Brown A

References (11)

Title : Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs - Wang_2012_Neurotoxicol_33_169
Author(s) : Wang Y , Oguntayo S , Wei Y , Wood E , Brown A , Jensen N , Auta J , Guiodotti A , Doctor BP , Nambiar MP
Ref : Neurotoxicology , 33 :169 , 2012
Abstract : The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at alpha5-, alpha2-, and alpha3- but low intrinsic efficacy at alpha1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 mug/kg pyridostigmine bromide 30 min prior to 2x LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2x LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.
ESTHER : Wang_2012_Neurotoxicol_33_169
PubMedSearch : Wang_2012_Neurotoxicol_33_169
PubMedID: 22245390

Title : Population genomic sequencing of Coccidioides fungi reveals recent hybridization and transposon control - Neafsey_2010_Genome.Res_20_938
Author(s) : Neafsey DE , Barker BM , Sharpton TJ , Stajich JE , Park DJ , Whiston E , Hung CY , McMahan C , White J , Sykes S , Heiman D , Young S , Zeng Q , Abouelleil A , Aftuck L , Bessette D , Brown A , FitzGerald M , Lui A , Macdonald JP , Priest M , Orbach MJ , Galgiani JN , Kirkland TN , Cole GT , Birren BW , Henn MR , Taylor JW , Rounsley SD
Ref : Genome Res , 20 :938 , 2010
Abstract : We have sequenced the genomes of 18 isolates of the closely related human pathogenic fungi Coccidioides immitis and Coccidioides posadasii to more clearly elucidate population genomic structure, bringing the total number of sequenced genomes for each species to 10. Our data confirm earlier microsatellite-based findings that these species are genetically differentiated, but our population genomics approach reveals that hybridization and genetic introgression have recently occurred between the two species. The directionality of introgression is primarily from C. posadasii to C. immitis, and we find more than 800 genes exhibiting strong evidence of introgression in one or more sequenced isolates. We performed PCR-based sequencing of one region exhibiting introgression in 40 C. immitis isolates to confirm and better define the extent of gene flow between the species. We find more coding sequence than expected by chance in the introgressed regions, suggesting that natural selection may play a role in the observed genetic exchange. We find notable heterogeneity in repetitive sequence composition among the sequenced genomes and present the first detailed genome-wide profile of a repeat-induced point mutation (RIP) process distinctly different from what has been observed in Neurospora. We identify promiscuous HLA-I and HLA-II epitopes in both proteomes and discuss the possible implications of introgression and population genomic data for public health and vaccine candidate prioritization. This study highlights the importance of population genomic data for detecting subtle but potentially important phenomena such as introgression.
ESTHER : Neafsey_2010_Genome.Res_20_938
PubMedSearch : Neafsey_2010_Genome.Res_20_938
PubMedID: 20516208
Gene_locus related to this paper: cocp7-c5p2u8 , cocp7-c5p5s7 , cocp7-c5pe69 , cocp7-c5pf68 , cocp7-c5pgk6 , cocim-j3ka92 , cocp7-c5phc6 , cocps-e9d3i4 , cocit-a0a0j8rde7 , cocps-e9csw0 , cocps-e9dgm8

Title : Evolution of genes and genomes on the Drosophila phylogeny - Clark_2007_Nature_450_203
Author(s) : Clark AG , Eisen MB , Smith DR , Bergman CM , Oliver B , Markow TA , Kaufman TC , Kellis M , Gelbart W , Iyer VN , Pollard DA , Sackton TB , Larracuente AM , Singh ND , Abad JP , Abt DN , Adryan B , Aguade M , Akashi H , Anderson WW , Aquadro CF , Ardell DH , Arguello R , Artieri CG , Barbash DA , Barker D , Barsanti P , Batterham P , Batzoglou S , Begun D , Bhutkar A , Blanco E , Bosak SA , Bradley RK , Brand AD , Brent MR , Brooks AN , Brown RH , Butlin RK , Caggese C , Calvi BR , Bernardo de Carvalho A , Caspi A , Castrezana S , Celniker SE , Chang JL , Chapple C , Chatterji S , Chinwalla A , Civetta A , Clifton SW , Comeron JM , Costello JC , Coyne JA , Daub J , David RG , Delcher AL , Delehaunty K , Do CB , Ebling H , Edwards K , Eickbush T , Evans JD , Filipski A , Findeiss S , Freyhult E , Fulton L , Fulton R , Garcia AC , Gardiner A , Garfield DA , Garvin BE , Gibson G , Gilbert D , Gnerre S , Godfrey J , Good R , Gotea V , Gravely B , Greenberg AJ , Griffiths-Jones S , Gross S , Guigo R , Gustafson EA , Haerty W , Hahn MW , Halligan DL , Halpern AL , Halter GM , Han MV , Heger A , Hillier L , Hinrichs AS , Holmes I , Hoskins RA , Hubisz MJ , Hultmark D , Huntley MA , Jaffe DB , Jagadeeshan S , Jeck WR , Johnson J , Jones CD , Jordan WC , Karpen GH , Kataoka E , Keightley PD , Kheradpour P , Kirkness EF , Koerich LB , Kristiansen K , Kudrna D , Kulathinal RJ , Kumar S , Kwok R , Lander E , Langley CH , Lapoint R , Lazzaro BP , Lee SJ , Levesque L , Li R , Lin CF , Lin MF , Lindblad-Toh K , Llopart A , Long M , Low L , Lozovsky E , Lu J , Luo M , Machado CA , Makalowski W , Marzo M , Matsuda M , Matzkin L , McAllister B , McBride CS , McKernan B , McKernan K , Mendez-Lago M , Minx P , Mollenhauer MU , Montooth K , Mount SM , Mu X , Myers E , Negre B , Newfeld S , Nielsen R , Noor MA , O'Grady P , Pachter L , Papaceit M , Parisi MJ , Parisi M , Parts L , Pedersen JS , Pesole G , Phillippy AM , Ponting CP , Pop M , Porcelli D , Powell JR , Prohaska S , Pruitt K , Puig M , Quesneville H , Ram KR , Rand D , Rasmussen MD , Reed LK , Reenan R , Reily A , Remington KA , Rieger TT , Ritchie MG , Robin C , Rogers YH , Rohde C , Rozas J , Rubenfield MJ , Ruiz A , Russo S , Salzberg SL , Sanchez-Gracia A , Saranga DJ , Sato H , Schaeffer SW , Schatz MC , Schlenke T , Schwartz R , Segarra C , Singh RS , Sirot L , Sirota M , Sisneros NB , Smith CD , Smith TF , Spieth J , Stage DE , Stark A , Stephan W , Strausberg RL , Strempel S , Sturgill D , Sutton G , Sutton GG , Tao W , Teichmann S , Tobari YN , Tomimura Y , Tsolas JM , Valente VL , Venter E , Venter JC , Vicario S , Vieira FG , Vilella AJ , Villasante A , Walenz B , Wang J , Wasserman M , Watts T , Wilson D , Wilson RK , Wing RA , Wolfner MF , Wong A , Wong GK , Wu CI , Wu G , Yamamoto D , Yang HP , Yang SP , Yorke JA , Yoshida K , Zdobnov E , Zhang P , Zhang Y , Zimin AV , Baldwin J , Abdouelleil A , Abdulkadir J , Abebe A , Abera B , Abreu J , Acer SC , Aftuck L , Alexander A , An P , Anderson E , Anderson S , Arachi H , Azer M , Bachantsang P , Barry A , Bayul T , Berlin A , Bessette D , Bloom T , Blye J , Boguslavskiy L , Bonnet C , Boukhgalter B , Bourzgui I , Brown A , Cahill P , Channer S , Cheshatsang Y , Chuda L , Citroen M , Collymore A , Cooke P , Costello M , D'Aco K , Daza R , De Haan G , DeGray S , DeMaso C , Dhargay N , Dooley K , Dooley E , Doricent M , Dorje P , Dorjee K , Dupes A , Elong R , Falk J , Farina A , Faro S , Ferguson D , Fisher S , Foley CD , Franke A , Friedrich D , Gadbois L , Gearin G , Gearin CR , Giannoukos G , Goode T , Graham J , Grandbois E , Grewal S , Gyaltsen K , Hafez N , Hagos B , Hall J , Henson C , Hollinger A , Honan T , Huard MD , Hughes L , Hurhula B , Husby ME , Kamat A , Kanga B , Kashin S , Khazanovich D , Kisner P , Lance K , Lara M , Lee W , Lennon N , Letendre F , LeVine R , Lipovsky A , Liu X , Liu J , Liu S , Lokyitsang T , Lokyitsang Y , Lubonja R , Lui A , Macdonald P , Magnisalis V , Maru K , Matthews C , McCusker W , McDonough S , Mehta T , Meldrim J , Meneus L , Mihai O , Mihalev A , Mihova T , Mittelman R , Mlenga V , Montmayeur A , Mulrain L , Navidi A , Naylor J , Negash T , Nguyen T , Nguyen N , Nicol R , Norbu C , Norbu N , Novod N , O'Neill B , Osman S , Markiewicz E , Oyono OL , Patti C , Phunkhang P , Pierre F , Priest M , Raghuraman S , Rege F , Reyes R , Rise C , Rogov P , Ross K , Ryan E , Settipalli S , Shea T , Sherpa N , Shi L , Shih D , Sparrow T , Spaulding J , Stalker J , Stange-Thomann N , Stavropoulos S , Stone C , Strader C , Tesfaye S , Thomson T , Thoulutsang Y , Thoulutsang D , Topham K , Topping I , Tsamla T , Vassiliev H , Vo A , Wangchuk T , Wangdi T , Weiand M , Wilkinson J , Wilson A , Yadav S , Young G , Yu Q , Zembek L , Zhong D , Zimmer A , Zwirko Z , Alvarez P , Brockman W , Butler J , Chin C , Grabherr M , Kleber M , Mauceli E , MacCallum I
Ref : Nature , 450 :203 , 2007
Abstract : Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
ESTHER : Clark_2007_Nature_450_203
PubMedSearch : Clark_2007_Nature_450_203
PubMedID: 17994087
Gene_locus related to this paper: droan-ACHE , droan-b3lx10 , droan-b3lx75 , droan-b3lxv7 , droan-b3ly87 , droan-b3lyh4 , droan-b3lyh5 , droan-b3lyh7 , droan-b3lyh9 , droan-b3lyi0 , droan-b3lyi2 , droan-b3lyi3 , droan-b3lyi4 , droan-b3lyj8 , droan-b3lyj9 , droan-b3lyx4 , droan-b3lyx5 , droan-b3lyx6 , droan-b3lyx7 , droan-b3lyx9 , droan-b3lz72 , droan-b3m1x3 , droan-b3m2d4 , droan-b3m3d9 , droan-b3m4e3 , droan-b3m5w1 , droan-b3m6i7 , droan-b3m7v2 , droan-b3m9a5 , droan-b3m9f4 , droan-b3m9p3 , droan-b3m254 , droan-b3m259 , droan-b3m260 , droan-b3m262 , droan-b3m524 , droan-b3m635 , droan-b3m845 , droan-b3m846 , droan-b3md01 , droan-b3mdh7 , droan-b3mdm6 , droan-b3mdw8 , droan-b3mee1 , droan-b3mf47 , droan-b3mf48 , droan-b3mg94 , droan-b3mgk2 , droan-b3mgn6 , droan-b3mii3 , droan-b3mjk2 , droan-b3mjk3 , droan-b3mjk4 , droan-b3mjk5 , droan-b3mjl2 , droan-b3mjl4 , droan-b3mjl7 , droan-b3mjl9 , droan-b3mjm8 , droan-b3mjm9 , droan-b3mjs6 , droan-b3mkr0 , droan-b3ml20 , droan-b3mly4 , droan-b3mly5 , droan-b3mly6 , droan-b3mmm8 , droan-b3mnb5 , droan-b3mny9 , droan-b3mtj5 , droan-b3muw4 , droan-b3muw8 , droan-b3n0e7 , droan-b3n2j7 , droan-b3n247 , droan-c5idb2 , droer-ACHE , droer-b3n5c7 , droer-b3n5d0 , droer-b3n5d8 , droer-b3n5d9 , droer-b3n5t7 , droer-b3n5y4 , droer-b3n7d2 , droer-b3n7d3 , droer-b3n7d4 , droer-b3n7k8 , droer-b3n8e4 , droer-b3n8f7 , droer-b3n8f8 , droer-b3n9e1 , droer-b3n319 , droer-b3n547 , droer-b3n549 , droer-b3n558 , droer-b3n560 , droer-b3n577 , droer-b3n612 , droer-b3nar5 , droer-b3nb91 , droer-b3nct9 , droer-b3nd53 , droer-b3ndh9 , droer-b3ndq8 , droer-b3ne66 , droer-b3ne67 , droer-b3ne97 , droer-b3nfk3 , droer-b3nfq9 , droer-b3nim7 , droer-b3nkn2 , droer-b3nm11 , droer-b3nmh4 , droer-b3nmy2 , droer-b3npx2 , droer-b3npx3 , droer-b3nq76 , droer-b3nqg9 , droer-b3nqm8 , droer-b3nr28 , droer-b3nrd3 , droer-b3nst4 , droer-b3nwa7 , droer-b3nyp5.1 , droer-b3nyp5.2 , droer-b3nyp6 , droer-b3nyp7 , droer-b3nyp8 , droer-b3nyp9 , droer-b3nyq3 , droer-b3nz06 , droer-b3nz14 , droer-b3nzj0 , droer-b3p0c0 , droer-b3p0c1 , droer-b3p0c2 , droer-b3p2x6 , droer-b3p2x7 , droer-b3p2x9 , droer-b3p2y1 , droer-b3p2y2 , droer-b3p6d4 , droer-b3p6d5 , droer-b3p6w3 , droer-b3p7b4 , droer-b3p7h9 , droer-b3p152 , droer-b3p486 , droer-b3p487 , droer-b3p488 , droer-b3p489 , droer-EST6 , droer-q670j5 , drogr-ACHE , drogr-b4iwp3 , drogr-b4iww3 , drogr-b4iwy3 , drogr-b4ixf7 , drogr-b4ixh4 , drogr-b4iyz5 , drogr-b4j2s2 , drogr-b4j2u8 , drogr-b4j3u1 , drogr-b4j3v3 , drogr-b4j4g7 , drogr-b4j4x9 , drogr-b4j6e6 , drogr-b4j9c9 , drogr-b4j9y4 , drogr-b4j156 , drogr-b4j384 , drogr-b4j605 , drogr-b4j685 , drogr-b4ja76 , drogr-b4jay5 , drogr-b4jcf0 , drogr-b4jcf1 , drogr-b4jdg6 , drogr-b4jdg7 , drogr-b4jdh6 , drogr-b4jdz1 , drogr-b4jdz2 , drogr-b4jdz4 , drogr-b4je66 , drogr-b4je79 , drogr-b4je82 , drogr-b4je88 , drogr-b4je89 , drogr-b4je90 , drogr-b4je91 , drogr-b4jf76 , drogr-b4jf79 , drogr-b4jf80 , drogr-b4jf81 , drogr-b4jf82 , drogr-b4jf83 , drogr-b4jf84 , drogr-b4jf85 , drogr-b4jf87 , drogr-b4jf91 , drogr-b4jf92 , drogr-b4jg66 , drogr-b4jgh0 , drogr-b4jgh1 , drogr-b4jgr9 , drogr-b4ji67 , drogr-b4jls2 , drogr-b4jnh9 , drogr-b4jpc6 , drogr-b4jpq3 , drogr-b4jpx9 , drogr-b4jql2 , drogr-b4jrh5 , drogr-b4jsb2 , drogr-b4jth3 , drogr-b4jti1 , drogr-b4jul5 , drogr-b4jur4 , drogr-b4jvh3 , drogr-b4jz00 , drogr-b4jz03 , drogr-b4jz04 , drogr-b4jz05 , drogr-b4jzh2 , drogr-b4k0u2 , drogr-b4k2r1 , drogr-b4k234 , drogr-b4k235 , drome-BEM46 , drome-CG3734 , drome-CG9953 , drome-CG11626 , drome-GH02439 , dromo-ACHE , dromo-b4k6a7 , dromo-b4k6a8 , dromo-b4k6q8 , dromo-b4k6q9 , dromo-b4k6r1 , dromo-b4k6r3 , dromo-b4k6r4 , dromo-b4k6r5 , dromo-b4k6r6 , dromo-b4k6r7 , dromo-b4k6r8 , dromo-b4k6r9 , dromo-b4k6s0 , dromo-b4k6s1 , dromo-b4k6s2 , dromo-b4k9c7 , dromo-b4k9d3 , dromo-b4k571 , dromo-b4k721 , dromo-b4ka74 , dromo-b4ka89 , dromo-b4kaj4 , dromo-b4kc20 , dromo-b4kcl2 , dromo-b4kcl3 , dromo-b4kd55.1 , dromo-b4kd55.2 , dromo-b4kd56 , dromo-b4kd57 , dromo-b4kde1 , dromo-b4kdg2 , dromo-b4kdh4 , dromo-b4kdh5 , dromo-b4kdh6 , dromo-A0A0Q9XDF2 , dromo-b4kdh8.1 , dromo-b4kdh8.2 , dromo-b4kg04 , dromo-b4kg05 , dromo-b4kg06 , dromo-b4kg16 , dromo-b4kg44 , dromo-b4kg90 , dromo-b4kh20 , dromo-b4kh21 , dromo-b4kht7 , dromo-b4kid3 , dromo-b4kik0 , dromo-b4kjx0 , dromo-b4kki1 , dromo-b4kkp6 , dromo-b4kkp8 , dromo-b4kkq8 , dromo-b4kkr0 , dromo-b4kkr3 , dromo-b4kkr4 , dromo-b4kks0 , dromo-b4kks1 , dromo-b4kks2 , dromo-b4kla1 , dromo-b4klv8 , dromo-b4knt4 , dromo-b4kp08 , dromo-b4kp16 , dromo-b4kqa6 , dromo-b4kqa7 , dromo-b4kqa8 , dromo-b4kqh1 , dromo-b4kst4 , dromo-b4ksy6 , dromo-b4kt84 , dromo-b4ktf5 , dromo-b4ktf6 , dromo-b4kvl3 , dromo-b4kvw2 , dromo-b4kwv4 , dromo-b4kwv5 , dromo-b4kxz6 , dromo-b4ky12 , dromo-b4ky36 , dromo-b4ky44 , dromo-b4kzu7 , dromo-b4l0n8 , dromo-b4l4u5 , dromo-b4l6l9 , dromo-b4l084 , drope-ACHE , drope-b4g3s6 , drope-b4g4p7 , drope-b4g6v4 , drope-b4g8m0 , drope-b4g8n6 , drope-b4g8n7 , drope-b4g9p2 , drope-b4g815 , drope-b4g816 , drope-b4gat7 , drope-b4gav5 , drope-b4gb05 , drope-b4gc08 , drope-b4gcr3 , drope-b4gdk2 , drope-b4gdl9 , drope-b4gdv9 , drope-b4gei8 , drope-b4gei9 , drope-b4gej0 , drope-b4ghz9 , drope-b4gj62 , drope-b4gj64 , drope-b4gj74 , drope-b4gkf4 , drope-b4gkv2 , drope-b4gky9 , drope-b4gl76 , drope-b4glf3 , drope-b4gmt3 , drope-b4gmt7 , drope-b4gmt9 , drope-b4gmu2 , drope-b4gmu3 , drope-b4gmu4 , drope-b4gmu5 , drope-b4gmu6 , drope-b4gmu7 , drope-b4gmv1 , drope-b4gn08 , drope-b4gpa7 , drope-b4gq13 , drope-b4grh7 , drope-b4gsf9 , drope-b4gsw4 , drope-b4gsw5 , drope-b4gsx2 , drope-b4gsx7 , drope-b4gsy6 , drope-b4gsy7 , drope-b4guj8 , drope-b4gw36 , drope-b4gzc2 , drope-b4gzc6 , drope-b4gzc7 , drope-b4h4p9 , drope-b4h5l3 , drope-b4h6a0 , drope-b4h6a8 , drope-b4h6a9 , drope-b4h6b0 , drope-b4h7m7 , drope-b4h462 , drope-b4h601 , drope-b4h602 , drope-b4hay1 , drope-b4hb18 , drope-est5a , drope-est5b , drope-est5c , drops-ACHE , drops-b5dhd2 , drops-b5dk96 , drops-b5dpe3 , drops-b5drp9 , drops-b5dwa7 , drops-b5dwa8 , drops-b5dz85 , drops-b5dz86 , drops-est5a , drops-est5b , drops-q29bq2 , drops-q29dd7 , drops-q29ew0 , drops-q291d5 , drops-q291e8 , drops-q293n1 , drops-q293n4 , drops-q293n5 , drops-q293n6 , drops-q294n6 , drops-q294n7 , drops-q294n9 , drops-q294p4 , drose-b4he97 , drose-b4hfu2 , drose-b4hg54 , drose-b4hga0 , drose-b4hgu9 , drose-b4hgv0 , drose-b4hgv3 , drose-b4hgv4 , drose-b4hhm8 , drose-b4hhs6 , drose-b4hie4 , drose-b4him9 , drose-b4hk63 , drose-b4hkj5 , drose-b4hr07 , drose-b4hr81 , drose-b4hre7 , drose-b4hs13 , drose-b4hsj9 , drose-b4hsk0 , drose-b4hsm8 , drose-b4hvr5 , drose-b4hwr7 , drose-b4hwr8 , drose-b4hwr9 , drose-b4hws6 , drose-b4hws7 , drose-b4hwt0 , drose-b4hwt2 , drose-b4hwu1 , drose-b4hwu2 , drose-b4hxs9 , drose-b4hxu4 , drose-b4hxz1 , drose-b4hyp8 , drose-b4hyp9 , drose-b4hyq0 , drose-b4hyz4 , drose-b4hyz5 , drose-b4i1k8 , drose-b4i2f3 , drose-b4i2w5 , drose-b4i4u3 , drose-b4i4u7 , drose-b4i4u9 , drose-b4i4v0 , drose-b4i4v1 , drose-b4i4v4 , drose-b4i4v5 , drose-b4i4v6 , drose-b4i4v7 , drose-b4i4v8 , drose-b4i4w0 , drose-b4i7s6 , drose-b4i133 , drose-b4i857 , drose-b4iam7 , drose-b4iam9 , drose-b4iaq6 , drose-b4icf6 , drose-b4icf7 , drose-b4id80 , drose-b4ifc5 , drose-b4ihv9 , drose-b4iie9 , drose-b4ilj8 , drose-b4in13 , drose-b4inj9 , drosi-ACHE , drosi-aes04a , drosi-b4nsh8 , drosi-b4q3d7 , drosi-b4q4w5 , drosi-b4q4y7 , drosi-b4q6h6 , drosi-b4q7u2 , drosi-b4q7u3 , drosi-b4q9c6 , drosi-b4q9c7 , drosi-b4q9d3 , drosi-b4q9d4 , drosi-b4q9r0 , drosi-b4q9r1 , drosi-b4q9r3 , drosi-b4q9s2 , drosi-b4q9s3 , drosi-b4q429 , drosi-b4q530 , drosi-b4q734 , drosi-b4q782 , drosi-b4q783 , drosi-b4q942 , drosi-b4qet1 , drosi-b4qfv6 , drosi-b4qge5 , drosi-b4qgh5 , drosi-b4qgs5 , drosi-b4qhf3 , drosi-b4qhf4 , drosi-b4qhi5 , drosi-b4qjr2 , drosi-b4qjr3 , drosi-b4qjv6 , drosi-b4qk23 , drosi-b4qk51 , drosi-b4qlt1 , drosi-b4qlz9 , drosi-b4qmn9 , drosi-b4qrq7 , drosi-b4qs01 , drosi-b4qs57 , drosi-b4qs82 , drosi-b4qs83 , drosi-b4qs84 , drosi-b4qs85 , drosi-b4qs86 , drosi-b4qsq1 , drosi-b4quk6 , drosi-b4qvg5 , drosi-b4qvg6 , drosi-b4qzn2 , drosi-b4qzn3 , drosi-b4qzn5 , drosi-b4qzn7 , drosi-b4qzn8 , drosi-b4qzp2 , drosi-b4qzp3 , drosi-b4qzp4 , drosi-b4qzp5 , drosi-b4qzp6 , drosi-b4qzp7 , drosi-b4r1a4 , drosi-b4r025 , drosi-b4r207 , drosi-b4r662 , drosi-este6 , drosi-q670k8 , drovi-ACHE , drovi-b4lev2 , drovi-b4lf33 , drovi-b4lf51 , drovi-b4lg54 , drovi-b4lg72 , drovi-b4lgc6 , drovi-b4lgd5 , drovi-b4lgg0 , drovi-b4lgk5 , drovi-b4lgn2 , drovi-b4lh17 , drovi-b4lh18 , drovi-b4lk43 , drovi-b4ll59 , drovi-b4ll60 , drovi-b4llm5 , drovi-b4lln3 , drovi-b4lmk4 , drovi-b4lmp0 , drovi-b4lnr4 , drovi-b4lp47 , drovi-b4lpd0 , drovi-b4lps0 , drovi-b4lqc6 , drovi-b4lr00 , drovi-b4lrp6 , drovi-b4lrw2 , drovi-b4lse7 , drovi-b4lse9 , drovi-b4lsf0 , drovi-b4lsn0 , drovi-b4lsq5 , drovi-b4lt32 , drovi-b4ltr1 , drovi-b4lui7 , drovi-b4lui9 , drovi-b4luj8 , drovi-b4luk0 , drovi-b4luk3 , drovi-b4luk8 , drovi-b4luk9 , drovi-b4lul0 , drovi-b4lve2 , drovi-b4lxi9 , drovi-b4lxj8 , drovi-b4lyf3 , drovi-b4lyq2 , drovi-b4lyq3 , drovi-b4lz07 , drovi-b4lz13 , drovi-b4lz14 , drovi-b4lz15 , drovi-b4m0j7 , drovi-b4m0s0 , drovi-b4m2b6 , drovi-b4m4h7 , drovi-b4m4h8 , drovi-b4m4i0 , drovi-b4m4i2 , drovi-b4m4i3.A , drovi-b4m4i3.B , drovi-b4m4i4 , drovi-b4m4i5 , drovi-b4m4i6 , drovi-b4m4i7 , drovi-b4m4i8 , drovi-b4m4i9 , drovi-b4m4j2 , drovi-b4m5a0 , drovi-b4m5a1 , drovi-b4m5a2 , drovi-b4m6b9 , drovi-b4m7k9 , drovi-b4m9g9 , drovi-b4m9h0 , drovi-b4m564 , drovi-b4m599 , drovi-b4m918 , drovi-b4mb87 , drovi-b4mc71 , drovi-b4mfa4 , drowi-ACHE , drowi-b4mjb9 , drowi-b4mkt7 , drowi-b4mlc1 , drowi-b4mp68 , drowi-b4mqe9 , drowi-b4mqf0.2 , drowi-b4mqf1 , drowi-b4mqf3 , drowi-b4mqf4 , drowi-b4mqf5 , drowi-b4mqq6 , drowi-b4mrd1 , drowi-b4mrk3 , drowi-b4mtl5 , drowi-b4mug2 , drowi-b4muj8 , drowi-b4mv18 , drowi-b4mw32 , drowi-b4mw85 , drowi-b4mwp2 , drowi-b4mwp6 , drowi-b4mwq5 , drowi-b4mwr0 , drowi-b4mwr8 , drowi-b4mwr9 , drowi-b4mwt1 , drowi-b4mwz7 , drowi-b4mxn5 , drowi-b4my54 , drowi-b4myg1 , drowi-b4myh5 , drowi-b4n0d4 , drowi-b4n1a7 , drowi-b4n1c8 , drowi-b4n3s9 , drowi-b4n3x7 , drowi-b4n4x9 , drowi-b4n4y0 , drowi-b4n6m1 , drowi-b4n6n0 , drowi-b4n6n7 , drowi-b4n6u6 , drowi-b4n7s6 , drowi-b4n7s7 , drowi-b4n7s8 , drowi-b4n899.1 , drowi-b4n8a1 , drowi-b4n8a2 , drowi-b4n8a3 , drowi-b4n8a4 , drowi-b4n8a9 , drowi-b4n023 , drowi-b4n075 , drowi-b4n543 , drowi-b4n888 , drowi-b4n889 , drowi-b4n891 , drowi-b4n893 , drowi-b4n895 , drowi-b4n897 , drowi-b4n898 , drowi-b4n899.2 , drowi-b4nae3 , drowi-b4ner8 , drowi-b4ng76 , drowi-b4nga7 , drowi-b4ngb5 , drowi-b4nhz9 , drowi-b4nj18 , drowi-b4nj19 , drowi-b4nja7 , drowi-b4nja8 , drowi-b4nja9 , drowi-b4njk8 , drowi-b4nkc8 , drowi-b4nky0 , drowi-b4nl36 , drowi-b4nm27 , drowi-b4nn59 , drowi-b4nnc1 , drowi-b4nng1 , drowi-b4nng2 , droya-ACHE , droya-aes04 , droya-b4itg2 , droya-b4itg6 , droya-b4itu9 , droya-b4iuv4 , droya-b4iuv5 , droya-b4nxe6 , droya-b4nxg5 , droya-b4nxg6 , droya-b4nxg8 , droya-b4nxw4 , droya-b4ny57 , droya-b4ny58 , droya-b4ny86 , droya-b4nzz8 , droya-b4p0b5 , droya-b4p0q9 , droya-b4p0r0 , droya-b4p0r7 , droya-b4p0r8 , droya-b4p0r9 , droya-b4p0s0 , droya-b4p0s2 , droya-b4p0t0 , droya-b4p0t1 , droya-b4p3h4 , droya-b4p3x8 , droya-b4p5g8 , droya-b4p6c9 , droya-b4p6l9 , droya-b4p6r1 , droya-b4p6r2 , droya-b4p7u4 , droya-b4p8w7 , droya-b4p023 , droya-b4p241 , droya-b4p774 , droya-b4pat9 , droya-b4pbl1 , droya-b4pd22 , droya-b4pd70 , droya-b4pdm8 , droya-b4pet9 , droya-b4pff9 , droya-b4pga7 , droya-b4pgu0 , droya-b4pig3 , droya-b4pjt8 , droya-b4pka2 , droya-b4plh2 , droya-b4pma3 , droya-b4pmv3 , droya-b4pmv4 , droya-b4pmv5 , droya-b4pn92 , droya-b4pp65 , droya-b4ppc5 , droya-b4ppc6 , droya-b4ppc7 , droya-b4ppc8 , droya-b4pq03 , droya-b4prg6B , droya-b4prg9 , droya-b4prh3 , droya-b4prh4 , droya-b4prh6 , droya-b4prh7 , droya-b4psz8 , droya-b4psz9 , droya-b4pv22 , droya-b4q0g5 , droya-b4q246 , droya-EST6 , droya-q71d76 , drowi-b4n7m9 , drope-b4gkk1 , droer-b3n5s3 , drose-b4i1w5 , drowi-a0a0q9x0t3 , drogr-b4jvm7 , dromo-b4ku70 , drovi-b4mcn9 , drovi-b4lty2 , drogr-b4jdu1 , drovi-a0a0q9wiq8 , dromo-b4kf70 , drosi-b2zi86 , droya-b4p2y4 , drose-b2zic5 , droer-b3n895

Title : Genome of the opportunistic pathogen Streptococcus sanguinis - Xu_2007_J.Bacteriol_189_3166
Author(s) : Xu P , Alves JM , Kitten T , Brown A , Chen Z , Ozaki LS , Manque P , Ge X , Serrano MG , Puiu D , Hendricks S , Wang Y , Chaplin MD , Akan D , Paik S , Peterson DL , Macrina FL , Buck GA
Ref : Journal of Bacteriology , 189 :3166 , 2007
Abstract : The genome of Streptococcus sanguinis is a circular DNA molecule consisting of 2,388,435 bp and is 177 to 590 kb larger than the other 21 streptococcal genomes that have been sequenced. The G+C content of the S. sanguinis genome is 43.4%, which is considerably higher than the G+C contents of other streptococci. The genome encodes 2,274 predicted proteins, 61 tRNAs, and four rRNA operons. A 70-kb region encoding pathways for vitamin B(12) biosynthesis and degradation of ethanolamine and propanediol was apparently acquired by horizontal gene transfer. The gene complement suggests new hypotheses for the pathogenesis and virulence of S. sanguinis and differs from the gene complements of other pathogenic and nonpathogenic streptococci. In particular, S. sanguinis possesses a remarkable abundance of putative surface proteins, which may permit it to be a primary colonizer of the oral cavity and agent of streptococcal endocarditis and infection in neutropenic patients.
ESTHER : Xu_2007_J.Bacteriol_189_3166
PubMedSearch : Xu_2007_J.Bacteriol_189_3166
PubMedID: 17277061
Gene_locus related to this paper: strsa-f0fga9 , strsv-a3cmd5 , strsv-a3cn30 , strsv-a3cn31 , strsv-a3cnb1 , strsv-a3cp66 , strsv-a3cpg5 , strsv-a3cqq7 , strsv-pepx , strsv-a3cnw9 , strsv-a3cm57

Title : Genome sequence, comparative analysis and haplotype structure of the domestic dog - Lindblad-Toh_2005_Nature_438_803
Author(s) : Lindblad-Toh K , Wade CM , Mikkelsen TS , Karlsson EK , Jaffe DB , Kamal M , Clamp M , Chang JL , Kulbokas EJ, 3rd , Zody MC , Mauceli E , Xie X , Breen M , Wayne RK , Ostrander EA , Ponting CP , Galibert F , Smith DR , deJong PJ , Kirkness E , Alvarez P , Biagi T , Brockman W , Butler J , Chin CW , Cook A , Cuff J , Daly MJ , Decaprio D , Gnerre S , Grabherr M , Kellis M , Kleber M , Bardeleben C , Goodstadt L , Heger A , Hitte C , Kim L , Koepfli KP , Parker HG , Pollinger JP , Searle SM , Sutter NB , Thomas R , Webber C , Baldwin J , Abebe A , Abouelleil A , Aftuck L , Ait-Zahra M , Aldredge T , Allen N , An P , Anderson S , Antoine C , Arachchi H , Aslam A , Ayotte L , Bachantsang P , Barry A , Bayul T , Benamara M , Berlin A , Bessette D , Blitshteyn B , Bloom T , Blye J , Boguslavskiy L , Bonnet C , Boukhgalter B , Brown A , Cahill P , Calixte N , Camarata J , Cheshatsang Y , Chu J , Citroen M , Collymore A , Cooke P , Dawoe T , Daza R , Decktor K , DeGray S , Dhargay N , Dooley K , Dorje P , Dorjee K , Dorris L , Duffey N , Dupes A , Egbiremolen O , Elong R , Falk J , Farina A , Faro S , Ferguson D , Ferreira P , Fisher S , FitzGerald M , Foley K , Foley C , Franke A , Friedrich D , Gage D , Garber M , Gearin G , Giannoukos G , Goode T , Goyette A , Graham J , Grandbois E , Gyaltsen K , Hafez N , Hagopian D , Hagos B , Hall J , Healy C , Hegarty R , Honan T , Horn A , Houde N , Hughes L , Hunnicutt L , Husby M , Jester B , Jones C , Kamat A , Kanga B , Kells C , Khazanovich D , Kieu AC , Kisner P , Kumar M , Lance K , Landers T , Lara M , Lee W , Leger JP , Lennon N , Leuper L , LeVine S , Liu J , Liu X , Lokyitsang Y , Lokyitsang T , Lui A , MacDonald J , Major J , Marabella R , Maru K , Matthews C , McDonough S , Mehta T , Meldrim J , Melnikov A , Meneus L , Mihalev A , Mihova T , Miller K , Mittelman R , Mlenga V , Mulrain L , Munson G , Navidi A , Naylor J , Nguyen T , Nguyen N , Nguyen C , Nicol R , Norbu N , Norbu C , Novod N , Nyima T , Olandt P , O'Neill B , O'Neill K , Osman S , Oyono L , Patti C , Perrin D , Phunkhang P , Pierre F , Priest M , Rachupka A , Raghuraman S , Rameau R , Ray V , Raymond C , Rege F , Rise C , Rogers J , Rogov P , Sahalie J , Settipalli S , Sharpe T , Shea T , Sheehan M , Sherpa N , Shi J , Shih D , Sloan J , Smith C , Sparrow T , Stalker J , Stange-Thomann N , Stavropoulos S , Stone C , Stone S , Sykes S , Tchuinga P , Tenzing P , Tesfaye S , Thoulutsang D , Thoulutsang Y , Topham K , Topping I , Tsamla T , Vassiliev H , Venkataraman V , Vo A , Wangchuk T , Wangdi T , Weiand M , Wilkinson J , Wilson A , Yadav S , Yang S , Yang X , Young G , Yu Q , Zainoun J , Zembek L , Zimmer A , Lander ES
Ref : Nature , 438 :803 , 2005
Abstract : Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
ESTHER : Lindblad-Toh_2005_Nature_438_803
PubMedSearch : Lindblad-Toh_2005_Nature_438_803
PubMedID: 16341006
Gene_locus related to this paper: canfa-1lipg , canfa-2neur , canfa-3neur , canfa-ACHE , canfa-BCHE , canfa-cauxin , canfa-CESDD1 , canfa-e2qsb1 , canfa-e2qsl3 , canfa-e2qsz2 , canfa-e2qvk3 , canfa-e2qw15 , canfa-e2qxs8 , canfa-e2qzs6 , canfa-e2r5t3 , canfa-e2r6f6 , canfa-e2r7e8 , canfa-e2r8v9 , canfa-e2r8z1 , canfa-e2r9h4 , canfa-e2r455 , canfa-e2rb70 , canfa-e2rcq9 , canfa-e2rd94 , canfa-e2rgi0 , canfa-e2rkq0 , canfa-e2rlz9 , canfa-e2rm00 , canfa-e2rqf1 , canfa-e2rss9 , canfa-f1p6w8 , canfa-f1p8b6 , canfa-f1p9d8 , canfa-f1p683 , canfa-f1pb79 , canfa-f1pgw0 , canfa-f1phd0 , canfa-f1phx2 , canfa-f1pke8 , canfa-f1pp08 , canfa-f1ppp9 , canfa-f1ps07 , canfa-f1ptf1 , canfa-f1pvp4 , canfa-f1pw93 , canfa-f1pwk3 , canfa-pafa , canfa-q1ert3 , canfa-q5jzr0 , canfa-e2rmb9 , canlf-f6v865 , canlf-e2rjg6 , canlf-e2r2h2 , canlf-f1p648 , canlf-f1pw90 , canlf-j9p8v6 , canlf-f1pcc4 , canlf-e2qxh0 , canlf-e2r774 , canlf-f1pf96 , canlf-e2rq56 , canlf-j9nwb1 , canlf-f1ptw2 , canlf-j9p8h1 , canlf-e2ree2 , canlf-f1prs1 , canlf-j9nus1 , canlf-e2rf91 , canlf-f1pg57 , canlf-f1q111

Title : Site-specific percutaneous absorption of methyl salicylate and VX in domestic swine - Duncan_2002_J.Appl.Toxicol_22_141
Author(s) : Duncan EJ , Brown A , Lundy P , Sawyer TW , Hamilton M , Hill I , Conley JD
Ref : J Appl Toxicol , 22 :141 , 2002
Abstract : The site specificity of the percutaneous absorption of methyl salicylate (MeS) and the organophosphate nerve agent VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate) was examined in anaesthetized domestic swine that were fully instrumented for physiological endpoints. Four different anatomical sites (ear, perineum, inguinal crease and epigastrium) were exposed to the MeS and the serum levels were measured over a 6-h time period. The dose absorbed at the ear region was 11 microg cm(-2) with an initial flux of 0.063 microg cm(-2)min(-1), whereas at the epigastrium region the dose absorbed was 3 microg cm(-2) with an initial flux of 0.025 microg cm(-2)min(-1). For this reason further studies were carried out with VX on the ear and the epigastrium only. In animals treated with agent on the epigastrium, blood cholinesterase (ChE) activity began to drop 90 min after application and continued to decline at a constant rate for the remainder of the experiment to ca. 25% of awake control activity. At this time there were negligible signs of poisoning and the medical prognosis was judged to be good. In contrast, the ChE activity in animals receiving VX on the ear decreased to 25% of awake control values within 45 min and levelled out at 5-6% by 120 min. Clinical signs of VX poisoning paralleled the ChE inhibition, progressing in severity over the duration of the exposure. It was judged that these animals would not survive. The dramatic site dependence of agent absorption leading to vastly different toxicological endpoints demonstrated in this model system has important ramifications for chemical protective suit development, threat assessment, medical countermeasures and contamination control protocols.
ESTHER : Duncan_2002_J.Appl.Toxicol_22_141
PubMedSearch : Duncan_2002_J.Appl.Toxicol_22_141
PubMedID: 12015792

Title : The genome of M. acetivorans reveals extensive metabolic and physiological diversity - Galagan_2002_Genome.Res_12_532
Author(s) : Galagan JE , Nusbaum C , Roy A , Endrizzi MG , Macdonald P , FitzHugh W , Calvo S , Engels R , Smirnov S , Atnoor D , Brown A , Allen N , Naylor J , Stange-Thomann N , DeArellano K , Johnson R , Linton L , McEwan P , McKernan K , Talamas J , Tirrell A , Ye W , Zimmer A , Barber RD , Cann I , Graham DE , Grahame DA , Guss AM , Hedderich R , Ingram-Smith C , Kuettner HC , Krzycki JA , Leigh JA , Li W , Liu J , Mukhopadhyay B , Reeve JN , Smith K , Springer TA , Umayam LA , White O , White RH , Conway de Macario E , Ferry JG , Jarrell KF , Jing H , Macario AJ , Paulsen I , Pritchett M , Sowers KR , Swanson RV , Zinder SH , Lander E , Metcalf WW , Birren B
Ref : Genome Res , 12 :532 , 2002
Abstract : Methanogenesis, the biological production of methane, plays a pivotal role in the global carbon cycle and contributes significantly to global warming. The majority of methane in nature is derived from acetate. Here we report the complete genome sequence of an acetate-utilizing methanogen, Methanosarcina acetivorans C2A. Methanosarcineae are the most metabolically diverse methanogens, thrive in a broad range of environments, and are unique among the Archaea in forming complex multicellular structures. This diversity is reflected in the genome of M. acetivorans. At 5,751,492 base pairs it is by far the largest known archaeal genome. The 4524 open reading frames code for a strikingly wide and unanticipated variety of metabolic and cellular capabilities. The presence of novel methyltransferases indicates the likelihood of undiscovered natural energy sources for methanogenesis, whereas the presence of single-subunit carbon monoxide dehydrogenases raises the possibility of nonmethanogenic growth. Although motility has not been observed in any Methanosarcineae, a flagellin gene cluster and two complete chemotaxis gene clusters were identified. The availability of genetic methods, coupled with its physiological and metabolic diversity, makes M. acetivorans a powerful model organism for the study of archaeal biology. [Sequence, data, annotations and analyses are available at http://www-genome.wi.mit.edu/.]
ESTHER : Galagan_2002_Genome.Res_12_532
PubMedSearch : Galagan_2002_Genome.Res_12_532
PubMedID: 11932238
Gene_locus related to this paper: metac-MA0077 , metac-MA0362 , metac-MA0419 , metac-MA0736 , metac-MA0993 , metac-MA1571 , metac-MA1856 , metac-MA1857 , metac-MA2002 , metac-MA2343 , metac-MA2629 , metac-MA2691 , metac-MA2743 , metac-MA2933 , metac-MA3611 , metac-MA3635 , metac-MA3920 , metac-META

Title : Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology - Perry_1995_Neurosci_64_385
Author(s) : Perry EK , Morris CM , Court JA , Cheng A , Fairbairn AF , McKeith IG , Irving D , Brown A , Perry RH
Ref : Neuroscience , 64 :385 , 1995
Abstract : High-affinity nicotine binding, considered to primarily reflect the presence of CNS alpha 4 beta 2 nicotinic receptor subunits, was examined autoradiographically in brain regions most severely affected by Alzheimer and Parkinson types of pathology. In the midbrain, the high density of binding associated with the pars compacta of the substantia nigra was extensively reduced (65-75%, particularly in the lateral portion) in both Lewy body dementia and Parkinson's disease. Since loss of dopaminergic neurons in Lewy body dementia was only moderate (40%), loss or down-regulation of the nicotinic receptor may precede degeneration of dopaminergic neurons in this region. In the dorsolateral tegmentum, where diffuse cholinergic perikarya are located, nicotine binding was highly significantly decreased in both Lewy body dementia and Parkinson's disease with almost no overlap between the normal and disease groups, indicative of a major pathological involvement in or around the pedunculopontine cholinergic neurons. In the hippocampus, binding was decreased around the granular layer in Lewy body dementia and Alzheimer's disease, although unchanged in the stratum lacunosum moleculare, where binding was relatively higher. Dense bands of receptor binding in the presubiculum and parahippocampal gyrus--areas of highest binding in human cortex--were diminished in Alzheimer's disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimer's disease throughout the cortical layers but in Lewy body dementia only in lower layers, in which Lewy bodies are concentrated. Abnormalities of the nicotinic receptor in the diseases examined appear to be closely associated with primary histopathological changes: dopaminergic cell loss in Parkinson's disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimer's disease. Loss or down-regulation of the receptor may precede neurodegeneration.
ESTHER : Perry_1995_Neurosci_64_385
PubMedSearch : Perry_1995_Neurosci_64_385
PubMedID: 7700528

Title : The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma - Welch_1995_Clin.Pharmacol.Ther_58_132
Author(s) : Welch RM , Brown A , Ravitch J , Dahl R
Ref : Clinical Pharmacology & Therapeutics , 58 :132 , 1995
Abstract : OBJECTIVE: To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma. METHODS: Cisatracurium was incubated in aqueous buffer at various pH values or in human and rat plasma maintained at pH 7.4 with HEPES buffer. Cisatracurium and the degradation products, laudanosine and the monoquaternary alcohol, were quantitated by HPLC with use of fluorescence detection. RESULTS: In Srenson's phosphate buffer, cisatracurium degraded spontaneously by a chemical process commonly referred to as "Hofmann elimination." The rate of degradation increased with increasing pH. From pH 6.4 to 7.8 there was a 6.5-fold increase in the rate of degradation of cisatracurium and, on a molar basis, the final decomposition product laudanosine accounted for all of the drug. At a pH of 7.4, cisatracurium degraded with a half-life of about 34.1 +/- 2.1 minutes. Cisatracurium incubated in human plasma degraded with a mean (+/- SD) half-life of 29.2 +/- 3.8 minutes, which is consistent with Hofmann elimination. Besides laudanosine, and unlike that observed in Srenson's phosphate buffer, significant amounts of the monoquaternary alcohol were formed that slowly degraded to laudanosine. The micromoles of laudanosine formed eventually accounted for the total amount of cisatracurium incubated with human plasma. The monoquaternary alcohol appears to be a product of ester hydrolysis of a monoquaternary acrylate formed during the first step in Hofmann elimination. Evidence for esterase involvement at this step in the degradation of cisatracurium was based on inhibition studies with O-cresyl benzodioxaphosphorin oxide (CBDP), a specific carboxylesterase inhibitor. The addition of CBDP to human plasma completely blocked the formation of monoquaternary alcohol and converted the degradation of cisatracurium to total Hofmann elimination. In rat plasma cisatracurium was hydrolyzed, with a half-life of only 3 1/2 minutes, by carboxylesterases. The addition of CBDP increased the half-life to 25 minutes, which is consistent with Hofmann elimination. CONCLUSION: In human plasma the rate-limiting step in the degradation of cisatracurium is Hofmann elimination, with the initial formation of a monoquaternary acrylate. The observation that the monoquaternary alcohol results from ester hydrolysis of the monoquaternary acrylate by plasma esterase(s) explains the presence of the monoquaternary alcohol metabolite in human plasma during clinical studies with cisatracurium. The rapid hydrolysis of cisatracurium by rat plasma relative to human indicates a major species difference in plasma esterase(s).
ESTHER : Welch_1995_Clin.Pharmacol.Ther_58_132
PubMedSearch : Welch_1995_Clin.Pharmacol.Ther_58_132
PubMedID: 7648763

Title : The molecular forms of acetylcholinesterase from Necator americanus (Nematoda), a hookworm parasite of the human intestine - Pritchard_1994_Eur.J.Biochem_219_317
Author(s) : Pritchard DI , Brown A , Toutant JP
Ref : European Journal of Biochemistry , 219 :317 , 1994
Abstract : Necator americanus (Nematoda: Strongyloidea), a human hookworm parasite, is known to release considerable amounts of acetylcholinesterase (AChE) [Pritchard, D. I., Leggett K. V., Rogan, M. T., McKean, P. G. & Brown, A. (1991) Necator americanus secretory acetylcholinesterase and its purification from excretory/secretory products by affinity chromatography, Parasite Immunol. 13, 187-199]. The present study deals with AChE activity recovered in sequential somatic extracts, and excretory/secretory products, of the adult stage of the parasite. 97% of AChE was extractable in low-salt and high-salt detergent-free buffers, and only 3% was solubilised by a further extraction in the presence of Triton X-100. AChE in all three extracts was affected by the AChE inhibitors eserine, bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide and edrophonium chloride, but was resistant to the effects of tetramonoisopropylpyrophosphortetramide, a butyrylcholinesterase inhibitor. Sucrose density centrifugation revealed that AChE in all somatic extracts (low-salt, high-salt and detergent) resolved almost exclusively as a single peak between 6.9-7.5 S, while excretory/secretory products resolved at 8.2 S. These values are all compatible with dimers of catalytic subunits and no evidence was found for the presence of higher oligomers such as asymmetric forms. The only sample to show a shift in sedimentation following the inclusion of detergent (Triton X-100, Brij 96) in the gradient was a component of the detergent-soluble extract, indicating the existence of a minor amphiphilic form. In low-salt-soluble and high-salt-soluble extracts, AChE was solubilised as a hydrophilic globular form, probably a dimeric G2. The analysis of diisopropylfluorophosphate-labelled extracts by SDS/PAGE, and unlabelled extracts by immunoblotting using a polyvalent antiserum to N. americanus AChE, indicated that the AChE isolated in each extract was biochemically and immunologically similar. The banding patterns obtained were comparable to that seen when purified AChE was analysed by SDS/PAGE and immunoblotted. This suggests that the basic catalytic subunit has a mass of 66-70 kDa with the active site being located in a 30-kDa domain. All experimental data indicate the existence of only one AChE class in Necator homologous to AChE of class B from Caenorhabditis elegans. The solubility characteristics and globular nature of this hookworm AChE suggest that its major function is as an excretory or secretory product. This again raises the question of the true biological function of this 'non-cholinergenic' nematode secretion.
ESTHER : Pritchard_1994_Eur.J.Biochem_219_317
PubMedSearch : Pritchard_1994_Eur.J.Biochem_219_317
PubMedID: 8306998

Title : The immunogenicity of hookworm (Necator americanus) acetylcholinesterase (AChE) in man - Brown_1993_Parasite.Immunol_15_195
Author(s) : Brown A , Pritchard DI
Ref : Parasite Immunology , 15 :195 , 1993
Abstract : A number of different but complementary approaches have been used to demonstrate the immunogenicity of Necator americanus acetylcholinesterase to infected individuals. Western blotting of parasite somatic extracts with human post-infection sera and a specific rabbit antiserum to AChE resulted in the development of almost identical antigen-recognition profiles. AChE-containing fractions produced by preparative iso-electric focusing were subsequently shown to be antigenic in ELISA using post-infection sera. This preliminary data was reinforced by the affinity purification of AChE by immobilized post-infection IgG, and the immunoprecipitation of AChE activity from ES by post-infection IgG. Finally, AChE purified by affinity chromatography on edrophonium chloride was shown to be antigenic by Western blotting, and in ELISA, against post-infection sera, although a degree of re-activity was also seen with normal human sera. This data is discussed in the context of the host-parasite relationship.
ESTHER : Brown_1993_Parasite.Immunol_15_195
PubMedSearch : Brown_1993_Parasite.Immunol_15_195
PubMedID: 8506114