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121.
Many gram-negative bacteria produce a specific set of N-acyl-L-homoserine-lactone (AHL) signaling molecules for the purpose of quorum sensing, which is a means of regulating coordinated gene expression in a cell-density-dependent manner. AHLs are produced from acylated acyl-carrier protein (acyl-ACP) and S-adenosyl-L-methionine by the AHL synthase enzyme. The appearance of specific AHLs is due in large part to the intrinsic specificity of the enzyme for subsets of acyl-ACP substrates. Structural studies of the Pantoea stewartii enzyme EsaI and AHL-sensitive bioassays revealed that threonine 140 in the acyl chain binding pocket directs the enzyme toward production of 3-oxo-homoserine lactones. Mass spectrometry was used to examine the range of AHL molecular species produced by AHL synthases under a variety of conditions. An AHL selective normal-phase chromatographic purification with addition of a deuterated AHL internal standard was followed by reverse-phase liquid chromatography-tandem mass spectrometry in order to obtain estimates of the relative amounts of different AHLs from biological samples. The AHLs produced by wild-type and engineered EsaI and LasI AHL synthases show that intrinsic specificity and different cellular conditions influence the production of AHLs. The threonine at position 140 in EsaI is important for the preference for 3-oxo-acyl-ACPs, but the role of the equivalent threonine in LasI is less clear. In addition, LasI expressed in Escherichia coli produces a high proportion of unusual AHLs with acyl chains consisting of an odd number of carbons. Furthermore, these studies offer additional methods that will be useful for surveying and quantitating AHLs from different sources. 相似文献
122.
Ioannis M. Stylianou Ron Korstanje Renhau Li Susan Sheehan Beverly Paigen Gary A. Churchill 《Mammalian genome》2006,17(1):22-36
Obesity is a highly heritable and genetically complex trait with hundreds of potential loci identified. An intercross of 513
F2 progeny between the SM/J × NZB/BINJ inbred mouse strains was generated to identify quantitative trait loci (QTL) that are
involved in the weight of four fat pads: mesenteric, inguinal, gonadal, and retroperitoneal. Sex and lean body weight were
treated as covariates in the analysis of these fat pads. This analysis uncoupled genetic effects related to overall body size
from those influencing the adiposity of a mouse. We identified multiple significant QTL. QTL alleles associated with increased
lean body weight and individual fat pad weights are contributed by the NZB background. Adiposity loci are distinct from these
body size QTLs and high-adiposity alleles are contributed by the SM background. An extended network of epistatic QTL is also
observed. A QTL on Chr 19 is the center of a network of eight interacting QTL, Chr 4 is the center of six, and Chr 17 the
center of four interacting QTL. We conclude that interacting networks of multiple genes characterize the regulation of fat
pad depots and body weight. Haplotype patterns and a literature-driven approach were used to generate hypotheses regarding
the identity of the genes and pathways underlying the QTL. 相似文献
123.
Quantitative trait loci for baseline erythroid traits 总被引:1,自引:0,他引:1
Luanne L. Peters Amy J. Lambert Weidong Zhang Gary A. Churchill Carlo Brugnara Orah S. Platt 《Mammalian genome》2006,17(4):298-309
A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait
locus/loci (QTL) analyses to identify chromosome (Chr) regions harboring genes influencing the baseline erythroid parameters
in F2 intercrosses between NZW/LacJ, SM/J, and C57BLKS/J inbred mice. We identified multiple significant QTL for red blood cell
(RBC) count, hemoglobin (Hgb) and hematocrit (Hct) levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH),
and mean cell hemoglobin concentration (CHCM). We identified four RBC count QTL: Rbcq1 (Chr 1, peak LOD score at 62 cM,), Rbcq2 (Chr 4, 60 cM), Rbcq3 (Chr 11, 34 cM), and Rbcq4 (Chr 10, 60 cM). Three MCV QTL were identified: Mcvq1 (Chr 7, 30 cM), Mvcq2 (Chr 11, 6 cM), and Mcvq3 (Chr 10, 60 cM). Single significant loci for Hgb (Hgbq1, Chr 16, 32 cM), Hct (Hctq1, Chr 3, 42 cM), and MCH (Mchq1, Chr 10, 60 cM) were identified. The data support the existence of a common RBC/MCH/MCV locus on Chr 10. Two QTL for CHCM
(Chcmq1, Chr 2, 48 cM; Chcmq2, Chr 9, 44 cM) and an interaction between Chcmq2 with a locus on Chr 19 were identified. These analyses emphasize the genetic complexity underlying the regulation of erythroid
peripheral blood traits in normal populations and suggest that genes not previously recognized as significantly impacting
normal erythropoiesis exist. 相似文献
124.
Ricardo A. Verdugo Christian F. Deschepper Gloria Mu?oz Daniel Pomp Gary A. Churchill 《Nucleic acids research》2009,37(17):5610-5618
Measurements of gene expression from microarray experiments are highly dependent on experimental design. Systematic noise can be introduced into the data at numerous steps. On Illumina BeadChips, multiple samples are assayed in an ordered series of arrays. Two experiments were performed using the same samples but different hybridization designs. An experiment confounding genotype with BeadChip and treatment with array position was compared to another experiment in which these factors were randomized to BeadChip and array position. An ordinal effect of array position on intensity values was observed in both experiments. We demonstrate that there is increased rate of false-positive results in the confounded design and that attempts to correct for confounded effects by statistical modeling reduce power of detection for true differential expression. Simple analysis models without post hoc corrections provide the best results possible for a given experimental design. Normalization improved differential expression testing in both experiments but randomization was the most important factor for establishing accurate results. We conclude that lack of randomization cannot be corrected by normalization or by analytical methods. Proper randomization is essential for successful microarray experiments. 相似文献
125.
Daniel Rosen Alexander M. Lewis Akiko Mizote Justyn M. Thomas Parvinder K. Aley Sridhar R. Vasudevan Raman Parkesh Antony Galione Minoru Izumi A. Ganesan Grant C. Churchill 《The Journal of biological chemistry》2009,284(50):34930-34934
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2+-releasing messenger. Biological data suggest that its receptor has two binding sites: one high-affinity locking site and one low-affinity opening site. To directly address the presence and function of these putative binding sites, we synthesized and tested analogues of the NAADP antagonist Ned-19. Ned-19 itself inhibits both NAADP-mediated Ca2+ release and NAADP binding. A fluorometry bioassay was used to assess NAADP-mediated Ca2+ release, whereas a radioreceptor assay was used to assess binding to the NAADP receptor (only at the high-affinity site). In Ned-20, the fluorine is para rather than ortho as in Ned-19. Ned-20 does not inhibit NAADP-mediated Ca2+ release but inhibits NAADP binding. Conversely, Ned-19.4 (a methyl ester of Ned-19) inhibits NAADP-mediated Ca2+ release but cannot inhibit NAADP binding. Furthermore, Ned-20 prevents the self-desensitization response characteristic of NAADP in sea urchin eggs, confirming that this response is mediated by a high-affinity allosteric site to which NAADP binds in the radioreceptor assay. Collectively, these data provide the first direct evidence for two binding sites (one high- and one low-affinity) on the NAADP receptor. 相似文献
126.
Leah C. Solberg Woods Nasim Ahmadiyeh Amber Baum Kazuhiro Shimomura Qian Li Donald F. Steiner Fred W. Turek Joseph S. Takahashi Gary A. Churchill Eva E. Redei 《Mammalian genome》2009,20(8):486-497
While diabetic patients often present with comorbid depression, the underlying mechanisms linking diabetes and depression
are unknown. The Wistar Kyoto (WKY) rat is a well-known animal model of depression and stress hyperreactivity. In addition,
the WKY rat is glucose intolerant and likely harbors diabetes susceptibility alleles. We conducted a quantitative trait loci
(QTL) analysis in the segregating F2 population of a WKY × Fischer 344 (F344) intercross. We previously published QTL analyses for depressive behavior and hypothalamic-pituitary-adrenal
(HPA) activity in this cross. In this study we report results from the QTL analysis for multiple metabolic phenotypes, including
fasting glucose, post-restraint stress glucose, postprandial glucose and insulin, and body weight. We identified multiple
QTLs for each trait and many of the QTLs overlap with those previously identified using inbred models of type 2 diabetes (T2D).
Significant correlations were found between metabolic traits and HPA axis measures, as well as forced swim test behavior.
Several metabolic loci overlap with loci previously identified for HPA activity and forced swim behavior in this F2 intercross, suggesting that the genetic mechanisms underlying these traits may be similar. These results indicate that WKY
rats harbor diabetes susceptibility alleles and suggest that this strain may be useful for dissecting the underlying genetic
mechanisms linking diabetes, HPA activity, and depression. 相似文献
127.
128.
Churchill ME 《Structure (London, England : 1993)》2006,14(9):1342-1344
Acyl-amino acids were discovered in the search for novel therapeutic agents produced by uncultured microorganisms. In this issue of Structure, Van Wagoner and Clardy (2006) find that the N-acyl-amino acid synthase FeeM bound to acyl-tyrosine is the latest member of the GCN5-related N-acyltransferase superfamily. 相似文献
129.
The ubiquitous, eukaryotic, high-mobility group box (HMGB) chromosomal proteins promote many chromatin-mediated cellular activities through their non-sequence-specific binding and bending of DNA. Minor-groove DNA binding by the HMG box results in substantial DNA bending toward the major groove owing to electrostatic interactions, shape complementarity, and DNA intercalation that occurs at two sites. Here, the structures of the complexes formed with DNA by a partially DNA intercalation-deficient mutant of Drosophila melanogaster HMGD have been determined by X-ray crystallography at a resolution of 2.85 Å. The six proteins and 50 bp of DNA in the crystal structure revealed a variety of bound conformations. All of the proteins bound in the minor groove, bridging DNA molecules, presumably because these DNA regions are easily deformed. The loss of the primary site of DNA intercalation decreased overall DNA bending and shape complementarity. However, DNA bending at the secondary site of intercalation was retained and most protein-DNA contacts were preserved. The mode of binding resembles the HMGB1 box A-cisplatin-DNA complex, which also lacks a primary intercalating residue. This study provides new insights into the binding mechanisms used by HMG boxes to recognize varied DNA structures and sequences as well as modulate DNA structure and DNA bending. 相似文献
130.
Margarida Ruas Katja Rietdorf Abdelilah Arredouani Lianne C. Davis Emyr Lloyd-Evans Heidi Koegel Timothy M. Funnell Anthony J. Morgan John A. Ward Keiko Watanabe Xiaotong Cheng Grant C. Churchill Michael X. Zhu Frances M. Platt Gary M. Wessel John Parrington Antony Galione 《Current biology : CB》2010,20(8):703-709