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81.
Violeta Muñoz-Fuentes Pilar Cacheiro Terrence F. Meehan Juan Antonio Aguilar-Pimentel Steve D. M. Brown Ann M. Flenniken Paul Flicek Antonella Galli Hamed Haseli Mashhadi Martin Hrabě de Angelis Jong Kyoung Kim K. C. Kent Lloyd Colin McKerlie Hugh Morgan Stephen A. Murray Lauryl M. J. Nutter Patrick T. Reilly John R. Seavitt Je Kyung Seong Michelle Simon Hannah Wardle-Jones Ann-Marie Mallon Damian Smedley Helen E. Parkinson the IMPC consortium 《Conservation Genetics》2018,19(4):995-1005
The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied. 相似文献
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83.
R Mallon L R Feldberg S C Kim K Collins D Wojciechowicz I Hollander E D Kovacs C Kohler 《Analytical biochemistry》2001,294(1):48-54
The Ras-MAPK signaling cascade transmits mitogenic stimuli from growth factor receptors and activated Ras to the cell nucleus. Inappropriate Ras activation is associated with approximately 30% of all human cancers. The kinase components of the Ras-MAPK signaling cascade are attractive targets for pharmaceutical intervention. Therefore, we have developed a high-throughput, nonradioactive ELISA method to monitor Raf and MEK1 kinase activity. In this assay system activated Raf phosphorylates and activates MEK1, which in turn phosphorylates MAPK. Antibodies that specifically detect phosphorylated MAPK (vs. nonphosphorylated MAPK) made enzyme-linked immunosorbent assay (ELISA) development possible. This assay detects inhibitors of Raf and/or MEK1 and has been used to screen large numbers of random compounds. The specific target of inhibition in the Raf/MEK1/MAPK ELISA can be subsequently identified by secondary assays which directly measure Raf phosphorylation of MEK1 or MEK1 phosphorylation of MAPK. 相似文献
84.
Likelihood-ratio statistics are proposed to test for heterogeneity in
nucleotide substitution rate among regions of a DNA sequence. The tests
examine three-sequence phylogenies, and two specific tests are proposed: a
test to detect rate heterogeneity among genic regions within a sequence,
over all evolutionary lineages; and a test to detect rate heterogeneity
among regions in a specific evolutionary lineage. Simulations examine the
ability of tests to detect a single region that varies in nucleotide
substitution rate relative to the remainder of the sequence. A 50-bp region
with a fivefold substitution-rate increase can be detected > or = 90% of
the time when it is found in all three lineages of the phylogeny, and a
50-bp region of fivefold rate increase can be detected with approximately
70% power when it is found in only one evolutionary lineage. Simulation
also examines the effect of transition- and transversion-rate differences.
The tests are applied to published DNA sequences. While the tests are
powerful, significant results can be difficult to interpret biologically.
相似文献
85.
J T Walker C W Mackerness D Mallon T Makin T Williets C W Keevil 《Journal of industrial microbiology & biotechnology》1995,15(4):384-390
Immuno-compromised patients are particularly susceptible to Legionnaires' Disease. After three cases of the disease occurred in a hospital, a continuous dosing regime using chlorine dioxide was initiated to replace chlorination of the water system. This study identified a number of factors which may have resulted in conditions that would encourage the growth of the water-borne pathogenLegionella pneumophila. The residual chlorination was inadequate for microbial control at the taps furthest from the four storage tanks, of which two were found to be in excess for demand. The temperature of the water in the storage tanks was also found to be above 20° C; a temperature that would encourage microbial growth. A back-up calorifier was present and was found to containL. pneumophila, and linseed oil-based sealants that provide nutrients for microbial growth were also prevalent as jointing compounds in the water circult. Although the shower heads were routinely disinfected, a requirement was identified to also disinfect the shower hoses. NoL. pneumophila were recovered from the water system after the chlorine reduced dioxide disinfection trial. Biofilm was also dramatically reduced after disinfection; however, small microcolonies were identified and proved to be metabolically active when tested with a metabolic indicator. Using light and fluorescence microscopy, the pipe samples removed from the water system were rapidly analysed for biofouling, complementing existing microbiological methods. 相似文献
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Alternative splicing associated with phenotypic plasticity in the bumble bee Bombus terrestris 下载免费PDF全文
J. Price M. C. Harrison R. L. Hammond S. Adams J. F. Gutierrez‐Marcos E. B. Mallon 《Molecular ecology》2018,27(4):1036-1043
Phenotypic plasticity is when one genome can produce more than one phenotype. The caste system found in many social insects is an important example of plasticity. Several studies have examined gene expression in social insect developmental and caste differences. Changes in gene expression, however, are not the only source of phenotypic plasticity. Here, we investigate the role of alternative splicing in the buff‐tailed bumble bee Bombus terrestris. We found that 5,458 genes in B. terrestris (40%) express more than one isoform. Larvae have the lowest level of splicing events, followed by adults and then pupae. We found that when an isoform is expressed in a given caste in the larval stage, it tends to be expressed in all castes at the larval stage. The same is true at the pupal stage. However, we see more complicated interactions between the adult castes with reproductive females showing different isoform expression compared to nonreproductive females and male adults showing the most distinct patterns. We found 455 isoform switching genes, that is genes, where one developmental stage, sex or caste uses a specific isoform and another type uses a different isoform. Among genes displaying isoform switching are some involved in the ecdysteriod pathway, an important system in insect behaviour. 相似文献
89.
Ariamala Gopalsamy Greg Ciszewski Mengxiao Shi Dan Berger Yongbo Hu Frederick Lee Larry Feldberg Eileen Frommer Steven Kim Karen Collins Donald Wojciechowicz Robert Mallon 《Bioorganic & medicinal chemistry letters》2009,19(24):6890-6892
Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases. 相似文献
90.
Kevin G. Chen Rebecca S. Hamilton Pamela G. Robey Barbara S. Mallon 《Journal of visualized experiments : JoVE》2014,(89)
Human pluripotent stem cells (hPSCs) hold great promise for regenerative medicine and biopharmaceutical applications. Currently, optimal culture and efficient expansion of large amounts of clinical-grade hPSCs are critical issues in hPSC-based therapies. Conventionally, hPSCs are propagated as colonies on both feeder and feeder-free culture systems. However, these methods have several major limitations, including low cell yields and generation of heterogeneously differentiated cells. To improve current hPSC culture methods, we have recently developed a new method, which is based on non-colony type monolayer (NCM) culture of dissociated single cells. Here, we present detailed NCM protocols based on the Rho-associated kinase (ROCK) inhibitor Y-27632. We also provide new information regarding NCM culture with different small molecules such as Y-39983 (ROCK I inhibitor), phenylbenzodioxane (ROCK II inhibitor), and thiazovivin (a novel ROCK inhibitor). We further extend our basic protocol to cultivate hPSCs on defined extracellular proteins such as the laminin isoform 521 (LN-521) without the use of ROCK inhibitors. Moreover, based on NCM, we have demonstrated efficient transfection or transduction of plasmid DNAs, lentiviral particles, and oligonucleotide-based microRNAs into hPSCs in order to genetically modify these cells for molecular analyses and drug discovery. The NCM-based methods overcome the major shortcomings of colony-type culture, and thus may be suitable for producing large amounts of homogeneous hPSCs for future clinical therapies, stem cell research, and drug discovery. 相似文献