全文获取类型
收费全文 | 3522篇 |
免费 | 290篇 |
国内免费 | 6篇 |
专业分类
3818篇 |
出版年
2023年 | 29篇 |
2022年 | 77篇 |
2021年 | 116篇 |
2020年 | 75篇 |
2019年 | 92篇 |
2018年 | 80篇 |
2017年 | 78篇 |
2016年 | 109篇 |
2015年 | 176篇 |
2014年 | 196篇 |
2013年 | 239篇 |
2012年 | 280篇 |
2011年 | 289篇 |
2010年 | 177篇 |
2009年 | 144篇 |
2008年 | 207篇 |
2007年 | 174篇 |
2006年 | 161篇 |
2005年 | 150篇 |
2004年 | 123篇 |
2003年 | 128篇 |
2002年 | 106篇 |
2001年 | 34篇 |
2000年 | 14篇 |
1999年 | 32篇 |
1998年 | 29篇 |
1997年 | 20篇 |
1996年 | 19篇 |
1995年 | 20篇 |
1994年 | 18篇 |
1993年 | 18篇 |
1992年 | 9篇 |
1991年 | 11篇 |
1988年 | 14篇 |
1986年 | 13篇 |
1985年 | 9篇 |
1984年 | 16篇 |
1983年 | 14篇 |
1982年 | 28篇 |
1981年 | 19篇 |
1980年 | 16篇 |
1979年 | 18篇 |
1978年 | 11篇 |
1977年 | 12篇 |
1973年 | 13篇 |
1972年 | 14篇 |
1971年 | 9篇 |
1969年 | 8篇 |
1967年 | 8篇 |
1960年 | 8篇 |
排序方式: 共有3818条查询结果,搜索用时 0 毫秒
31.
Aaron M. Bender Rebecca L. Weiner Vincent B. Luscombe Sonia Ajmera Hyekyung P. Cho Sichen Chang Xiaoyan Zhan Alice L. Rodriguez Colleen M. Niswender Darren W. Engers Thomas M. Bridges P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(15):3576-3581
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp = 2.1, Kp,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. 相似文献
32.
Ali NA Gaughan AA Orosz CG Baran CP McMaken S Wang Y Eubank TD Hunter M Lichtenberger FJ Flavahan NA Lawler J Marsh CB 《PloS one》2008,3(4):e1914
Latency Associated Peptide (LAP) binds TGF-beta1, forming a latent complex. Currently, LAP is presumed to function only as a sequestering agent for active TGF-beta1. Previous work shows that LAP can induce epithelial cell migration, but effects on leukocytes have not been reported. Because of the multiplicity of immunologic processes in which TGF-beta1 plays a role, we hypothesized that LAP could function independently to modulate immune responses. In separate experiments we found that LAP promoted chemotaxis of human monocytes and blocked inflammation in vivo in a murine model of the delayed-type hypersensitivity response (DTHR). These effects did not involve TGF-beta1 activity. Further studies revealed that disruption of specific LAP-thrombospondin-1 (TSP-1) interactions prevented LAP-induced responses. The effect of LAP on DTH inhibition depended on IL-10. These data support a novel role for LAP in regulating monocyte trafficking and immune modulation. 相似文献
33.
34.
Rafaela Magalhães Brandão Maria das Graças Cardoso Luís Roberto Batista Alex Rodrigues Silva Caetano Ana Carolina Cortez Lemos Maria Alice Martins David Lee Nelson Juliano Elvis De Oliveira 《Letters in applied microbiology》2022,74(5):765-776
Poly(lactic acid) (PLA) nanofibres containing different proportions of the essential oils from Ocimum basilicum L. and Ocimum gratissimum L. were prepared by solution blow spinning method. The essential oils were extracted by hydrodistillation and characterized by gas chromatography. MEV, contact angle, DSC and FTIR were used to characterize the nanofibres. The effect of bioative nanofibres on the growth of the fungus and on the production of ochratoxin A were evaluated using the fumigation test. Linalool, 1·8-cineole and camphor were the principal components of the essential oil from O. basilicum, and eugenol was the principal constituent in the oil from O. gratissimum. An increase in the average diameter of the nanofibres was observed with the addition of the essential oils. The essential oils acted as a plasticizer, resulting in a reduction in the crystallinity of the PLA. The encapsulation of essential oils in PLA nanofibres was verified by FTIR. An effective antifungal and antimicotoxygenic activity against Aspergillus ochraceus and Aspergillus westerdjikiae was observed for the bioative nanofibres. These results confirm the potential of PLA nanofibres containing the essential oils for the control of toxigenic fungi that cause the deterioration of food and are harmful to human health. 相似文献
35.
Dawson Ian K. van Breugel Paulo Coe Richard Kindt Roeland van Zonneveld Maarten Lillesø Jens-Peter B. Graudal Lars Muchugi Alice Russell Joanne Jamnadass Ramni 《Tree Genetics & Genomes》2017,13(4):1-17
Tree Genetics & Genomes - Forest and woodland landscape restoration is a key undertaking of renewed interest for forestry and conservation practitioners, but is hampered by the lack of... 相似文献
36.
Arthas Flabouris Savvy Nandal Luke Vater Katerina Flabouris Alice O’Connell Campbell Thompson 《PloS one》2015,10(12)
Background
Observation charts are the primary tool for recording patient vital signs. They have a critical role in documenting triggers for a multi-tiered escalation response to the deteriorating patient. The objectives of this study were to ascertain the prevalence and incidence of triggers, trigger modifications and escalation response (Call) amongst general medical and surgical inpatients following the introduction of an observation and response chart (ORC).Methods
Prospective (prevalence), over two 24-hour periods, and retrospective (incidence), over entire hospital stay, observational study of documented patient observations intended to trigger one of three escalation responses, being a MER—Medical Emergency Response [highest tier], MDT—Multidisciplinary Team [admitting team], or Nurse—senior ward nurse [lowest tier] response amongst adult general medical and surgical patients.Results
Prevalence: 416 patients, 321 (77.2%) being medical admissions, median age 76 years (IQR 62, 85) and 95 (22.8%) Not for Resuscitation (NFR). Overall, 193 (46.4%) patients had a Trigger, being 17 (4.1%) MER, 45 (10.8%) MDT and 178 (42.8%) Nurse triggers. 60 (14.4%) patients had a Call, and 72 (17.3%) a modified Trigger. Incidence: 206 patients, of similar age, of whom 166 (80.5%) had a Trigger, 122 (59.2%) a Call, and 91 (44.2%) a modified Trigger. Prevalence and incidence of failure to Call was 33.2% and 68% of patients, respectively, particular for Nurse Triggers (26.7% and 62.1%, respectively). The number of Modifications, Calls, and failure to Call, correlated with the number of Triggers (0.912 [p<0.01], 0.631 [p<0.01], 0.988 [p<0.01]).Conclusion
Within a multi-tiered response system for the detection and response to the deteriorating patient Triggers, their Modifications and failure to Call are common, particularly within the lower tiers of escalation. The number of Triggers and their Modifications may erode the structure, compliance, and potential efficacy of structured observation and response charts within a multi-tiered response system. 相似文献37.
38.
We have previously shown that regulatory CD25(+)CD4(+) T cells are resistant to clonal deletion induced by viral superantigen in vivo. In this work we report that isolated CD25(+)CD4(+) T cells activated in vitro by anti-CD3 Ab are resistant to Fas-induced apoptosis, in contrast to their CD25(-)CD4(+) counterparts. Resistance of CD25(+)CD4(+) T cells to Fas-dependent activation-induced cell death is not linked to their inability to produce IL-2 or to their ability to produce IL-10. The sensitivity of both populations to Fas-induced apoptosis can be modulated in vitro by changing the CD25(+)CD4(+):CD25(-)CD4(+) T cell ratio. The sensitivity of CD25(-)CD4(+) T cells to apoptosis can be reduced, while the sensitivity of CD25(+)CD4(+) T cells can be enhanced. Modulation of Fas-dependent apoptosis is associated with changes in cytokine production. However, while CD25(-)CD4(+) T cell apoptosis is highly dependent on IL-2 (production of which is inhibited by CD25(+)CD4(+) T cells in coculture), modulation of CD25(+)CD4(+) T cell apoptosis is IL-2 independent. Taken together, these results suggest that CD25(+)CD4(+) and CD25(-)CD4(+) T cell sensitivity to Fas-dependent apoptosis is dynamically modulated during immune responses; this modulation appears to help maintain a permanent population of regulatory T cells required to control effector T cells. 相似文献
39.
Karina Fontana Gerson E. R. Campos Robert S. Staron Maria Alice da Cruz-H?fling 《PloS one》2013,8(11)
In an attempt to shorten recovery time and improve performance, strength and endurance athletes occasionally turn to the illicit use of anabolic-androgenic steroids (AAS). This study evaluated the effects of AAS treatment on the muscle mass and phenotypic characteristics of transgenic mice subjected to a high-intensity, aerobic training program (5d/wk for 6 weeks). The transgenic mice (CETP+/-LDLr-/+) were engineered to exhibit a lipid profile closer to humans. Animals were divided into groups of sedentary (Sed) and/or training (Ex) mice (each treated orally with AAS or gum arabic/vehicle: Sed-C, Sed-M, ex-C, ex-M). The effects of AAS (mesterolone: M) on specific phenotypic adaptations (muscle wet weight, cross-sectional area, and fiber type composition) in three hindlimb muscles (soleus:SOL, tibialis anterior:TA and gastrocnemius:GAS) were assessed. In order to detect subtle changes in fiber type profile, the entire range of fiber types (I, IC, IIAC, IIA, IIAD, IID, IIDB, IIB) was delineated using mATPase histochemistry. Body weight gain occurred throughout the study for all groups. However, the body weight gain was significantly minimized with exercise. This effect was blunted with mesterolone treatment. Both AAS treatment (Sed-M) and high-intensity, aerobic training (ex-C) increased the wet weights of all three muscles and induced differential hypertrophy of pure and hybrid fibers. Combination of AAS and training (ex-M) resulted in enhanced hypertrophy. In the SOL, mesterolone treatment (Sed-M and ex-M) caused dramatic increases in the percentages of fiber types IC, IIAC, IIAD, IID, with concomitant decrease in IIA, but had minimal impact on fiber type percentages in the predominantly fast muscles. Overall, the AAS-induced differential adaptive changes amounted to significant fiber type transformations in the fast-to-slow direction in SOL. AAS treatment had a significant effect on muscle weights and fiber type composition in SOL, TA and GAS which was even maximized in animals subjected to metabolically high-intensity aerobic exercise. 相似文献
40.
Elodie Lainey Alice Wolfromm Abdul Qader Sukkurwala Jean-Baptiste Micol Pierre Fenaux Lorenzo Galluzzi Oliver Kepp Guido Kroemer 《Cell cycle (Georgetown, Tex.)》2013,12(18):2978-2991
By means of an unbiased, automated fluorescence microscopy-based screen, we identified the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib as potent enhancers of the differentiation of HL-60 acute myeloid leukemia (AML) cells exposed to suboptimal concentrations of vitamin A (all-trans retinoic acid, ATRA) or vitamin D (1α,25-hydroxycholecalciferol, VD). Erlotinib and gefitinib alone did not promote differentiation, yet stimulated the acquisition of morphological and biochemical maturation markers (including the expression of CD11b and CD14 as well as increased NADPH oxidase activity) when combined with either ATRA or VD. Moreover, the combination of erlotinib and ATRA or VD synergistically induced all the processes that are normally linked to terminal hematopoietic differentiation, namely, a delayed proliferation arrest in the G0/G1 phase of the cell cycle, cellular senescence, and apoptosis. Erlotinib potently inhibited the (auto)phosphorylation of mitogen-activated protein kinase 14 (MAPK14, best known as p38MAPK) and SRC family kinases (SFKs). If combined with the administration of ATRA or VD, the inhibition of p38MAPK or SFKs with specific pharmacological agents mimicked the pro-differentiation activity of erlotinib. These data were obtained with 2 distinct AML cell lines (HL-60 and MOLM-13 cells) and could be confirmed on primary leukemic blasts isolated from the circulation of AML patients. Altogether, these findings point to a new regimen for the treatment of AML, in which naturally occurring pro-differentiation agents (ATRA or VD) may be combined with EGFR inhibitors. 相似文献