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131.
Stacey L. Edwards Rosalina M. Yorks Logan M. Morrison Christopher M. Hoover Kenneth G. Miller 《Genetics》2015,201(1):91-116
The functional integrity of neurons requires the bidirectional active transport of synaptic vesicles (SVs) in axons. The kinesin motor KIF1A transports SVs from somas to stable SV clusters at synapses, while dynein moves them in the opposite direction. However, it is unclear how SV transport is regulated and how SVs at clusters interact with motor proteins. We addressed these questions by isolating a rare temperature-sensitive allele of Caenorhabditis elegans unc-104 (KIF1A) that allowed us to manipulate SV levels in axons and dendrites. Growth at 20° and 14° resulted in locomotion rates that were ∼3 and 50% of wild type, respectively, with similar effects on axonal SV levels. Corresponding with the loss of SVs from axons, mutants grown at 14° and 20° showed a 10- and 24-fold dynein-dependent accumulation of SVs in their dendrites. Mutants grown at 14° and switched to 25° showed an abrupt irreversible 50% decrease in locomotion and a 50% loss of SVs from the synaptic region 12-hr post-shift, with no further decreases at later time points, suggesting that the remaining clustered SVs are stable and resistant to retrograde removal by dynein. The data further showed that the synapse-assembly proteins SYD-1, SYD-2, and SAD-1 protected SV clusters from degradation by motor proteins. In syd-1, syd-2, and sad-1 mutants, SVs accumulate in an UNC-104-dependent manner in the distal axon region that normally lacks SVs. In addition to their roles in SV cluster stability, all three proteins also regulate SV transport. 相似文献
132.
Lisheng Kong Patrick von Aderkas Stacey J. Owen Tia Wagner Suzanne R. Abrams 《Trees - Structure and Function》2011,25(6):1103-1110
In lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.), cone bud initiation within long-shoot buds varies according to genotype. We chose to study hormone profiles of
two genotypes that differed significantly in cone yield. Phytohormone profiles were established by high performance liquid
chromatography–electrospray ionization tandem mass spectrometry in multiple reaction monitoring mode with samples collected
from genotypes 299 and 233, the typically high and low cone producers. Generally, concentrations of trans-zeatin-O-glucoside were higher in genotype 299, whereas dihydrozeatin concentrations were higher in genotype 233. Both isopentenyl
adenine and isopentenyl adenosine were present at higher concentrations in genotype 233. The ratio of total quantifiable zeatin
(Z)-type cytokinins to isopentenyl (iP)-type cytokinins was approximately threefold higher in genotype 299 during female cone
bud differentiation. In genotype 299, ABA concentration was significantly lower than in genotype 233 on the first sampling
date, while the phaseic acid concentration was lower consistently throughout the period investigated. Dihydrophaseic acid
was present in low concentrations in most samples of genotype 233, but was not quantifiable in genotype 299. Our study reveals
that long-shoot buds of the high cone-producing genotype had higher ratios of Z-type cytokinins to iP-type cytokinins than
were found in the low cone-producing genotype. High cone-producing buds also contained less ABA, phaseic acid and dihydrophaseic
acid during female cone bud differentiation. 相似文献
133.
Gilbert AM Bursavich MG Lombardi S Adedoyin A Dwyer JM Hughes Z Kern JC Khawaja X Rosenzweig-Lipson S Moore WJ Neal SJ Olsen M Rizzo SJ Springer D 《Bioorganic & medicinal chemistry letters》2011,21(1):195-199
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC50s <50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Ki: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). 相似文献
134.
LaMarche MJ Leeds JA Dzink-Fox J Mullin S Patane MA Rann EM Tiamfook S 《Bioorganic & medicinal chemistry letters》2011,21(11):3210-3215
Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare 4-thiazolyl imidazole analogs of 1. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based antibacterial template. 相似文献
135.
Zheng X Hudyma TW Martin SW Bergstrom C Ding M He F Romine J Poss MA Kadow JF Chang CH Wan J Witmer MR Morin P Camac DM Sheriff S Beno BR Rigat KL Wang YK Fridell R Lemm J Qiu D Liu M Voss S Pelosi L Roberts SB Gao M Knipe J Gentles RG 《Bioorganic & medicinal chemistry letters》2011,21(10):2925-2929
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC50 = 0.07 μM, %F = 18), are reported. 相似文献
136.
137.
138.
Tang CS Tang WK So MT Miao XP Leung BM Yip BH Leon TY Ngan ES Lui VC Chen Y Chan IH Chung PH Liu XL Wu XZ Wong KK Sham PC Cherny SS Tam PK Garcia-Barceló MM 《PloS one》2011,6(1):e16181
The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. 相似文献
139.
Luong MX Auerbach J Crook JM Daheron L Hei D Lomax G Loring JF Ludwig T Schlaeger TM Smith KP Stacey G Xu RH Zeng F 《Cell Stem Cell》2011,8(4):357-359
Human embryonic and induced pluripotent stem cell lines are being generated at a rapid pace and now number in the thousands. We propose a standard nomenclature and suggest the use of a centralized database for all cell line names and a minimum set of information for reporting new derivations. 相似文献
140.
van Zuylen WJ Garceau V Idris A Schroder K Irvine KM Lattin JE Ovchinnikov DA Perkins AC Cook AD Hamilton JA Hertzog PJ Stacey KJ Kellie S Hume DA Sweet MJ 《PloS one》2011,6(1):e15723