of culture. A mathematical model was developed to establish a correlation between the contractile amplitude and the cell distribution within the scaffold. Taken together, our findings suggest that the contractile function of engineered cardiac constructs positively correlates with low compressive stiffness of the scaffold. 相似文献
947.
Effects of leachates of the invasive plant, Ageratina adenophora (Sprengel) on soil microbial community 下载免费PDF全文
The invasive plant Ageratina adenophora (Sprengel) changed soil microbial communities in the invaded area to facilitate its growth and inhibit native plants. However, little is known about the driving forces underlying the alteration of soil biota. Leachates from root and aerial part (stem and leaves) of A. adenophora were mixed into soil to imitate field invasion processes for evaluation of its impact on invasion of soil microbial community. The results indicated that soil microbial community was significantly changed when the soil taken from the newly-invaded area was treated with A. adenophora root and aerial part leachates for 3 and 5 weeks, respectively. The biota of newly invaded soil treated with concentration of 100 mg/mL A.adenophora leachates was much closer to that of heavily invaded soil, but was significantly different from that of control soil (newly invaded soil without treatment). A.adenophora leachates promoted growth of the seven dominant rhizosphere bacterial species in the invaded soil. The effect of A.adenophora leachates on soil biota and dominant rhizosphere bacteria was positively correlated with the concentration of leachates, however, the effect of root leachates was stronger than the aerial part leachates. It is assumed that A.adenophora change soil microbial community via nutritional and chemical communication, which helps it in better colonization of the invaded soil. 相似文献
948.
Chi-Pang Chuck Lin-Tat Chong Chao Chen Hak-Fun Chow David Chi-Cheong Wan Kam-Bo Wong 《PloS one》2010,5(10)
Background
The 3C-like protease (3CLpro) of severe acute respiratory syndrome-coronavirus is required for autoprocessing of the polyprotein, and is a potential target for treating coronaviral infection.Methodology/Principal Findings
To obtain a thorough understanding of substrate specificity of the protease, a substrate library of 198 variants was created by performing saturation mutagenesis on the autocleavage sequence at P5 to P3'' positions. The substrate sequences were inserted between cyan and yellow fluorescent proteins so that the cleavage rates were monitored by in vitro fluorescence resonance energy transfer. The relative cleavage rate for different substrate sequences was correlated with various structural properties. P5 and P3 positions prefer residues with high β-sheet propensity; P4 prefers small hydrophobic residues; P2 prefers hydrophobic residues without β-branch. Gln is the best residue at P1 position, but observable cleavage can be detected with His and Met substitutions. P1'' position prefers small residues, while P2'' and P3'' positions have no strong preference on residue substitutions. Noteworthy, solvent exposed sites such as P5, P3 and P3'' positions favour positively charged residues over negatively charged one, suggesting that electrostatic interactions may play a role in catalysis. A super-active substrate, which combined the preferred residues at P5 to P1 positions, was found to have 2.8 fold higher activity than the wild-type sequence.Conclusions/Significance
Our results demonstrated a strong structure-activity relationship between the 3CLpro and its substrate. The substrate specificity profiled in this study may provide insights into a rational design of peptidomimetic inhibitors. 相似文献949.
Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue invitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells(ESCs) and induced pluripotent stem cells(i PS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although i PS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-basedtherapy for ocular diseases. 相似文献
950.
Aini Wan Dongsheng Xu Kedong Liu Lin Peng Yanfei Cai Yun Chen 《Preparative biochemistry & biotechnology》2017,47(7):678-686
Insulin-like growth factor-1 (IGF-1) plays a crucial role in cell development, differentiation, and metabolism, and has been a potential therapeutic agent for many diseases. Chinese hamster ovary (CHO) cells are widely used for production of recombinant therapeutic proteins, but the expression level of IGF-1 in CHO cells is very low (1,500?µg/L) and the half-life of IGF-1 in blood circulation is only 4.5?min according to previous studies. Therefore, IGF-1 was fused to long-circulating serum protein human serum albumin (HSA) and expressed in CHO cells. After 8-day fed-batch culture, the expression level of HSA–IGF-1 reached 100?mg/L. The fusion protein HSA–IGF-1 was purified with a recovery of 35% using a two-step chromatographic procedure. According to bioactivity assay, the purified HSA–IGF-1 could stimulate the proliferation of NIH3T3 cells in a dose-dependent fashion and promote the cell-cycle progression. Besides this, HSA–IGF-1 could bind to IGF-1 receptor on cell membrane and activate the intracellular PI3K/AKT signaling pathway. Our study suggested that HSA fusion technology carried out in CHO cells not only provided bioactivity in HSA–IGF-1 for further research but also offered a beneficial strategy to produce other similar cytokines in CHO cells. 相似文献