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排序方式: 共有288条查询结果,搜索用时 234 毫秒
91.
Jason A. Bubier Jeremy J. Jay Christopher L. Baker Susan E. Bergeson Hiroshi Ohno Pamela Metten John C. Crabbe Elissa J. Chesler 《Genetics》2014,197(4):1377-1393
Extensive genetic and genomic studies of the relationship between alcohol drinking preference and withdrawal severity have been performed using animal models. Data from multiple such publications and public data resources have been incorporated in the GeneWeaver database with >60,000 gene sets including 285 alcohol withdrawal and preference-related gene sets. Among these are evidence for positional candidates regulating these behaviors in overlapping quantitative trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration of functional genomics experimental results revealed a single QTL positional candidate gene in one of the loci common to both preference and withdrawal. Functional validation studies in Ap3m2 knockout mice confirmed these relationships. Genetic validation involves confirming the existence of segregating polymorphisms that could account for the phenotypic effect. By exploiting recent advances in mouse genotyping, sequence, epigenetics, and phylogeny resources, we confirmed that Ap3m2 resides in an appropriately segregating genomic region. We have demonstrated genetic and alcohol-induced regulation of Ap3m2 expression. Although sequence analysis revealed no polymorphisms in the Ap3m2-coding region that could account for all phenotypic differences, there are several upstream SNPs that could. We have identified one of these to be an H3K4me3 site that exhibits strain differences in methylation. Thus, by making cross-species functional genomics readily computable we identified a common QTL candidate for two related bio-behavioral processes via functional evidence and demonstrate sufficiency of the genetic locus as a source of variation underlying two traits. 相似文献
92.
Y Deng J Zhao D Sakurai KM Kaufman JC Edberg RP Kimberly DL Kamen GS Gilkeson CO Jacob RH Scofield CD Langefeld JA Kelly ME Alarcón-Riquelme BIOLUPUS GENLES Networks JB Harley TJ Vyse BI Freedman PM Gaffney KM Sivils JA James TB Niewold RM Cantor W Chen BH Hahn EE Brown PROFILE BP Tsao 《Arthritis research & therapy》2012,14(Z3):A5
93.
Crabbe JC 《Genes, Brain & Behavior》2012,11(4):375-386
In biomedical research, one key stage of translating basic science knowledge to clinical practice is the reconciliation of phenotypes employed for laboratory animal studies with those important for the clinical condition. Alcohol dependence (AD) is a prototypic complex genetic trait. There is a long history of behaviour-genetic studies of AD in both human subjects and various genetic animal models. This review assesses the state of the art in our understanding of the genetic contributions to AD. In particular, it primarily focuses on the phenotypes studied in mouse genetic animal models, comparing them to the aspects of the human condition they are intended to target. It identifies several features of AD where genetic animal models have been particularly useful, and tries to identify understudied areas where there is good promise for further genetic animal model work. 相似文献
94.
4-Pyridin-5-yl-2-(3,4,5-trimethoxyphenylamino)pyrimidines: potent and selective inhibitors of ZAP 70
Moffat D Davis P Hutchings M Davis J Berg D Batchelor M Johnson J O'Connell J Martin R Crabbe T Delgado J Perry M 《Bioorganic & medicinal chemistry letters》1999,9(23):3351-3356
Activation of the tyrosine kinase ZAP 70 has been shown to be crucial to the transduction of the T-cell receptor signalling pathway, which leads ultimately to proliferation, cytokine gene expression and T-cell effector functions. A series of 2-phenylaminopyrimidines have been identified as potent and selective inhibitors of ZAP 70. 相似文献
95.
Alexander R Balasundaram A Batchelor M Brookings D Crépy K Crabbe T Deltent MF Driessens F Gill A Harris S Hutchinson G Kulisa C Merriman M Mistry P Parton T Turner J Whitcombe I Wright S 《Bioorganic & medicinal chemistry letters》2008,18(15):4316-4320
4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth. 相似文献
96.
97.
Regulation of cellular adhesion molecule expression in murine oocytes, peri-implant ation and post-implantation embryos 总被引:2,自引:0,他引:2
DAVID P LU LINA TIAN CHRIS O'''' NEILL NICHOLAS JC KING Department of Pathology University of Sydney NSW AustraliaHuman Reproduction Unit Department of Physiology University of Sydney Royal North Shore Hospital NSW Australia 《Cell research》2002,(Z2)
Expression of the adhesion molecules, ICAM-1, VCAM-1, NCAM, CD44, CD49d (VLA-4, a chain), and CDlla (LFA-1, a chain) on mouse oocytes, and pre- and peri-implantation stage embryos was examined by quantitative indirect immunofluorescence microscopy. ICAM-1 was most strongly expressed at the oocyte stage, gradually declining almost to undetectable levels by the expanded blastocyst stage. NCAM, also expressed maximally on the oocyte, declined to undetectable levels beyond the morula stage. On the other hand, CD44 declined from highest expression at the oocyte stage to show a second maximum at the compacted 8-cell/morula. This molecule exhibited high expression around contact areas between trophecto-derm and zona pellucida during blastocyst hatching. CD49d was highly expressed in the oocyte, remained significantly expressed throughout and after blastocyst hatching was expressed on the polar trophecto-derm. Like CD44, CD49d declined to undetectable levels at the blastocyst outgrowth stage. Expression of both 相似文献
98.
99.
Microsatellite allele frequencies in humans and chimpanzees, with implications for constraints on allele size 总被引:24,自引:6,他引:18
The distributions of allele sizes at eight simple-sequence repeat (SSR) or
microsatellite loci in chimpanzees are found and compared with the
distributions previously obtained from several human populations. At
several loci, the differences in average allele size between chimpanzees
and humans are sufficiently small that there might be a constraint on the
evolution of average allele size. Furthermore, a model that allows for a
bias in the mutation process shows that for some loci a weak bias can
account for the observations. Several alleles at one of the loci (Mfd 59)
were sequenced. Differences between alleles of different lengths were found
to be more complex than previously assumed. An 8-base-pair deletion was
present in the nonvariable region of the chimpanzee locus. This locus
contains a previously unrecognized repeated region, which is imperfect in
humans and perfect in chimpanzees. The apparently greater opportunity for
mutation conferred by the two perfect repeat regions in chimpanzees is
reflected in the higher variance in repeat number at Mfd 59 in chimpanzees
than in humans. These data indicate that interspecific differences in
allele length are not always attributable to simple changes in the number
of repeats.
相似文献
100.
M. J. Perry J. O’Connell C. Walker T. Crabbe D. Baldock A. Russell S. Lumb Z. Huang D. Howat R. Allen M. Merriman J. Walls T. Daniel B. Hughes F. Laliberte G. A. Higgs R. J. Owens 《Cell biochemistry and biophysics》1998,29(1-2):113-132
We present the in vitro characterization of a novel phosphodiesterase type 4 inhibitor, CDP840 (R-[+]-4-[2-{3-cyclopentyloxy-4-methoxyphenyl}-2-phenylethyl]pyridine), which has shown efficacy in a phase II allergen challenge
study in asthmatics without adverse effects. CDP840 potently inhibits PDE-4 isoenzymes (IC50 2–30 nM) without any effect on PDE-1, 2, 3, 5, and 7 (IC50>100 μM). It exhibited no significant selectivity in inhibiting human recombinant isoenzymes PDE-4A, B, C or D and was equally active
against the isoenzymes lacking UCR1 (PDE-4B2 and PDE-4D2). In contrast to rolipram, CDP840 acted as a simple competitive inhibitor
of all PDE-4 isoenzymes. Studies with rolipram indicated a heterogeneity within all the preparations of PDE-4 isoenzymes,
indicative of rolipram inhibiting the catalytic activity of PDE-4 with both a low or high affinity. These observations were
confirmed by the use of a PDE-4A variant, PDE-4A330–886, which rolipram inhibited with low affinity (IC50=1022 nM). CDP840 in contrast inhibited this PDE-4A variant with similar potency (IC50=3.9 nM), which was in good agreement with theK
d of 4.8 nM obtained from [3H]-CDP840 binding studies. Both CDP840 and rolipram inhibited the high-affinity binding of [3H]-rolipram binding to PDE-4A, B, C and D with similarK
d app (7–19 nM and 3–5 nM, respectively). Thus, the activity of CDP840 at the [3H]-rolipram binding site was in agreement with the inhibitor’s activity at the catalytic site. However, rolipram was ∼100-fold
more potent than CDP840 at inhibiting the binding of [3H]-rolipram to mouse brain in vivo. These data clearly demonstrate that CDP840 is a potent selective inhibitor of all PDE-4
isoenzymes. In contrast to rolipram, CDP840 was well-tolerated in humans. This difference, however, cannot at present be attributed
to either isoenzyme selectivity or lack of activity in vitro at the high-affinity rolipram binding site (Sr). 相似文献