全文获取类型
收费全文 | 521篇 |
免费 | 42篇 |
专业分类
563篇 |
出版年
2022年 | 7篇 |
2021年 | 12篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 6篇 |
2015年 | 21篇 |
2014年 | 13篇 |
2013年 | 32篇 |
2012年 | 27篇 |
2011年 | 20篇 |
2010年 | 20篇 |
2009年 | 15篇 |
2008年 | 14篇 |
2007年 | 32篇 |
2006年 | 17篇 |
2005年 | 13篇 |
2004年 | 11篇 |
2003年 | 17篇 |
2002年 | 13篇 |
2001年 | 6篇 |
2000年 | 11篇 |
1999年 | 15篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 10篇 |
1993年 | 8篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 4篇 |
1989年 | 11篇 |
1988年 | 7篇 |
1987年 | 18篇 |
1986年 | 13篇 |
1985年 | 6篇 |
1984年 | 9篇 |
1983年 | 9篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1979年 | 4篇 |
1978年 | 9篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 6篇 |
1974年 | 6篇 |
1973年 | 7篇 |
1972年 | 5篇 |
1970年 | 4篇 |
1961年 | 3篇 |
排序方式: 共有563条查询结果,搜索用时 15 毫秒
51.
52.
N,N′-Dialkylaminoalkylcarbonyl (DAAC) and aminoalkylcarbonyl (AAC) prodrugs of phenolic drugs acetaminophen (APAP) and naltrexone (NTX) are reported. The effects of incorporation of a basic amine group into the promoiety of an acyl prodrug of a phenolic drug on its skin permeation properties are also presented. DAAC-APAP prodrugs were synthesized via a three-step procedure starting with haloalkylcarbonyl esters which were reacted with five different amines: dimethylamine, diethylamine, dipropylamine, morpholine, and piperidine. The spacing between the amino group and the carbonyl group of the acyl group was 1-3 CH2. After the hydrolysis of the ester, the carboxylic acid product was subsequently coupled with the parent drug via a dicyclohexyl carbodiimide (DCC) mediated coupling to yield the DAAC-APAP-HCl prodrugs in excellent yields. The AAC prodrugs were synthesized using commercially available Boc-protected amino acids using DCC or EDCI as coupling agents. The yields of the prodrugs synthesized using these two different methods have been compared. Half-lives (t1/2) of a few members of the DAAC and AAC series were measured in buffer (pH 6.0, 20 mM). The members evaluated in hydrolysis experiments exhibit a t1/2 range of 15-113 min. Among AAC-APAP prodrugs, the isopropyl group in valinate-APAP-HCl exerted a steric effect that increased the t1/2 value for this prodrug compared to alaninate-APAP-HCl or prolinate-APAP-HCl. The 2-morpholinylacetate-APAP prodrug was able to achieve twice the flux of APAP in in vitro diffusion cell experiments through hairless mouse skin. 相似文献
53.
Elevated serum concentrations of follicle-stimulating hormone (FSH) are associated with diminished bone density in women, beginning years before menopause and the decline in estradiol. We hypothesized that FSH promotes development of myeloid cells toward the bone-resorbing osteoclast phenotype. This was tested by isolating peripheral blood mononuclear cells from nine healthy adults, incubating them in the presence of FSH at three different concentrations spanning the physiological range, and then measuring the expression of receptor activator for NF-κB (RANK, a surface marker for osteoclasts) on CD14(+) cells by flow cytometry. In the absence of FSH, 3.3±0.5% of the cells expressed high levels of the receptor (RANK(high)). Increasing concentrations of FSH caused a biphasic dose-response, with a maximal (1.5-fold) increase in RANK(high) cells achieved with 50 mIU/ml FSH (P=0.02). Cytokines that influence development of osteoclasts were also measured in culture supernatants: macrophage colony stimulating factor (M-CSF), osteoprotegerin (OPG) and tumor necrosis factor-α (TNFα) concentrations were not significantly influenced by FSH, whereas RANK-ligand was undetectable. This study supports the concept that the elevated circulating concentrations of FSH during perimenopause may contribute to the increased rate of bone loss by promoting the development of osteoclast precursor cells. 相似文献
54.
Hjelmeland AB Wu Q Heddleston JM Choudhary GS MacSwords J Lathia JD McLendon R Lindner D Sloan A Rich JN 《Cell death and differentiation》2011,18(5):829-840
Malignant gliomas are lethal cancers that display cellular hierarchies with cancer stem cells at the apex. Glioma stem cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer stem cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer stem cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer stem cell phenotype, and that culturing cancer cells at lower pH reflective of endogenous tumor conditions may better retain the cellular heterogeneity found in tumors. 相似文献
55.
Scarf D Miles K Sloan A Goulter N Hegan M Seid-Fatemi A Harper D Colombo M 《PloS one》2011,6(1):e14589
Slot machines are the most common and addictive form of gambling. In the current study, we recorded from single neurons in the 'prefrontal cortex' of pigeons while they played a slot-machine-like task. We identified four categories of neurons that coded for different aspects of our slot-machine-like task. Reward-Proximity neurons showed a linear increase in activity as the opportunity for a reward drew near. I-Won neurons fired only when the fourth stimulus of a winning (four-of-a-kind) combination was displayed. I-Lost neurons changed their firing rate at the presentation of the first nonidentical stimulus, that is, when it was apparent that no reward was forthcoming. Finally, Near-Miss neurons also changed their activity the moment it was recognized that a reward was no longer available, but more importantly, the activity level was related to whether the trial contained one, two, or three identical stimuli prior to the display of the nonidentical stimulus. These findings not only add to recent neurophysiological research employing simulated gambling paradigms, but also add to research addressing the functional correspondence between the avian NCL and primate PFC. 相似文献
56.
Among its many roles, the HIV-1 accessory protein Vpu performs a viroporin function and also antagonizes the host cell restriction factor tetherin through its transmembrane domain. BIT225 is a small molecule inhibitor that specifically targets the Vpu viroporin function, which, in macrophages, resulted in late stage inhibition of virus release and decreased infectivity of released virus, a phenotype similar to tetherin-mediated restriction. Here, we investigated whether BIT225 might mediate its antiviral function, at least in part, via inhibition of Vpu-mediated tetherin antagonism. Using T-cell lines inducible for tetherin expression, we found that BIT225 does not exert its antiviral function by inhibiting Vpu-mediated tetherin downmodulation from the cell surface, the main site of action of tetherin activity. In addition, results from a bioluminescence resonance energy transfer (BRET) assay showed that the Vpu-tetherin interaction was not affected by BIT225. Our data provide support for the concept that tetherin antagonism and viroporin function are separable on the Vpu transmembrane and that viroporin function might be cell-type dependent. Further, this work contributes to the characterization of BIT225 as an inhibitor that specifically targets the viroporin function of Vpu. 相似文献
57.
58.
59.
RR interval variability is inversely related to inflammatory markers: the CARDIA study 总被引:4,自引:0,他引:4
Sloan RP McCreath H Tracey KJ Sidney S Liu K Seeman T 《Molecular medicine (Cambridge, Mass.)》2007,13(3-4):178-184
Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the "cholinergic anti-inflammatory pathway." Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b=-0.08 and -0.17 for HF and LF power, P<0.001 respectively) and CRP (log mg/L b=-0.14 and -0.26 for HF and LF power, P<0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans. 相似文献
60.
Gossip is a subject that has been studied by researchers from an array of disciplines with various foci and methods. We measured
the content of language use by members of a competitive sports team across 18 months, integrating qualitative ethnographic
methods with quantitative sampling and analysis. We hypothesized that the use of gossip will vary significantly depending
on whether it is used for self-serving or group-serving purposes. Our results support a model of gossip derived from multilevel
selection theory that expects gossip to serve group-beneficial rules when rewards are partitioned at the group level on a
scale that permits mutual monitoring. We integrate our case study with earlier studies of gossip conducted by anthropologists,
psychologists, and management researchers.
Kevin M. Kniffin studies cooperation within and among organizations. Kniffin is presently an Honorary Fellow of the University
of Wisconsin-Madison’s Department of Anthropology. Kniffin has consulted for a variety of clients, including community-development
organizations, labor unions, and credit unions.
David Sloan Wilson is an evolutionary biologist interested in a broad range of issues relevant to human behavior. He has authored
numerous articles and books, including most recently Darwin’s Cathedral: Evolution, Religion, and the Nature of Society (University of Chicago Press, 2002). Wilson is a professor of biological sciences and anthropology and Director of Evolutionary
Studies (EvoS) at SUNY-Binghamton. 相似文献