全文获取类型
收费全文 | 1877篇 |
免费 | 170篇 |
国内免费 | 3篇 |
出版年
2022年 | 10篇 |
2021年 | 34篇 |
2020年 | 12篇 |
2019年 | 16篇 |
2018年 | 35篇 |
2017年 | 27篇 |
2016年 | 43篇 |
2015年 | 79篇 |
2014年 | 80篇 |
2013年 | 133篇 |
2012年 | 139篇 |
2011年 | 116篇 |
2010年 | 80篇 |
2009年 | 89篇 |
2008年 | 113篇 |
2007年 | 127篇 |
2006年 | 107篇 |
2005年 | 117篇 |
2004年 | 106篇 |
2003年 | 97篇 |
2002年 | 96篇 |
2001年 | 19篇 |
2000年 | 12篇 |
1999年 | 21篇 |
1998年 | 19篇 |
1997年 | 21篇 |
1996年 | 7篇 |
1995年 | 14篇 |
1994年 | 20篇 |
1993年 | 14篇 |
1992年 | 13篇 |
1991年 | 12篇 |
1990年 | 21篇 |
1989年 | 26篇 |
1988年 | 13篇 |
1987年 | 11篇 |
1986年 | 10篇 |
1985年 | 11篇 |
1984年 | 11篇 |
1983年 | 12篇 |
1982年 | 6篇 |
1981年 | 9篇 |
1980年 | 8篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1974年 | 9篇 |
1970年 | 5篇 |
1968年 | 5篇 |
排序方式: 共有2050条查询结果,搜索用时 15 毫秒
51.
Alastair J. King Marc R. Arnone Maureen R. Bleam Katherine G. Moss Jingsong Yang Kelly E. Fedorowicz Kimberly N. Smitheman Joseph A. Erhardt Angela Hughes-Earle Laurie S. Kane-Carson Robert H. Sinnamon Hongwei Qi Tara R. Rheault David E. Uehling Sylvie G. Laquerre 《PloS one》2013,8(7)
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor. 相似文献
52.
Previous studies have shown that elevated nitric oxide (NO) reduces adhesion in diatom, bacterial and animal cells. This article reports experiments designed to investigate whether elevated NO reduces the adhesion of zoospores of the green alga Ulva, an important fouling species. Surface-normalised values of NO were measured using the fluorescent indicator DAF-FM DA and parallel hydrodynamic measurements of adhesion strength were made. Elevated levels of NO caused by the addition of the exogenous NO donor SNAP reduced spore settlement by 20% and resulted in lower adhesion strength. Addition of the NO scavenger cPTIO abolished the effects of SNAP on adhesion. The strength of attachment and NO production by spores in response to four coatings (Silastic® T2; Intersleek® 700; Intersleek® 900 and polyurethane) shows that reduced adhesion is correlated with an increase in NO production. It is proposed that in spores of Ulva, NO is used as an intracellular signalling molecule to detect how conducive a surface is for settlement and adhesion. The effect of NO on the adhesion of a range of organisms suggests that NO-releasing coatings could have the potential to control fouling. 相似文献
53.
Significantly higher numbers of zoospores of the fouling, green alga Enteromorpha adhered to silicone elastomers cured by dibutyltin dilaurate (DBTDL) than to identical polymers cured by dibutyltin diacetate (DBTDA). Enhanced zoospore adhesion was shown to be due to the presence of DBTDL and the effect was concentration‐dependent. Further experiments revealed that enhanced zoospore adhesion also occurred to glass coverslips coated with lauric acid (C12) and other saturated fatty acids. The possibility that fatty acids may act as chemical cues (chemoattractants), guiding motile zoospores to the substratum for settlement in the natural environment is discussed. Settlement of other fouling organisms to DBTDL‐cured silicone elastomers is currently being investigated. 相似文献
54.
Isabel Thome Michala E. Pettitt Maureen E. Callow James A. Callow Michael Grunze Axel Rosenhahn 《Biofouling》2013,29(5):501-510
Conditioning, ie the adsorption of proteins and other macromolecules, is the first process that occurs in the natural environment once a surface is immersed in seawater, but no information is available either regarding the conditioning of surfaces by artificial seawater or whether conditioning affects data obtained from laboratory assays. A range of self-assembled monolayers (SAMs) with different chemical terminations was used to investigate the time-dependent formation of conditioning layers in commercial and self-prepared artificial seawaters. Subsequently, these results were compared with conditioning by solutions in which zoospores of the green alga Ulva linza had been swimming. Spectral ellipsometry and contact angle measurements as well as infrared reflection absorption spectroscopy (IRRAS) were used to reveal the thickness and chemical composition of the conditioning layers. The extent that surface preconditioning affected the settlement of zoospores of U. linza was also investigated. The results showed that in standard spore settlement bioassays (45–60 min), the influence of a molecular conditioning layer is likely to be small, although more substantial effects are possible at longer settlement times. 相似文献
55.
A simple method to measure the degradation of antifouling biocides is described which measures the loss of biocidal activity from seawater by bioassay. The bioassay employs either the ship‐fouling diatom Amphora or the brine shrimp Anemia. Loss of bioaclivity from sterile seawater indicates abiotic degradation whilst loss of bioactivity from natural seawater indicates biodegradation. Results are presented for three biocides, viz. the trihalomethylthio compound, N‐dichlorofluoromethylthio‐N’,N'‐dimethyl‐N‐phenyl‐sulphamide (Preventol A4S), di‐n‐octylamine, and the isothiazolone compound 4,5‐dichloro‐2‐n‐octyl‐4‐isothiazolin‐3‐one (Sea‐Nine 211). 相似文献
56.
Elisa Martinelli Marianna Suffredini Antonella Glisenti Michala E. Pettitt Maureen E. Callow 《Biofouling》2013,29(5):529-541
Amphiphilic diblock copolymers, Sz6 and Sz12, consisting of a poly(dimethylsiloxane) block (average degree of polymerisation = 132) and a PEGylated-fluoroalkyl modified polystyrene block (Sz, average degree of polymerisation = 6, 12) were prepared by atom transfer radical polymerization (ATRP). Coatings were obtained from blends of either block copolymer (1–10 wt%) with a poly(dimethylsiloxane) (PDMS) matrix. The coating surface presented a simultaneous hydrophobic and lipophobic character, owing to the strong surface segregation of the lowest surface energy fluoroalkyl chains of the block copolymer. Surface chemical composition and wettability of the films were affected by exposure to water. Block copolymer Sz6 was also blended with PDMS and a 0.1 wt% amount of multiwall carbon nanotubes (CNT). The excellent fouling-release (FR) properties of these new coatings against the macroalga Ulva linza essentially resulted from the inclusion of the amphiphilic block copolymer, while the addition of CNT did not appear to improve the FR properties. 相似文献
57.
Yun Ma Jessica J. Krueger Sara N. Redmon Sasidhar Uppuganti Jeffry S. Nyman Maureen K. Hahn Florent Elefteriou 《The Journal of biological chemistry》2013,288(42):30105-30113
Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual. 相似文献
58.
The toxigenic diatom Pseudo‐nitzschia cuspidata, isolated from the U.S. Pacific Northwest, was examined in unialgal batch cultures to evaluate domoic acid (DA) toxicity and growth as a function of light, N substrate, and growth phase. Experiments conducted at saturating (120 μmol photons · m?2 · s?1) and subsaturating (40 μmol photons · m?2 · s?1) photosynthetic photon flux density (PPFD), demonstrate that P. cuspidata grows significantly faster at the higher PPFD on all three N substrates tested [nitrate (NO3?), ammonium (NH4+), and urea], but neither cellular toxicity nor exponential growth rates were strongly associated with one N source over the other at high PPFD. However, at the lower PPFD, the exponential growth rates were approximately halved, and the cells were significantly more toxic regardless of N substrate. Urea supported significantly faster growth rates, and cellular toxicity varied as a function of N substrate with NO3?‐supported cells being significantly more toxic than both NH4+‐ and urea‐supported cells at the low PPFD. Kinetic uptake parameters were determined for another member of the P. pseudodelicatissima complex, P. fryxelliana. After growth of these cells on NO3? they exhibited maximum specific uptake rates (Vmax) of 22.7, 29.9, 8.98 × 10?3 · h?1, half‐saturation constants (Ks) of 1.34, 2.14, 0.28 μg‐at N · L?1, and affinity values (α) of 17.0, 14.7, 32.5 × 10?3 · h?1/(μg‐at N · L?1) for NO3?, NH4+ and urea, respectively. These labo‐ratory results demonstrate the capability of P. cuspidata to grow and produce DA on both oxidized and reduced N substrates during both exponential and stationary growth phases, and the uptake kinetic results for the pseudo‐cryptic species, P. fryxelliana suggest that reduced N sources from coastal runoff could be important for maintenance of these small pennate diatoms in U.S. west coast blooms, especially during times of low ambient N concentrations. 相似文献
59.
Lisa R. W. Plano Tomoyuki Shibata Anna C. Garza Jonathan Kish Jay M. Fleisher Christopher D. Sinigalliano Maribeth L. Gidley Kelly Withum Samir M. Elmir Suzanne Hower Charlene R. Jackson John B. Barrett Timothy Cleary Maureen Davidson Johnnie Davis Sampa Mukherjee Lora E. Fleming Helena M. Solo-Gabriele 《Microbial ecology》2013,65(4):1039-1051
Reports of Staphylococcus aureus including methicillin-resistant S. aureus (MRSA) detected in marine environments have occurred since the early 1990s. This investigation sought to isolate and characterize S. aureus from marine waters and sand at a subtropical recreational beach, with and without bathers present, in order to investigate possible sources and to identify the risks to bathers of exposure to these organisms. During 40 days over 17 months, 1,001 water and 36 intertidal sand samples were collected by either bathers or investigators at a subtropical recreational beach. Methicillin-sensitive S. aureus (MSSA) and MRSA were isolated and identified using selective growth media and an organism-specific molecular marker. Antimicrobial susceptibility, staphylococcal cassette chromosome mec (SCCmec) type, pulsed-field gel electrophoresis (PFGE) pattern, multi-locus sequence type (MLST), and staphylococcal protein A (spa) type were characterized for all MRSA. S. aureus was isolated from 248 (37 %) bather nearby water samples at a concentration range of <2–780 colony forming units per ml, 102 (31 %) ambient water samples at a concentration range of <2–260 colony forming units per ml, and 9 (25 %) sand samples. Within the sand environment, S. aureus was isolated more often from above the intertidal zone than from intermittently wet or inundated sand. A total of 1334 MSSA were isolated from 37 sampling days and 22 MRSA were isolated from ten sampling days. Seventeen of the 22 MRSA were identified by PFGE as the community-associated MRSA USA300. MRSA isolates were all SCCmec type IVa, encompassed five spa types (t008, t064, t622, t688, and t723), two MLST types (ST8 and ST5), and 21 of 22 isolates carried the genes for Panton–Valentine leukocidin. There was a correlation (r?=?0.45; p?=?0.05) between the daily average number of bathers and S. aureus in the water; however, no association between exposure to S. aureus in these waters and reported illness was found. This report supports the concept that humans are a potential direct source for S. aureus in marine waters. 相似文献
60.
John N. Freskos Bethel Asmelash Kimberly R. Gaston Amol Karwa Tim A. Marzan Maureen A. Nickols Thomas E. Rogers Tasha Schoenstein Carolyn J. Sympson Bich Vu 《Bioorganic & medicinal chemistry letters》2013,23(20):5566-5570
We describe the synthesis, MMP-2 and 9 potency, and in vitro evaluation of a series of α-sulfone hydroxmate MMP inhibitors conjugated to a series of dyes with different absorption/emission lamina maxima’s that can be used to visualize tumors. 相似文献