Author Report for: Zheng HNo contact information in database for Zheng H
Guo D, Zheng Y, Gan Z, Guo Y, Jiang S, Yang F, Xiong F, Zheng H Ref: Front Genet, 13:814295, 2022 : PubMed ESTHER: Guo_2022_Front.Genet_13_814295 PubMedSearch: Guo 2022 Front.Genet 13 814295 PubMedID: 35368694 Abstract Hypertriglyceridemia is an important contributor to atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Familial hypertriglyceridemia is often caused by mutations in genes involved in triglyceride metabolism. Here, we investigated the disease-causing gene mutations in a Chinese family with hypertriglyceridemia and assessed the functional significance in vitro. Whole-exome sequencing (WES) was performed revealing that the severe hypertriglyceridemic proband carried a missense mutation (c.590G > A) in exon 5 of the LPL gene, as well as a missense mutation (c.1523C > T) in exon 10 of the LMF1 gene. Conservation analysis by Polyphen-2 showed that the 508 locus in the LMF1 protein and 197 locus in the LPL protein were highly conserved between different species. I-TASSER analysis indicated that the LMF1 c.1523C > T mutation and the LPL c.590G > A mutation changed the tertiary structure of the protein. A decrease in mRNA and protein expression was observed in 293T cells transfected with plasmids carrying the LMF1 c.1523C > T mutation. Subcellular localization showed that both wild-type (WT) and mutant LMF1 protein were localized at the cell cytoplasm. In the cell medium and cell lysates, these LMF1 and LPL gene mutations both caused a decreased LPL mass. Moreover, the combination of LMF1 and LPL gene mutations significantly decreased LPL levels compared to their individual effects on the LPL concentration. Both the clinical and in vitro data suggest that severe hypertriglyceridemia was of digenic origin caused by LMF1 and LPL mutation double heterozygosity in this patient. Title: Catalytically active inclusion bodies (CatIBs) induced by terminally attached self-assembling coiled-coil domains: To enhance the stability of (R)-hydroxynitrile lyase Pei X, Wang J, Zheng H, Xiao Q, Wang A, Su W Ref: Enzyme Microb Technol, 153:109915, 2022 : PubMed ESTHER: Pei_2022_Enzyme.Microb.Technol_153_109915 PubMedSearch: Pei 2022 Enzyme.Microb.Technol 153 109915 PubMedID: 34670185 Abstract The catalytically-active inclusion bodies (CatIBs) represent a promising strategy for immobilizing enzyme without additional carriers and chemicals, which has aroused great attention in academic and industrial communities. In this work, we discovered two natural parallel right-handed coiled-coil tetramer peptides from PDB database by a structural mining strategy. The two self-assembling peptides, NSPdoT from rotavirus and HVdoT from human Vasodilator-stimulated phosphoprotein, efficiently induced the CatIBs formation of a (R)-Hydroxynitrile lyase from Arabidopsis thaliana (AtHNL) in Escherichia coli cells. This is convenient to simultaneously purify and immobilize the target proteins as biocatalysts. As expected, HVdoT-AtHNL and NSPdoT-AtHNL possessed drastically increased tolerance toward lower pH values, which will be very critical to synthesize cyanohydrins under acidic condition for suppressing the non-enzymatic side reaction. In addition. AtHNL-CatIBs are produced at high yield in host cells as bioactive microparticles, which exhibited high thermal and pH stabilities. Therefore, the CatIBs method represent a promising application for the immobilization of enzymes in the biocatalysis field. Title: Efficacy and safety of DBPR108 (prusogliptin) as an add-on to metformin therapy in patients with type 2 diabetes mellitus: A 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III clinical trial Xu J, Ling H, Geng J, Huang Y, Xie Y, Zheng H, Niu H, Zhang T, Yuan J, Xiao X Ref: Diabetes Obes Metab, :, 2022 : PubMed ESTHER: Xu_2022_Diabetes.Obes.Metab__ PubMedSearch: Xu 2022 Diabetes.Obes.Metab PubMedID: 35791646 Inhibitor(s) related to this paper: Prusogliptin Abstract AIMS: To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl-peptidase-4 (DPP-4) inhibitor, as an add-on therapy in patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with metformin. MATERIALS AND METHODS: In this 24-week, multi-center, randomized, double-blind, placebo-controlled, superiority, phase III study, adult T2DM patients with glycated hemoglobin A1c (HbA1c) levels ranging from 7.0-9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108+metformin and placebo+metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add-on therapy to metformin. RESULTS: At week 24, the least-square (LS) mean (standard error [SE]) change from baseline in HbA1c was significantly greater in the DBPR108 group (-0.70% [0.09%]) than that in the placebo group (-0.07% [0.11%]) (P-value <0.001), with a treatment difference of -0.63% (95% confidence interval [CI]: -0.87, -0.39) on full analysis set. A higher proportion of patients achieved an HbA1c >=6.5% (19.7% vs. 8.5%) and HbA1c >=7.0% (50.0% vs. 21.1%) at week 24 in the DBPR108+metformin group. Furthermore, add-on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2-hour postprandial plasma glucose (2-h PPG) without causing weight gain. The overall frequency of adverse events (AEs) was similar between the two groups. CONCLUSIONS: DBPR108 as add-on therapy to metformin offered a significant improvement in glycemic control, was superior to metformin monotherapy (placebo), and was safe and well-tolerated in T2DM patients that is inadequately controlled with metformin. This article is protected by copyright. All rights reserved. Title: Conjugation with inulin improves the environmental stability of haloalkane dehalogenase DhaA Shan Y, Yu W, Shen L, Guo X, Zheng H, Zhong J, Hu T, Han Y Ref: Enzyme Microb Technol, 149:109832, 2021 : PubMed ESTHER: Shan_2021_Enzyme.Microb.Technol_149_109832 PubMedSearch: Shan 2021 Enzyme.Microb.Technol 149 109832 PubMedID: 34311877 Abstract Haloalkane dehalogenase DhaA catalyzes the hydrolytic cleavage of carbon-halogen bonds and produces alcohol, a proton and a halide. However, DhaA suffers from the poor environmental stability, such as sensitivity to high temperature, low pH, hypersaline and organic solvent. In order to improve the environmental stability of DhaA, DhaA was covalently conjugated with inulin, a hydrophilic polysaccharide in the present study. Each DhaA was averagely conjugated with 7-8 inulin molecules. The conjugated inulin could form a hydration layer around DhaA, which increased the conformational rigidity and decreased the entropy of the enzyme. Conjugation of inulin maintained 75.5 % of the enzymatic activity of DhaA and slightly altered the structure of DhaA. As compared with DhaA, the conjugate (inu-DhaA) showed slightly different kinetic parameters (K(m) of 2.9 micromol/L and K(cat) of 1.0 s(-1)). Inulin conjugation could delay the structural unfolding and/or slow the protonation process of DhaA under undesirable environment, including the long-term storage, low pH, hypersaline and organic solvent stability. As a result, the environmental stability of DhaA was markedly increased upon conjugation with inulin. Thus, inulin conjugation was an effective approach to enhance the environmental stability of DhaA. Title: Conjugation of haloalkane dehalogenase DhaA with arabinogalactan to increase its stability Wang M, Yu W, Shen L, Zheng H, Guo X, Zhong J, Hu T Ref: J Biotechnol, 335:47, 2021 : PubMed ESTHER: Wang_2021_J.Biotechnol_335_47 PubMedSearch: Wang 2021 J.Biotechnol 335 47 PubMedID: 34118331 Abstract Haloalkane dehalogenase DhaA can catalyze the hydrolytic cleavage of carbonhalogen bonds, along with production of the corresponding alcohol, a proton and a halide. However, DhaA suffers from poor environmental tolerance, such as sensitivity to high temperature, low pH and hypersaline. Arabinogalactan (AG) is a hydrophilic polysaccharide with highly branched long chains. DhaA was conjugated with AG to improve the environmental stability of DhaA in the present study. Each DhaA was averagely conjugated with 4-5 AG molecules. Conjugation of AG essentially maintained the enzymatic activity of DhaA (91.4 %) without apparent structural alteration. The hydration layer formed by AG could reduce the solvent accessible area of DhaA and slow the protonation process, thereby improving the pH and high salt stability of DhaA. In particular, the remaining activities of the conjugate (AG-DhaA) were 35.3 % after treatment at pH4.0 for 1 h, and 80.8 % in 1 M NaCl after treatment for 16 h. As compared with DhaA, AG-DhaA showed slightly different kinetic parameters (K M of 1.90 micromol/L and k cat of 2.60 s -1). Title: An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease Ghosh A, Comerota MM, Wan D, Chen F, Propson NE, Hwang SH, Hammock BD, Zheng H Ref: Sci Transl Med, 12:, 2020 : PubMed ESTHER: Ghosh_2020_Sci.Transl.Med_12_ PubMedSearch: Ghosh 2020 Sci.Transl.Med 12 PubMedID: 33298560 Inhibitor(s) related to this paper: TPPU Abstract Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer's disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD beta amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced beta amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD. Title: Simulated revelation of the adsorption behaviours of acetylcholinesterase on charged self-assembled monolayers Yang S, Liu J, Zheng H, Zhong J, Zhou J Ref: Nanoscale, :, 2020 : PubMed ESTHER: Yang_2020_Nanoscale__ PubMedSearch: Yang 2020 Nanoscale PubMedID: 32022070 Abstract An acetylcholinesterase (AChE)-based electrochemical biosensor, as a promising alternative to detect organophosphates (OPs) and carbamate pesticides, has gained considerable attention in recent years, due to the advantages of simplicity, rapidity, reliability and low cost. The bio-activity of AChE immobilized on the surface and the direct electron transfer (DET) rate between an enzyme and an electrode directly determined the analytical performances of the AChE-based biosensor, and experimental studies have shown that the charged surfaces have a strong impact on the detectability of the AChE-based biosensor. Therefore, it is very important to reveal the behaviour of AChE in bulk solution and on charged surfaces at the molecular level. In this work, the adsorption orientation and conformation of AChE from Torpedo californica (TcAChE) on oppositely charged self-assembled monolayers (SAMs), COOH-SAM and NH2-SAM with different surface charge densities, were investigated by parallel tempering Monte Carlo (PTMC) and all-atom molecular dynamics simulations (AAMD). Simulation results show that TcAChE could spontaneously and stably adsorb on two oppositely charged surfaces by the synergy of an electric dipole and charged residue patch, and opposite orientations were observed. The active-site gorge of TcAChE is oriented toward the surface with the "end-on" orientation and the active sites are close to the surface when it is adsorbed on the positively charged surface and the tunnel cost for the substrate is lower than that on the negatively charged surface and in bulk solution, while for TcAChE adsorbed on the negatively charged surface, the active site of TcAChE is far away from the surface and the active-site gorge is oriented toward the solution with a "back-on" orientation. It suggests that the positively charged surface could provide a better microenvironment for the efficient bio-catalytic reaction and quick DET between TcAChE and the electrode surface. Moreover, the RMSD, RMSF, dipole moment, gyration radius, eccentricity and superimposed structures show that only a slight conformational change occurred on the relatively flexible structure of TcAChE during simulations, and the native conformation is well preserved after adsorption. This work helps us better comprehend the adsorption mechanism of TcAChE on charged surfaces and might provide some guidelines for the development of new TcAChE-based amperometric biosensors for the detection of organophosphorus pesticides. Title: Electrostatic Effect of Functional Surfaces on the Activity of Adsorbed Enzymes: Simulations and Experiments Zheng H, Yang SJ, Zheng YC, Cui Y, Zhang Z, Zhong JY, Zhou J Ref: ACS Appl Mater Interfaces, 12:35676, 2020 : PubMed ESTHER: Zheng_2020_ACS.Appl.Mater.Interfaces_12_35676 PubMedSearch: Zheng 2020 ACS.Appl.Mater.Interfaces 12 35676 PubMedID: 32649833 Abstract The efficient immobilization of haloalkane dehalogenase (DhaA) on carriers with retaining of its catalytic activity is essential for its application in environmental remediation. In this work, adsorption orientation and conformation of DhaA on different functional surfaces were investigated by computer simulations; meanwhile, the mechanism of varying the catalytic activity was also probed. The corresponding experiments were then carried out to verify the simulation results. (The simulations of DhaA on SAMs provided parallel insights into DhaA adsorption in carriers. Then, the theory-guided experiments were carried out to screen the best surface functional groups for DhaA immobilization.) The electrostatic interaction was considered as the main impact factor for the regulation of enzyme orientation, conformation, and enzyme bioactivity during DhaA adsorption. The synergy of overall conformation, enzyme substrate tunnel structural parameters, and distance between catalytic active sites and surfaces codetermined the catalytic activity of DhaA. Specifically, it was found that the positively charged surface with suitable surface charge density was helpful for the adsorption of DhaA and retaining its conformation and catalytic activity and was favorable for higher enzymatic catalysis efficiency in haloalkane decomposition and environmental remediation. The neutral, negatively charged surfaces and positively charged surfaces with high surface charge density always caused relatively larger DhaA conformation change and decreased catalytic activity. This study develops a strategy using a combination of simulation and experiment, which can be essential for guiding the rational design of the functionalization of carriers for enzyme adsorption, and provides a practical tool to rationally screen functional groups for the optimization of adsorbed enzyme functions on carriers. More importantly, the strategy is general and can be applied to control behaviors of different enzymes on functional carrier materials. Title: High NDRG3 expression facilitates HCC metastasis by promoting nuclear translocation of beta-catenin Shi J, Zheng H, Yuan L Ref: BMB Rep, 52:451, 2019 : PubMed ESTHER: Shi_2019_BMB.Rep_52_451 PubMedSearch: Shi 2019 BMB.Rep 52 451 PubMedID: 31072445 Gene_locus related to this paper: human-NDRG3 Abstract NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/beta-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/beta-catenin signaling and enhanced CSC-like properties were responsible for NDRG3- mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of beta-catenin, as well as provides a potential therapeutic target for future therapeutic interventions. [BMB Reports 2019; 52(7): 451-456]. Title: Excipient-free nanodispersion of 7-ethyl-10-hydroxycamptothecin exerts potent therapeutic effects against pancreatic cancer cell lines and patient-derived xenografts Zhang L, Zhou J, Yan Y, Zhou X, Zhou Q, Du R, Hu S, Ge W, Huang Y and Wang W <5 more author(s)> Zhang L, Zhou J, Yan Y, Zhou X, Zhou Q, Du R, Hu S, Ge W, Huang Y, Xu H, Kong Y, Zheng H, Ding Y, Shen Y, Wang W (- 5) Ref: Cancer Letters, 465:36, 2019 : PubMed ESTHER: Zhang_2019_Cancer.Lett_465_36 PubMedSearch: Zhang 2019 Cancer.Lett 465 36 PubMedID: 31479691 Abstract Irinotecan (CPT-11) is an anti-tumor drug and formulated as nanomedicines to reduce side effects and improve efficacy. In vivo, CPT-11 must be hydrolyzed by carboxylesterase to its active form 7-ethyl-10-hydroxycamptothecin (SN-38) to exert anti-tumor activity, but the lack of this enzyme in humans causes inefficient generation of SN-38. Thus, direct delivery of SN-38, not relying on carboxylesterase, will potentially achieve higher efficacy. However, it is difficult to effectively formulate SN-38 using current excipients due to its hydrophobicity and tendency to crystallize. Herein, we report the nanodispersion of SN-38 with its amphiphilic prodrug, CPT-11, as an effective treatment for pancreatic cancer (PC). SN-38 and CPT-11 formed stable nanoparticles without any other excipients, and showed potent cytotoxicity against PC cells in vitro, slowed tumor growth in vivo, namely subcutaneously and orthotopically xenografted mice, with minimal adverse effects, and prolonged their overall survival. Even in clinically-relevant patient-derived xenograft (PDX) models, the nanodispersion showed greater anti-tumor efficacy than CPT-11. Importantly, the nanodispersion directly released SN-38, resulting in carboxylesterase-independent anti-tumor activity, in contrast to carboxylesterase-dependent CPT-11. These characteristics may enable the excipient-free nanodispersion to exert potent therapeutic effects in patients. Title: An effective immobilized haloalkane dehalogenase DhaA from Rhodococcus rhodochrous by adsorption, crosslink and PEGylation on meso-cellular foam Zheng H, Yu WL, Guo X, Zhao YZ, Cui Y, Hu T, Zhong JY Ref: Int J Biol Macromol, 125:1016, 2019 : PubMed ESTHER: Zheng_2019_Int.J.Biol.Macromol_125_1016 PubMedSearch: Zheng 2019 Int.J.Biol.Macromol 125 1016 PubMedID: 30576728 Abstract Haloalkane dehalogenase DhaA catalyzes the hydrolysis of halogenated compounds by cleavage of the carbon-halogen bond. However, DhaA suffers from poor environmental stability and difficult recovery, which significantly increase the cost of DhaA. Here, an effective enzyme immobilization strategy was developed to overcome the disadvantages of DhaA. DhaA was physically absorbed with amine-functionalized meso-cellular foam (MCF). The MCF-absorbed DhaA (MD) was intermolecularly crosslinked with 8-arm PEG Nhydroxysuccinimide ester and then PEGylated by maleimide-thiol chemistry. DhaA from Rhodococcus rhodochrous was absorbed at a loading capacity of 100mg/g in MD. The bulk crystallinity and morphology of MCF were largely maintained. The immobilized DhaA (MD-P1-P2) showed a lower Michaelis constant (Km, 0.588mM) than DhaA (0.905mM), along with an extremely low leaching ratio of DhaA (1.1%) from MCF. MD-P1-P2 exhibited a high stability in the extreme environmental conditions, as reflected by the remaining activity of 99.8% in 40% (v/v) DMSO for 5h, 87.3% in 3M urea solution for 1h, 25.9% at pH3.0, and 51.8% at room temperature for 30days. Thus, our study was expected to develop an effective immobilized DhaA for practical application. Title: Fluorescein as a Visible-Light-Induced Oxidase Mimic for Signal-Amplified Colorimetric Assay of Carboxylesterase by an Enzymatic Cascade Reaction Liu L, Sun C, Yang J, Shi Y, Long Y, Zheng H Ref: Chemistry, 24:6148, 2018 : PubMed ESTHER: Liu_2018_Chemistry_24_6148 PubMedSearch: Liu 2018 Chemistry 24 6148 PubMedID: 29493016 Abstract We have found that fluorescein possesses high visible-light-induced oxidase mimetic activity and could transform colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB) without unstable and destructive H2 O2 under visible-light illumination. Instead, fluorescein uses oxygen as a mild and green electron acceptor, and its activity can be easily controlled by the switching "on/off" of visible light. In addition, the visible-light-induced catalytic mechanism was elucidated in detail and, as the main reactive species h(+) and O2(.-) accounted for TMB oxidation. Based on the fact that fluorescein diacetate (FDA) possessed no activity and generated active fluorescein in situ in the presence of carboxylesterase (CaE), a signal-amplified sensing platform through a cascade reaction for CaE detection was constructed. Our proposed sensing system displayed excellent analytical performance for the detection of CaE in a wide linear range from 0.040 to 20 U L(-1) with a low detection limit of 0.013 U L(-1) . This work not only changes the conventional concept that fluorescein is generally considered to be photocatalytically inert, but also provides a novel sensing strategy by tailoring the enzyme mimetic activity of fluorescein derivatives with analyte. Title: PEGylation with the thiosuccinimido butylamine linker significantly increases the stability of haloalkane dehalogenase DhaA Zhao YZ, Yu WL, Zheng H, Guo X, Guo N, Hu T, Zhong JY Ref: J Biotechnol, 254:25, 2017 : PubMed ESTHER: Zhao_2017_J.Biotechnol_254_25 PubMedSearch: Zhao 2017 J.Biotechnol 254 25 PubMedID: 28587829 Abstract Haloalkane dehalogenase (HLD) can catalyze the hydrolytic dehalogenation of halogenated compounds. However, HLD suffers from the poor stability to resist the environmental stress. PEGylation is an effective approach to enhance the stability of enzymes. The linker is an important stabilization factor of PEGylation. Thus, the linkers of the PEGylated HLD were optimized to improve the stability of HLD in the present study. The PEGylated haloalkane dehalogenase DhaAs with methylamine (Ml), carbamate (Cm) and thiosuccinimido butylamine (Tb) linkers were prepared, respectively. The effects of the Ml, Cm and Tb linkers on the stability of the PEGylated DhaAs were investigated under different environmental stresses. Among the three linkers, the Tb linker showed the highest efficacy to improve the stability of the PEGylated DhaA. The Tb linker significantly increased the thermal stability of the PEGylated DhaA by slowing its structural unfolding, and the pH stability of the PEGylated DhaA by slowing the protonation process. In addition, the PEGylated DhaA with the Tb linker showed the maximum resistance to high ionic strength (1M NaCl) and organic solvent (40% DMSO). PEGylation with the Tb linker is of general interest to effectively improve the stability of proteins, particularly the protein with poor stability. Title: Thyroglobulin gene mutations in Chinese patients with congenital hypothyroidism Hu X, Chen R, Fu C, Fan X, Wang J, Qian J, Yi S, Li C, Luo J and Shen Y <9 more author(s)> Hu X, Chen R, Fu C, Fan X, Wang J, Qian J, Yi S, Li C, Luo J, Su J, Zhang S, Xie B, Zheng H, Lai Y, Chen Y, Li H, Gu X, Chen S, Shen Y (- 9) Ref: Mol Cell Endocrinol, 423:60, 2016 : PubMed ESTHER: Hu_2016_Mol.Cell.Endocrinol_423_60 PubMedSearch: Hu 2016 Mol.Cell.Endocrinol 423 60 PubMedID: 26777470 Gene_locus related to this paper: human-TG Abstract Mutations in Thyroglobulin (TG) are common genetic causes of congenital hypothyroidism (CH). But the TG mutation spectrum and its frequency in Chinese CH patients have not been investigated. Here we conducted a genetic screening of TG gene in a cohort of 382 Chinese CH patients. We identified 22 rare non-polymorphic variants including six truncating variants and 16 missense variants of unknown significance (VUS). Seven patients carried homozygous pathogenic variants, and three patients carried homozygous or compound heterozygous VUS. 48 out of 382 patients carried one of 18 heterozygous VUS which is significantly more often than their occurrences in control cohort (P < 0.0001). Unique to Asian population, the c.274+2T>G variant is the most common pathogenic variant with an allele frequency of 0.021. The prevalence of CH due to TG gene defect in Chinese population was estimated to be approximately 1/101,000. Our study uncovered ethnicity specific TG mutation spectrum and frequency. Title: Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication Li W, Zhu Z, Cao W, Yang F, Zhang X, Li D, Zhang K, Li P, Mao R and Zheng H <1 more author(s)> Li W, Zhu Z, Cao W, Yang F, Zhang X, Li D, Zhang K, Li P, Mao R, Liu X, Zheng H (- 1) Ref: Mol Immunol, 75:112, 2016 : PubMed ESTHER: Li_2016_Mol.Immunol_75_112 PubMedSearch: Li 2016 Mol.Immunol 75 112 PubMedID: 27267271 Abstract The enzymatic activities of esterase D (ESD) are involved in many human diseases. However, no antiviral property of ESD has been described to date. Foot-and-mouth disease virus (FMDV) is the etiological agent of foot-and-mouth disease. In this study, we showed that FMDV infection triggered ESD expression. Overexpression of ESD significantly suppressed FMDV replication and knockdown of ESD expression enhanced virus replication, showing an essential antiviral role of ESD. Furthermore, we found that Sendai-virus-induced interferon (IFN) signaling was enhanced by upregulation of ESD, and ESD promoted activation of the IFN-beta promoter simulated by IFN regulatory factor (IRF)3 or its upstream molecules (retinoic acid-inducible gene-I, melanoma differentiation-associated protein 5, virus-induced signaling adaptor and TANK binding kinase 1). Detailed analysis revealed that ESD protein enhanced IRF3 phosphorylation during FMDV infection. Overexpression of ESD also promoted the expression of various antiviral interferon-stimulated genes (ISGs) and knockdown of ESD impaired the expression of these antiviral genes during FMDV infection. Our findings demonstrate a new mechanism evolved by ESD to enhance type I IFN signal transduction and suppress viral replication during FMDV infection. Title: Efficient production of (2)H, (13)C, (15)N-enriched industrial enzyme Rhizopus chinensis lipase with native disulfide bonds Zhang M, Yu XW, Swapna GV, Xiao R, Zheng H, Sha C, Xu Y, Montelione GT Ref: Microb Cell Fact, 15:123, 2016 : PubMed ESTHER: Zhang_2016_Microb.Cell.Fact_15_123 PubMedSearch: Zhang 2016 Microb.Cell.Fact 15 123 PubMedID: 27411547 Abstract BACKGROUND: In order to use most modern methods of NMR spectroscopy to study protein structure and dynamics, isotope-enriched protein samples are essential. Especially for larger proteins (>20 kDa), perdeuterated and Ile (delta1), Leu, and Val methyl-protonated protein samples are required for suppressing nuclear relaxation to provide improved spectral quality, allowing key backbone and side chain resonance assignments needed for protein structure and dynamics studies. Escherichia coli and Pichia pastoris are two of the most popular expression systems for producing isotope-enriched, recombinant protein samples for NMR investigations. The P. pastoris system can be used to produce (13)C, (15)N-enriched and even (2)H,(13)C, (15)N-enriched protein samples, but efficient methods for producing perdeuterated proteins with Ile (delta1), Leu and Val methyl-protonated groups in P. pastoris are still unavailable. Glycosylation heterogeneity also provides challenges to NMR studies. E. coli expression systems are efficient for overexpressing perdeuterated and Ile (delta1), Leu, Val methyl-protonated protein samples, but are generally not successful for producing secreted eukaryotic proteins with native disulfide bonds. Title: Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke Lin J, Zheng H, Cucchiara BL, Li J, Zhao X, Liang X, Wang C, Li H, Mullen MT and Wang Y <1 more author(s)> Lin J, Zheng H, Cucchiara BL, Li J, Zhao X, Liang X, Wang C, Li H, Mullen MT, Johnston SC, Wang Y (- 1) Ref: Neurology, 85:1585, 2015 : PubMed ESTHER: Lin_2015_Neurology_85_1585 PubMedSearch: Lin 2015 Neurology 85 1585 PubMedID: 26311748 Abstract OBJECTIVE: To determine the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) measured in the acute period and the short-term risk of recurrent vascular events in patients with TIA or minor stroke. Title: Polyamine transporters and polyamines increase furfural tolerance during xylose fermentation with ethanologenic Escherichia coli strain LY180 Geddes RD, Wang X, Yomano LP, Miller EN, Zheng H, Shanmugam KT, Ingram LO Ref: Applied Environmental Microbiology, 80:5955, 2014 : PubMed ESTHER: Geddes_2014_Appl.Environ.Microbiol_80_5955 PubMedSearch: Geddes 2014 Appl.Environ.Microbiol 80 5955 PubMedID: 25063650 Gene_locus related to this paper: ecoli-fes, ecoli-yaim, ecoli-YfhR Abstract Expression of genes encoding polyamine transporters from plasmids and polyamine supplements increased furfural tolerance (growth and ethanol production) in ethanologenic Escherichia coli LY180 (in AM1 mineral salts medium containing xylose). This represents a new approach to increase furfural tolerance and may be useful for other organisms. Microarray comparisons of two furfural-resistant mutants (EMFR9 and EMFR35) provided initial evidence for the importance of polyamine transporters. Each mutant contained a single polyamine transporter gene that was upregulated over 100-fold (microarrays) compared to that in the parent LY180, as well as a mutation that silenced the expression of yqhD. Based on these genetic changes, furfural tolerance was substantially reconstructed in the parent, LY180. Deletion of potE in EMFR9 lowered furfural tolerance to that of the parent. Deletion of potE and puuP in LY180 also decreased furfural tolerance, indicating functional importance of the native genes. Of the 8 polyamine transporters (18 genes) cloned and tested, half were beneficial for furfural tolerance (PotE, PuuP, PlaP, and PotABCD). Supplementing AM1 mineral salts medium with individual polyamines (agmatine, putrescine, and cadaverine) also increased furfural tolerance but to a smaller extent. In pH-controlled fermentations, polyamine transporter plasmids were shown to promote the metabolism of furfural and substantially reduce the time required to complete xylose fermentation. This increase in furfural tolerance is proposed to result from polyamine binding to negatively charged cellular constituents such as nucleic acids and phospholipids, providing protection from damage by furfural. Title: A Novel Risk Haplotype of ALOX5AP Gene is Associated with Ischemic Stroke in Chinese Han Population Yang D, He Y, Li M, Shi C, Song G, Wang Q, Fan Y, Feng Q, Zheng H Ref: Journal of Molecular Neuroscience, 53:493, 2014 : PubMed ESTHER: Yang_2014_J.Mol.Neurosci_53_493 PubMedSearch: Yang 2014 J.Mol.Neurosci 53 493 PubMedID: 24198186 Abstract Previous studies have implicated that two at-risk haplotypes (HapA and HapB) of gene-encoding 5-lipoxygenase-activating protein (ALOX5AP) were significantly associated with stroke. The aim of this study was to explore the association between haplotypes of ALOX5AP gene and risk for ischemic stroke (IS) in Chinese Han population. A total of 492 patients with IS and 490 matched control subjects were recruited. Six ALOX5AP SNPs (SG13S377, SG13S114, SG13S41, SG13S89, SG13S32 and SG13S35) were genotyped by SNaPshot minisequence technique. A common genetic variant SG13S114/AA in the ALOX5AP gene was associated with IS in this Chinese cohort (OR = 2.514, 95 % CI = 1.667 ~ 3.790). HapA (TGA) and HapB (AAAG) had no significant difference in the patients (36.3 and 18.5 %, respectively) and controls (37.6 and 16.3 %, respectively) (P = 0.631 and P = 0.375, respectively). But, the frequency of Hap (GAAG) was significantly higher in the patients than that in the controls after Bonferroni's adjustment (P = 0.006). To conclude, SG13S114/AA of the ALOX5AP gene was associated with an increased risk for IS. A novel risk haplotype, Hap (GAAG) was a genetic risk factor for IS in this Chinese population. Title: Dynamics of fecal microbial communities in children with diarrhea of unknown etiology and genomic analysis of associated Streptococcus lutetiensis Jin D, Chen C, Li L, Lu S, Li Z, Zhou Z, Jing H, Xu Y, Du P and Xu J <8 more author(s)> Jin D, Chen C, Li L, Lu S, Li Z, Zhou Z, Jing H, Xu Y, Du P, Wang H, Xiong Y, Zheng H, Bai X, Sun H, Wang L, Ye C, Gottschalk M, Xu J (- 8) Ref: BMC Microbiol, 13:141, 2013 : PubMed ESTHER: Jin_2013_BMC.Microbiol_13_141 PubMedSearch: Jin 2013 BMC.Microbiol 13 141 PubMedID: 23782707 Abstract BACKGROUND: The sequences of the 16S rRNA genes extracted from fecal samples provide insights into the dynamics of fecal microflora. This potentially gives valuable etiological information for patients whose conditions have been ascribed to unknown pathogens, which cannot be accomplished using routine culture methods. We studied 33 children with diarrhea who were admitted to the Children's Hospital in Shanxi Province during 2006. Title: Genomic and secretomic analyses reveal unique features of the lignocellulolytic enzyme system of Penicillium decumbens Liu G, Zhang L, Wei X, Zou G, Qin Y, Ma L, Li J, Zheng H, Wang S and Qu Y <4 more author(s)> Liu G, Zhang L, Wei X, Zou G, Qin Y, Ma L, Li J, Zheng H, Wang S, Wang C, Xun L, Zhao GP, Zhou Z, Qu Y (- 4) Ref: PLoS ONE, 8:e55185, 2013 : PubMed ESTHER: Liu_2013_PLoS.ONE_8_E55185 PubMedSearch: Liu 2013 PLoS.ONE 8 E55185 PubMedID: 23383313 Gene_locus related to this paper: peno1-s7zjd1, peno1-s8aym9, peno1-s7zcd7, peno1-s8aui7, peno1-s7zba9, peno1-s7z7w2, peno1-s7zkn6, peno1-s8ak78, peno1-s7z721, peno1-s8ajn6, peno1-s7zqw4, peno1-s8bba0, peno1-s8b4w2, peno1-s7zta4, peno1-s8a1h3, peno1-s8aiq5, peno1-s8ba66, peno1-s7zxp5, penox-poxo Abstract Many Penicillium species could produce extracellular enzyme systems with good lignocellulose hydrolysis performance. However, these species and their enzyme systems are still poorly understood and explored due to the lacking of genetic information. Here, we present the genomic and secretomic analyses of Penicillium decumbens that has been used in industrial production of lignocellulolytic enzymes in China for more than fifteen years. Comparative genomics analysis with the phylogenetically most similar species Penicillium chrysogenum revealed that P. decumbens has evolved with more genes involved in plant cell wall degradation, but fewer genes in cellular metabolism and regulation. Compared with the widely used cellulase producer Trichoderma reesei, P. decumbens has a lignocellulolytic enzyme system with more diverse components, particularly for cellulose binding domain-containing proteins and hemicellulases. Further, proteomic analysis of secretomes revealed that P. decumbens produced significantly more lignocellulolytic enzymes in the medium with cellulose-wheat bran as the carbon source than with glucose. The results expand our knowledge on the genetic information of lignocellulolytic enzyme systems in Penicillium species, and will facilitate rational strain improvement for the production of highly efficient enzyme systems used in lignocellulose utilization from Penicillium species. Title: Draft Genome Sequence of Ralstonia solanacearum Race 4 Biovar 4 Strain SD54 Shan W, Yang X, Ma W, Yang Y, Guo X, Guo J, Zheng H, Li G, Xie B Ref: Genome Announc, 1:, 2013 : PubMed ESTHER: Shan_2013_Genome.Announc_1_e00890 PubMedSearch: Shan 2013 Genome.Announc 1 e00890 PubMedID: 24356823 Gene_locus related to this paper: ralso-PCAD Abstract Ralstonia solanacearum is an important etiological agent that can cause serious bacterial wilt in a very wide range of potential host plants, including ginger. Here, we report the complete genome sequence of R. solanacearum SD54, a race 4 biovar 4 (R4B4) strain from a diseased ginger plant in China. Title: ContigScape: a Cytoscape plugin facilitating microbial genome gap closing Tang B, Wang Q, Yang M, Xie F, Zhu Y, Zhuo Y, Wang S, Gao H, Ding X and Zheng H <2 more author(s)> Tang B, Wang Q, Yang M, Xie F, Zhu Y, Zhuo Y, Wang S, Gao H, Ding X, Zhang L, Zhao G, Zheng H (- 2) Ref: BMC Genomics, 14:289, 2013 : PubMed ESTHER: Tang_2013_BMC.Genomics_14_289 PubMedSearch: Tang 2013 BMC.Genomics 14 289 PubMedID: 23627759 Gene_locus related to this paper: myctu-cut3, myctu-cutas1, myctu-cutas2, myctu-Rv0160c, myctu-Rv1069c, myctu-RV1215C, myctu-Rv2045c, myctu-RV3452, myctu-Rv3802c, amyor-r4tdn6, amyor-r4sys4, amyor-r4svp2, amyor-r4t193, amyor-r4t8c7, amyor-r4t8w6, amyor-r4t1x8, amyor-r4stv4, amyor-r4t7z6, 9pseu-r4sx12 Abstract BACKGROUND: With the emergence of next-generation sequencing, the availability of prokaryotic genome sequences is expanding rapidly. A total of 5,276 genomes have been released since 2008, yet only 1,692 genomes were complete. The final phase of microbial genome sequencing, particularly gap closing, is frequently the rate-limiting step either because of complex genomic structures that cause sequence bias even with high genomic coverage, or the presence of repeat sequences that may cause gaps in assembly. Title: The genome of the hydatid tapeworm Echinococcus granulosus Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y and Wang S <21 more author(s)> Zheng H, Zhang W, Zhang L, Zhang Z, Li J, Lu G, Zhu Y, Wang Y, Huang Y, Liu J, Kang H, Chen J, Wang L, Chen A, Yu S, Gao Z, Jin L, Gu W, Wang Z, Zhao L, Shi B, Wen H, Lin R, Jones MK, Brejova B, Vinar T, Zhao G, McManus DP, Chen Z, Zhou Y, Wang S (- 21) Ref: Nat Genet, 45:1168, 2013 : PubMed ESTHER: Zheng_2013_Nat.Genet_45_1168 PubMedSearch: Zheng 2013 Nat.Genet 45 1168 PubMedID: 24013640 Gene_locus related to this paper: echgr-k4epc5, echmu-u6hbw4, echgr-w6ugl0, echgr-w6u7y4, echgr-w6vaq5, echgr-a0a068wxj3, echgr-a0a068wgw1, echgr-a0a068wl60 Abstract Cystic echinococcosis (hydatid disease), caused by the tapeworm E. granulosus, is responsible for considerable human morbidity and mortality. This cosmopolitan disease is difficult to diagnose, treat and control. We present a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 genes. Comparisons with the genome sequences from other taxa show that E. granulosus has acquired a spectrum of genes, including the EgAgB family, whose products are secreted by the parasite to interact and redirect host immune responses. We also find that genes in bile salt pathways may control the bidirectional development of E. granulosus, and sequence differences in the calcium channel subunit EgCavbeta1 may be associated with praziquantel sensitivity. Our study offers insights into host interaction, nutrient acquisition, strobilization, reproduction, immune evasion and maturation in the parasite and provides a platform to facilitate the development of new, effective treatments and interventions for echinococcosis control. Title: Draft genome sequence of marine Streptomyces sp. strain W007, which produces angucyclinone antibiotics with a benz[a]anthracene skeleton Qin S, Zhang H, Li F, Zhu B, Zheng H Ref: Journal of Bacteriology, 194:1628, 2012 : PubMed ESTHER: Qin_2012_J.Bacteriol_194_1628 PubMedSearch: Qin 2012 J.Bacteriol 194 1628 PubMedID: 22374958 Gene_locus related to this paper: 9actn-h0b8d4, 9acto-h0b5v2, 9acto-h0bkj3, 9acto-h0bln7, 9acto-h0blv8, 9acto-h0brh7, strgg-b1vzw6, 9acto-h0b9i4, 9acto-h0bn07, 9actn-h0bay1 Abstract A series of angucyclinone antibiotics have been isolated from marine Streptomyces sp. strain W007 and identified. Here, a draft genome sequence of Streptomyces sp. W007 is presented. The genome contains an intact biosynthetic gene cluster for angucyclinone antibiotics, which provides insight into the combinatorial biosynthesis of angucyclinone antibiotics produced by marine streptomycetes. Title: Complete genome sequence of Amycolatopsis mediterranei S699 based on de novo assembly via a combinatorial sequencing strategy Tang B, Zhao W, Zheng H, Zhuo Y, Zhang L, Zhao GP Ref: Journal of Bacteriology, 194:5699, 2012 : PubMed ESTHER: Tang_2012_J.Bacteriol_194_5699 PubMedSearch: Tang 2012 J.Bacteriol 194 5699 PubMedID: 23012281 Gene_locus related to this paper: amymu-d8hpp2, amyms-g0fkj6 Abstract The genome of Amycolatopsis mediterranei S699 was resequenced and assembled de novo. By comparing the sequences of S699 previously released and that of A. mediterranei U32, about 10 kb of major indels was found to differ between the two S699 genomes, and the differences are likely attributable to their different assembly strategies. Title: Genomic and transcriptomic insights into the thermo-regulated biosynthesis of validamycin in Streptomyces hygroscopicus 5008 Wu H, Qu S, Lu C, Zheng H, Zhou X, Bai L, Deng Z Ref: BMC Genomics, 13:337, 2012 : PubMed ESTHER: Wu_2012_BMC.Genomics_13_337 PubMedSearch: Wu 2012 BMC.Genomics 13 337 PubMedID: 22827618 Gene_locus related to this paper: strhj-h2k4a5 Abstract BACKGROUND: Streptomyces hygroscopicus 5008 has been used for the production of the antifungal validamycin/jinggangmycin for more than 40 years. A high yield of validamycin is achieved by culturing the strain at 37 degreesC, rather than at 30 degreesC for normal growth and sporulation. The mechanism(s) of its thermo-regulated biosynthesis was largely unknown. RESULTS: The 10,383,684-bp genome of strain 5008 was completely sequenced and composed of a linear chromosome, a 164.57-kb linear plasmid, and a 73.28-kb circular plasmid. Compared with other Streptomyces genomes, the chromosome of strain 5008 has a smaller core region and shorter terminal inverted repeats, encodes more alpha/beta hydrolases, major facilitator superfamily transporters, and Mg2+/Mn2+-dependent regulatory phosphatases. Transcriptomic analysis revealed that the expression of 7.5% of coding sequences was increased at 37 degreesC, including biosynthetic genes for validamycin and other three secondary metabolites. At 37 degreesC, a glutamate dehydrogenase was transcriptionally up-regulated, and further proved its involvement in validamycin production by gene replacement. Moreover, efficient synthesis and utilization of intracellular glutamate were noticed in strain 5008 at 37 degreesC, revealing glutamate as the nitrogen source for validamycin biosynthesis. Furthermore, a SARP-family regulatory gene with enhanced transcription at 37 degreesC was identified and confirmed to be positively involved in the thermo-regulation of validamycin production by gene inactivation and transcriptional analysis. CONCLUSIONS: Strain 5008 seemed to have evolved with specific genomic components to facilitate the thermo-regulated validamycin biosynthesis. The data obtained here will facilitate future studies for validamycin yield improvement and industrial bioprocess optimization. Title: Bacterial biosynthesis and maturation of the didemnin anti-cancer agents Xu Y, Kersten RD, Nam SJ, Lu L, Al-Suwailem AM, Zheng H, Fenical W, Dorrestein PC, Moore BS, Qian PY Ref: Journal of the American Chemical Society, 134:8625, 2012 : PubMed ESTHER: Xu_2012_J.Am.Chem.Soc_134_8625 PubMedSearch: Xu 2012 J.Am.Chem.Soc 134 8625 PubMedID: 22458477 Abstract The anti-neoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B's development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine alpha-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process. Complete genome sequence analysis of the 6,513,401 bp T. mobilis strain KA081020-065 with its five circular replicons revealed the putative didemnin biosynthetic gene cluster (did) on the 1,126,962 bp megaplasmid pTM3. The did locus encodes a 13-module hybrid non-ribosomal peptide synthetase-polyketide synthase enzyme complex organized in a collinear arrangement for the synthesis of the fatty acylglutamine ester derivatives didemnins X and Y rather than didemnin B as first anticipated. Imaging mass spectrometry of T. mobilis bacterial colonies captured the time-dependent extracellular conversion of the didemnin X and Y precursors to didemnin B, in support of an unusual post-synthetase activation mechanism. Significantly, the discovery of the didemnin biosynthetic gene cluster may provide a long-term solution to the supply problem that presently hinders this group of marine natural products and pave the way for the genetic engineering of new didemnin congeners. Title: Edwardsiella comparative phylogenomics reveal the new intra/inter-species taxonomic relationships, virulence evolution and niche adaptation mechanisms Yang M, Lv Y, Xiao J, Wu H, Zheng H, Liu Q, Zhang Y, Wang Q Ref: PLoS ONE, 7:e36987, 2012 : PubMed ESTHER: Yang_2012_PLoS.ONE_7_E36987 PubMedSearch: Yang 2012 PLoS.ONE 7 E36987 PubMedID: 22590641 Gene_locus related to this paper: 9gamm-a0a076lfv2 Abstract Edwardsiella bacteria are leading fish pathogens causing huge losses to aquaculture industries worldwide. E. tarda is a broad-host range pathogen that infects more than 20 species of fish and other animals including humans while E. ictaluri is host-adapted to channel catfish causing enteric septicemia of catfish (ESC). Thus, these two species consist of a useful comparative system for studying the intricacies of pathogen evolution. Here we present for the first time the phylogenomic comparisons of 8 genomes of E. tarda and E. ictaluri isolates. Genome-based phylogenetic analysis revealed that E. tarda could be separate into two kinds of genotypes (genotype I, EdwGI and genotype II, EdwGII) based on the sequence similarity. E. tarda strains of EdwGI were clustered together with the E. ictaluri lineage and showed low sequence conservation to E. tarda strains of EdwGII. Multilocus sequence analysis (MLSA) of 48 distinct Edwardsiella strains also supports the new taxonomic relationship of the lineages. We identified the type III and VI secretion systems (T3SS and T6SS) as well as iron scavenging related genes that fulfilled the criteria of a key evolutionary factor likely facilitating the virulence evolution and adaptation to a broad range of hosts in EdwGI E. tarda. The surface structure-related genes may underlie the adaptive evolution of E. ictaluri in the host specification processes. Virulence and competition assays of the null mutants of the representative genes experimentally confirmed their contributive roles in the evolution/niche adaptive processes. We also reconstructed the hypothetical evolutionary pathway to highlight the virulence evolution and niche adaptation mechanisms of Edwardsiella. This study may facilitate the development of diagnostics, vaccines, and therapeutics for this under-studied pathogen. Title: From antioxidant chelators to site-activated multi-target chelators targeting hypoxia inducing factor, beta-amyloid, acetylcholinesterase and monoamine oxidase A/B Zheng H, Fridkin M, Youdim MB Ref: Mini Rev Med Chem, 12:364, 2012 : PubMed ESTHER: Zheng_2012_Mini.Rev.Med.Chem_12_364 PubMedSearch: Zheng 2012 Mini.Rev.Med.Chem 12 364 PubMedID: 22303968 Abstract Chelators hold great promise as disease-modifying drugs for Alzheimer's therapy, and recent research efforts have focused on designing multi-target chelators with increased targeting and efficacy through rational drug design. In this review, we discuss our research studies on the rational design of new multi-target chelators with the potential not only to simultaneously modulate several disease-related targets, but also contain features designed to improve the BBB permeability, increase the brain targeting, and minimize potential side effects. These new chelators include neuroprotective chelators with brain selective monoamine oxidase (MAO) A/B inhibitory activity, acetylcholinesterase (AChE) inhibitors with site-activated chelating and neurogenesis activity, and AChE-MAO A/B inhibitors with site-activated chelating and neurogenesis activity.. Title: From anti-Parkinson's drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer's disease Zheng H, Amit T, Bar-Am O, Fridkin M, Youdim MB, Mandel SA Ref: J Alzheimers Dis, 30:1, 2012 : PubMed ESTHER: Zheng_2012_J.Alzheimers.Dis_30_1 PubMedSearch: Zheng 2012 J.Alzheimers.Dis 30 1 PubMedID: 22387411 Inhibitor(s) related to this paper: M30D Abstract Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-beta and amyloid-beta protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways. Title: Novel chelators targeting cell cycle arrest, acetylcholinesterase, and monoamine oxidase for Alzheimer's therapy Zheng H, Fridkin M, Youdim MB Ref: Curr Drug Targets, 13:1089, 2012 : PubMed ESTHER: Zheng_2012_Curr.Drug.Targets_13_1089 PubMedSearch: Zheng 2012 Curr.Drug.Targets 13 1089 PubMedID: 22676912 Abstract The recent finding that acetylcholinesterase (AChE) colocalizes with beta-amyloid (Abeta), promotes and accelerates Abeta aggregation has renewed an intense interest in developing new multitarget AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. In this review, we first briefly discuss the linkage and complex interplay among the three characteristic hallmarks of Alzheimer's disease (AD): amyloid (Abeta) plaques, neurofibrillary tangles (NFTs), and cholinergic hypofunction. We then review the recent studies on the four marketed cholinesterase inhibitors in term of their multiple activities, potential disease-modifying effects, and the underlying mechanisms of these actions. We finally focus on a new emerging strategy or multitarget AChE inhibitors as effective drugs for AD therapy. We explore some examples of multitarget ChE inhibitors developed in our own and other laboratories, which were purposely designed to address multiple AD etiological targets. These new AChE inhibitors hold great promise for improving cognitive functions in AD patients, slowing down the disease progression, as well as treating behavior problems related to AD. Title: Genome analyses of Icelandic strains of Sulfolobus islandicus, model organisms for genetic and virus-host interaction studies Guo L, Brugger K, Liu C, Shah SA, Zheng H, Zhu Y, Wang S, Lillestol RK, Chen L and Garrett RA <5 more author(s)> Guo L, Brugger K, Liu C, Shah SA, Zheng H, Zhu Y, Wang S, Lillestol RK, Chen L, Frank J, Prangishvili D, Paulin L, She Q, Huang L, Garrett RA (- 5) Ref: Journal of Bacteriology, 193:1672, 2011 : PubMed ESTHER: Guo_2011_J.Bacteriol_193_1672 PubMedSearch: Guo 2011 J.Bacteriol 193 1672 PubMedID: 21278296 Gene_locus related to this paper: sulir-f0nbu1, sulso-APEH1, sulso-APEH3, sulso-dlhh, sulir-f0ndq1 Abstract The genomes of two Sulfolobus islandicus strains obtained from Icelandic solfataras were sequenced and analyzed. Strain REY15A is a host for a versatile genetic toolbox. It exhibits a genome of minimal size, is stable genetically, and is easy to grow and manipulate. Strain HVE10/4 shows a broad host range for exceptional crenarchaeal viruses and conjugative plasmids and was selected for studying their life cycles and host interactions. The genomes of strains REY15A and HVE10/4 are 2.5 and 2.7 Mb, respectively, and each genome carries a variable region of 0.5 to 0.7 Mb where major differences in gene content and gene order occur. These include gene clusters involved in specific metabolic pathways, multiple copies of VapBC antitoxin-toxin gene pairs, and in strain HVE10/4, a 50-kb region rich in glycosyl transferase genes. The variable region also contains most of the insertion sequence (IS) elements and high proportions of the orphan orfB elements and SMN1 miniature inverted-repeat transposable elements (MITEs), as well as the clustered regular interspaced short palindromic repeat (CRISPR)-based immune systems, which are complex and diverse in both strains, consistent with them having been mobilized both intra- and intercellularly. In contrast, the remainder of the genomes are highly conserved in their protein and RNA gene syntenies, closely resembling those of other S. islandicus and Sulfolobus solfataricus strains, and they exhibit only minor remnants of a few genetic elements, mainly conjugative plasmids, which have integrated at a few tRNA genes lacking introns. This provides a possible rationale for the presence of the introns. Title: Complete sequencing and pan-genomic analysis of Lactobacillus delbrueckii subsp. bulgaricus reveal its genetic basis for industrial yogurt production Hao P, Zheng H, Yu Y, Ding G, Gu W, Chen S, Yu Z, Ren S, Oda M and Zhao G <4 more author(s)> Hao P, Zheng H, Yu Y, Ding G, Gu W, Chen S, Yu Z, Ren S, Oda M, Konno T, Wang S, Li X, Ji ZS, Zhao G (- 4) Ref: PLoS ONE, 6:e15964, 2011 : PubMed ESTHER: Hao_2011_PLoS.ONE_6_E15964 PubMedSearch: Hao 2011 PLoS.ONE 6 E15964 PubMedID: 21264216 Gene_locus related to this paper: lacda-q1g8l1, lacdl-pip Abstract Lactobacillus delbrueckii subsp. bulgaricus (Lb. bulgaricus) is an important species of Lactic Acid Bacteria (LAB) used for cheese and yogurt fermentation. The genome of Lb. bulgaricus 2038, an industrial strain mainly used for yogurt production, was completely sequenced and compared against the other two ATCC collection strains of the same subspecies. Specific physiological properties of strain 2038, such as lysine biosynthesis, formate production, aspartate-related carbon-skeleton intermediate metabolism, unique EPS synthesis and efficient DNA restriction/modification systems, are all different from those of the collection strains that might benefit the industrial production of yogurt. Other common features shared by Lb. bulgaricus strains, such as efficient protocooperation with Streptococcus thermophilus and lactate production as well as well-equipped stress tolerance mechanisms may account for it being selected originally for yogurt fermentation industry. Multiple lines of evidence suggested that Lb. bulgaricus 2038 was genetically closer to the common ancestor of the subspecies than the other two sequenced collection strains, probably due to a strict industrial maintenance process for strain 2038 that might have halted its genome decay and sustained a gene network suitable for large scale yogurt production. Title: Complete genome sequence of Bacillus thuringiensis subsp. chinensis strain CT-43 He J, Wang J, Yin W, Shao X, Zheng H, Li M, Zhao Y, Sun M, Wang S, Yu Z Ref: Journal of Bacteriology, 193:3407, 2011 : PubMed ESTHER: He_2011_J.Bacteriol_193_3407 PubMedSearch: He 2011 J.Bacteriol 193 3407 PubMedID: 21551307 Gene_locus related to this paper: bacan-BA3703, bacan-BA5009, bacan-DHBF, bacce-BC0192, bacce-BC0968, bacce-BC1788, bacce-BC2141, bacce-BC4854, bacce-BC4862, bacce-PHAC, baccr-pepx Abstract Bacillus thuringiensis has been widely used as an agricultural biopesticide for a long time. As a producing strain, B. thuringiensis subsp. chinensis strain CT-43 is highly toxic to lepidopterous and dipterous insects. It can form various parasporal crystals consisting of Cry1Aa3, Cry1Ba1, Cry1Ia14, Cry2Aa9, and Cry2Ab1. During fermentation, it simultaneously generates vegetative insecticidal protein Vip3Aa10 and the insecticidal nucleotide analogue thuringiensin. Here, we report the finished, annotated genome sequence of B. thuringiensis strain CT-43. Title: Comparative genomic and transcriptomic analysis revealed genetic characteristics related to solvent formation and xylose utilization in Clostridium acetobutylicum EA 2018 Hu S, Zheng H, Gu Y, Zhao J, Zhang W, Yang Y, Wang S, Zhao G, Yang S, Jiang W Ref: BMC Genomics, 12:93, 2011 : PubMed ESTHER: Hu_2011_BMC.Genomics_12_93 PubMedSearch: Hu 2011 BMC.Genomics 12 93 PubMedID: 21284892 Gene_locus related to this paper: cloab-CAC2917, cloab-q97db4, cloac-CAC0719, cloac-CAC1022, cloac-CAC1962, cloac-CAC2246, cloac-CAC3407, cloac-CAP0071, cloac-pnbae Abstract BACKGROUND: Clostridium acetobutylicum, a gram-positive and spore-forming anaerobe, is a major strain for the fermentative production of acetone, butanol and ethanol. But a previously isolated hyper-butanol producing strain C. acetobutylicum EA 2018 does not produce spores and has greater capability of solvent production, especially for butanol, than the type strain C. acetobutylicum ATCC 824. Title: Draft genome sequence of the marine bacterium Streptomyces griseoaurantiacus M045, which produces novel manumycin-type antibiotics with a pABA core component Li F, Jiang P, Zheng H, Wang S, Zhao G, Qin S, Liu Z Ref: Journal of Bacteriology, 193:3417, 2011 : PubMed ESTHER: Li_2011_J.Bacteriol_193_3417 PubMedSearch: Li 2011 J.Bacteriol 193 3417 PubMedID: 21551298 Gene_locus related to this paper: 9acto-f3ngb7, 9acto-f3nim7, 9acto-f3ntg3, 9acto-f3nmw3, 9actn-f3nh76, 9actn-f3nh94 Abstract Streptomyces griseoaurantiacus M045, isolated from marine sediment, produces manumycin and chinikomycin antibiotics. Here we present a high-quality draft genome sequence of S. griseoaurantiacus M045, the first marine Streptomyces species to be sequenced and annotated. The genome encodes several gene clusters for biosynthesis of secondary metabolites and has provided insight into genomic islands linking secondary metabolism to functional adaptation in marine S. griseoaurantiacus M045. Title: The complete genome sequence of Mycoplasma bovis strain Hubei-1 Li Y, Zheng H, Liu Y, Jiang Y, Xin J, Chen W, Song Z Ref: PLoS ONE, 6:e20999, 2011 : PubMed ESTHER: Li_2011_PLoS.One_6_e20999 PubMedSearch: Li 2011 PLoS.One 6 e20999 PubMedID: 21731639 Abstract Infection by Mycoplasma bovis (M. bovis) can induce diseases, such as pneumonia and otitis media in young calves and mastitis and arthritis in older animals. Here, we report the finished and annotated genome sequence of M. bovis strain Hubei-1, a strain isolated in 2008 that caused calf pneumonia on a Chinese farm. The genome of M. bovis strain Hubei-1 contains a single circular chromosome of 953,114 bp with a 29.37% GC content. We identified 803 open reading frames (ORFs) that occupy 89.5% of the genome. While 34 ORFs were Hubei-1 specific, 662 ORFs had orthologs in the M. bovis type strain PG45 genome. Genome analysis validated lateral gene transfer between M. bovis and the Mycoplasma mycoides subspecies mycoides, while phylogenetic analysis found that the closest M. bovis neighbor is Mycoplasma agalactiae. Glycerol may be the main carbon and energy source of M. bovis, and most of the biosynthesis pathways were incomplete. We report that 47 lipoproteins, 12 extracellular proteins and 18 transmembrane proteins are phase-variable and may help M. bovis escape the immune response. Besides lipoproteins and phase-variable proteins, genomic analysis found two possible pathogenicity islands, which consist of four genes and 11 genes each, and several other virulence factors including hemolysin, lipoate protein ligase, dihydrolipoamide dehydrogenase, extracellular cysteine protease and 5'-nucleotidase. Title: Complete genome sequence of Haloarcula hispanica, a Model Haloarchaeon for studying genetics, metabolism, and virus-host interaction Liu H, Wu Z, Li M, Zhang F, Zheng H, Han J, Liu J, Zhou J, Wang S, Xiang H Ref: Journal of Bacteriology, 193:6086, 2011 : PubMed ESTHER: Liu_2011_J.Bacteriol_193_6086 PubMedSearch: Liu 2011 J.Bacteriol 193 6086 PubMedID: 21994921 Gene_locus related to this paper: halma-q5uym0 Abstract Haloarcula hispanica is an extremely halophilic archaeon that has an unusually low restriction barrier and is therefore significant for studying archaeal genetics, metabolism, and virus-host interactions. Here we report the complete genome sequence (3,890,005 bp) of H. hispanica strain CGMCC 1.2049, consisting of two chromosomes and one megaplasmid. Title: Manipulating the expression rate and enantioselectivity of an epoxide hydrolase by using directed evolution Reetz MT, Zheng H Ref: Chembiochem, 12:1529, 2011 : PubMed ESTHER: Reetz_2011_Chembiochem_12_1529 PubMedSearch: Reetz 2011 Chembiochem 12 1529 PubMedID: 21567703 Abstract We describe here a strategy to improve the expression efficiency and enantioselectivity of Aspergillus niger epoxide hydrolase (ANEH) by directed evolution. Based on a blue-colony screening system using the LacZalpha (beta-galactosidase alpha peptide) complementation solubility reporter, several ANEH variants out of 15 000 transformants from a random-mutagenesis library were identified that show improved recombinant expression in E. coli. Among them, Pro221Ser was subsequently used as a template for iterative saturation mutagenesis (ISM) at sites around the ANEH binding pocket. Following four rounds of ISM, a highly enantioselective mutant was identified that catalyzes the hydrolytic kinetic resolution of racemic glycidyl phenyl ether with a selectivity factor of E=160 in favor of the (S)-diol compared to WT ANEH characterized by E=4.6. Expression of this mutant is 50 times higher than that of WT ANEH. It also serves as an excellent stereoselective catalyst in the hydrolytic kinetic resolution and desymmetrization of several other structurally diverse epoxides. Title: Genome sequence of a porcine extraintestinal pathogenic Escherichia coli strain Tan C, Xu Z, Zheng H, Liu W, Tang X, Shou J, Wu B, Wang S, Zhao GP, Chen H Ref: Journal of Bacteriology, 193:5038, 2011 : PubMed ESTHER: Tan_2011_J.Bacteriol_193_5038 PubMedSearch: Tan 2011 J.Bacteriol 193 5038 PubMedID: 21742868 Gene_locus related to this paper: ecoli-IROD, ecoli-IROE, ecoli-ycfp, ecoli-YFBB, ecoli-ypt1, ecoli-yqia Abstract Extraintestinal pathogenic Escherichia coli (ExPEC) is an important pathogen which can infect humans and animals and cause many diseases outside the intestine. Here, we report the first draft genome sequence of a porcine ExPEC strain, PCN033, isolated from a pig with meningitis. Title: Genome sequence of the insect pathogenic fungus Cordyceps militaris, a valued traditional Chinese medicine Zheng P, Xia Y, Xiao G, Xiong C, Hu X, Zhang S, Zheng H, Huang Y, Zhou Y and Wang C <4 more author(s)> Zheng P, Xia Y, Xiao G, Xiong C, Hu X, Zhang S, Zheng H, Huang Y, Zhou Y, Wang S, Zhao GP, Liu X, St Leger RJ, Wang C (- 4) Ref: Genome Biol, 12:R116, 2011 : PubMed ESTHER: Zheng_2011_Genome.Biol_12_R116 PubMedSearch: Zheng 2011 Genome.Biol 12 R116 PubMedID: 22112802 Gene_locus related to this paper: cormm-g3jhe4, cormm-g3j5w5, cormm-g3jjs8, cormm-g3jj84, cormm-g3j580, cormm-g3jkl0, cormi-a0a2h4sj63, cormm-g3jpf2 Abstract BACKGROUND: Species in the ascomycete fungal genus Cordyceps have been proposed to be the teleomorphs of Metarhizium species. The latter have been widely used as insect biocontrol agents. Cordyceps species are highly prized for use in traditional Chinese medicines, but the genes responsible for biosynthesis of bioactive components, insect pathogenicity and the control of sexuality and fruiting have not been determined. Title: Comparative proteogenomic analysis of the Leptospira interrogans virulence-attenuated strain IPAV against the pathogenic strain 56601 Zhong Y, Chang X, Cao XJ, Zhang Y, Zheng H, Zhu Y, Cai C, Cui Z, Li YY and Guo XK <6 more author(s)> Zhong Y, Chang X, Cao XJ, Zhang Y, Zheng H, Zhu Y, Cai C, Cui Z, Li YY, Jiang XG, Zhao GP, Wang S, Li Y, Zeng R, Li X, Guo XK (- 6) Ref: Cell Res, 21:1210, 2011 : PubMed ESTHER: Zhong_2011_Cell.Res_21_1210 PubMedSearch: Zhong 2011 Cell.Res 21 1210 PubMedID: 21423275 Gene_locus related to this paper: lepin-q72tt9 Abstract The virulence-attenuated Leptospira interrogans serovar Lai strain IPAV was derived by prolonged laboratory passage from a highly virulent ancestral strain isolated in China. We studied the genetic variations of IPAV that render it avirulent via comparative analysis against the pathogenic L. interrogans serovar Lai strain 56601. The complete genome sequence of the IPAV strain was determined and used to compare with, and then rectify and reannotate the genome sequence of strain 56601. Aside from their highly similar genomic structure and gene order, a total of 33 insertions, 53 deletions and 301 single-nucleotide variations (SNVs) were detected throughout the genome of IPAV directly affecting 101 genes, either in their 5' upstream region or within their coding region. Among them, the majority of the 44 functional genes are involved in signal transduction, stress response, transmembrane transport and nitrogen metabolism. Comparative proteomic analysis based on quantitative liquid chromatography (LC)-MS/MS data revealed that among 1 627 selected pairs of orthologs, 174 genes in the IPAV strain were upregulated, with enrichment mainly in classes of energy production and lipid metabolism. In contrast, 228 genes in strain 56601 were upregulated, with the majority enriched in the categories of protein translation and DNA replication/repair. The combination of genomic and proteomic approaches illustrated that altered expression or mutations in critical genes, such as those encoding a Ser/Thr kinase, carbon-starvation protein CstA, glutamine synthetase, GTP-binding protein BipA, ribonucleotide-diphosphate reductase and phosphate transporter, and alterations in the translational profile of lipoproteins or outer membrane proteins are likely to account for the virulence attenuation in strain IPAV. Title: Complete genome sequence of Bacillus thuringiensis mutant strain BMB171 He J, Shao X, Zheng H, Li M, Wang J, Zhang Q, Li L, Liu Z, Sun M and Yu Z <1 more author(s)> He J, Shao X, Zheng H, Li M, Wang J, Zhang Q, Li L, Liu Z, Sun M, Wang S, Yu Z (- 1) Ref: Journal of Bacteriology, 192:4074, 2010 : PubMed ESTHER: He_2010_J.Bacteriol_192_4074 PubMedSearch: He 2010 J.Bacteriol 192 4074 PubMedID: 20525827 Gene_locus related to this paper: bacan-BA3703, bacan-DHBF, bacce-BC0192, bacce-BC0968, bacce-BC1677, bacce-BC1788, bacce-BC2141, bacce-BC2171, bacce-BC2456, bacce-BC2458, bacce-BC3133, bacce-BC4102, bacce-BC4854, bacce-BC4862, bacce-BC5130, bacce-PHAC, baccr-pepx Abstract Bacillus thuringiensis has been widely used as a biopesticide for a long time. Here we report the finished and annotated genome sequence of B. thuringiensis mutant strain BMB171, an acrystalliferous mutant strain with a high transformation frequency obtained and stocked in our laboratory. Title: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT Ref: Journal of Neuroscience, 30:2442, 2010 : PubMed ESTHER: Hernandez_2010_J.Neurosci_30_2442 PubMedSearch: Hernandez 2010 J.Neurosci 30 2442 PubMedID: 20164328 Abstract Early Alzheimer's disease (AD) is marked by cholinergic hypofunction, neuronal marker loss, and decreased nicotinic acetylcholine receptor (nAChR) density from the cortex and hippocampus. alpha7 nAChRs expressed on cholinergic projection neurons and target regions have been implicated in neuroprotection against beta-amyloid (Abeta) toxicity and maintenance of the septohippocampal phenotype. We tested the role that alpha7 nAChRs perform in the etiology of early AD by genetically deleting the alpha7 nAChR subunit from the Tg2576 mouse model for AD and assessing animals for cognitive function and septohippocampal integrity. Thus, Tg2576 mice transgenic for mutant human amyloid precursor protein (APP) were crossed with alpha7 nAChR knock-out mice (A7KO) to render an animal with elevated Abeta in the absence of alpha7 nAChRs (A7KO-APP). We found that learning and memory deficits seen in 5-month-old APP mice are more severe in the A7KO-APP animals. Analyses of animals in early-stage preplaque cognitive decline revealed signs of neurodegeneration in A7KO-APP hippocampus as well as loss of cholinergic functionality in the basal forebrain and hippocampus. These changes occurred concomitant with the appearance of a dodecameric oligomer of Abeta that was absent from all other genotypic groups, generating the hypothesis that increased soluble oligomeric Abeta may underlie additional impairment of A7KO-APP cognitive function. Thus, alpha7 nAChRs in a mouse model for early-stage AD appear to serve a neuroprotective role through maintenance of the septohippocampal cholinergic phenotype and preservation of hippocampal integrity possibly through influences on Abeta accumulation and oligomerization. Title: Optimization of lipase-catalyzed transesterification of lard for biodiesel production using response surface methodology Huang Y, Zheng H, Yan Y Ref: Appl Biochem Biotechnol, 160:504, 2010 : PubMed ESTHER: Huang_2010_Appl.Biochem.Biotechnol_160_504 PubMedSearch: Huang 2010 Appl.Biochem.Biotechnol 160 504 PubMedID: 18931953 Abstract Biodiesel, an alternative diesel fuel made from renewable biological resources, has become more and more attractive recently. Combined use of two immobilized lipases with complementary position specificity instead of one lipase is a potential way to significantly reduce cost of lipase-catalyzed biodiesel production. In this study, the process of biodiesel production from lard catalyzed by the combined use of Novozym435 (non-specific) and Lipozyme TLIM (1,3-specific) was optimized by response surface methodology. The optimal reaction conditions were 0.04 of amount of lipase/oil (w/w), 0.49 of proportion of Novozym435/total lipases (w/w), 0.55 of quantity of tert-butanol/oil (v/v), 5.12 of quantity of methanol/oil (mol/mol), and 20 h of reaction time, by which 97.2% of methyl ester (ME) yield was attained, very close to the predicted value (97.6%). This optimal reaction condition could be true of other similar reactions with plant and animal oil resources; their ME yield could be higher than 95%. The lipases regenerated by washing with organic solvent after each reaction cycle could be continuously reused for 20 cycles without any loss of activity, exhibiting very high manipulation stability. Title: The sequence and de novo assembly of the giant panda genome Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B and Yang H <103 more author(s)> Li R, Fan W, Tian G, Zhu H, He L, Cai J, Huang Q, Cai Q, Li B, Bai Y, Zhang Z, Zhang Y, Wang W, Li J, Wei F, Li H, Jian M, Nielsen R, Li D, Gu W, Yang Z, Xuan Z, Ryder OA, Leung FC, Zhou Y, Cao J, Sun X, Fu Y, Fang X, Guo X, Wang B, Hou R, Shen F, Mu B, Ni P, Lin R, Qian W, Wang G, Yu C, Nie W, Wang J, Wu Z, Liang H, Min J, Wu Q, Cheng S, Ruan J, Wang M, Shi Z, Wen M, Liu B, Ren X, Zheng H, Dong D, Cook K, Shan G, Zhang H, Kosiol C, Xie X, Lu Z, Li Y, Steiner CC, Lam TT, Lin S, Zhang Q, Li G, Tian J, Gong T, Liu H, Zhang D, Fang L, Ye C, Zhang J, Hu W, Xu A, Ren Y, Zhang G, Bruford MW, Li Q, Ma L, Guo Y, An N, Hu Y, Zheng Y, Shi Y, Li Z, Liu Q, Chen Y, Zhao J, Qu N, Zhao S, Tian F, Wang X, Wang H, Xu L, Liu X, Vinar T, Wang Y, Lam TW, Yiu SM, Liu S, Huang Y, Yang G, Jiang Z, Qin N, Li L, Bolund L, Kristiansen K, Wong GK, Olson M, Zhang X, Li S, Yang H (- 103) Ref: Nature, 463:311, 2010 : PubMed ESTHER: Li_2010_Nature_463_311 PubMedSearch: Li 2010 Nature 463 311 PubMedID: 20010809 Gene_locus related to this paper: ailme-ABH15, ailme-ACHE, ailme-BCHE, ailme-d2gtv3, ailme-d2gty9, ailme-d2gu87, ailme-d2gu97, ailme-d2gve7, ailme-d2gwu1, ailme-d2gx08, ailme-d2gyt0, ailme-d2gz36, ailme-d2gz37, ailme-d2gz38, ailme-d2gz39, ailme-d2gz40, ailme-d2h5r9, ailme-d2h7b7, ailme-d2h9c9, ailme-d2h794, ailme-d2hau7, ailme-d2hau8, ailme-d2hcd9, ailme-d2hdi6, ailme-d2heu6, ailme-d2hga4, ailme-d2hqw5, ailme-d2hs98, ailme-d2hsx4, ailme-d2hti6, ailme-d2htv3, ailme-d2htz6, ailme-d2huc7, ailme-d2hwj8, ailme-d2hwy7, ailme-d2hxm1, ailme-d2hyc8, ailme-d2hyv2, ailme-d2hz11, ailme-d2hza3, ailme-d2hzr4, ailme-d2i1l4, ailme-d2i2g8, ailme-g1l7m3, ailme-g1lu36, ailme-g1m769, ailme-g1mc29, ailme-g1mdj8, ailme-g1mdr5, ailme-g1mfp4, ailme-g1mfx5, ailme-g1lj41, ailme-g1lm28, ailme-g1l3u1, ailme-g1l7l1, ailme-g1m5i3, ailme-g1l2f6, ailme-g1lji5, ailme-g1lqk3, ailme-g1l8s9, ailme-d2h717, ailme-d2h718, ailme-d2h719, ailme-d2h720, ailme-g1m5v0, ailme-g1m5y7, ailme-g1lkt7, ailme-g1l2a1, ailme-g1lsc8, ailme-g1lrp4, ailme-d2gv02, ailme-g1mik5, ailme-g1ljr1, ailme-g1lxw7, ailme-d2h8b5, ailme-d2h2r2, ailme-d2h9w7, ailme-g1meh3, ailme-g1m719 Abstract Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes. Title: Complete genome sequence of Bifidobacterium longum JDM301 Wei YX, Zhang ZY, Liu C, Zhu YZ, Zhu YQ, Zheng H, Zhao GP, Wang S, Guo XK Ref: Journal of Bacteriology, 192:4076, 2010 : PubMed ESTHER: Wei_2010_J.Bacteriol_192_4076 PubMedSearch: Wei 2010 J.Bacteriol 192 4076 PubMedID: 20525832 Gene_locus related to this paper: biflj-d6zvy3, biflo-BL0073, biflo-BL0336, biflo-BL0581, biflo-BL0582, biflo-BL1109, biflo-BL1514, biflo-PTRB, bifln-c2gtr2 Abstract Bifidobacteria, known as probiotic bacteria, are high-G+C Gram-positive bacteria which naturally inhabit the human gastrointestinal tract and vagina. Recently, we completely sequenced Bifidobacterium longum JDM301, which is a widely used Chinese commercial strain with several probiotic properties. Title: Intracellular trafficking and synaptic function of APL-1 in Caenorhabditis elegans Wiese M, Antebi A, Zheng H Ref: PLoS ONE, 5:, 2010 : PubMed ESTHER: Wiese_2010_PLoS.One_5_ PubMedSearch: Wiese 2010 PLoS.One 5 PubMedID: 20862215 Abstract BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of beta-amyloid plaques in the brain. Plaques are composed of the amyloid-beta peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality. METHODOLOGY/PRINCIPAL FINDINGS: We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads to the retention of APL-1 in the cell body. CONCLUSIONS/SIGNIFICANCE: Our results reveal novel insights into the intracellular trafficking of APL-1 and we report a functional role for APL-1 in synaptic transmission. Title: Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism Zhao W, Zhong Y, Yuan H, Wang J, Zheng H, Wang Y, Cen X, Xu F, Bai J and Zhao GP <16 more author(s)> Zhao W, Zhong Y, Yuan H, Wang J, Zheng H, Wang Y, Cen X, Xu F, Bai J, Han X, Lu G, Zhu Y, Shao Z, Yan H, Li C, Peng N, Zhang Z, Zhang Y, Lin W, Fan Y, Qin Z, Hu Y, Zhu B, Wang S, Ding X, Zhao GP (- 16) Ref: Cell Res, 20:1096, 2010 : PubMed ESTHER: Zhao_2010_Cell.Res_20_1096 PubMedSearch: Zhao 2010 Cell.Res 20 1096 PubMedID: 20567260 Gene_locus related to this paper: amyme-ester, amymu-d8hj63, amymu-d8hka5, amymu-d8hl19, amymu-d8hp99, amymu-d8hpp2, amymu-d8htc9, amymu-d8hu68, amymu-d8hu87, amymu-d8hy40, amymu-d8hy73, amymu-d8i2j5, amymu-d8i4g6, amymu-d8i8i8, amymu-d8hri1, amymu-d8hsx7, amymu-d8hzu8, amymu-d8i5g7, amyms-g0g7f0, amymu-a0a0h3cwx4, amymu-a0a0h3d2a5, amymu-a0a0h3d6r8 Abstract Amycolatopsis mediterranei is used for industry-scale production of rifamycin, which plays a vital role in antimycobacterial therapy. As the first sequenced genome of the genus Amycolatopsis, the chromosome of strain U32 comprising 10,236,715 base pairs, is one of the largest prokaryotic genomes ever sequenced so far. Unlike the linear topology found in streptomycetes, this chromosome is circular, particularly similar to that of Saccharopolyspora erythraea and Nocardia farcinica, representing their close relationship in phylogeny and taxonomy. Although the predicted 9,228 protein-coding genes in the A. mediterranei genome shared the greatest number of orthologs with those of S. erythraea, it was unexpectedly followed by Streptomyces coelicolor rather than N. farcinica, indicating the distinct metabolic characteristics evolved via adaptation to diverse ecological niches. Besides a core region analogous to that common in streptomycetes, a novel 'quasi-core' with typical core characteristics is defined within the non-core region, where 21 out of the total 26 gene clusters for secondary metabolite production are located. The rifamycin biosynthesis gene cluster located in the core encodes a cytochrome P450 enzyme essential for the conversion of rifamycin SV to B, revealed by comparing to the highly homologous cluster of the rifamycin B-producing strain S699 and further confirmed by genetic complementation. The genomic information of A. mediterranei demonstrates a metabolic network orchestrated not only for extensive utilization of various carbon sources and inorganic nitrogen compounds but also for effective funneling of metabolic intermediates into the secondary antibiotic synthesis process under the control of a seemingly complex regulatory mechanism. Title: Manipulating the stereoselectivity of limonene epoxide hydrolase by directed evolution based on iterative saturation mutagenesis Zheng H, Reetz MT Ref: Journal of the American Chemical Society, 132:15744, 2010 : PubMed ESTHER: Zheng_2010_J.Am.Chem.Soc_132_15744 PubMedSearch: Zheng 2010 J.Am.Chem.Soc 132 15744 PubMedID: 20958062 Abstract Limonene epoxide hydrolase from Rhodococcus erythropolis DCL 14 (LEH) is known to be an exceptional epoxide hydrolase (EH) because it has an unusual secondary structure and catalyzes the hydrolysis of epoxides by a rare one-step mechanism in contrast to the usual two-step sequence. From a synthetic organic viewpoint it is unfortunate that LEH shows acceptable stereoselectivity essentially only in the hydrolysis of the natural substrate limonene epoxide, which means that this EH cannot be exploited as a catalyst in asymmetric transformations of other substrates. In the present study, directed evolution using iterative saturation mutagenesis (ISM) has been tested as a means to engineer LEH mutants showing broad substrate scope with high stereoselectivity. By grouping individual residues aligning the binding pocket correctly into randomization sites and performing saturation mutagenesis iteratively using a reduced amino acid alphabet, mutants were obtained which catalyze the desymmetrization of cyclopentene-oxide with stereoselective formation of either the (R,R)- or the (S,S)-diol on an optional basis. The mutants prove to be excellent catalysts for the desymmetrization of other meso-epoxides and for the hydrolytic kinetic resolution of racemic substrates, without performing new mutagenesis experiments. Since less than 5000 tranformants had to be screened for achieving these results, this study contributes to the generalization of ISM as a fast and reliable method for protein engineering. In order to explain some of the stereoselective consequences of the observed mutations, a simple model based on molecular dynamics simulations has been proposed. Title: Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy Zheng H, Youdim MB, Fridkin M Ref: ACS Chemical Biology, 5:603, 2010 : PubMed ESTHER: Zheng_2010_ACS.Chem.Biol_5_603 PubMedSearch: Zheng 2010 ACS.Chem.Biol 5 603 PubMedID: 20455574 Abstract Chelators have the potential to treat the underlying cause of Alzheimer's disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead 2 inhibited both AChE and MAO in vitro, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound 2 can be activated by inhibition of AChE to release an active chelator M30. M30 has been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound 2 was less cytotoxic and more lipophilic than the brain-permeable chelator M30. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson's disease and cancer where specific elimination of metals in cancer cells is required. Title: Site-activated chelators derived from anti-Parkinson drug rasagiline as a potential safer and more effective approach to the treatment of Alzheimer's disease Zheng H, Fridkin M, Youdim MB Ref: Neurochem Res, 35:2117, 2010 : PubMed ESTHER: Zheng_2010_Neurochem.Res_35_2117 PubMedSearch: Zheng 2010 Neurochem.Res 35 2117 PubMedID: 20981484 Inhibitor(s) related to this paper: M30D Abstract chelators can modulate beta-amyloid accumulation, protect against tau hyperphosphorylation, and block metal-related oxidative stress, and thereby hold considerable promise as effective anti-AD drugs. At present, a growing interest is focusing on increasing the efficacy and targeting of chelators through drug design. To this end, we have developed a new class of multifunctional prochelators from three FDA- approved drugs rasagiline, rivastigmine, and donepezil or tacrine. HLA20 A was designed by merging the important pharmacophores of rasagiline, rivastigmine, and donepezil into our newly developed multifunctional chelator HLA20. M30D was constructed using the key pharmacophoric moieties from rasagiline, rivastigmine, and tacrine. Experiments showed that both compounds possess potent anti-acetylcholinesterase (AChE) activity in vitro with weak inhibition of butyrylcholinesterase (BuChE), and without significant metal-binding activity. M30D was found also to be a highly potent MAO A inhibitor with moderate inhibition of MAO B in vitro. Both HLA20 and M30D can be activated by inhibition of AChE to release active chelators HLA20 and M30, respectively. HLA20 and M30 have been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compared with the activated chelator HLA20 or M30, both HLA20A and M30D exhibited lower cytotoxicity in SH-SY5Y neuroblastoma cells, substantiating the prochelator strategy for minimizing toxicity associated with poor targeted chelators. Title: Donepezil improves episodic memory in young individuals vulnerable to the effects of sleep deprivation Chuah LY, Chong DL, Chen AK, Rekshan WR, 3rd, Tan JC, Zheng H, Chee MW Ref: Sleep, 32:999, 2009 : PubMed ESTHER: Chuah_2009_Sleep_32_999 PubMedSearch: Chuah 2009 Sleep 32 999 PubMedID: 19725251 Abstract STUDY OBJECTIVES: We investigated if donepezil, a long-acting orally administered cholinesterase inhibitor, would reduce episodic memory deficits associated with 24 h of sleep deprivation. DESIGN: Double-blind, placebo-controlled, crossover study involving 7 laboratory visits over 2 months. Participants underwent 4 functional MRI scans; 2 sessions (donepezil or placebo) followed a normal night's sleep, and 2 sessions followed a night of sleep deprivation. SETTING: The study took place in a research laboratory. PARTICIPANTS: 26 young, healthy volunteers with no history of any sleep, psychiatric, or neurologic disorders. INTERVENTIONS: 5 mg of donepezil was taken once daily for approximately 17 days. MEASUREMENTS AND RESULTS: Subjects were scanned while performing a semantic judgment task and tested for word recognition outside the scanner 45 minutes later. Sleep deprivation increased the frequency of non-responses at encoding and impaired delayed recognition. No benefit of donepezil was evident when participants were well rested. When sleep deprived, individuals who showed greater performance decline improved with donepezil, whereas more resistant individuals did not benefit. Accompanying these behavioral effects, there was corresponding modulation of task-related activation in functionally relevant brain regions. Brain regions identified in relation to donepezil-induced alteration in non-response rates could be distinguished from regions relating to improved recognition memory. This suggests that donepezil can improve delayed recognition in sleep-deprived persons by improving attention as well as enhancing memory encoding. CONCLUSIONS: Donepezil reduced decline in recognition performance in individuals vulnerable to the effects of sleep deprivation. Additionally, our findings demonstrate the utility of combined fMRI-behavior evaluation in psychopharmacological studies. Title: The genome of the cucumber, Cucumis sativus L Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B and Du Y <77 more author(s)> Huang S, Li R, Zhang Z, Li L, Gu X, Fan W, Lucas WJ, Wang X, Xie B, Ni P, Ren Y, Zhu H, Li J, Lin K, Jin W, Fei Z, Li G, Staub J, Kilian A, van der Vossen EA, Wu Y, Guo J, He J, Jia Z, Tian G, Lu Y, Ruan J, Qian W, Wang M, Huang Q, Li B, Xuan Z, Cao J, Asan, Wu Z, Zhang J, Cai Q, Bai Y, Zhao B, Han Y, Li Y, Li X, Wang S, Shi Q, Liu S, Cho WK, Kim JY, Xu Y, Heller-Uszynska K, Miao H, Cheng Z, Zhang S, Wu J, Yang Y, Kang H, Li M, Liang H, Ren X, Shi Z, Wen M, Jian M, Yang H, Zhang G, Yang Z, Chen R, Ma L, Liu H, Zhou Y, Zhao J, Fang X, Fang L, Liu D, Zheng H, Zhang Y, Qin N, Li Z, Yang G, Yang S, Bolund L, Kristiansen K, Li S, Zhang X, Wang J, Sun R, Zhang B, Jiang S, Du Y (- 77) Ref: Nat Genet, 41:1275, 2009 : PubMed ESTHER: Huang_2009_Nat.Genet_41_1275 PubMedSearch: Huang 2009 Nat.Genet 41 1275 PubMedID: 19881527 Gene_locus related to this paper: cucsa-a0a0a0ktw5, cucsa-a0a0a0lnt6, cucsa-a0a0a0kpn7, cucsa-a0a0a0lvt9, cucsa-a0a0a0kdx8, cucsa-a0a0a0m228, cucsa-a0a0a0kz31, cucsa-a0a0a0k5t5, cucsa-a0a0a0kfs7, cucsa-a0a0a0kjj7, cucsa-a0a0a0kzs7, cucsa-a0a0a0l0a6, cucsa-a0a0a0l4w4, cucsa-a0a0a0lpz0, cucsa-a0a0a0ls66 Abstract Cucumber is an economically important crop as well as a model system for sex determination studies and plant vascular biology. Here we report the draft genome sequence of Cucumis sativus var. sativus L., assembled using a novel combination of traditional Sanger and next-generation Illumina GA sequencing technologies to obtain 72.2-fold genome coverage. The absence of recent whole-genome duplication, along with the presence of few tandem duplications, explains the small number of genes in the cucumber. Our study establishes that five of the cucumber's seven chromosomes arose from fusions of ten ancestral chromosomes after divergence from Cucumis melo. The sequenced cucumber genome affords insight into traits such as its sex expression, disease resistance, biosynthesis of cucurbitacin and 'fresh green' odor. We also identify 686 gene clusters related to phloem function. The cucumber genome provides a valuable resource for developing elite cultivars and for studying the evolution and function of the plant vascular system. Title: The complete genome of Comamonas testosteroni reveals its genetic adaptations to changing environments Ma YF, Zhang Y, Zhang JY, Chen DW, Zhu Y, Zheng H, Wang SY, Jiang CY, Zhao GP, Liu SJ Ref: Applied Environmental Microbiology, 75:6812, 2009 : PubMed ESTHER: Ma_2009_Appl.Environ.Microbiol_75_6812 PubMedSearch: Ma 2009 Appl.Environ.Microbiol 75 6812 PubMedID: 19734336 Gene_locus related to this paper: comt2-d0iwv3, comt2-d0iyk2, comt2-d0izv6, comt2-d0j1z3, comt2-d0j233, comte-b7wt77, comte-b7wvy1, comte-b7wwl1, comte-b7wz02, comte-b7x0f1, comte-b7x2b9, comte-b7x5l7, comte-d8d555, comte-TESD, comte-b7wth6, comt2-d0j2k4 Abstract Members of the gram-negative, strictly aerobic genus Comamonas occur in various environments. Here we report the complete genome of Comamonas testosteroni strain CNB-2. Strain CNB-2 has a circular chromosome that is 5,373,643 bp long and has a G+C content of 61.4%. A total of 4,803 open reading frames (ORFs) were identified; 3,514 of these ORFs are functionally assigned to energy production, cell growth, signal transduction, or transportation, while 866 ORFs encode hypothetical proteins and 423 ORFs encode purely hypothetical proteins. The CNB-2 genome has many genes for transportation (22%) and signal transduction (6%), which allows the cells to respond and adapt to changing environments. Strain CNB-2 does not assimilate carbohydrates due to the lack of genes encoding proteins involved in glycolysis and pentose phosphate pathways, and it contains many genes encoding proteins involved in degradation of aromatic compounds. We identified 66 Tct and nine TRAP-T systems and a complete tricarboxylic acid cycle, which may allow CNB-2 to take up and metabolize a range of carboxylic acids. This nutritional bias for carboxylic acids and aromatic compounds enables strain CNB-2 to occupy unique niches in environments. Four different sets of terminal oxidases for the respiratory system were identified, and they putatively functioned at different oxygen concentrations. This study conclusively revealed at the genomic level that the genetic versatility of C. testosteroni is vital for competition with other bacteria in its special niches. Title: Clinicopathologic features between multicentric occurence and intrahepatic metastasis of multiple hepatocellular carcinomas related to HBV Wang J, Li Q, Sun Y, Zheng H, Cui Y, Li H, Zhou H, Hao X Ref: Surg Oncol, 18:25, 2009 : PubMed ESTHER: Wang_2009_Surg.Oncol_18_25 PubMedSearch: Wang 2009 Surg.Oncol 18 25 PubMedID: 18640032 Abstract AIMS: To clarify the incidence of multicentric occurrence (MO) and intrahepatic metastasis (IM) for hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) in China and to identify the differences between them. PATIENTS AND METHODS: Histopathologic features of multiple tumors in 82 cases with HCC were analyzed. The two groups, the origin was determinable as of multicentric occurrence or as of intrahepatic metastasis, were analyzed for their survival rate, disease-free survival and clinicopathologic differences. RESULTS: According to histological findings, 19.5% and 69.5% patients were considered to be MO and IM, respectively. In total 73 cases from the histopathological method were selected and divided into group MO (16 cases) and the group IM (57 cases). Analysis of stepwise regression identified that: Child's stage, cholinesterase (host factors), tumor size, histological grade and positive portal vein invasion (tumor factors) were the most important discriminating factors between MO and IM (p<0.05). As for their prognosis, Kaplan-Meier and Log rank test showed the survival rate in group MO was significantly better than that in the group IM (p=0.003). No statistical significance was found between the disease-free survival in group MO and that in group IM (p=0.141). The analysis of Cox's proportional hazards model showed that tumor type (MO or IM) and Child's stage were the important prognostic factors (p=0.002 and 0.014, respectively). CONCLUSIONS: The incidence of MO in patients with multiple HCCs related to HBV is only about 20%, which is lower than that of Japan. Child's stage, cholinesterase (host factors), tumor size, histological grade and positive portal vein invasion (tumor factors) are the most important discriminating factors between MO and IM. The prognosis of patients with MO compared to IM is significantly better and tumor type (MO or IM) and Child's stage are important prognostic factors. Title: Genome sequence of the versatile fish pathogen Edwardsiella tarda provides insights into its adaptation to broad host ranges and intracellular niches Wang Q, Yang M, Xiao J, Wu H, Wang X, Lv Y, Xu L, Zheng H, Wang S and Zhang Y <2 more author(s)> Wang Q, Yang M, Xiao J, Wu H, Wang X, Lv Y, Xu L, Zheng H, Wang S, Zhao G, Liu Q, Zhang Y (- 2) Ref: PLoS ONE, 4:e7646, 2009 : PubMed ESTHER: Wang_2009_PLoS.ONE_4_E7646 PubMedSearch: Wang 2009 PLoS.ONE 4 E7646 PubMedID: 19865481 Gene_locus related to this paper: edwte-d0zav8, edwte-d0zg19, edwtf-e0t1p5, edwte-d0za01, edwte-d0z9v1 Abstract BACKGROUND: Edwardsiella tarda is the etiologic agent of edwardsiellosis, a devastating fish disease prevailing in worldwide aquaculture industries. Here we describe the complete genome of E. tarda, EIB202, a highly virulent and multi-drug resistant isolate in China. METHODOLOGY/PRINCIPAL FINDINGS: E. tarda EIB202 possesses a single chromosome of 3,760,463 base pairs containing 3,486 predicted protein coding sequences, 8 ribosomal rRNA operons, and 95 tRNA genes, and a 43,703 bp conjugative plasmid harboring multi-drug resistant determinants and encoding type IV A secretion system components. We identified a full spectrum of genetic properties related to its genome plasticity such as repeated sequences, insertion sequences, phage-like proteins, integrases, recombinases and genomic islands. In addition, analysis also indicated that a substantial proportion of the E. tarda genome might be devoted to the growth and survival under diverse conditions including intracellular niches, with a large number of aerobic or anaerobic respiration-associated proteins, signal transduction proteins as well as proteins involved in various stress adaptations. A pool of genes for secretion systems, pili formation, nonfimbrial adhesions, invasions and hemagglutinins, chondroitinases, hemolysins, iron scavenging systems as well as the incomplete flagellar biogenesis might feature its surface structures and pathogenesis in a fish body. CONCLUSION/SIGNIFICANCE: Genomic analysis of the bacterium offered insights into the phylogeny, metabolism, drug-resistance, stress adaptation, and virulence characteristics of this versatile pathogen, which constitutes an important first step in understanding the pathogenesis of E. tarda to facilitate construction of a practical effective vaccine used for combating fish edwardsiellosis. Title: Clinical, experimental, and genomic differences between intermediately pathogenic, highly pathogenic, and epidemic Streptococcus suis Ye C, Zheng H, Zhang J, Jing H, Wang L, Xiong Y, Wang W, Zhou Z, Sun Q and Xu J <3 more author(s)> Ye C, Zheng H, Zhang J, Jing H, Wang L, Xiong Y, Wang W, Zhou Z, Sun Q, Luo X, Du H, Gottschalk M, Xu J (- 3) Ref: J Infect Dis, 199:97, 2009 : PubMed ESTHER: Ye_2009_J.Infect.Dis_199_97 PubMedSearch: Ye 2009 J.Infect.Dis 199 97 PubMedID: 19016627 Gene_locus related to this paper: strsu-a4vws4, strsu-q673u2, strsy-a4vus4 Abstract BACKGROUND: Streptococcus suis emerged to cause an unusual outbreak of streptococcal toxic-shock-like syndrome (STSLS) in 2005. The mechanisms involved are unknown. METHODS: Clinical, laboratory, and epidemiologic data on patients infected with culture-confirmed S. suis were analyzed. The strain involved in the outbreak, "epidemic" strain ST7, was compared with both a classical highly pathogenic strain, ST1, and an intermediately pathogenic strain, ST25, to determine both its capacity to induce cytokines in experimentally infected mice and its genomic difference. RESULTS: Of 38 patients infected with culture-confirmed S. suis, 14 presented with STSLS. During the early phase of the disease, serum levels of interleukin (IL)-1beta, IL-6, IL-8, IL-12p70, interferon-gamma, and tumor necrosis factor-alpha were more elevated in patients with STSLS than in those with meningitis only. Serum levels of proinflammatory cytokines were significantly higher in mice infected with ST7 than in those infected with either ST1 or ST25. Genomic comparisons with ST25 showed that ST1 had acquired 132 genomic islands, including 5 pathogenicity islands, and that ST7, the epidemic strain, had acquired an additional 5 genomic islands. CONCLUSION: Intermediately pathogenic strain ST25 has evolved to become highly pathogenic strain ST1, which, in turn, has more recently evolved to become epidemic strain ST7. ST7 has the ability to stimulate the production of massive amounts of proinflammatory cytokines, leading to STSLS. Title: Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer's therapy Zheng H, Youdim MB, Fridkin M Ref: Journal of Medicinal Chemistry, 52:4095, 2009 : PubMed ESTHER: Zheng_2009_J.Med.Chem_52_4095 PubMedSearch: Zheng 2009 J.Med.Chem 52 4095 PubMedID: 19485411 Abstract A novel strategy to develop site-activated multifunctional chelators for targeting multiple etiologies of Alzheimer's disease is reported. The novel prochelator HLA20A with improved cytotoxicity shows little affinity for metal ions until it is activated by binding and inhibiting acetylcholinesterase (AChE), releasing an active chelator HLA20 that modulates amyloid precursor protein (APP) regulation and beta-amyloid (Abeta) reduction, suppresses oxidative stress, and passivates excess metal ions (Fe, Cu, and Zn) in the brain. Title: Dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia exhibits activity against a substrate containing a 4-hydroxyproline residue Nakajima Y, Ito K, Toshima T, Egawa T, Zheng H, Oyama H, Wu YF, Takahashi E, Kyono K, Yoshimoto T Ref: Journal of Bacteriology, 190:7819, 2008 : PubMed ESTHER: Nakajima_2008_J.Bacteriol_190_7819 PubMedSearch: Nakajima 2008 J.Bacteriol 190 7819 PubMedID: 18820015 Gene_locus related to this paper: xanma-P95782 Abstract The crystal structure of dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia was determined at 2.8-A resolution by the multiple isomorphous replacement method, using platinum and selenomethionine derivatives. The crystals belong to space group P4(3)2(1)2, with unit cell parameters a = b = 105.9 A and c = 161.9 A. Dipeptidyl aminopeptidase IV is a homodimer, and the subunit structure is composed of two domains, namely, N-terminal beta-propeller and C-terminal catalytic domains. At the active site, a hydrophobic pocket to accommodate a proline residue of the substrate is conserved as well as those of mammalian enzymes. Stenotrophomonas dipeptidyl aminopeptidase IV exhibited activity toward a substrate containing a 4-hydroxyproline residue at the second position from the N terminus. In the Stenotrophomonas enzyme, one of the residues composing the hydrophobic pocket at the active site is changed to Asn611 from the corresponding residue of Tyr631 in the porcine enzyme, which showed very low activity against the substrate containing 4-hydroxyproline. The N611Y mutant enzyme was generated by site-directed mutagenesis. The activity of this mutant enzyme toward a substrate containing 4-hydroxyproline decreased to 30.6% of that of the wild-type enzyme. Accordingly, it was considered that Asn611 would be one of the major factors involved in the recognition of substrates containing 4-hydroxyproline. Title: Novel inhibitor for prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis and details of substrate-recognition mechanism Xu Y, Nakajima Y, Ito K, Zheng H, Oyama H, Heiser U, Hoffmann T, Gartner UT, Demuth HU, Yoshimoto T Ref: Journal of Molecular Biology, 375:708, 2008 : PubMed ESTHER: Xu_2008_J.Mol.Biol_375_708 PubMedSearch: Xu 2008 J.Mol.Biol 375 708 PubMedID: 18042490 Gene_locus related to this paper: porgi-q7muw6 Inhibitor(s) related to this paper: Alanyl-Isoleucyl-pyrrolidin-boronic-acid Abstract A new inhibitor, H-Ala-Ile-pyrrolidin-2-yl boronic acid, was developed as an inhibitor against prolyl tripeptidyl aminopeptidase with a K(i) value of 88.1 nM. The structure of the prolyl tripeptidyl aminopeptidase complexed with the inhibitor (enzyme-inhibitor complex) was determined at 2.2 A resolution. The inhibitor was bound to the active site through a covalent bond between Ser603 and the boron atom of the inhibitor. This structure should closely mimic the structure of the reaction intermediate between the enzyme and substrate. We previously proposed that two glutamate residues, Glu205 and Glu636, are involved in the recognition of substrates. In order to clarify the function of these glutamate residues in substrate recognition, three mutant enzymes, E205A, E205Q, and E636A were generated by site-directed mutagenesis. The E205A mutant was expressed as an inclusion body. The E205Q mutant was expressed in soluble form, but no activity was detected. Here, the structures of the E636A mutant and its complex with the inhibitor were determined. The inhibitor was located at almost the same position as in the wild-type enzyme-inhibitor complex. The amino group of the inhibitor interacted with Glu205 and the main-chain carbonyl group of Gln203. In addition, a water molecule in the place of Glu636 of the wild-type enzyme interacted with the amino group of the inhibitor. This water molecule was located near the position of Glu636 in the wild-type and formed a hydrogen bond with Gln203. The k(cat)/K(M) values of the E636A mutant toward the two substrates used were smaller than those of the wild-type by two orders of magnitude. The K(i) value of our inhibitor for the E636A mutant was 48.8 microM, which was 554-fold higher than that against the wild-type enzyme. Consequently, it was concluded that Glu205 and Glu636 are significant residues for the N-terminal recognition of a substrate. Title: Genome biology of Actinobacillus pleuropneumoniae JL03, an isolate of serotype 3 prevalent in China Xu Z, Zhou Y, Li L, Zhou R, Xiao S, Wan Y, Zhang S, Wang K, Li W and Chen H <16 more author(s)> Xu Z, Zhou Y, Li L, Zhou R, Xiao S, Wan Y, Zhang S, Wang K, Li W, Jin H, Kang M, Dalai B, Li T, Liu L, Cheng Y, Zhang L, Xu T, Zheng H, Pu S, Wang B, Gu W, Zhang XL, Zhu GF, Wang S, Zhao GP, Chen H (- 16) Ref: PLoS ONE, 3:e1450, 2008 : PubMed ESTHER: Xu_2008_PLoS.ONE_3_E1450 PubMedSearch: Xu 2008 PLoS.ONE 3 E1450 PubMedID: 18197260 Gene_locus related to this paper: actp2-a3n347, actp7-b3h2v1, actp7-b3h2x2, actpj-b0bpm3, actpj-b0bqd8 Abstract Actinobacillus pleuropneumoniae is the etiologic agent of porcine contagious pleuropneumonia, a cause of considerable world wide economic losses in the swine industry. We sequenced the complete genome of A. pleuropneumoniae, JL03, an isolate of serotype 3 prevalent in China. Its genome is a single chromosome of 2,242,062 base pairs containing 2,097 predicted protein-coding sequences, six ribosomal rRNA operons, and 63 tRNA genes. Preliminary analysis of the genomic sequence and the functions of the encoded proteins not only confirmed the present physiological and pathological knowledge but also offered new insights into the metabolic and virulence characteristics of this important pathogen. We identified a full spectrum of genes related to its characteristic chemoheterotrophic catabolism of fermentation and respiration with an incomplete TCA system for anabolism. In addition to confirming the lack of ApxI toxin, identification of a nonsense mutation in apxIVA and a 5'-proximal truncation of the flp operon deleting both its promoter and the flp1flp2tadV genes have provided convincing scenarios for the low virulence property of JL03. Comparative genomic analysis using the available sequences of other serotypes, probable strain (serotype)-specific genomic islands related to capsular polysaccharides and lipopolysaccharide O-antigen biosyntheses were identified in JL03, which provides a foundation for future research into the mechanisms of serotypic diversity of A. pleuropneumoniae. Title: Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases Youdim MB, Fridkin M, Zheng H Ref: Mech Ageing Dev, 126:317, 2005 : PubMed ESTHER: Youdim_2005_Mech.Ageing.Dev_126_317 PubMedSearch: Youdim 2005 Mech.Ageing.Dev 126 317 PubMedID: 15621213 Inhibitor(s) related to this paper: Ladostigil Abstract Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions. Title: The Genomes of Oryza sativa: a history of duplications Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S and Yang H <88 more author(s)> Yu J, Wang J, Lin W, Li S, Li H, Zhou J, Ni P, Dong W, Hu S, Zeng C, Zhang J, Zhang Y, Li R, Xu Z, Li X, Zheng H, Cong L, Lin L, Yin J, Geng J, Li G, Shi J, Liu J, Lv H, Li J, Deng Y, Ran L, Shi X, Wang X, Wu Q, Li C, Ren X, Li D, Liu D, Zhang X, Ji Z, Zhao W, Sun Y, Zhang Z, Bao J, Han Y, Dong L, Ji J, Chen P, Wu S, Xiao Y, Bu D, Tan J, Yang L, Ye C, Xu J, Zhou Y, Yu Y, Zhang B, Zhuang S, Wei H, Liu B, Lei M, Yu H, Li Y, Xu H, Wei S, He X, Fang L, Huang X, Su Z, Tong W, Tong Z, Ye J, Wang L, Lei T, Chen C, Chen H, Huang H, Zhang F, Li N, Zhao C, Huang Y, Li L, Xi Y, Qi Q, Li W, Hu W, Tian X, Jiao Y, Liang X, Jin J, Gao L, Zheng W, Hao B, Liu S, Wang W, Yuan L, Cao M, McDermott J, Samudrala R, Wong GK, Yang H (- 88) Ref: PLoS Biol, 3:e38, 2005 : PubMed ESTHER: Yu_2005_PLoS.Biol_3_e38 PubMedSearch: Yu 2005 PLoS.Biol 3 e38 PubMedID: 15685292 Gene_locus related to this paper: orysa-Q7XTC5, orysa-Q852M6, orysa-Q8GSE8, orysa-Q9S7P1, orysa-Q9FYP7, orysa-Q5ZBH3, orysa-Q5ZA26, orysa-Q5JLP6, orysa-Q8H5P9, orysa-Q8H5P5, orysa-Q7F1Y5, orysa-Q949C9, orysa-cbp1, orysa-cbp3, orysa-cbpx, orysa-Q33B71, orysa-Q8GSJ3, orysa-LPL1, orysa-Q6YSZ8, orysa-Q8S5X5, orysa-Q8LIG3, orysa-Q6K7F5, orysa-Q7F1B1, orysa-Q8H4S9, orysa-Q69UB1, orysa-Q9FW17, orysa-Q337C3, orysa-Q7F959, orysa-Q84QZ6, orysa-Q84QY7, orysa-Q851E3, orysa-Q6YTH5, orysa-Q0JK71, orysa-Q8S1D9, orysa-Q5N8V4, orysa-Q0JCY4, orysa-Q8GTK2, orysa-B9EWJ8, orysa-Q8H3K6, orysa-Q6ZDG8, orysa-Q6ZDG6, orysa-Q6ZDG5, orysa-Q6ZDG4, orysa-Q5NAI4, orysa-Q658B2, orysa-Q5JMQ8, orysa-Q5QMD9, orysa-Q5N7L1, orysa-Q8RYV9, orysa-Q8H3R3, orysa-Q5SNH3, orysa-Q8W0F0, orysa-pir7a, orysa-pir7b, orysa-q2qlm4, orysa-q2qm78, orysa-q2qm82, orysa-q2qn31, orysa-q2qnj4, orysa-q2qnt9, orysa-q2qur1, orysa-q2qx94, orysa-q2qyi1, orysa-q2qyj1, orysa-q2r051, orysa-q2r077, orysa-q2ram0, orysa-q2rat1, orysa-q2rbb3, orysa-Q4VWY7, orysa-q5na00, orysa-q5nbu1, orysa-Q5QLC0, orysa-q5smv5, orysa-Q5VP27, orysa-q5vrt2, orysa-q5w6c5, orysa-q5z5a3, orysa-q5z9i2, orysa-q5z417, orysa-q5z901, orysa-Q5ZAM8, orysa-Q5ZBI5, orysa-Q5ZCR3, orysa-q6atz0, orysa-q6ave2, orysa-q6f358, orysa-q6h6s1, orysa-q6h7i6, orysa-q6i5q3, orysa-q6i5u7, orysa-q6j657, orysa-q6k3d9, orysa-q6k4q2, orysa-q6k880, orysa-q6l5b6, orysa-Q6L5F5, orysa-q6l556, orysj-q6yse8, orysa-q6yy42, orysa-q6yzk1, orysa-q6z8b1, orysa-q6z995, orysa-q6zc62, orysa-q6zia4, orysa-q6zjq6, orysa-q7x7y5, orysa-Q7XC50, orysa-q7xej4, orysa-q7xem8, orysa-q7xkj9, orysa-q7xr62, orysa-q7xr63, orysa-q7xr64, orysa-q7xsg1, orysa-q7xsq2, orysa-q7xts6, orysa-q7xv53, orysa-Q7XVB5, orysa-Q8L562, orysa-Q8LQS5, orysa-Q8RZ40, orysa-Q8RZ79, orysa-Q8S0U8, orysa-Q8S0V0, orysa-Q8S125, orysa-Q8SAY7, orysa-Q8SAY9, orysa-Q8W3C6, orysa-Q8W3F2, orysa-Q8W3F4, orysa-Q8W3F6, orysa-Q9LHX5, orysa-q33aq0, orysa-q53lh1, orysa-q53m20, orysa-q53nd8, orysa-q60e79, orysa-q60ew8, orysa-q67iz2, orysa-q67iz3, orysa-q67iz7, orysa-q67iz8, orysa-q67j02, orysa-q67j05, orysa-q67j07, orysa-q67j09, orysa-q67j10, orysa-q67tr6, orysa-q67tv0, orysa-q67uz1, orysa-q67v34, orysa-q67wz5, orysa-q69j38, orysa-q69k08, orysa-q69md7, orysa-q69me0, orysa-q69pf3, orysa-q69ti3, orysa-q69xr2, orysa-q69y12, orysa-q69y21, orysa-q75hy2, orysa-q75i01, orysa-Q94JD7, orysa-Q0J0A4, orysa-q651a8, orysa-q651z3, orysa-q652g4, orysa-q688m0, orysa-q688m8, orysa-q688m9, orysa-Q6H8G1, orysi-a2wn01, orysi-a2xc83, orysi-a2yh83, orysi-a2z179, orysi-a2zef2, orysi-b8a7e6, orysi-b8a7e7, orysi-b8bfe5, orysi-b8bhp9, orysj-a3b9l8, orysj-b9eub8, orysj-b9eya5, orysj-b9fi05, orysj-b9fkb0, orysj-b9fn42, orysj-b9gbb7, orysj-cgep, orysj-PLA7, orysj-q0d4u5, orysj-q0djj0, orysj-q0jaf0, orysj-q5jl22, orysj-q5jlw7, orysj-q5z419, orysj-q6h7q9, orysj-q6yvk6, orysj-q6z6i1, orysj-q7f8x1, orysj-q7xcx3, orysj-q9fwm6, orysj-q10j20, orysj-q10ss2, orysj-q69uw6, orysj-q94d71, orysj-q338c0, orysi-b8bly4, orysj-b9gbs4, orysi-a2zb88, orysj-b9gbs1, orysi-b8b698, orysj-pla4, orysj-pla1 Abstract We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000-40,000. Only 2%-3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family. Title: Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis Wang R, Dineley KT, Sweatt JD, Zheng H Ref: Neuroscience, 126:305, 2004 : PubMed ESTHER: Wang_2004_Neurosci_126_305 PubMedSearch: Wang 2004 Neurosci 126 305 PubMedID: 15207348 Abstract Alzheimer's disease is a learning and memory disorder pathologically characterized by the deposition of beta-amyloid plaques and loss of neurons and synapses in affected areas of the brain. Mutations in presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD), and are associated with accelerated plaque deposition. However, since the function of PS1 is pleiotropic, we reasoned that the FAD mutations may alter multiple PS1-mediated pathways, and the combination of which may account for the early onset nature of the disease phenotype. Using the PS1M146V knockin mice in which the M146V mutation was incorporated into the endogenous mouse PS1 gene, we report here that the FAD mutation results in impaired hippocampus-dependent associative learning, as measured by a contextual fear conditioning paradigm, at 3 months of age. This is correlated with reduced adult neurogenesis in the dentate gyrus. However, short-term and long-term synaptic plasticity in both area CA1 and dentate gyrus are not affected. Our results suggest that impaired adult neurogenesis may contribute to the memory deficit associated with FAD. Title: Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins Dineley KT, Xia X, Bui D, Sweatt JD, Zheng H Ref: Journal of Biological Chemistry, 277:22768, 2002 : PubMed ESTHER: Dineley_2002_J.Biol.Chem_277_22768 PubMedSearch: Dineley 2002 J.Biol.Chem 277 22768 PubMedID: 11912199 Abstract Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated beta-amyloid, beta-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when beta-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated alpha 7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for beta-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of alpha 7 nicotinic receptors. | |||||||
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