Author Report for: Fu YNo contact information in database for Fu Y
Huang Y, Li H, Wang Z, Fu Y, Chen Y, Wang X Ref: Food Chem, 429:136943, 2023 : PubMed ESTHER: Huang_2023_Food.Chem_429_136943 PubMedSearch: Huang 2023 Food.Chem 429 136943 PubMedID: 37517224 Abstract While branched-chain fatty acids (BCFA)-enriched triacylglycerols (TAG) has various health benefits, its preparation has not been reported. This study aimed to synthesize high-purity BCFA-enriched structured TAG. First, BCFA was enriched from lanolin through saponification, calcification, and urea complexation. Next, BCFA-enriched TAG was synthesized by enzymatic esterification of BCFA and glycerol. Then, lipases were screened by molecular docking and practical experiments, which suggested that Lipozyme 435 was the best lipase for esterification since it had the lowest binding energy. Structured TAG containing 92.23% BCFA was synthesized under conditions optimized by single-factor experiments. Furthermore, molecular distillation was adapted to remove excess fatty acids and small molecule impurities. Finally, high-purity BCFA-enriched structured lipid containing 70.26% TAG was obtained. Overall, this study successfully developed a method for synthesizing BCFA-enriched structured TAG, which holds great promise for applications in value-added foods. Title: The phospholipase effector Tle1(Vc) promotes Vibrio cholerae virulence by killing competitors and impacting gene expression Liu M, Wang H, Liu Y, Tian M, Wang Z, Shu RD, Zhao MY, Chen WD, Fu Y Ref: Gut Microbes, 15:2241204, 2023 : PubMed ESTHER: Liu_2023_Gut.Microbes_15_2241204 PubMedSearch: Liu 2023 Gut.Microbes 15 2241204 PubMedID: 37526354 Abstract Vibrio cholerae utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner. However, the impact of T6SS and its secreted effectors on physiological behavior remains poorly understood. In this study, we present Tle1(Vc), a phospholipase effector in atypical pathogenic V. cholerae E1 that is secreted by T6SS via its interaction with VgrG1(E1). Tle1(Vc) contains a DUF2235 domain and belongs to the Tle1 (type VI lipase effector) family. Bacterial toxicity assays, lipase activity assays and site-directed mutagenesis revealed that Tle1(Vc) possessed phospholipase A(1) activity and phospholipase A(2) activity, and that Tle1(Vc)-induced toxicity required a serine residue (S356) and two aspartic acid residues (D417 and D496). Cells intoxication with Tle1(Vc) lead to membrane depolarization and alter membrane permeability. Tli1(tox-), a cognate immunity protein, directly interacts with Tle1(Vc) to neutralize its toxicity. Moreover, Tle1(Vc) can kill multiple microorganisms by T6SS and promote in vivo fitness of V. cholerae through mediating antibacterial activity. Tle1(Vc) induces bacterial motility by increasing the expression of flagellar-related genes independently of functional T6SS and the tit-for-tat (TFT) response, where Pseudomonas aeruginosa uses its T6SS-H1 cluster to counterattack other offensive attackers. Our study also demonstrated that the physical puncture of E1 T6SS can induce a moderate TFT response, which is essential to the Tle1(Vc)-mediated strong TFT response, maximizing effector functions. Overall, our study characterized the antibacterial mechanism of phospholipase effector Tle1(Vc) and its multiple physiological significance. Title: How Closely Does Induced Agarwood's Biological Activity Resemble That of Wild Agarwood? Ma S, Huang M, Fu Y, Qiao M, Li Y Ref: Molecules, 28:, 2023 : PubMed ESTHER: Ma_2023_Molecules_28_ PubMedSearch: Ma 2023 Molecules 28 PubMedID: 37049682 Abstract Continuous innovation in artificially-induced agarwood technology is increasing the amount of agarwood and substantially alleviating shortages. Agarwood is widely utilized in perfumes and fragrances; however, it is unclear whether the overall pharmacological activity of induced agarwood can replace wild agarwood for medicinal use. In this study, the volatile components, total chromone content, and the differences in the overall activities of wild agarwood and induced agarwood, including the antioxidant, anti-acetylcholinesterase, and anti-glucosidase activity were all determined. The results indicated that both induced and wild agarwood's chemical makeup contains sesquiterpenes and 2-(2-phenylethyl)chromones. The total chromone content in generated agarwood can reach 82.96% of that in wild agarwood. Induced agarwood scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)) radicals and inhibited acetylcholinesterase activity and alpha-glucosidase activity with IC(50) values of 0.1873 mg/mL, 0.0602 mg/mL, 0.0493 mg/mL, and 0.2119 mg/mL, respectively, reaching 80.89%, 93.52%, 93.52%, and 69.47% of that of wild agarwood, respectively. Accordingly, the results distinguished that induced agarwood has the potential to replace wild agarwood in future for use in medicine because it has a similar chemical makeup to wild agarwood and has comparable antioxidant, anti-acetylcholinesterase, and anti-glucosidase capabilities. Title: Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain Du F, Cao R, Chen L, Sun J, Shi Y, Fu Y, Hammock BD, Zheng Z, Liu Z, Chen G Ref: Acta Pharm Sin B, 12:1377, 2022 : PubMed ESTHER: Du_2022_Acta.Pharm.Sin.B_12_1377 PubMedSearch: Du 2022 Acta.Pharm.Sin.B 12 1377 PubMedID: 35530144 Inhibitor(s) related to this paper: EC5026 Abstract Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (+/-)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain. Title: Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis Fu Y, Zhao D, Zhou Y, Lu J, Kang L, Jiang X, Xu R, Ding Z, Zou Y Ref: Genes (Basel), 13:, 2022 : PubMed ESTHER: Fu_2022_Genes.(Basel)_13_ PubMedSearch: Fu 2022 Genes.(Basel) 13 PubMedID: 35886059 Abstract Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein-protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape's three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARalpha), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARalpha, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment. Title: Sclerotinia sclerotiorum SsCut1 Modulates Virulence and Cutinase Activity Gong Y, Fu Y, Xie J, Li B, Chen T, Lin Y, Chen W, Jiang D, Cheng J Ref: J Fungi (Basel), 8:, 2022 : PubMed ESTHER: Gong_2022_J.Fungi.(Basel)_8_ PubMedSearch: Gong 2022 J.Fungi.(Basel) 8 PubMedID: 35628781 Gene_locus related to this paper: scls1-a7erz9 Abstract The plant cuticle is one of the protective layers of the external surface of plant tissues. Plants use the cuticle layer to reduce water loss and resist pathogen infection. Fungi release cell wall-degrading enzymes to destroy the epidermis of plants to achieve the purpose of infection. Sclerotinia sclerotiorum secretes a large amount of cutinase to disrupt the cuticle layer of plants during the infection process. In order to further understand the role of cutinase in the pathogenic process of S. sclerotiorum, the S. sclerotiorum cutinsae 1 (SsCut1) gene was cloned and analyzed. The protein SsCut1 contains the conserved cutinase domain and a fungal cellulose-binding domain. RT-qPCR results showed that the expression of SsCut1 was significantly upregulated during infection. Split-Marker recombination was utilized for the deletion of the SsCut1 gene, deltaSsCut1 mutants showed reduced cutinase activity and virulence, but the deletion of the SsCut1 gene had no effect on the growth rate, colony morphology, oxalic acid production, infection cushion formation and sclerotial development. Complementation with the wild-type SsCut1 allele restored the cutinase activity and virulence to the wild-type level. Interestingly, expression of SsCut1 in plants can trigger defense responses, but it also enhanced plant susceptibility to SsCut1 gene knock-out mutants. Taken together, our finding demonstrated that the SsCut1 gene promotes the virulence of S. sclerotiorum by enhancing its cutinase activity. Title: Recombinant AcMNPV-gp64-EGFP and synergist triphenyl phosphate, an effective combination against Spodoptera frugiperda Jiao R, Fu Y Ref: Biotechnol Lett, :, 2022 : PubMed ESTHER: Jiao_2022_Biotechnol.Lett__ PubMedSearch: Jiao 2022 Biotechnol.Lett PubMedID: 35922646 Inhibitor(s) related to this paper: TPHP Abstract OBJECTIVES: AcMNPV is a kind of microbial insecticide that can significantly relieve the resistance of Spodoptera frugiperda to chemical pesticides. TPP is a widely used synergist, which can reduce the use of pesticides by inhibiting carboxylesterase. It is emergently needed to develop a biological control way of Spodoptera frugiperda. RESULTS: GP64 mediates low-pH-triggered membrane fusion during entry by endocytosis and participates in AcMNPV particle budding. We explored the synergistic anti-insect activity of AcMNPV-gp64-EGFP and TPP. AcMNPV-gp64-EGFP could increase progeny virus proliferation and accelerate the transcription of 38k and vp39 genes. TPP could inhibit the carboxylesterase activity in the midgut of Spodoptera frugiperda larvae infected with AcMNPV-gp64-EGFP and enhance the virulence of AcMNPV-gp64-EGFP to Spodoptera frugiperda. CONCLUSIONS: TPP targeted carboxylesterase inhibition so that AcMNPV-gp64-EGFP could escape the antiviral response in insect hosts. It provided a novel strategy for the prevention of Spodoptera frugiperda. Title: Ethanol and its nonoxidative metabolites promote acute liver injury by inducing ER stress, adipocyte death and lipolysis Park SH, Seo W, Xu MJ, Mackowiak B, Lin Y, He Y, Fu Y, Hwang S, Kim SJ and Gao B <5 more author(s)> Park SH, Seo W, Xu MJ, Mackowiak B, Lin Y, He Y, Fu Y, Hwang S, Kim SJ, Guan Y, Feng D, Yu L, Lehner R, Liangpunsakul S, Gao B (- 5) Ref: Cell Mol Gastroenterol Hepatol, :, 2022 : PubMed ESTHER: Park_2022_Cell.Mol.Gastroenterol.Hepatol__ PubMedSearch: Park 2022 Cell.Mol.Gastroenterol.Hepatol PubMedID: 36243320 Abstract BACKGROUND & AIMS: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease (ALD). However, the underlying mechanisms remain elusive. We investigated if oxidative and non-oxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influence the development of acute liver injury in a single ethanol binge model. METHODS & RESULTS: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. Oral administration of a single dose of ethanol induced acute liver injury and hepatic ER stress in chow- or HFD-fed mice. Disruption of the alcohol dehydrogenase 1 (Adh1) gene elevated blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the aldehyde dehydrogenase 2 (Aldh2) gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies revealed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, increased adipocyte death and lipolysis, contributing to acute liver injury. Elevated serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice post ethanol gavage with higher levels in Adh1 knockout mice than that in wild-type mice. Deletion of the carboxylesterase 1d (Ces1d) gene in mice markedly reduced acute ethanol-induced elevation of blood FAEE levels with slight but significant reduction of serum aminotransferase levels. CONCLUSION: Ethanol and its non-oxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis. Title: Fluorescence-activated droplet sorting of PET degrading microorganisms Qiao Y, Hu R, Chen D, Wang L, Wang Z, Yu H, Fu Y, Li C, Dong Z and Du W <1 more author(s)> Qiao Y, Hu R, Chen D, Wang L, Wang Z, Yu H, Fu Y, Li C, Dong Z, Weng YX, Du W (- 1) Ref: J Hazard Mater, 424:127417, 2022 : PubMed ESTHER: Qiao_2022_J.Hazard.Mater_424_127417 PubMedSearch: Qiao 2022 J.Hazard.Mater 424 127417 PubMedID: 34673397 Abstract Enzymes that can decompose synthetic plastics such as polyethylene terephthalate (PET) are urgently needed. Still, a bottleneck remains due to a lack of techniques for detecting and sorting environmental microorganisms with vast diversity and abundance. Here, we developed a fluorescence-activated droplet sorting (FADS) pipeline for high-throughput screening of PET-degrading microorganisms or enzymes (PETases). The pipeline comprises three steps: generation and incubation of droplets encapsulating single cells, picoinjection of fluorescein dibenzoate (FDBz) as the fluorogenic probe, and screening of droplets to obtain PET-degrading cells. We characterized critical factors associated with this method, including specificity and sensitivity for discriminating PETase from other enzymes. We then optimized its performance and compatibility with environmental samples. The system was used to screen a wastewater sample from a PET textile mill. We successfully obtained PET-degrading species from nine different genera. Moreover, two putative PETases from isolates Kineococcus endophyticus Un-5 and Staphylococcus epidermidis Un-C2-8 were genetically derived, heterologously expressed, and preliminarily validated for PET-degrading activities. We speculate that the FADS pipeline can be widely adopted to discover new plastic-degrading microorganisms and enzymes in various environments and may be utilized in the directed evolution of degrading enzymes using synthetic biology. Title: A novel pomegranate-inspired bifunctional electrode materials design for acetylcholinesterase biosensor and methanol oxidation reaction Wei W, Tang H, Dong S, Fu Y, Huang T Ref: Bioelectrochemistry, 145:108094, 2022 : PubMed ESTHER: Wei_2022_Bioelectrochemistry_145_108094 PubMedSearch: Wei 2022 Bioelectrochemistry 145 108094 PubMedID: 35299151 Abstract A pomegranate-inspired bifunctional electrode material based on Ni/NiO nanoparticle embedded in nitrogen-doped, partially graphitized carbon framework (Ni/NiO@NPGC) was designed and prepared for the construction of novel electrochemical biosensor and methanol oxidation reaction (MOR). Profiting from itsspecialstructureandfunction, Ni/NiO@NPGC was employed as a matrix immobilizing acetylcholinesterase (AChE) for methyl parathion (MP) sensor. The developed biosensor was proved to have wide linear range (1.0 x 10(-14)-1.0 x 10(-8) g mL(-1)), low detection limit (3.5 x 10(-15) g mL(-1)), and good stability for the determination of MP in practical samples. In addition, the Ni/NiO@NPGC electrode exhibited high electrocatalytic activity (specific activity 73.1 mA cm(-2)) and durability for the MOR in alkaline medium. The results were mainly attributed to the pomegranate-like architecture structure with pyridinic N and carbon frame of Ni/NiO@NPGC, which ensured the electrochemical activities of all nanoparticles and immobilization of enzyme. In addition, the metal oxide was well dispersed to prevent from self-agglomeration and kept mass transfer paths. The work provides a reference for the development of high-performance bifunctional electrode material for the biosensor and MOR. Title: Nuclear access of DNlg3 c-terminal fragment and its function in regulating innate immune response genes Xie H, Liu S, Fu Y, Cheng Q, Wang P, Bi CL, Wang R, Chen MM, Fang M Ref: Biochemical & Biophysical Research Communications, 641:93, 2022 : PubMed ESTHER: Xie_2022_Biochem.Biophys.Res.Commun_641_93 PubMedSearch: Xie 2022 Biochem.Biophys.Res.Commun 641 93 PubMedID: 36525929 Abstract Neuroligins (NLGNs) are one of the autism susceptibility genes, however, the mechanism that how dysfunction of NLGNs leads to Autism remains unclear. More and more studies have shown that the transcriptome alteration may be one of the important factors to generate Autism. Therefore, we are very concerned about whether Neuroligins would affect transcriptional regulation, which may at last lead to Autism. As a single-transmembrane receptor, proteolytic cleavage is one of the most important posttranslational modifications of NLGN proteins. In this study, we demonstrated the existence of DNlg3 C-terminal fragment. Studies in the S2 cells and HEK293T cells showed the evidence for nuclear access of the DNlg3 C-terminal fragment. Then we identified the possible targets of DNlg3 C-terminal fragment after its nuclear access by RNA-seq. The bioinformatics analysis indicated the transcriptome alteration between dnlg3 null flies and wild type flies focused on genes for the innate immune responses. These results were consistent with the infection hypotheses for autism. Our study revealed the nuclear access ability of DNlg3 c-terminal fragment and its possible function in transcriptional regulation of the innate immune response genes. This work provides the new links between synaptic adhesion molecule NLGNs and immune activation, which may help us to get a deeper understanding on the relationship between NLGNs and Autism. Title: The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Huang J, You H, Zhang D and Zhang H <3 more author(s)> Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Huang J, You H, Zhang D, Mao F, Zhu J, Wang H, Zhang H (- 3) Ref: Eur Journal of Medicinal Chemistry, 229:114045, 2021 : PubMed ESTHER: Li_2021_Eur.J.Med.Chem_229_114045 PubMedSearch: Li 2021 Eur.J.Med.Chem 229 114045 PubMedID: 34922191 Abstract Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT(1A) receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT(1A) receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression. Title: Enhanced Production of (S)-2-arylpropionic Acids by Protein Engineering and Whole-Cell Catalysis Liu X, Zhao M, Fan X, Fu Y Ref: Front Bioeng Biotechnol, 9:697677, 2021 : PubMed ESTHER: Liu_2021_Front.Bioeng.Biotechnol_9_697677 PubMedSearch: Liu 2021 Front.Bioeng.Biotechnol 9 697677 PubMedID: 34307324 Gene_locus related to this paper: 9zzzz-Est924 Abstract Esterases are important biocatalysts for chemical synthesis. Several bHSL family esterases have been used to prepare (S)-2-arylpropionic acids with stronger anti-inflammatory effects via kinetic resolution. Here, we presented the discovery of key residues that controlled the enantioselectivity of bHSL family esterases to ethyl 2-arylpropionates, through careful analysis of the structural information and molecular docking. A new bHSL family esterase, Est924, was identified as a promising catalyst for kinetic resolution of racemic ethyl 2-arylpropionates with slight (R)-stereopreference. Using Est924 as the starting enzyme, protein engineering was conducted at hotspots, and the substitution of A203 was proved to enhance the enantioselectivity. The stereopreference of the mutant M1 (A203W) was inverted to ethyl (S)-2-arylpropionates, and this stereopreference was further improved in variant M3 (I202F/A203W/G208F). In addition, the optimal variant, M3, was also suitable for the resolution of ibuprofen ethyl ester and ketoprofen ethyl ester, and their efficient (S)-isomers were synthesized. Next, the whole-cell catalyst harboring M3 was used to prepare (S)-ketoprofen. (S)-ketoprofen with 86%ee was produced by whole-cell catalyst with a single freeze-thaw cycle, and the cells could be reused for at least five cycles. Our results suggested that Est924 variants could kinetically resolve economically important racemates for industrial production and further offer the opportunity for the rational design of enzyme enantioselectivity. Moreover, it is an economical process to prepare optically pure (S)-ketoprofen and (S)-naproxen by using an engineered strain harboring M3 as the catalyst. Title: Reshaping the active pocket of esterase Est816 for resolution of economically important racemates Liu X, Zhao M, Fan XJ, Fu Y Ref: Catal Sci Technol, :, 2021 : PubMed ESTHER: Liu_2021_Catal.Sci.Technol__ PubMedSearch: Liu 2021 Catal.Sci.Technol Gene_locus related to this paper: 9bact-i6yrg4 Abstract Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with high E values were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases. Title: Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate Zhou Y, Fu Y, Yin W, Li J, Wang W, Bai F, Xu S, Gong Q, Peng T and Liu H <7 more author(s)> Zhou Y, Fu Y, Yin W, Li J, Wang W, Bai F, Xu S, Gong Q, Peng T, Hong Y, Zhang D, Liu Q, Xu Y, Xu HE, Zhang H, Jiang H, Liu H (- 7) Ref: Journal of Medicinal Chemistry, 64:1844, 2021 : PubMed ESTHER: Zhou_2021_J.Med.Chem_64_1844 PubMedSearch: Zhou 2021 J.Med.Chem 64 1844 PubMedID: 33570950 Gene_locus related to this paper: human-ACHE Inhibitor(s) related to this paper: H0L-7D9O, H1R-7D9Q, H0R-7D9P Abstract The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD. Title: One-pot cascade synthesis of benzopyrans and dihydropyrano[c]chromenes catalyzed by lipase TLIM Fu Y, Lu Z, Ma X, Fang K, He X, Xu H, Hu Y Ref: Bioorg Chem, 99:103888, 2020 : PubMed ESTHER: Fu_2020_Bioorg.Chem_99_103888 PubMedSearch: Fu 2020 Bioorg.Chem 99 103888 PubMedID: 32388204 Abstract Lipase TLIM was reported to be an efficient, commercially available and reusable catalyst for the Knoevenagel-Michael cascade reactions of aldehydes, malononitrile/ethyl cyanoacetate and 4-hydroxycoumarin/1, 3-cyclohexanedione/dimedone in aqueous DMSO. This methodology presents many superiorities such as simple procedure, mild reaction conditions, commercially available and reusable catalyst, high substrate applicability, the ability to be scaled up, and good to excellent yields. Title: Effects of Different Dietary Flavonoids on Dipeptidyl Peptidase-IV Activity and Expression: Insights into Structure-Activity Relationship Gao F, Fu Y, Yi J, Gao A, Jia Y, Cai S Ref: Journal of Agricultural and Food Chemistry, 68:12141, 2020 : PubMed ESTHER: Gao_2020_J.Agric.Food.Chem_68_12141 PubMedSearch: Gao 2020 J.Agric.Food.Chem 68 12141 PubMedID: 33063510 Abstract The inhibitory effects of 30 dietary flavonoids on dipeptidyl peptidase-IV (DPP-IV) were investigated to illustrate their quantitative structure-activity relationship (QSAR) and further explore their inhibition at the cellular level. Results of in vitro experiment show that isorhamnetin-3-O-glucoside (IC(50), 6.53 +/- 0.280 microM) had the strongest inhibition followed by cyanidin-3-O-glucoside (IC(50), 8.26 +/- 0.143 microM) and isorhamnetin-3-O-rutinoside (IC(50), 8.57 +/- 0.422 microM). A 3D QSAR model [comparative molecular field analysis, q(2) = 0.502, optimum number of components (ONC) = 3, R(2) = 0.983, F = 404.378, standard error of estimation (SEE) = 0.070, and two descriptors; comparative similarity index analysis, q(2) = 0.580, ONC = 10, R(2) = 0.999, F = 1617.594, SEE = 0.022, and four descriptors] indicates that the DPP-IV inhibition of flavonoid was facilitated by crucial structural factors. Position 3 of ring C favored bulky, hydrogen bond acceptors and hydrophilic and electron-donating substituents. The presence of minor and electron-withdrawing groups at position 4' of ring B and positions 5 and 7 of ring A could improve DPP-IV inhibition. Moreover, the three flavonoids mentioned above could effectively suppress DPP-IV activity and expression in Caco-2 cells. This work may supply new insights into dietary flavonoids as DPP-IV inhibitors for controlling blood glucose. Title: Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China Li Y, Fu Y, Hu K, Zhang Y, Chen J, Zhang S, Zhang B, Liu Y Ref: Ecotoxicology & Environmental Safety, 196:110548, 2020 : PubMed ESTHER: Li_2020_Ecotoxicol.Environ.Saf_196_110548 PubMedSearch: Li 2020 Ecotoxicol.Environ.Saf 196 110548 PubMedID: 32278140 Abstract As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer. Title: Bio-/Nanoimmobilization Platform Based on Bioinspired Fibrin-Bone@Polydopamine-Shell Adhesive Composites for Biosensing Zhang L, Liu Z, Zha S, Liu G, Zhu W, Xie Q, Li Y, Ying Y, Fu Y Ref: ACS Appl Mater Interfaces, 11:47311, 2019 : PubMed ESTHER: Zhang_2019_ACS.Appl.Mater.Interfaces_11_47311 PubMedSearch: Zhang 2019 ACS.Appl.Mater.Interfaces 11 47311 PubMedID: 31742992 Abstract Inspired by blood coagulation and mussel adhesion, we report novel adhesive fibrin-bone@polydopamine (PDA)-shell composite matrix as highly efficient immobilization platform for biomacromolecules and nanomaterials. Fibrin, as a bioglue, and PDA, as a chemical adhesive, are integrated in a one-pot simultaneous polymerization consisting of biopolymerization of fibrinogen and chemical polymerization of dopamine. Fibrin fibers act as adhesive bones to construct scaffold, while PDA coat on the scaffold to form adhesive shell, generating 3D porous composite matrix with unique bone@shell structure. Two types of enzymes (glucose oxidase and acetylcholinesterase) and Au nanoparticles were adopted as respective model biomolecules and nanomaterials to investigate the immobilization capability of the matrix. The bionanocomposites showed high efficiency in capturing nanoparticles and enzymes, as well as significant mass-transfer and biocatalysis efficiencies. Therefore, the bionanocomposites exhibited significant potential in biosensing of glucose and paraoxon with limits of detection down to 5.2 muM and 4 ppt, respectively. The biological-chemical-combined polymerization strategy and composite platform with high immobilization capacity and mass-transfer efficiency open up a novel way for the preparation of high-performance bionanocomposites for various applications, in particular, biosensing. Title: Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson's Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage Zou J, Chen Z, Liang C, Fu Y, Wei X, Lu J, Pan M, Guo Y, Liao X and Wang Q <5 more author(s)> Zou J, Chen Z, Liang C, Fu Y, Wei X, Lu J, Pan M, Guo Y, Liao X, Xie H, Wu D, Li M, Liang L, Wang P, Wang Q (- 5) Ref: Aging Dis, 9:51, 2018 : PubMed ESTHER: Zou_2018_Aging.Dis_9_51 PubMedSearch: Zou 2018 Aging.Dis 9 51 PubMedID: 29392081 Abstract Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson's disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores' distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD. Title: Increased NDRG1 expression attenuate trophoblast invasion through ERK/MMP-9 pathway in preeclampsia Fu Y, Wei J, Dai X, Ye Y Ref: Placenta, 51:76, 2017 : PubMed ESTHER: Fu_2017_Placenta_51_76 PubMedSearch: Fu 2017 Placenta 51 76 PubMedID: 28292472 Abstract OBJECTIVE: The aim of this study was to investigate the expression of N-myc downstream-regulated gene1(NDRG1)in the placentas of pregnancies complicated with early-onset and late-onset preeclampsia (PE) and its underlying mechanism on the pathophysiology of PE. Title: Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents Li X, Wang H, Lu Z, Zheng X, Ni W, Zhu J, Fu Y, Lian F, Zhang N and Mao F <2 more author(s)> Li X, Wang H, Lu Z, Zheng X, Ni W, Zhu J, Fu Y, Lian F, Zhang N, Li J, Zhang H, Mao F (- 2) Ref: Journal of Medicinal Chemistry, 59:8326, 2016 : PubMed ESTHER: Li_2016_J.Med.Chem_59_8326 PubMedSearch: Li 2016 J.Med.Chem 59 8326 PubMedID: 27552582 Inhibitor(s) related to this paper: SCHEMBL19305555 Abstract Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 muM, SI > 196; 5t, IC50 = 0.067 muM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Abeta aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease. Title: Synaptic proteins and receptors defects in autism spectrum disorders Chen J, Yu S, Fu Y, Li X Ref: Front Cell Neurosci, 8:276, 2014 : PubMed ESTHER: Chen_2014_Front.Cell.Neurosci_8_276 PubMedSearch: Chen 2014 Front.Cell.Neurosci 8 276 PubMedID: 25309321 Abstract Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms contribute to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways. Title: Use of a carboxylesterase inhibitor of phenylmethanesulfonyl fluoride to stabilize epothilone D in rat plasma for a validated UHPLC-MS/MS assay Yuan L, Fu Y, Zhang D, Xia YQ, Peng Q, Aubry AF, Arnold ME Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 969C:60, 2014 : PubMed ESTHER: Yuan_2014_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_969C_60 PubMedSearch: Yuan 2014 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 969C 60 PubMedID: 25151331 Abstract A sensitive, accurate and rugged UHPLC-MS/MS method was developed and validated for the quantitation of Epothilone D (EpoD), a microtubule stabilizer in development for treatment of Alzeimer's disease, in rat plasma. The ester group in EpoD can be hydrolyzed by esterases in blood or plasma, which creates a stability concern for the bioanalysis of EpoD. Species differences in the stability of EpoD in plasma were observed. Carboxylesterases were identified as the likely esterases responsible for the hydrolysis of EpoD in plasma ex vivo, and the cause of the species different stability. Phenylmethanesulfonyl fluoride, a carboxylesterase inhibitor, was used to stabilize EpoD in rat blood during sample collection, processing, and storage. A systematic method screening and optimization strategy was used to improve the assay sensitivity and minimize potential bioanalytical risks. The stabilized plasma samples were extracted by liquid-liquid extraction. Chromatographic separation was achieved on an Acquity UPLC BEH Phenyl column with a gradient elution. EpoD and its stable isotope labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 0.100 to 100ng/mL was fitted to a 1/x2 weighted linear regression model. The intra-assay precision was within +/-3.6% CV and inter-assay precision was within +/-4.2% CV. The assay accuracy was within +/-8.3% of the nominal values. Assay recovery of EpoD was high ( approximately 90%) and matrix effect was minimal (1.02-1.05). EpoD was stable in stabilized rat plasma for at least 30h at room temperature, 180 days at -20 degrees C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in toxicology studies. Title: Casuarinines A-J, Lycodine-Type Alkaloids from Lycopodiastrum casuarinoides Tang Y, Fu Y, Xiong J, Li M, Ma GL, Yang GX, Wei BG, Zhao Y, Zhang HY, Hu JF Ref: Journal of Natural Products, 76:1475, 2013 : PubMed ESTHER: Tang_2013_J.Nat.Prod_76_1475 PubMedSearch: Tang 2013 J.Nat.Prod 76 1475 PubMedID: 23941108 Abstract Ten new lycodine-type alkaloids, named casuarinines A-J (1-10), along with eight known analogues (11-18), were isolated from the whole plant of Lycopodiastrum casuarinoides . The new structures were established by spectroscopic methods and chemical transformations. Casuarinines A-D (1-4) and J (10) are common lycodine alkaloids possessing four connected six-membered rings, while tricyclic casuarinines E-H (5-8) are the piperidine ring cleavage products. In particular, casuarinine I (9) has an unprecedented five-membered tetrahydropyrrole ring instead of the piperidine ring. A plausible biosynthetic pathway to 9 is proposed. Among the compounds reported, casuarinine H (8) exhibited significant neuroprotective effect against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells, while casuarinines C (3) and I (9) showed moderate inhibitory activity against acetylcholinesterase (AChE). Title: Discovery of novel 2,6-disubstituted pyridazinone derivatives as acetylcholinesterase inhibitors Xing W, Fu Y, Shi Z, Lu D, Zhang H, Hu Y Ref: Eur Journal of Medicinal Chemistry, 63C:95, 2013 : PubMed ESTHER: Xing_2013_Eur.J.Med.Chem_63C_95 PubMedSearch: Xing 2013 Eur.J.Med.Chem 63C 95 PubMedID: 23466605 Abstract 2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BCHE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders. Title: Three-dimensional ordered macroporous (3DOM) composite for electrochemical study on acetylcholinesterase inhibition induced by endogenous neurotoxin Teng Y, Fu Y, Xu L, Lin B, Wang Z, Xu Z, Jin L, Zhang W Ref: J Phys Chem B, 116:11180, 2012 : PubMed ESTHER: Teng_2012_J.Phys.Chem.B_116_11180 PubMedSearch: Teng 2012 J.Phys.Chem.B 116 11180 PubMedID: 22946763 Abstract In this paper, an electrochemical acetylcholinesterase (AChE) inhibition assay based on three-dimensional ordered macroporous (3DOM) composite was conducted. The 3DOM composite was first fabricated on the glassy carbon electrode by electropolymerization of aniline in the presence of ionic liquid (IL) on a sacrificial silica nanospheres template. After the silica nanospheres were etched, an IL-doped polyaniline (IL-PANI) film with 3DOM morphology was formed. Then, gold nanoparticles (AuNPs) were decorated on the IL-PANI film by electrodeposition. The immobilized AChE on the 3DOM composite displayed favorable affinity to substrate acetylthiocholine chloride (ATCh), and the 3DOM composite showed excellent electrocatalytic effect on thiocholine, the hydrolysis product of ATCh. The presence of IL and AuNPs could improve the sensitivity by accelerating the electron transfer. The designed AChE biosensor was successfully applied to evaluate the AChE inhibition induced by endogenous neurotoxin 1(R),2N-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)-NMSal]. The results demonstrate that (R)-NMSal exerts a considerable effect on AChE activity, and the inhibition is reversible. The developed method offers a new approach for AChE inhibition assay, which is of great benefit in understanding the mechanism behind neurotoxin-induced neurodegenerative disorders. Title: Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice Dineley KT, Kayed R, Neugebauer V, Fu Y, Zhang W, Reese LC, Taglialatela G Ref: Journal of Neuroscience Research, 88:2923, 2010 : PubMed ESTHER: Dineley_2010_J.Neurosci.Res_88_2923 PubMedSearch: Dineley 2010 J.Neurosci.Res 88 2923 PubMedID: 20544830 Abstract Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. Title: A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, in healthy subjects and patients Huang F, Fu Y Ref: Curr Clin Pharmacol, 5:115, 2010 : PubMed ESTHER: Huang_2010_Curr.Clin.Pharmacol_5_115 PubMedSearch: Huang 2010 Curr.Clin.Pharmacol 5 115 PubMedID: 20156150 Abstract Galantamine is a reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Following oral administration, galantamine is rapidly absorbed and reaches C(max) in approximately one hour for immediate release (IR) tablets and four hours for extended-release (ER) capsules. Food has no clinically important effects on the absorption of galantamine. Galantamine displays dose-proportional pharmacokinetics over a dose range of 8-32 mg and 8-24 mg for IR and ER formulations, respectively. The elimination half-life of galantamine is about 7-8 hours. Galantamine has low protein binding (28.3-33.8%) and has an apparent steady-state volume of distribution (V(ss)) of 193 L. Approximately 20-25% of the galantamine dose administered is excreted unchanged in urine. No clinically significant effects of age, gender, and race have been observed on galantamine pharmacokinetics. The exposures to galantamine in patients with moderate and severe renal impairment are 37% and 67% higher, respectively than in healthy subjects, whereas the exposure to galantamine is approximately 30% higher in patients with moderate hepatic impairment. Co-administration of galantamine with ketoconazole (CYP 3A4 strong inhibitor) or paroxetine (CYP 2D6 strong inhibitor) leads to a 30% and 40% increase, respectively, in galantamine exposure compared to galantamine given alone. 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: Identification and characterization of HTD2: a novel gene negatively regulating tiller bud outgrowth in rice Liu W, Wu C, Fu Y, Hu G, Si H, Zhu L, Luan W, He Z, Sun Z Ref: Planta, 230:649, 2009 : PubMed ESTHER: Liu_2009_Planta_230_649 PubMedSearch: Liu 2009 Planta 230 649 PubMedID: 19579033 Gene_locus related to this paper: orysj-Q10QA5 Abstract Tiller number is highly regulated by controlling the formation of tiller bud and its subsequent outgrowth in response to endogenous and environmental signals. Here, we identified a rice mutant htd2 from one of the 15,000 transgenic rice lines, which is characterized by a high tillering and dwarf phenotype. Phenotypic analysis of the mutant showed that the mutation did not affect formation of tiller bud, but promoted the subsequent outgrowth of tiller bud. To isolate the htd2 gene, a map-based cloning strategy was employed and 17 new insertions-deletions (InDels) markers were developed. A high-resolution physical map of the chromosomal region around the htd2 gene was made using the F(2) and F(3) population. Finally, the gene was mapped in 12.8 kb region between marker HT41 and marker HT52 within the BAC clone OSJNBa0009J13. Cloning and sequencing of the target region from the mutant showed that the T-DNA insertion caused a 463 bp deletion between the promoter and first exon of an esterase/lipase/thioesterase family gene in the 12.8 kb region. Furthermore, transgenic rice with reduced expression level of the gene exhibited an enhanced tillering and dwarf phenotype. Accordingly, the esterase/lipase/thioesterase family gene (TIGR locus Os03g10620) was identified as the HTD2 gene. HTD2 transcripts were expressed mainly in leaf. Loss of function of HTD2 resulted in a significantly increased expression of HTD1, D10 and D3, which were involved in the strigolactone biosynthetic pathway. The results suggest that the HTD2 gene could negatively regulate tiller bud outgrowth by the strigolactone pathway. Title: The B73 maize genome: complexity, diversity, and dynamics Schnable PS, Ware D, Fulton RS, Stein JC, Wei F, Pasternak S, Liang C, Zhang J, Fulton L and Wilson RK <147 more author(s)> Schnable PS, Ware D, Fulton RS, Stein JC, Wei F, Pasternak S, Liang C, Zhang J, Fulton L, Graves TA, Minx P, Reily AD, Courtney L, Kruchowski SS, Tomlinson C, Strong C, Delehaunty K, Fronick C, Courtney B, Rock SM, Belter E, Du F, Kim K, Abbott RM, Cotton M, Levy A, Marchetto P, Ochoa K, Jackson SM, Gillam B, Chen W, Yan L, Higginbotham J, Cardenas M, Waligorski J, Applebaum E, Phelps L, Falcone J, Kanchi K, Thane T, Scimone A, Thane N, Henke J, Wang T, Ruppert J, Shah N, Rotter K, Hodges J, Ingenthron E, Cordes M, Kohlberg S, Sgro J, Delgado B, Mead K, Chinwalla A, Leonard S, Crouse K, Collura K, Kudrna D, Currie J, He R, Angelova A, Rajasekar S, Mueller T, Lomeli R, Scara G, Ko A, Delaney K, Wissotski M, Lopez G, Campos D, Braidotti M, Ashley E, Golser W, Kim H, Lee S, Lin J, Dujmic Z, Kim W, Talag J, Zuccolo A, Fan C, Sebastian A, Kramer M, Spiegel L, Nascimento L, Zutavern T, Miller B, Ambroise C, Muller S, Spooner W, Narechania A, Ren L, Wei S, Kumari S, Faga B, Levy MJ, McMahan L, Van Buren P, Vaughn MW, Ying K, Yeh CT, Emrich SJ, Jia Y, Kalyanaraman A, Hsia AP, Barbazuk WB, Baucom RS, Brutnell TP, Carpita NC, Chaparro C, Chia JM, Deragon JM, Estill JC, Fu Y, Jeddeloh JA, Han Y, Lee H, Li P, Lisch DR, Liu S, Liu Z, Nagel DH, McCann MC, SanMiguel P, Myers AM, Nettleton D, Nguyen J, Penning BW, Ponnala L, Schneider KL, Schwartz DC, Sharma A, Soderlund C, Springer NM, Sun Q, Wang H, Waterman M, Westerman R, Wolfgruber TK, Yang L, Yu Y, Zhang L, Zhou S, Zhu Q, Bennetzen JL, Dawe RK, Jiang J, Jiang N, Presting GG, Wessler SR, Aluru S, Martienssen RA, Clifton SW, McCombie WR, Wing RA, Wilson RK (- 147) Ref: Science, 326:1112, 2009 : PubMed ESTHER: Schnable_2009_Science_326_1112 PubMedSearch: Schnable 2009 Science 326 1112 PubMedID: 19965430 Gene_locus related to this paper: maize-b4ffc7, maize-b6u7e1, maize-c0pcy5, maize-c0pgf7, maize-c0pgw1, maize-c0pfl3, maize-b4fpr7, maize-k7vy73, maize-a0a096swr3, maize-k7v3i9, maize-b6u9v9, maize-a0a3l6e780, maize-b4fv80, maize-a0a1d6nse2, maize-c4j9a1 Abstract We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize. Title: Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors Shi YF, Zhang HY, Wang W, Fu Y, Xia Y, Tang XC, Bai DL, He XC Ref: Acta Pharmacol Sin, 30:1195, 2009 : PubMed ESTHER: Shi_2009_Acta.Pharmacol.Sin_30_1195 PubMedSearch: Shi 2009 Acta.Pharmacol.Sin 30 1195 PubMedID: 19578388 Abstract AIM: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Title: Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase Zhu Y, Xiao K, Ma L, Xiong B, Fu Y, Yu H, Wang W, Wang X, Hu D and Shen J <6 more author(s)> Zhu Y, Xiao K, Ma L, Xiong B, Fu Y, Yu H, Wang W, Wang X, Hu D, Peng H, Li J, Gong Q, Chai Q, Tang X, Zhang H, Shen J (- 6) Ref: Bioorganic & Medicinal Chemistry, 17:1600, 2009 : PubMed ESTHER: Zhu_2009_Bioorg.Med.Chem_17_1600 PubMedSearch: Zhu 2009 Bioorg.Med.Chem 17 1600 PubMedID: 19162488 Abstract To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients. Title: Mapping and expression analysis of chicken NDRG1 and NDRG3 genes Tian Y, Xu M, Fu Y, Yuan A, Wang D, Li G, Liu G, Lu L Ref: Biochemical Genetics, 46:677, 2008 : PubMed ESTHER: Tian_2008_Biochem.Genet_46_677 PubMedSearch: Tian 2008 Biochem.Genet 46 677 PubMedID: 18751885 Abstract N-myc downstream-regulated genes 1 and 3 (NDRG1 and NDRG3) are members of the alpha/beta hydrolase superfamily. Phylogenetic analysis of the family demonstrated that human NDRG1 and 3 belong to a subfamily. The mapping and gene expression patterns of these genes represent one step toward further investigation into their possible roles in the chicken (Gallus gallus). To map these genes in the chicken chromosome, a 6000 rads chicken-hamster radiation hybrid panel (ChickRH6) was used. Primers were designed according to the published human sequences for amplification of those two genes. We compared the corresponding human mRNA sequences with the predicted coding sequences of the chicken NDRG1 and 3 genes and found that the assembled contigs shared a high percentage of similarity with the human genes. PCR of samples from ChickRH6 revealed that the locations of NDRG1 and 3 are linked to the markers MYC (58 cRs away, LOD score 4.52) and SEQ0265 (10 cRs away, LOD score 17.81), respectively. This result adds two new markers to the chicken RH map, and it reinforces that the RH technique is indeed a powerful tool for mapping genes due to its rapidity, precision, convenience, and reproducibility. In addition, we detected the gene expression and distribution of chicken NDRG1 and 3 in seven tissues, including heart, liver, spleen, lung, muscle, brain, and thymus, by RT-PCR, and found that NDRG1 is relatively ubiquitously expressed in all the tested tissues and highly expressed in heart and liver, whereas NDRG3 is high in heart, muscle, and brain. Title: Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor Wang ZF, Yan J, Fu Y, Tang XC, Feng S, He XC, Bai DL Ref: Cellular Molecular Neurobiology, 28:245, 2008 : PubMed ESTHER: Wang_2008_Cell.Mol.Neurobiol_28_245 PubMedSearch: Wang 2008 Cell.Mol.Neurobiol 28 245 PubMedID: 17786550 Abstract (1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia. Title: Up-regulation of brain nicotinic acetylcholine receptors in the rat during long-term self-administration of nicotine: disproportionate increase of the alpha6 subunit Parker SL, Fu Y, McAllen K, Luo J, McIntosh JM, Lindstrom JM, Sharp BM Ref: Molecular Pharmacology, 65:611, 2004 : PubMed ESTHER: Parker_2004_Mol.Pharmacol_65_611 PubMedSearch: Parker 2004 Mol.Pharmacol 65 611 PubMedID: 14978239 Abstract In male rats continually self-administering nicotine (approximately 1.5 mg free base/kg/day), we found a significant increase of nicotinic acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas. A large increase of high-affinity Epb binding sites was apparent in the ventral tegmentum/substantia nigra, nucleus tractus solitarii, nucleus accumbens, thalamus/subthalamus, parietal cortex, hypothalamus, and amygdala. A smaller but significant up-regulation of high-affinity Epb sites was seen in the piriform cortex, hippocampus, caudate/putamen, and cerebellar cortex. The up-regulation of nAChRs, shown by immunoadsorption and Western blotting, involved alpha4, alpha6, and beta2 subunits. As a consequence of long-term self-administration of nicotine, the alpha6 immunoreactive (IR) binding of either labeled Epb or 125I-alpha-conotoxin MII increased to a much greater extent than did alpha4 or beta2 IR binding of Epb. In addition, the beta2 IR binding of Epb was consistently enhanced to a greater extent than was alpha4. These findings may reflect a larger surface membrane retention of alpha6-containing and, to some degree, beta2-containing nAChRs compared with alpha4-containing nAChRs during long-term self-administration of nicotine. Title: Effects of galantamine, a nicotinic allosteric potentiating ligand, on nicotine-induced catecholamine release in hippocampus and nucleus accumbens of rats Sharp BM, Yatsula M, Fu Y Ref: Journal of Pharmacology & Experimental Therapeutics, 309:1116, 2004 : PubMed ESTHER: Sharp_2004_J.Pharmacol.Exp.Ther_309_1116 PubMedSearch: Sharp 2004 J.Pharmacol.Exp.Ther 309 1116 PubMedID: 14769831 Abstract Galantamine, a drug for treatment of Alzheimer's disease, is a novel cholinergic agent with a dual mode of action that inhibits acetylcholinesterase and allosterically modulates nicotinic cholinergic receptors (nAChRs). Nicotine stimulates catecholamine secretion, inducing hippocampal norepinephrine (NE) release, and improves memory consolidation. Thus, the effect of galantamine on nicotine-induced hippocampal NE secretion was investigated. This was compared with the effect of galantamine on nicotine-induced dopamine (DA) release within the nucleus accumbens of the same rat. Nicotine (0.025-0.09 mg/kg i.v.) dose dependently increased NE and DA levels in microdialysates from the hippocampus and nucleus accumbens, respectively, of freely moving rats. Pretreatment with galantamine (3.0 mg/kg s.c.) 3 h before nicotine either potentiated NE responses to doses of nicotine that were ineffective alone (0.025-0.045 mg/kg) or significantly enhanced (0.065 mg/kg) NE responses, whereas galantamine was ineffective when administered 2 or 4 h before nicotine. In contrast to its effects on NE, galantamine did not alter accumbal DA responses to any dose of nicotine. These selective effects of galantamine on nicotine-stimulated NE secretion may reflect differences in local neural circuits that use nAChRs to modulate hippocampal NE versus accumbal DA release. Title: Huperzine A, a promising anti-Alzheimer?s agent, reduces staurosporine-induced apoptosis in NG108-15 cells. Xiao XQ, Wu DC, Gao Y, Fu Y, Lee NT, Ho WL, Tsim KWK, Han YF Ref: Cholinergic Mechanisms, CRC Press, :733, 2004 : PubMed ESTHER: Xiao_2004_Cholinergic.Mechanisms.CRC.Press__733 PubMedSearch: Xiao 2004 Cholinergic.Mechanisms.CRC.Press 733 Title: Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation Zhou J, Fu Y, Tang XC Ref: Neuroscience Letters, 306:53, 2001 : PubMed ESTHER: Zhou_2001_Neurosci.Lett_306_53 PubMedSearch: Zhou 2001 Neurosci.Lett 306 53 PubMedID: 11403956 Abstract Huperzine A (HupA) and donepezil, two novel selective acetylcholinesterase inhibitors available for Alzheimer's disease, were tested for their ability to alleviate injury from oxygen-glucose deprivation (OGD) in the rat pheochromocytoma line PC12 cells. OGD for 30 min triggered death in more than 50% of cells, along with major changes in morphology and biochemistry including elevated levels of lipid peroxide, superoxide disamutase activity and lactate. Cells pretreated for 2 h with HupA or donepezil showed improved survival and reduced biochemical and morphologic signs of toxicity (statistically significant over the range from 10 microM down to 1.0 and 0.1 microM, respectively). Our results indicated that HupA and donepezil protected PC12 cells against OGD-induced toxicity, most likely by alleviating disturbances of oxidative and energy metabolism. Title: Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB Ref: Cancer Research, 60:749, 2000 : PubMed ESTHER: Guan_2000_Cancer.Res_60_749 PubMedSearch: Guan 2000 Cancer.Res 60 749 PubMedID: 10676663 Gene_locus related to this paper: human-NDRG1 Abstract A gene related to cell differentiation was identified by differential display as a candidate suppressor of metastases in colon cancer. This gene, with a full-length cDNA of 3 kb, is expressed in normal colon and primary colon cancer tissues and cell lines but not in their metastatic counterparts. A GenBank search found that it is identical to a recently cloned gene, differentiation-related gene-1 (Drg-1), isolated from differentiated HT-29 colon cancer cells. Stable transfection of the SW620 metastatic colon cancer cell line with Drg-1 cDNA induced morphological changes consistent with differentiation and up-regulated the expression of several colonic epithelial cell differentiation markers (alkaline phosphatase, carcinoembryonic antigen, and E-cadherin). Moreover, the expression of Drg-1 is controlled by several known cell differentiation reagents, such as ligands of peroxisome proliferator-activated receptor gamma (troglitazone and BRL46593) and of retinoid X receptor (LG268), and histone deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and tributyrin). A synergistic induction of Drg-1 expression was seen with the combination of tributyrin and a low dose of 5'-aza-2'-dexoycytidine (100 nM), an inhibitor of DNA methylation. Functional studies revealed that overexpression of Drg-1 in metastatic colon cancer cells reduced in vitro invasion through Matrigel and suppressed in vivo liver metastases in nude mice. We propose that Drg-1 suppresses colon cancer metastasis by inducing colon cancer cell differentiation and partially reversing the metastatic phenotype. Title: The DNA sequence of human chromosome 22 Dunham I, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP and O'Brien KP <207 more author(s)> Dunham I, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage AK, Bagguley C, Bailey J, Barlow KF, Bates KN, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Buck D, Burgess J, Burrill WD, Burton J, Carder C, Carter NP, Chen Y, Clark G, Clegg SM, Cobley VE, Cole CG, Collier RE, Connor R, Conroy D, Corby NR, Coville GJ, Cox AV, Davis J, Dawson E, Dhami PD, Dockree C, Dodsworth SJ, Durbin RM, Ellington AG, Evans KL, Fey JM, Fleming K, French L, Garner AA, Gilbert JGR, Goward ME, Grafham DV, Griffiths MND, Hall C, Hall RE, Hall-Tamlyn G, Heathcott RW, Ho S, Holmes S, Hunt SE, Jones MC, Kershaw J, Kimberley AM, King A, Laird GK, Langford CF, Leversha MA, Lloyd C, Lloyd DM, Martyn ID, Mashreghi-Mohammadi M, Matthews LH, Mccann OT, Mcclay J, Mclaren S, McMurray AA, Milne SA, Mortimore BJ, Odell CN, Pavitt R, Pearce AV, Pearson D, Phillimore BJCT, Phillips SH, Plumb RW, Ramsay H, Ramsey Y, Rogers L, Ross MT, Scott CE, Sehra HK, Skuce CD, Smalley S, Smith ML, Soderlund C, Spragon L, Steward CA, Sulston JE, Swann RM, Vaudin M, Wall M, Wallis JM, Whiteley MN, Willey DL, Williams L, Williams SA, Williamson H, Wilmer TE, Wilming L, Wright CL, Hubbard T, Bentley DR, Beck S, Rogers J, Shimizu N, Minoshima S, Kawasaki K, Sasaki T, Asakawa S, Kudoh J, Shintani A, Shibuya K, Yoshizaki Y, Aoki N, Mitsuyama S, Roe BA, Chen F, Chu L, Crabtree J, Deschamps S, Do A, Do T, Dorman A, Fang F, Fu Y, Hu P, Hua A, Kenton S, Lai H, Lao HI, Lewis J, Lewis S, Lin S-P, Loh P, Malaj E, Nguyen T, Pan H, Phan S, Qi S, Qian Y, Ray L, Ren Q, Shaull S, Sloan D, Song L, Wang Q, Wang Y, Wang Z, White J, Willingham D, Wu H, Yao Z, Zhan M, Zhang G, Chissoe S, Murray J, Miller N, Minx P, Fulton R, Johnson D, Bemis G, Bentley D, Bradshaw H, Bourne S, Cordes M, Du Z, Fulton L, Goela D, Graves T, Hawkins J, Hinds K, Kemp K, Latreille P, Layman D, Ozersky P, Rohlfing T, Scheet P, Walker C, Wamsley A, Wohldmann P, Pepin K, Nelson J, Korf I, Bedell JA, Hillier L, Mardis E, Waterston R, Wilson R, Emanuel BS, Shaikh T, Kurahashi H, Saitta S, Budarf ML, McDermid HE, Johnson A, Wong ACC, Morrow BE, Edelmann L, Kim UJ, Shizuya H, Simon MI, Dumanski JP, Peyrard M, Kedra D, Seroussi E, Fransson I, Tapia I, Bruder CE, O'Brien KP (- 207) Ref: Nature, 402:489, 1999 : PubMed ESTHER: Dunham_1999_Nature_402_489 PubMedSearch: Dunham 1999 Nature 402 489 PubMedID: 10591208 Gene_locus related to this paper: human-CES5A, human-SERHL2 Abstract Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome. Title: Singlet oxygen-mediated inactivation of acetylcholinesterase: a comparison of purified enzyme in solution and enzyme bound to K562 leukemia cells Deadwyler G, Sima PD, Fu Y, Kanofsky JR Ref: Photochem Photobiol, 65:884, 1997 : PubMed ESTHER: Deadwyler_1997_Photochem.Photobiol_65_884 PubMedSearch: Deadwyler 1997 Photochem.Photobiol 65 884 PubMedID: 9155262 Abstract We have compared the singlet oxygen-mediated inactivation of acetylcholinesterase (ACE) in solution with the inactivation of ACE on the surface of K562 leukemia cells. In solution, the actions of the singlet-oxygen quenchers, methionine, azide, disodium [N,N'-ethylenebis (5-sulfosalicylideneimminato)]nickelate(II) (Ni-chelate 1) and disodium [(N,N'-2,3-propionic acid)bis(5-sulfosal-icylideneimminato)] nickelate(II) (Ni-chelate 2) could be explained quantitatively by assuming their only mechanism of action was to quench singlet oxygen. The singlet oxygen quenchers, azide, Ni-chelate 1 and Ni-chelate 2, caused smaller inhibitions in the rate of singlet oxygen-mediated inactivation of ACE on K562 cells than ACE in solution. The effects of these quenchers and of deuterium oxide were interpreted using a mathematical model of singlet-oxygen quenching and diffusion to estimate the lifetime of singlet oxygen near the cell surface. The azide quenching data and the deuterium-oxide data gave lifetimes of 0.9 +/- 0.2 microsecond and 0.45 +/- 0.15 microsecond, respectively. The increases in ACE inactivation lifetime caused by the nickel chelates were anomalously large. The unexpectedly large quenching due to the nickel chelates may have been due to a nonuniform distribution of the chelates in the cytoplasm with a large concentration of the chelate near the cell membrane. Title: Cloning and characterization of a gene (LIP1) which encodes a lipase from the pathogenic yeast Candida albicans Fu Y, Ibrahim AS, Fonzi W, Zhou X, Ramos CF, Ghannoum MA Ref: Microbiology, 143 ( Pt 2):331, 1997 : PubMed ESTHER: Fu_1997_Microbiology_143 ( Pt 2)_331 PubMedSearch: Fu 1997 Microbiology 143 ( Pt 2) 331 PubMedID: 9043110 Gene_locus related to this paper: canal-LIP1 Abstract Extracellular phospholipases are demonstrated virulence factors for a number of pathogenic microbes. The opportunistic pathogen Candida albicans is known to secrete phospholipases and these have been correlated with strain virulence. In an attempt to clone C. albicans genes encoding secreted phospholipases, Saccharomyces cerevisiae was transformed with a C. albicans genomic library and screened for lipolytic activity on egg-yolk agar plates, a traditional screen for phospholipase activity. Two identical clones were obtained which exhibited lipolytic activity. Nucleotide sequence analysis identified an ORF encoding a protein of 351 amino acid residues. Although no extensive homologies were identified, the sequence contained the Gly-X-Ser-X-Gly motif found in prokaryotic and eukaryotic lipases, suggesting a similar activity for the encoded protein. Indeed, culture supernatants from complemented yeast cells contained abundant hydrolytic activity against a triglyceride substrate and had no phospholipase activity. The data suggest that C. albicans, in addition to phospholipases, also has lipases. Southern blot analyses revealed that C. albicans may contain a lipase gene (LIP) family, and that a lipase gene(s) may be present in Candida parapsilosis, Candida tropicalis and Candida krusei, but not in Candida pseudotropicalis, Candida glabrata or S. cerevisiae. Northern blot analyses showed that expression of the LIP1 transcript, the cloned gene which encodes a lipase, was detected only when C. albicans was grown in media containing Tween 80, other Tweens or triglycerides as the sole carbon source, and not in Sabouraud Dextrose Broth or yeast/peptone/dextrose media. Additionally, carbohydrate supplementation inhibited LIP1 expression. Cloning this gene will allow the construction of LIP1-deficient null mutants which will be critical in determining the role of this gene in candidal virulence. | |||||||
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