Fan S

References (16)

Title : Visualization of production and remediation of acetaminophen-induced liver injury by a carboxylesterase-2 enzyme-activatable near-infrared fluorescent probe - Yang_2023_Talanta_269_125418
Author(s) : Yang B , Ding X , Zhang Z , Li J , Fan S , Lai J , Su R , Wang X , Wang B
Ref : Talanta , 269 :125418 , 2023
Abstract : Acetaminophen (APAP) overdose, also known as APAP poisoning, may directly result in hepatic injury, acute liver failure and even death. Nowadays, APAP-induced liver injury (AILI) has become an urgent public health issue in the developing world so the early accurate diagnosis and the revelation of underlying molecular mechanism of AILI are of great significance. As a major detoxifying organ, liver is responsible for metabolizing chemical substances, in which human carboxylesterase-2 (CES2) is present. Hence, we chose CES2 as an effective biomarker for evaluating AILI. By developing a CES2-activatable and water-soluble fluorescent probe PFQ-E with superior affinity (K(m) = 5.9 microM), great sensitivity (limit of detection = 1.05 ng/mL), near-infrared emission (655 nm) and large Stokes shift (135 nm), activity and distribution of CES2 in cells were determined or imaged effectively. More importantly, the APAP-induced hepatotoxicity and the underlying molecular mechanism of pathogenesis of AILI were investigated by measuring the "light-up" response of PFQ-E towards endogenous CES2 in vivo for the first time. Based on the superior performance of the probe PFQ-E for sensing CES2, we believe that it has broad potential in clinical diagnosis and therapy response evaluation of AILI.
ESTHER : Yang_2023_Talanta_269_125418
PubMedSearch : Yang_2023_Talanta_269_125418
PubMedID: 37988783

Title : Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function - Lee_2023_J.Biol.Chem__104586
Author(s) : Lee H , Chofflet N , Liu J , Fan S , Lu Z , Rojas M , Penndorf P , Bailey A , Russell W , Machius M , Ren G , Takahashi H , Rudenko G
Ref : Journal of Biological Chemistry , :104586 , 2023
Abstract : MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs) which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III (FN3) domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that wild-type MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1beta, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1:NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft.
ESTHER : Lee_2023_J.Biol.Chem__104586
PubMedSearch : Lee_2023_J.Biol.Chem__104586
PubMedID: 36889589

Title : Structural insights into the oligomeric effects on catalytic activity of a decameric feruloyl esterase and its application in ferulic acid production - Du_2023_Int.J.Biol.Macromol__126540
Author(s) : Du G , Wang Y , Zhang Y , Yu H , Liu S , Ma X , Cao H , Wei X , Wen B , Li Z , Fan S , Zhou H , Xin F
Ref : Int J Biol Macromol , :126540 , 2023
Abstract : Oligomeric feruloyl esterase (FAE) has great application prospect in industry due to its potentially high stability and fine-tuned activity. However, the relationship between catalytic capability and oligomeric structure remains undetermined. Here we identified and characterized a novel, cold-adapted FAE (BtFae) derived from Bacteroides thetaiotaomicron. Structural studies unraveled that BtFae adopts a barrel-like decameric architecture unique in esterase families. By disrupting the interface, the monomeric variant exhibited significantly reduced catalytic activity and stability toward methyl ferulate, potentially due to its impact on the flexibility of the catalytic triad. Additionally, our results also showed that the monomerization of BtFae severely decreased the ferulic acid release from de-starched wheat bran and insoluble wheat arabinoxylan by 75 % and 80 %, respectively. Collectively, this study revealed novel connections between oligomerization and FAE catalytic function, which will benefit for further protein engineering of FAEs at the quaternary structure level for improved industrial applications.
ESTHER : Du_2023_Int.J.Biol.Macromol__126540
PubMedSearch : Du_2023_Int.J.Biol.Macromol__126540
PubMedID: 37634773
Gene_locus related to this paper: bactn-BT4077

Title : Comparative metaproteomics reveal co-contribution of onion maggot and its gut microbiota to phoxim resistance - Zhou_2023_Ecotoxicol.Environ.Saf_267_115649
Author(s) : Zhou F , Liang Q , Zhao X , Wu X , Fan S , Zhang X
Ref : Ecotoxicology & Environmental Safety , 267 :115649 , 2023
Abstract : Pesticide resistance inflicts significant economic losses on a global scale each year. To address this pressing issue, substantial efforts have been dedicated to unraveling the resistance mechanisms, particularly the newly discovered microbiota-derived pesticide resistance in recent decades. Previous research has predominantly focused on investigating microbiota-derived pesticide resistance from the perspective of the pest host, associated microbes, and their interactions. However, a gap remains in the quantification of the contribution by the pest host and associated microbes to this resistance. In this study, we investigated the toxicity of phoxim by examining one resistant and one sensitive Delia antiqua strain. We also explored the critical role of associated microbiota and host in conferring phoxim resistance. In addition, we used metaproteomics to compare the proteomic profile of the two D. antiqua strains. Lastly, we investigated the activity of detoxification enzymes in D. antiqua larvae and phoxim-degrading gut microbes, and assessed their respective contributions to phoxim resistance in D. antiqua. The results revealed contributions by D. antiqua and its gut bacteria to phoxim resistance. Metaproteomics showed that the two D. antiqua strains expressed different protein profiles. Detoxifying enzymes including Glutathione S-transferases, carboxylesterases, Superoxide Dismutase, Glutathione Peroxidase, and esterase B1 were overexpressed in the resistant strain and dominated in differentially expressed insect proteins. In addition, organophosphorus hydrolases combined with a group of ABC type transporters were overexpressed in the gut microbiota of resistant D. antiqua compared to the sensitive strain. 85.2% variation of the larval mortality resulting from phoxim treatment could be attributed to the combined effects of proteins from both from gut bacteria and D. antiqua, while the individual contribution of proteins from gut bacteria or D. antiqua alone accounted for less than 10% of the variation in larval mortality caused by phoxim. The activity of the overexpressed insect enzymes and the phoxim-degrading activity of gut bacteria in resistant D. antiqua larvae were further confirmed. This work enhances our understanding of microbiota-derived pesticide resistance and illuminates new strategies for controlling pesticide resistance in the context of insect-microbe mutualism.
ESTHER : Zhou_2023_Ecotoxicol.Environ.Saf_267_115649
PubMedSearch : Zhou_2023_Ecotoxicol.Environ.Saf_267_115649
PubMedID: 37913580

Title : Different toxicity to liver and gill of zebrafish by selenium nanoparticles derived from bio\/chemical methods - Fan_2022_Environ.Sci.Pollut.Res.Int__
Author(s) : Fan S , Yang Y , Sun L , Yu B , Dai C , Qu Y
Ref : Environ Sci Pollut Res Int , : , 2022
Abstract : With the wide application of selenium nanoparticles (SeNPs) in pharmaceutical fields, the toxicity assessment is of great significance. In this study, zebrafish were selected as model organisms to compare the toxicity of SeNPs derived from biological and chemical methods. The results showed that the size of bio-SeNPs was about 5-fold bigger than chem-SeNPs. When exposed to SeNPs for 96 h, LC(50) of bio-SeNPs and chem-SeNPs was 1.668 mg/L and 0.699 mg/L, respectively. Compared with the control, the results showed a significant increase in oxidative toxicity index (P < 0.05), such as glutathione (GSH), superoxide dismutase (SOD) of the liver, and gill in SeNPs-treated group. The neurotoxicity index, such as acetylcholinesterase (AchE) and Na(+)-K(+)-ATP enzyme activity, was significantly decreased both in the liver and gill (P < 0.05). It was found that the toxicity of bio-SeNPs to the liver and gill of zebrafish was lower than chem-SeNPs and the toxicity to the liver was higher than gill. In this study, the toxicity of chem-SeNPs and bio-SeNPs to the target organs of zebrafish were systematically evaluated, which provided the basis for the safe application of SeNPs synthesized by different pathways.
ESTHER : Fan_2022_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Fan_2022_Environ.Sci.Pollut.Res.Int__
PubMedID: 35445301

Title : A reverse catalytic triad Asp containing loop shaping a wide substrate binding pocket of a feruloyl esterase from Lactobacillus plantarum - Zhang_2021_Int.J.Biol.Macromol_184_92
Author(s) : Zhang H , Wen B , Liu Y , Du G , Wei X , Khandaker S , Zhou H , Fan S , Wang F , Wang Y , Xin F
Ref : Int J Biol Macromol , 184 :92 , 2021
Abstract : Feruloyl esterase is an indispensable biocatalyst in food processing, pesticide and pharmaceutical industries, catalyzing the cleavage of the ester bond cross-linked between the polysaccharide side chain of hemicellulose and ferulic acid in plant cell walls. LP_0796 from Lactobacillus plantarum was identified as a feruloyl esterase that may have potential applications in the food industry, but the lack of the substrate recognition and catalytic mechanisms limits its application. Here, LP_0796 showed the highest activity towards methyl caffeate at pH 6.6 and 40 degreesC. The crystal structure of LP_0796 was determined at 2.5 A resolution and featured a catalytic triad Asp195-containing loop facing the opposite direction, thus forming a wider substrate binding pocket. Molecular docking simulation and site-directed mutagenesis studies further demonstrated that in addition to the catalytic triad (Ser94, Asp195, His225), Arg125 and Val128 played essential roles in the function of the active site. Our data also showed that Asp mutation of Ala23 and Ile198 increased the catalytic efficiency to 4- and 5-fold, respectively. Collectively, this work provided a better understanding of the substrate recognition and catalytic mechanisms of LP_0796 and may facilitate the future protein design of this important feruloyl esterase.
ESTHER : Zhang_2021_Int.J.Biol.Macromol_184_92
PubMedSearch : Zhang_2021_Int.J.Biol.Macromol_184_92
PubMedID: 34116094
Gene_locus related to this paper: lacpl-LP.0796

Title : Interplay between hevin, SPARC, and MDGAs: modulators of neurexin-neuroligin transsynaptic bridges - Fan_2021_Structure__
Author(s) : Fan S , Gangwar SP , Machius M , Rudenko G
Ref : Structure , : , 2021
Abstract : Hevin is secreted by astrocytes and its synaptogenic effects are antagonized by the related protein, SPARC. Hevin stabilizes neurexin-neuroligin transsynaptic bridges in vivo. A third protein, membrane-tethered MDGA, blocks these bridges. Here, we reveal the molecular underpinnings of a regulatory network formed by this trio of proteins. The hevin FS-EC structure differs from SPARC, in that the EC domain appears rearranged around a conserved core. The FS domain is structurally conserved and it houses nanomolar affinity binding sites for neurexin and neuroligin. SPARC also binds neurexin and neuroligin, competing with hevin, so its antagonist action is rooted in its shortened N-terminal region. Strikingly, the hevin FS domain competes with MDGA for an overlapping binding site on neuroligin, while the hevin EC domain binds the extracellular matrix protein collagen (like SPARC), so that this trio of proteins can regulate neurexin-neuroligin transsynaptic bridges and also extracellular matrix interactions, impacting synapse formation and ultimately neural circuits.
ESTHER : Fan_2021_Structure__
PubMedSearch : Fan_2021_Structure__
PubMedID: 33535026

Title : Challenges in Fluorescence Detection of Chemical Warfare Agent Vapors Using Solid-State Films - Fan_2019_Adv.Mater__e1905785
Author(s) : Fan S , Zhang G , Dennison GH , FitzGerald N , Burn PL , Gentle IR , Shaw PE
Ref : Adv Mater , :e1905785 , 2019
Abstract : Organophosphorus (OP)-based nerve agents are extremely toxic and potent acetylcholinesterase inhibitors and recent attacks involving nerve agents highlight the need for fast detection and intervention. Fluorescence-based detection, where the sensing material undergoes a chemical reaction with the agent causing a measurable change in the luminescence, is one method for sensing and identifying nerve agents. Most studies use the simulants diethylchlorophosphate and di-iso-propylfluorophosphate to evaluate the performance of sensors due to their reduced toxicity relative to OP nerve agents. While detection of nerve agent simulants in solution is relatively widely reported, there are fewer reports on vapor detection using solid-state sensors. Herein, progress in organic semiconductor sensing materials developed for solid-state detection of OP-based nerve agent vapors is reviewed. The effect of acid impurities arising from the hydrolysis of simulants and nerve agents on the efficacy and selectivity of the reported sensing materials is also discussed. Indeed, in some cases it is unclear whether it is the simulant that is detected or the acid hydrolysis products. Finally, it is highlighted that while analyte diffusion into the sensing film is critical in the design of fast, responsive sensing systems, it is an area that is currently not well studied.
ESTHER : Fan_2019_Adv.Mater__e1905785
PubMedSearch : Fan_2019_Adv.Mater__e1905785
PubMedID: 31692155

Title : Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction - Yan_2019_Molecules_24_
Author(s) : Yan M , Zhang Z , Liu Z , Zhang C , Zhang J , Fan S , Yang Z
Ref : Molecules , 24 : , 2019
Abstract : Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug-drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with beta-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing.
ESTHER : Yan_2019_Molecules_24_
PubMedSearch : Yan_2019_Molecules_24_
PubMedID: 31717501
Gene_locus related to this paper: human-CES1

Title : A novel chlorpyrifos hydrolase CPD from Paracoccus sp. TRP: Molecular cloning, characterization and catalytic mechanism - Fan_2018_Electron.J.Biotechnol_31_10
Author(s) : Fan S , Li K , Yan Y , Wang J , Qiao C , Yang T , Jia Y , Zhao B
Ref : Electronic Journal of Biotechnology , 31 :10 , 2018
Abstract : Background: Biodegradation is a reliable approach for efficiently eliminating persistent pollutants such as chlorpyrifos. Despite many bacteria or fungi isolated from contaminated environment and capable of degrading chlorpyrifos, limited enzymes responsible for its degradation have been identified, let alone the catalytic mechanism of the enzymes. Results: In present study, the gene cpd encoding a chlorpyrifos hydrolase was cloned by analysis of genomic sequence of Paracoccus sp. TRP. Phylogenetic analysis and BLAST indicated that CPD was a novel member of organophosphate hydrolases. The purified CPD enzyme, with conserved catalytic triad (Ser155-Asp251-His281) and motif Gly-Asp-Ser-Ala-Gly, was significantly inhibited by PMSF, a serine modifier. Molecular docking between CPD and chlorpyrifos showed that Ser155 was adjacent to chlorpyrifos, which indicated that Ser155 may be the active amino acid involved in chlorpyrifos degradation. This speculation was confirmed by site-directed mutagenesis of Ser155Ala accounting for the decreased activity of CPD towards chlorpyrifos. According to the key role of Ser155 in chlorpyrifos degradation and molecular docking conformation, the nucleophilic catalytic mechanism for chlorpyrifos degradation by CPD was proposed. Conclusion: The novel enzyme CPD was capable of hydrolyze chlorpyrifos and Ser155 played key role during degradation of chlorpyrifos.
ESTHER : Fan_2018_Electron.J.Biotechnol_31_10
PubMedSearch : Fan_2018_Electron.J.Biotechnol_31_10
PubMedID:
Gene_locus related to this paper: 9rhob-a0a1x7ll67

Title : Excellent Degradation Performance of a Versatile Phthalic Acid Esters-Degrading Bacterium and Catalytic Mechanism of Monoalkyl Phthalate Hydrolase - Fan_2018_Int.J.Mol.Sci_19_
Author(s) : Fan S , Wang J , Yan Y , Jia Y
Ref : Int J Mol Sci , 19 : , 2018
Abstract : Despites lots of characterized microorganisms that are capable of degrading phthalic acid esters (PAEs), there are few isolated strains with high activity towards PAEs under a broad range of environmental conditions. In this study, Gordonia sp. YC-JH1 had advantages over its counterparts in terms of di(2-ethylhexyl) phthalate (DEHP) degradation performance. It possessed an excellent degradation ability in the range of 20(-)50 degrees C, pH 5.0(-)12.0, or 0(-)8% NaCl with the optimal degradation condition 40 degrees C and pH 10.0. Therefore, strain YC-JH1 appeared suitable for bioremediation application at various conditions. Metabolites analysis revealed that DEHP was sequentially hydrolyzed by strain YC-JH1 to mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid (PA). The hydrolase MphG1 from strain YC-JH1 hydrolyzed monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-n-hexyl phthalate (MHP), and MEHP to PA. According to molecular docking and molecular dynamics simulation between MphG1 and monoalkyl phthalates (MAPs), some key residues were detected, including the catalytic triad (S125-H291-D259) and the residues R126 and F54 potentially binding substrates. The mutation of these residues accounted for the reduced activity. Together, the mechanism of MphG1 catalyzing MAPs was elucidated, and would shed insights into catalytic mechanism of more hydrolases.
ESTHER : Fan_2018_Int.J.Mol.Sci_19_
PubMedSearch : Fan_2018_Int.J.Mol.Sci_19_
PubMedID: 30231475
Gene_locus related to this paper: 9acto-q2mhh5

Title : DWARF14 is a non-canonical hormone receptor for strigolactone - Yao_2016_Nature_536_469
Author(s) : Yao R , Ming Z , Yan L , Li S , Wang F , Ma S , Yu C , Yang M , Chen L , Li Y , Yan C , Miao D , Sun Z , Yan J , Sun Y , Wang L , Chu J , Fan S , He W , Deng H , Nan F , Li J , Rao Z , Lou Z , Xie D
Ref : Nature , 536 :469 , 2016
Abstract : Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The alpha/beta hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone.
ESTHER : Yao_2016_Nature_536_469
PubMedSearch : Yao_2016_Nature_536_469
PubMedID: 27479325
Gene_locus related to this paper: arath-AtD14

Title : Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs - Zhou_2014_Molecules_19_19718
Author(s) : Zhou M , Liu M , He X , Yu H , Wu D , Yao Y , Fan S , Zhang P , Shi W , Zhong B
Ref : Molecules , 19 :19718 , 2014
Abstract : In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
ESTHER : Zhou_2014_Molecules_19_19718
PubMedSearch : Zhou_2014_Molecules_19_19718
PubMedID: 25438082

Title : The genomic substrate for adaptive radiation in African cichlid fish - Brawand_2014_Nature_513_375
Author(s) : Brawand D , Wagner CE , Li YI , Malinsky M , Keller I , Fan S , Simakov O , Ng AY , Lim ZW , Bezault E , Turner-Maier J , Johnson J , Alcazar R , Noh HJ , Russell P , Aken B , Alfoldi J , Amemiya C , Azzouzi N , Baroiller JF , Barloy-Hubler F , Berlin A , Bloomquist R , Carleton KL , Conte MA , D'Cotta H , Eshel O , Gaffney L , Galibert F , Gante HF , Gnerre S , Greuter L , Guyon R , Haddad NS , Haerty W , Harris RM , Hofmann HA , Hourlier T , Hulata G , Jaffe DB , Lara M , Lee AP , MacCallum I , Mwaiko S , Nikaido M , Nishihara H , Ozouf-Costaz C , Penman DJ , Przybylski D , Rakotomanga M , Renn SC , Ribeiro FJ , Ron M , Salzburger W , Sanchez-Pulido L , Santos ME , Searle S , Sharpe T , Swofford R , Tan FJ , Williams L , Young S , Yin S , Okada N , Kocher TD , Miska EA , Lander ES , Venkatesh B , Fernald RD , Meyer A , Ponting CP , Streelman JT , Lindblad-Toh K , Seehausen O , Di Palma F
Ref : Nature , 513 :375 , 2014
Abstract : Cichlid fishes are famous for large, diverse and replicated adaptive radiations in the Great Lakes of East Africa. To understand the molecular mechanisms underlying cichlid phenotypic diversity, we sequenced the genomes and transcriptomes of five lineages of African cichlids: the Nile tilapia (Oreochromis niloticus), an ancestral lineage with low diversity; and four members of the East African lineage: Neolamprologus brichardi/pulcher (older radiation, Lake Tanganyika), Metriaclima zebra (recent radiation, Lake Malawi), Pundamilia nyererei (very recent radiation, Lake Victoria), and Astatotilapia burtoni (riverine species around Lake Tanganyika). We found an excess of gene duplications in the East African lineage compared to tilapia and other teleosts, an abundance of non-coding element divergence, accelerated coding sequence evolution, expression divergence associated with transposable element insertions, and regulation by novel microRNAs. In addition, we analysed sequence data from sixty individuals representing six closely related species from Lake Victoria, and show genome-wide diversifying selection on coding and regulatory variants, some of which were recruited from ancient polymorphisms. We conclude that a number of molecular mechanisms shaped East African cichlid genomes, and that amassing of standing variation during periods of relaxed purifying selection may have been important in facilitating subsequent evolutionary diversification.
ESTHER : Brawand_2014_Nature_513_375
PubMedSearch : Brawand_2014_Nature_513_375
PubMedID: 25186727
Gene_locus related to this paper: oreni-i3j014 , oreni-i3iw22 , oreni-i3iwp5 , oreni-i3j6k7 , oreni-i3jhp1 , oreni-i3jeq5 , oreni-i3kf65 , oreni-i3j210 , oreni-i3j221 , oreni-i3k9y3 , oreni-i3k5p0 , oreni-i3jwi4 , oreni-i3jv26 , oreni-i3k9m0 , 9cich-a0a3p9d5c0 , oreni-i3knk8 , 9cich-a0a3b4hcr5 , 9cich-a0a3p9dbr8 , oreni-i3k1a6 , oreni-i3jq62 , 9cich-a0a3p9dgm2 , neobr-a0a3q4g2a1 , oreni-i3jdv9 , neobr-a0a3q4hk25 , oreni-i3jbm3 , oreni-i3jbm2 , oreni-i3jds8 , 9cich-a0a3b4hbf8 , 9cich-a0a3p9ars6 , neobr-a0a3q4ghw9 , oreni-i3kx89 , 9cich-a0a3p9d359 , oreni-i3kaa3 , 9cich-a0a3p9bvw3

Title : Genetic amplification of PPME1 in gastric and lung cancer and its potential as a novel therapeutic target - Li_2014_Cancer.Biol.Ther_15_128
Author(s) : Li J , Han S , Qian Z , Su X , Fan S , Fu J , Liu Y , Yin X , Gao Z , Zhang J , Yu DH , Ji Q
Ref : Cancer Biol Ther , 15 :128 , 2014
Abstract : Protein phosphatase methylesterase 1 (PPME1) is a protein phosphatase 2A (PP2A)-specific methyl esterase that negatively regulates PP2A through demethylation at its carboxy terminal leucine 309 residue. Emerging evidence shows that the upregulation of PPME1 is associated with poor prognosis in glioblastoma patients. By performing an array comparative genomic hybridization analysis to detect copy number changes, we have been the first to identify PPME1 gene amplification in 3.8% (5/131) of Chinese gastric cancer (GC) samples and 3.1% (4/124) of Chinese lung cancer (LC) samples. This PPME1 gene amplification was confirmed by fluorescence in situ hybridization analysis and is correlated with elevated protein expression, as determined by immunohistochemistry analysis. To further investigate the role of PPME1 amplification in tumor growth, short-hairpin RNA-mediated gene silencing was employed. A knockdown of PPME1 expression resulted in a significant inhibition of cell proliferation and induction of cell apoptosis in PPME1-amplified human cancer cell lines SNU668 (GC) and Oka-C1 (LC), but not in nonamplified MKN1 (GC) and HCC95 (LC) cells. The PPME1 gene knockdown also led to a consistent decrease in PP2A demethylation at leucine 309, which was correlated with the downregulation of cellular Erk and AKT phosphorylation. Our data indicate that PPME1 could be an attractive therapeutic target for a subset of GCs and LCs.
ESTHER : Li_2014_Cancer.Biol.Ther_15_128
PubMedSearch : Li_2014_Cancer.Biol.Ther_15_128
PubMedID: 24253382
Gene_locus related to this paper: human-PPME1

Title : Association of the G-250A promoter polymorphism in the hepatic lipase gene with the risk of type 2 diabetes mellitus - Ou_2013_Ann.Endocrinol.(Paris)_74_45
Author(s) : Ou L , Yao L , Guo Y , Fan S
Ref : Ann Endocrinol (Paris) , 74 :45 , 2013
Abstract : OBJECTIVE: Variants in hepatic lipase (HL) gene which is a lipolytic enzyme involved in the metabolism of plasma lipoprotein and regulating lipid and lipoprotein metabolism are potential candidate genes for type 2 diabetes. Association of the polymorphisms in the promoter region of the HL gene (LIPC) to the plasma HDL-C concentration has been investigated. In this study, we investigated whether the G-250A polymorphism of LIPC is associated with type 2 diabetes in Chinese Han population. SUBJECTS AND
METHODS: A total of 130 patients with type 2 diabetes and 133 healthy subjects as control were randomly selected from January 2008 to January 2011 in endocrine wards of Zhengzhou People's Hospital. The G-250A polymorphisms were studied by polymerase chain reaction and restriction fragment length polymorphism. A logistic regression analysis was performed to determine the association between the rare allele and type 2 diabetes mellitus.
RESULTS: The frequency of the -250A allele was 0.297 in the T2DM group and 0.388 in the control group (P<0.05), with the difference remaining significant.
CONCLUSIONS: Patients who are carrying of the -250A allele in the promoter of the LIPC gene are susceptible to type 2 diabetes mellitus in Chinese Han population.
ESTHER : Ou_2013_Ann.Endocrinol.(Paris)_74_45
PubMedSearch : Ou_2013_Ann.Endocrinol.(Paris)_74_45
PubMedID: 23351562