Thomas R

References (5)

Title : Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration - Bakht_2023_Molecules_28_
Author(s) : Bakht MA , Pooventhiran T , Thomas R , Kamal M , Din IU , Rehman NU , Ali I , Ajmal N , Ahsan MJ
Ref : Molecules , 28 : , 2023
Abstract : Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a-h) in the presence of the catalyst Pd-HPW/SiO(2) and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski's rule of five.
ESTHER : Bakht_2023_Molecules_28_
PubMedSearch : Bakht_2023_Molecules_28_
PubMedID: 36838935

Title : A phase II trial of huperzine A in mild to moderate Alzheimer disease - Rafii_2011_Neurology_76_1389
Author(s) : Rafii MS , Walsh S , Little JT , Behan K , Reynolds B , Ward C , Jin S , Thomas R , Aisen PS
Ref : Neurology , 76 :1389 , 2011
Abstract : OBJECTIVE Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata that may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use for Alzheimer disease (AD). METHODS: We assessed the safety, tolerability, and efficacy of huperzine A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo (n = 70) or huperzine A (200 ug BID [n = 70] or 400 ug BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase. The primary analysis assessed the cognitive effects of huperzine A 200 ug BID (change in Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-Cog] at week 16 at 200 ug BID compared to placebo). Secondary analyses assessed the effect of huperzine A 400 ug BID, as well as effect on other outcomes including Mini-Mental State Examination, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer's Disease Cooperative Study Activities of Daily Living scale, and Neuropsychiatric Inventory (NPI). RESULTS: Huperzine A 200 ug BID did not influence change in ADAS-Cog at 16 weeks. In secondary analyses, huperzine A 400 ug BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks vs 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement vs 0.34-point improvement in the placebo arm (p = 0.07) at week 16. Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose. CONCLUSION: The primary efficacy analysis did not show cognitive benefit with huperzine A 200 ug BID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that huperzine A 200 ug BID has no demonstrable cognitive effect in patients with mild to moderate AD.
ESTHER : Rafii_2011_Neurology_76_1389
PubMedSearch : Rafii_2011_Neurology_76_1389
PubMedID: 21502597

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 : A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome - Mural_2002_Science_296_1661
Author(s) : Mural RJ , Adams MD , Myers EW , Smith HO , Miklos GL , Wides R , Halpern A , Li PW , Sutton GG , Nadeau J , Salzberg SL , Holt RA , Kodira CD , Lu F , Chen L , Deng Z , Evangelista CC , Gan W , Heiman TJ , Li J , Li Z , Merkulov GV , Milshina NV , Naik AK , Qi R , Shue BC , Wang A , Wang J , Wang X , Yan X , Ye J , Yooseph S , Zhao Q , Zheng L , Zhu SC , Biddick K , Bolanos R , Delcher AL , Dew IM , Fasulo D , Flanigan MJ , Huson DH , Kravitz SA , Miller JR , Mobarry CM , Reinert K , Remington KA , Zhang Q , Zheng XH , Nusskern DR , Lai Z , Lei Y , Zhong W , Yao A , Guan P , Ji RR , Gu Z , Wang ZY , Zhong F , Xiao C , Chiang CC , Yandell M , Wortman JR , Amanatides PG , Hladun SL , Pratts EC , Johnson JE , Dodson KL , Woodford KJ , Evans CA , Gropman B , Rusch DB , Venter E , Wang M , Smith TJ , Houck JT , Tompkins DE , Haynes C , Jacob D , Chin SH , Allen DR , Dahlke CE , Sanders R , Li K , Liu X , Levitsky AA , Majoros WH , Chen Q , Xia AC , Lopez JR , Donnelly MT , Newman MH , Glodek A , Kraft CL , Nodell M , Ali F , An HJ , Baldwin-Pitts D , Beeson KY , Cai S , Carnes M , Carver A , Caulk PM , Center A , Chen YH , Cheng ML , Coyne MD , Crowder M , Danaher S , Davenport LB , Desilets R , Dietz SM , Doup L , Dullaghan P , Ferriera S , Fosler CR , Gire HC , Gluecksmann A , Gocayne JD , Gray J , Hart B , Haynes J , Hoover J , Howland T , Ibegwam C , Jalali M , Johns D , Kline L , Ma DS , MacCawley S , Magoon A , Mann F , May D , McIntosh TC , Mehta S , Moy L , Moy MC , Murphy BJ , Murphy SD , Nelson KA , Nuri Z , Parker KA , Prudhomme AC , Puri VN , Qureshi H , Raley JC , Reardon MS , Regier MA , Rogers YH , Romblad DL , Schutz J , Scott JL , Scott R , Sitter CD , Smallwood M , Sprague AC , Stewart E , Strong RV , Suh E , Sylvester K , Thomas R , Tint NN , Tsonis C , Wang G , Williams MS , Williams SM , Windsor SM , Wolfe K , Wu MM , Zaveri J , Chaturvedi K , Gabrielian AE , Ke Z , Sun J , Subramanian G , Venter JC , Pfannkoch CM , Barnstead M , Stephenson LD
Ref : Science , 296 :1661 , 2002
Abstract : The high degree of similarity between the mouse and human genomes is demonstrated through analysis of the sequence of mouse chromosome 16 (Mmu 16), which was obtained as part of a whole-genome shotgun assembly of the mouse genome. The mouse genome is about 10% smaller than the human genome, owing to a lower repetitive DNA content. Comparison of the structure and protein-coding potential of Mmu 16 with that of the homologous segments of the human genome identifies regions of conserved synteny with human chromosomes (Hsa) 3, 8, 12, 16, 21, and 22. Gene content and order are highly conserved between Mmu 16 and the syntenic blocks of the human genome. Of the 731 predicted genes on Mmu 16, 509 align with orthologs on the corresponding portions of the human genome, 44 are likely paralogous to these genes, and 164 genes have homologs elsewhere in the human genome; there are 14 genes for which we could find no human counterpart.
ESTHER : Mural_2002_Science_296_1661
PubMedSearch : Mural_2002_Science_296_1661
PubMedID: 12040188
Gene_locus related to this paper: mouse-ABH15 , mouse-Ces3b , mouse-Ces4a , mouse-dpp4 , mouse-FAP , mouse-Lipg , mouse-Q8C1A9 , mouse-rbbp9 , mouse-SERHL , mouse-SPG21 , mouse-w4vsp6

Title : The sequence of the human genome - Venter_2001_Science_291_1304
Author(s) : Venter JC , Adams MD , Myers EW , Li PW , Mural RJ , Sutton GG , Smith HO , Yandell M , Evans CA , Holt RA , Gocayne JD , Amanatides P , Ballew RM , Huson DH , Wortman JR , Zhang Q , Kodira CD , Zheng XH , Chen L , Skupski M , Subramanian G , Thomas PD , Zhang J , Gabor Miklos GL , Nelson C , Broder S , Clark AG , Nadeau J , McKusick VA , Zinder N , Levine AJ , Roberts RJ , Simon M , Slayman C , Hunkapiller M , Bolanos R , Delcher A , Dew I , Fasulo D , Flanigan M , Florea L , Halpern A , Hannenhalli S , Kravitz S , Levy S , Mobarry C , Reinert K , Remington K , Abu-Threideh J , Beasley E , Biddick K , Bonazzi V , Brandon R , Cargill M , Chandramouliswaran I , Charlab R , Chaturvedi K , Deng Z , Di Francesco V , Dunn P , Eilbeck K , Evangelista C , Gabrielian AE , Gan W , Ge W , Gong F , Gu Z , Guan P , Heiman TJ , Higgins ME , Ji RR , Ke Z , Ketchum KA , Lai Z , Lei Y , Li Z , Li J , Liang Y , Lin X , Lu F , Merkulov GV , Milshina N , Moore HM , Naik AK , Narayan VA , Neelam B , Nusskern D , Rusch DB , Salzberg S , Shao W , Shue B , Sun J , Wang Z , Wang A , Wang X , Wang J , Wei M , Wides R , Xiao C , Yan C , Yao A , Ye J , Zhan M , Zhang W , Zhang H , Zhao Q , Zheng L , Zhong F , Zhong W , Zhu S , Zhao S , Gilbert D , Baumhueter S , Spier G , Carter C , Cravchik A , Woodage T , Ali F , An H , Awe A , Baldwin D , Baden H , Barnstead M , Barrow I , Beeson K , Busam D , Carver A , Center A , Cheng ML , Curry L , Danaher S , Davenport L , Desilets R , Dietz S , Dodson K , Doup L , Ferriera S , Garg N , Gluecksmann A , Hart B , Haynes J , Haynes C , Heiner C , Hladun S , Hostin D , Houck J , Howland T , Ibegwam C , Johnson J , Kalush F , Kline L , Koduru S , Love A , Mann F , May D , McCawley S , McIntosh T , McMullen I , Moy M , Moy L , Murphy B , Nelson K , Pfannkoch C , Pratts E , Puri V , Qureshi H , Reardon M , Rodriguez R , Rogers YH , Romblad D , Ruhfel B , Scott R , Sitter C , Smallwood M , Stewart E , Strong R , Suh E , Thomas R , Tint NN , Tse S , Vech C , Wang G , Wetter J , Williams S , Williams M , Windsor S , Winn-Deen E , Wolfe K , Zaveri J , Zaveri K , Abril JF , Guigo R , Campbell MJ , Sjolander KV , Karlak B , Kejariwal A , Mi H , Lazareva B , Hatton T , Narechania A , Diemer K , Muruganujan A , Guo N , Sato S , Bafna V , Istrail S , Lippert R , Schwartz R , Walenz B , Yooseph S , Allen D , Basu A , Baxendale J , Blick L , Caminha M , Carnes-Stine J , Caulk P , Chiang YH , Coyne M , Dahlke C , Mays A , Dombroski M , Donnelly M , Ely D , Esparham S , Fosler C , Gire H , Glanowski S , Glasser K , Glodek A , Gorokhov M , Graham K , Gropman B , Harris M , Heil J , Henderson S , Hoover J , Jennings D , Jordan C , Jordan J , Kasha J , Kagan L , Kraft C , Levitsky A , Lewis M , Liu X , Lopez J , Ma D , Majoros W , McDaniel J , Murphy S , Newman M , Nguyen T , Nguyen N , Nodell M , Pan S , Peck J , Peterson M , Rowe W , Sanders R , Scott J , Simpson M , Smith T , Sprague A , Stockwell T , Turner R , Venter E , Wang M , Wen M , Wu D , Wu M , Xia A , Zandieh A , Zhu X
Ref : Science , 291 :1304 , 2001
Abstract : A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
ESTHER : Venter_2001_Science_291_1304
PubMedSearch : Venter_2001_Science_291_1304
PubMedID: 11181995
Gene_locus related to this paper: human-AADAC , human-ABHD1 , human-ABHD10 , human-ABHD11 , human-ACHE , human-BCHE , human-LDAH , human-ABHD18 , human-CMBL , human-ABHD17A , human-KANSL3 , human-LIPA , human-LYPLAL1 , human-NDRG2 , human-NLGN3 , human-NLGN4X , human-NLGN4Y , human-PAFAH2 , human-PREPL , human-RBBP9 , human-SPG21