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941.
Jaison J. Omoto Matthew J. Maestas Ali Rahnama-Vaghef Ye E. Choi Gerardo Salto Jr. Rachel V. Sanchez Cynthia M. Anderson Sepehr Eskandari 《The Journal of membrane biology》2012,245(12):841-857
The aims of this study were to optimize the experimental conditions for labeling extracellularly oriented, solvent-exposed cysteine residues of ??-aminobutyric acid transporter 1 (GAT1) with the membrane-impermeant sulfhydryl reagent [2-(trimethylammonium)ethyl]methanethiosulfonate (MTSET) and to characterize the functional and pharmacological consequences of labeling on transporter steady-state and presteady-state kinetic properties. We expressed human GAT1 in Xenopus laevis oocytes and used radiotracer and electrophysiological methods to assay transporter function before and after sulfhydryl modification with MTSET. In the presence of NaCl, transporter exposure to MTSET (1?C2.5?mM for 5?C20?min) led to partial inhibition of GAT1-mediated transport, and this loss of function was completely reversed by the reducing reagent dithiothreitol. MTSET treatment had no functional effect on the mutant GAT1 C74A, whereas the membrane-permeant reagents N-ethylmaleimide and tetramethylrhodamine-6-maleimide inhibited GABA transport mediated by GAT1 C74A. Ion replacement experiments indicated that MTSET labeling of GAT1 could be driven to completion when valproate replaced chloride in the labeling buffer, suggesting that valproate induces a GAT1 conformation that significantly increases C74 accessibility to the extracellular fluid. Following partial inhibition by MTSET, there was a proportional reduction in both the presteady-state and steady-state macroscopic signals, and the functional and pharmacological properties of the remaining signals were indistinguishable from those of unlabeled GAT1. Therefore, covalent modification of GAT1 at C74 results in completely nonfunctional as well as electrically silent transporters. 相似文献
942.
943.
Daniela Waltrick Cynthia Awruch Colin Simpfendorfer 《Reviews in Fish Biology and Fisheries》2012,22(4):849-859
Embryonic diapause is a temporary suspension of development at any stage of embryogenesis, which prolongs the gestation period, allowing parturition to occur in conditions that are more suitable for newborns. This reproductive trait is widespread among all vertebrates, including elasmobranchs. Although it has only been confirmed in two elasmobranchs (Rhizoprionodon taylori and Dasyatis say), evidence indicates that at least 14 species of rays and two sharks undergo diapause, suggesting that this form of reproduction exists within a wide range of elasmobranch reproductive modes, including lecithotrophs and matrotrophs. Where it has been studied, embryogenesis is arrested at the blastodisc stage and preserved in the uterus for periods from four to 10?months. There are still many questions that remain unanswered concerning the knowledge on the biology of most diapausing species but it is clear that species benefit differently from this reproductive trait. As in other vertebrates, it is likely that environmental cues and hormones (especially progesterone and prolactin) are involved in the control of diapause in elasmobranchs, however rigorous testing of current hypothesis remains to be carried out. 相似文献
944.
Ramurthy S Costales A Jansen JM Levine B Renhowe PA Shafer CM Subramanian S 《Bioorganic & medicinal chemistry letters》2012,22(4):1678-1681
Compounds belonging to several scaffolds-quinazolines, quinolines and quinoxalines-were designed and synthesized as Raf kinase inhibitors. Scaffolds were assessed for in vitro Braf(V600E) inhibition, and overall kinase selectivity. Pharmacokinetic parameters for one of the scaffolds were also determined. 相似文献
945.
946.
Rac signaling in breast cancer: a tale of GEFs and GAPs 总被引:1,自引:0,他引:1
Wertheimer E Gutierrez-Uzquiza A Rosemblit C Lopez-Haber C Sosa MS Kazanietz MG 《Cellular signalling》2012,24(2):353-362
Rac GTPases, small G-proteins widely implicated in tumorigenesis and metastasis, transduce signals from tyrosine-kinase, G-protein-coupled receptors (GPCRs), and integrins, and control a number of essential cellular functions including motility, adhesion, and proliferation. Deregulation of Rac signaling in cancer is generally a consequence of enhanced upstream inputs from tyrosine-kinase receptors, PI3K or Guanine nucleotide Exchange Factors (GEFs), or reduced Rac inactivation by GTPase Activating Proteins (GAPs). In breast cancer cells Rac1 is a downstream effector of ErbB receptors and mediates migratory responses by ErbB1/EGFR ligands such as EGF or TGFα and ErbB3 ligands such as heregulins. Recent advances in the field led to the identification of the Rac-GEF P-Rex1 as an essential mediator of Rac1 responses in breast cancer cells. P-Rex1 is activated by the PI3K product PIP3 and Gβγ subunits, and integrates signals from ErbB receptors and GPCRs. Most notably, P-Rex1 is highly overexpressed in human luminal breast tumors, particularly those expressing ErbB2 and estrogen receptor (ER). The P-Rex1/Rac signaling pathway may represent an attractive target for breast cancer therapy. 相似文献
947.
Zhao M Batista A Cunningham JP Chestek C Rivera-Alvidrez Z Kalmar R Ryu S Shenoy K Iyengar S 《Journal of computational neuroscience》2012,32(3):479-497
Interactions among neurons are a key component of neural signal processing. Rich neural data sets potentially containing evidence
of interactions can now be collected readily in the laboratory, but existing analysis methods are often not sufficiently sensitive
and specific to reveal these interactions. Generalized linear models offer a platform for analyzing multi-electrode recordings
of neuronal spike train data. Here we suggest an L
1-regularized logistic regression model (L
1
L method) to detect short-term (order of 3 ms) neuronal interactions. We estimate the parameters in this model using a coordinate
descent algorithm, and determine the optimal tuning parameter using a Bayesian Information Criterion. Simulation studies show
that in general the L
1
L method has better sensitivities and specificities than those of the traditional shuffle-corrected cross-correlogram (covariogram)
method. The L
1
L method is able to detect excitatory interactions with both high sensitivity and specificity with reasonably large recordings,
even when the magnitude of the interactions is small; similar results hold for inhibition given sufficiently high baseline
firing rates. Our study also suggests that the false positives can be further removed by thresholding, because their magnitudes
are typically smaller than true interactions. Simulations also show that the L
1
L method is somewhat robust to partially observed networks. We apply the method to multi-electrode recordings collected in
the monkey dorsal premotor cortex (PMd) while the animal prepares to make reaching arm movements. The results show that some
neurons interact differently depending on task conditions. The stronger interactions detected with our L
1
L method were also visible using the covariogram method. 相似文献
948.
Bryda EC Johnson NT Ohlemiller KK Besch-Williford CL Moore E Bram RJ 《Mammalian genome》2012,23(3-4):270-276
Calcium-modulating cyclophilin ligand (Caml) is a ubiquitously expressed cytoplasmic protein that is involved in multiple signaling and developmental pathways. An observation in our laboratory of a protein-protein interaction between Caml and the cytoplasmic region of Cadherin23 led us to speculate that Caml might be important in the inner ear and play a role in the development and/or function of hair cells. To address this question, we generated a mouse line in which Caml expression was eliminated in Atoh1-expressing cells of the inner ear upon administration of tamoxifen. Tamoxifen was administered immediately after birth to neonates to assess the effect of loss of Caml in the inner ear during postnatal development. Hearing in treated animals was tested by auditory brain stem response (ABR) analysis and cochlear pathology was evaluated by light microscopy. Lack of Caml expression in the inner ear leads to severe loss of cochlear hair cells and complete deafness. Elucidating the role of Caml in the inner ear will aid our understanding of the molecular pathways important for auditory development and function. 相似文献
949.
Robitaille C Dai S Waters C Loukine L Bancej C Quach S Ellison J Campbell N Tu K Reimer K Walker R Smith M Blais C Quan H 《CMAJ》2012,184(1):E49-E56
Background:
Hypertension is a leading risk factor for cardiovascular diseases. Our objectives were to examine the prevalence and incidence of diagnosed hypertension in Canada and compare mortality among people with and without diagnosed hypertension.Methods:
We obtained data from linked health administrative databases from each province and territory for adults aged 20 years and older. We used a validated case definition to identify people with hypertension diagnosed between 1998/99 and 2007/08. We excluded pregnant women from the analysis.Results:
This retrospective population-based study included more than 26 million people. In 2007/08, about 6 million adults (23.0%) were living with diagnosed hypertension and about 418 000 had a new diagnosis. The age-standardized prevalence increased significantly from 12.5% in 1998/99 to 19.6% in 2007/08, and the incidence decreased from 2.7 to 2.4 per 100. Among people aged 60 years and older, the prevalence was higher among women than among men, as was the incidence among people aged 75 years and older. The prevalence and incidence were highest in the Atlantic region. For all age groups, all-cause mortality was higher among adults with diagnosed hypertension than among those without diagnosed hypertension.Interpretation:
The overall prevalence of diagnosed hypertension in Canada from 1998 to 2008 was high and increasing, whereas the incidence declined during the same period. These findings highlight the need to continue monitoring the effectiveness of efforts for managing hypertension and to enhance public health programs aimed at preventing hypertension.Globally, raised blood pressure is the leading risk factor for death, accounting for about 13% of all deaths,1,2 and it is the strongest risk factor for lost years of healthy life.1 Left untreated, hypertension can increase the risk of stroke, coronary artery disease, dementia, heart and kidney failure, and other chronic diseases.3–6 Managing hypertension through lifestyle modification or the use of antihypertensive medications, or both, can help mitigate these outcomes.7 Over the past decades in Canada, mortality associated with cardiovascular diseases has decreased,8 partly because of increased awareness and diagnosis of hypertension and better control of blood pressure.9,10 However, the prevalence of hypertension remains high, and currently there are no mechanisms to track new cases at the national level.To date, information about hypertension in Canada has been mainly obtained by health surveys conducted at the provincial or national levels. Such surveys typically provide prevalence (not incidence) data and include limited data about trends over time.11–15 National health surveys in Canada are resource intensive, do not include information about people who live in remote areas or institutions, and may underestimate hypertension prevalence because of recall bias and non-response.16 The use of administrative data that is population-based and routinely collected, such as physician claims and hospital discharge data, allows for a more comprehensive picture of this condition. Other important advantages of using administrative data include the readiness of the data to be analyzed, cost-efficiency, wide geographic coverage and the relatively complete capture of patient contact with the health care system (i.e., less prone to selection bias).Several recent studies in Canada and the United States have established valid methods for using administrative data to identify cases of hypertension.16–23 In a study conducted in Ontario involving women and men aged 20 years and older, Tu and colleagues found that the prevalence and incidence of diagnosed hypertension were 24.5% in 2005 and 3.2% in 2004, respectively.24 We used the same validated case definition to examine the prevalence and incidence of diagnosed hypertension in Canada from 1998/99 to 2007/08 by age and by province and territory. We also compared all-cause mortality by age and sex among those with and without diagnosed hypertension. 相似文献950.
Hany Siha Debraj Das Yuling Fu Yinggan Zheng Cynthia M. Westerhout Robert F. Storey Stefan James Lars Wallentin Paul W. Armstrong 《CMAJ》2012,184(10):1135-1142