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排序方式: 共有92条查询结果,搜索用时 15 毫秒
41.
Boyle CD Chackalamannil S Clader JW Greenlee WJ Josien HB Kaminski JJ Kozlowski JA McCombie SW Nazareno DV Tagat JR Wang Y Zhou G Billard W Binch H Crosby G Cohen-Williams M Coffin VL Cox KA Grotz DE Duffy RA Ruperto V Lachowicz JE 《Bioorganic & medicinal chemistry letters》2001,11(17):2311-2314
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates. 相似文献
42.
Pigeonpea genomics initiative (PGI): an international effort to improve crop productivity of pigeonpea (Cajanus cajan L.) 总被引:1,自引:0,他引:1
Varshney RK Penmetsa RV Dutta S Kulwal PL Saxena RK Datta S Sharma TR Rosen B Carrasquilla-Garcia N Farmer AD Dubey A Saxena KB Gao J Fakrudin B Singh MN Singh BP Wanjari KB Yuan M Srivastava RK Kilian A Upadhyaya HD Mallikarjuna N Town CD Bruening GE He G May GD McCombie R Jackson SA Singh NK Cook DR 《Molecular breeding : new strategies in plant improvement》2010,26(3):393-408
Pigeonpea (Cajanus cajan), an important food legume crop in the semi-arid regions of the world and the second most important pulse crop in India, has an average crop productivity of 780 kg/ha. The relatively low crop yields may be attributed to non-availability of improved cultivars, poor crop husbandry and exposure to a number of biotic and abiotic stresses in pigeonpea growing regions. Narrow genetic diversity in cultivated germplasm has further hampered the effective utilization of conventional breeding as well as development and utilization of genomic tools, resulting in pigeonpea being often referred to as an ‘orphan crop legume’. To enable genomics-assisted breeding in this crop, the pigeonpea genomics initiative (PGI) was initiated in late 2006 with funding from Indian Council of Agricultural Research under the umbrella of Indo-US agricultural knowledge initiative, which was further expanded with financial support from the US National Science Foundation’s Plant Genome Research Program and the Generation Challenge Program. As a result of the PGI, the last 3 years have witnessed significant progress in development of both genetic as well as genomic resources in this crop through effective collaborations and coordination of genomics activities across several institutes and countries. For instance, 25 mapping populations segregating for a number of biotic and abiotic stresses have been developed or are under development. An 11X-genome coverage bacterial artificial chromosome (BAC) library comprising of 69,120 clones have been developed of which 50,000 clones were end sequenced to generate 87,590 BAC-end sequences (BESs). About 10,000 expressed sequence tags (ESTs) from Sanger sequencing and ca. 2 million short ESTs by 454/FLX sequencing have been generated. A variety of molecular markers have been developed from BESs, microsatellite or simple sequence repeat (SSR)-enriched libraries and mining of ESTs and genomic amplicon sequencing. Of about 21,000 SSRs identified, 6,698 SSRs are under analysis along with 670 orthologous genes using a GoldenGate SNP (single nucleotide polymorphism) genotyping platform, with large scale SNP discovery using Solexa, a next generation sequencing technology, is in progress. Similarly a diversity array technology array comprising of ca. 15,000 features has been developed. In addition, >600 unique nucleotide binding site (NBS) domain containing members of the NBS-leucine rich repeat disease resistance homologs were cloned in pigeonpea; 960 BACs containing these sequences were identified by filter hybridization, BES physical maps developed using high information content fingerprinting. To enrich the genomic resources further, sequenced soybean genome is being analyzed to establish the anchor points between pigeonpea and soybean genomes. In addition, Solexa sequencing is being used to explore the feasibility of generating whole genome sequence. In summary, the collaborative efforts of several research groups under the umbrella of PGI are making significant progress in improving molecular tools in pigeonpea and should significantly benefit pigeonpea genetics and breeding. As these efforts come to fruition, and expanded (depending on funding), pigeonpea would move from an ‘orphan legume crop’ to one where genomics-assisted breeding approaches for a sustainable crop improvement are routine. 相似文献
43.
van Halm VP Nurmohamed MT Twisk JW Dijkmans BA Voskuyl AE 《Arthritis research & therapy》2006,8(5):R151-6
Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study
investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs)
in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data
on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of
the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or
methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD
group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant
CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX,
SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence
of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever'
and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased
CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated
with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in
particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and
subsequently clinically overt CVD. 相似文献
44.
Eric J. Gilbert Guowei Zhou Michael K.C. Wong Ling Tong Bandarpalle B. Shankar Chunli Huang Joseph Kelly Brian J. Lavey Stuart W. McCombie Lei Chen Razia Rizvi Youhao Dong Youheng Shu Joseph A. Kozlowski Neng-Yang Shih R. William Hipkin Waldemar Gonsiorek Asra Malikzay Charles A. Lunn Len Favreau Daniel J. Lundell 《Bioorganic & medicinal chemistry letters》2010,20(2):608-611
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described. 相似文献
45.
Shilpi Paul Alex Kuo Thomas Schalch Hannes Vogel Leemor Joshua-Tor W. Richard McCombie Or Gozani Molly Hammell Alea A. Mills 《Cell reports》2013,3(1):92-102
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46.
Hodges E Molaro A Dos Santos CO Thekkat P Song Q Uren PJ Park J Butler J Rafii S McCombie WR Smith AD Hannon GJ 《Molecular cell》2011,44(1):17-28
DNA methylation has been implicated as an epigenetic component of mechanisms that stabilize cell-fate decisions. Here, we have characterized the methylomes of human female hematopoietic stem/progenitor cells (HSPCs) and mature cells from the myeloid and lymphoid lineages. Hypomethylated regions (HMRs) associated with lineage-specific genes were often methylated in the opposing lineage. In HSPCs, these sites tended to show intermediate, complex patterns that resolve to uniformity upon differentiation, by increased or decreased methylation. Promoter HMRs shared across diverse cell types typically display a constitutive core that expands and contracts in a lineage-specific manner to fine-tune the expression of associated genes. Many newly identified intergenic HMRs, both constitutive and lineage specific, were enriched for factor binding sites with an implied role in genome organization and regulation of gene expression, respectively. Overall, our studies represent an important reference data set and provide insights into directional changes in DNA methylation as cells adopt terminal fates. 相似文献
47.
Lee EK Cibrian-Jaramillo A Kolokotronis SO Katari MS Stamatakis A Ott M Chiu JC Little DP Stevenson DW McCombie WR Martienssen RA Coruzzi G Desalle R 《PLoS genetics》2011,7(12):e1002411
A novel result of the current research is the development and implementation of a unique functional phylogenomic approach that explores the genomic origins of seed plant diversification. We first use 22,833 sets of orthologs from the nuclear genomes of 101 genera across land plants to reconstruct their phylogenetic relationships. One of the more salient results is the resolution of some enigmatic relationships in seed plant phylogeny, such as the placement of Gnetales as sister to the rest of the gymnosperms. In using this novel phylogenomic approach, we were also able to identify overrepresented functional gene ontology categories in genes that provide positive branch support for major nodes prompting new hypotheses for genes associated with the diversification of angiosperms. For example, RNA interference (RNAi) has played a significant role in the divergence of monocots from other angiosperms, which has experimental support in Arabidopsis and rice. This analysis also implied that the second largest subunit of RNA polymerase IV and V (NRPD2) played a prominent role in the divergence of gymnosperms. This hypothesis is supported by the lack of 24nt siRNA in conifers, the maternal control of small RNA in the seeds of flowering plants, and the emergence of double fertilization in angiosperms. Our approach takes advantage of genomic data to define orthologs, reconstruct relationships, and narrow down candidate genes involved in plant evolution within a phylogenomic view of species' diversification. 相似文献
48.
Genome sequencing is now affordable, but assembling plant genomes de novo remains challenging. We assess the state of the art of assembly and review the best practices for the community. 相似文献
49.
De novo gene disruptions in children on the autistic spectrum 总被引:2,自引:0,他引:2
Iossifov I Ronemus M Levy D Wang Z Hakker I Rosenbaum J Yamrom B Lee YH Narzisi G Leotta A Kendall J Grabowska E Ma B Marks S Rodgers L Stepansky A Troge J Andrews P Bekritsky M Pradhan K Ghiban E Kramer M Parla J Demeter R Fulton LL Fulton RS Magrini VJ Ye K Darnell JC Darnell RB Mardis ER Wilson RK Schatz MC McCombie WR Wigler M 《Neuron》2012,74(2):285-299
Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the?fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. 相似文献
50.
Maria C Lebre Christina L Jonckheere Maarten C Kraan Arno WR van Kuijk Jan D Bos Menno de Rie Danielle M Gerlag Paul P Tak 《Arthritis research & therapy》2012,14(5):R200