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991.
Hanbiao Yang Xiao-Fa Lin Fernando Padilla Stephen D. Gabriel Gabrielle Heilek Changhua Ji Surya Sankuratri André deRosier Pamela Berry David M. Rotstein 《Bioorganic & medicinal chemistry letters》2009,19(1):209-213
Replacement of the cyclic carbamate in our previously disclosed 1-oxa-3,9-diazaspiro[5.5]undecan-2-one template led to the discovery of two novel series of 3,9-diazaspiro[5.5]undecane and undeca-2-one CCR5 antagonists. The synthesis, SAR, and antiviral activities of these two series are described. One compound (32) was found to have attractive combination of antiviral potency, selectivity, and pharmacokinetic profile. The asymmetric synthesis of 32 was also accomplished and both enantiomers were equally potent. 相似文献
992.
Mark D. Rosen Craig R. Woods Steven D. Goldberg Michael D. Hack A. Dawn Bounds Young Yang Pamela C. Wagaman Victor K. Phuong Angela P. Ameriks Terrance D. Barrett Kimon C. Kanelakis Jui Chang Nigel P. Shankley Michael H. Rabinowitz 《Bioorganic & medicinal chemistry letters》2009,19(23):6548-6551
A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase. The synthesis, structure–activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed. 相似文献
993.
994.
Tessa M. Geel Bernardina T. van der Gun Lou F. de Leij Arūnas Šilanskas Alfred Pingoud Pamela M. McLaughlin Marianne G. Rots 《Experimental cell research》2009,315(15):2487-1260
TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18®:DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas. 相似文献
995.
996.
997.
Pamela Osenkowski Hua Li Wenjuan Ye Lorene Aeschbach Michael S. Wolfe Huilin Li 《Journal of molecular biology》2009,385(2):642-652
γ-Secretase, an integral membrane protein complex, catalyzes the intramembrane cleavage of the β-amyloid precursor protein (APP) during the neuronal production of the amyloid β-peptide. As such, the protease has emerged as a key target for developing agents to treat and prevent Alzheimer's disease. Existing biochemical studies conflict on the oligomeric assembly state of the protease complex, and its detailed structure is not known. Here, we report that purified active human γ-secretase in digitonin has a total molecular mass of ∼ 230 kDa when measured by scanning transmission electron microscopy. This result supports a complex that is monomeric for each of the four component proteins. We further report the three-dimensional structure of the γ-secretase complex at 12 Å resolution as obtained by cryoelectron microscopy and single-particle image reconstruction. The structure reveals several domains on the extracellular side, three solvent-accessible low-density cavities, and a potential substrate-binding surface groove in the transmembrane region of the complex. 相似文献
998.
Pamela H. Cameron Eric Chevet Olivier Pluquet David Y. Thomas John J. M. Bergeron 《The Journal of biological chemistry》2009,284(50):34570-34579
Calnexin is a type I integral membrane phosphoprotein resident of the endoplasmic reticulum. Its intraluminal domain has been deduced to function as a lectin chaperone coordinating the timing of folding of newly synthesized N-linked glycoproteins of the secretory pathway. Its C-terminal cytosolic oriented extension has an ERK1 phosphorylation site at Ser563 affecting calnexin association with the translocon. Here we find an additional function for calnexin phosphorylation at Ser563 in endoplasmic reticulum quality control. A low dose of the misfolding agent l-azetidine 2-carboxylic acid slows glycoprotein maturation and diminishes the extent and rate of secretion of newly synthesized secretory α1-antitrypsin. Under these conditions the phosphorylation of calnexin is enhanced at Ser563. Inhibition of this phosphorylation by the MEK1 inhibitor PD98059 enhanced the extent and rate of α1-antitrypsin secretion comparable with that achieved by inhibiting α-mannosidase activity with kifunensine. This is the first report in which the phosphorylation of calnexin is linked to the efficiency of secretion of a cargo glycoprotein. 相似文献
999.
Blanca M Herrera Helen E Lockstone Jennifer M Taylor Quin F Wills Pamela J Kaisaki Amy Barrett Carme Camps Christina Fernandez Jiannis Ragoussis Dominique Gauguier Mark I McCarthy Cecilia M Lindgren 《BMC medical genomics》2009,2(1):1-11
Background
The methods used for sample selection and processing can have a strong influence on the expression values obtained through microarray profiling. Laser capture microdissection (LCM) provides higher specificity in the selection of target cells compared to traditional bulk tissue selection methods, but at an increased processing cost. The benefit gained from the higher tissue specificity realized through LCM sampling is evaluated in this study through a comparison of microarray expression profiles obtained from same-samples using bulk and LCM processing.Methods
Expression data from ten lung adenocarcinoma samples and six adjacent normal samples were acquired using LCM and bulk sampling methods. Expression values were evaluated for correlation between sample processing methods, as well as for bias introduced by the additional linear amplification required for LCM sample profiling.Results
The direct comparison of expression values obtained from the bulk and LCM sampled datasets reveals a large number of probesets with significantly varied expression. Many of these variations were shown to be related to bias arising from the process of linear amplification, which is required for LCM sample preparation. A comparison of differentially expressed genes (cancer vs. normal) selected in the bulk and LCM datasets also showed substantial differences. There were more than twice as many down-regulated probesets identified in the LCM data than identified in the bulk data. Controlling for the previously identified amplification bias did not have a substantial impact on the differences identified in the differentially expressed probesets found in the bulk and LCM samples.Conclusion
LCM-coupled microarray expression profiling was shown to uniquely identify a large number of differentially expressed probesets not otherwise found using bulk tissue sampling. The information gain realized from the LCM sampling was limited to differential analysis, as the absolute expression values obtained for some probesets using this study's protocol were biased during the second round of amplification. Consequently, LCM may enable investigators to obtain additional information in microarray studies not easily found using bulk tissue samples, but it is of critical importance that potential amplification biases are controlled for. 相似文献1000.
Jeanne M. Ferrante Alicja K. Piasecki Pamela A. Ohman‐Strickland Benjamin F. Crabtree 《Obesity (Silver Spring, Md.)》2009,17(9):1710-1716
Despite the growing epidemic of extreme obesity in the United States, weight management is not adequately addressed in primary care. This study assessed family physicians' practices and attitudes regarding care of extremely obese patients and factors associated with them. A cross‐sectional, self‐administered survey was mailed to 500 family physicians in New Jersey (NJ) during March–May 2008. Measures included knowledge, weight management approaches, attitudes toward managing obesity, challenges with examinations, availability of supplies, and strategies to improve care. Response rate was 53% (N = 255). Bariatric surgery and weight loss medications were infrequently recommended, particularly in physicians with higher volume of extremely obese patients (odds ratio (OR) 0.38; 95% confidence interval (CI) 0.23, 0.62 and OR 0.51; 95% CI 0.31, 0.85 for surgery and medications, respectively). Higher knowledge was associated with increased frequency of recommendations of weight loss medications (P < 0.0001) and bariatric surgery (P < 0.0001). There was a high prevalence of negative attitudes, particularly in younger physicians and those with lower patient volume. Increased knowledge of weight‐loss diets was associated with less dislike in discussing weight loss (P < 0.0001), less frustration (P = 0.0001), less belief that treatment is often ineffective (P < 0.0001), and less pessimism about patient success (P = 0.0002). Many providers encountered challenges performing examinations on extremely obese patients. More education of primary care physicians, particularly on bariatric surgery, specific examination techniques, and availability of community resources for obese persons is needed. Further research is needed to determine if interventions to increase knowledge of physicians will lead to less negative attitudes toward weight loss and extremely obese patients. 相似文献