全文获取类型
收费全文 | 1661篇 |
免费 | 184篇 |
国内免费 | 18篇 |
出版年
2022年 | 12篇 |
2021年 | 28篇 |
2020年 | 17篇 |
2019年 | 19篇 |
2018年 | 20篇 |
2017年 | 14篇 |
2016年 | 27篇 |
2015年 | 47篇 |
2014年 | 63篇 |
2013年 | 58篇 |
2012年 | 62篇 |
2011年 | 76篇 |
2010年 | 64篇 |
2009年 | 48篇 |
2008年 | 61篇 |
2007年 | 88篇 |
2006年 | 70篇 |
2005年 | 52篇 |
2004年 | 66篇 |
2003年 | 67篇 |
2002年 | 59篇 |
2001年 | 63篇 |
2000年 | 42篇 |
1999年 | 42篇 |
1998年 | 27篇 |
1997年 | 18篇 |
1996年 | 15篇 |
1995年 | 20篇 |
1993年 | 17篇 |
1992年 | 34篇 |
1991年 | 34篇 |
1990年 | 22篇 |
1989年 | 36篇 |
1988年 | 33篇 |
1987年 | 28篇 |
1986年 | 43篇 |
1985年 | 32篇 |
1984年 | 24篇 |
1983年 | 15篇 |
1981年 | 17篇 |
1980年 | 18篇 |
1979年 | 21篇 |
1978年 | 13篇 |
1977年 | 20篇 |
1976年 | 14篇 |
1975年 | 19篇 |
1974年 | 15篇 |
1973年 | 21篇 |
1968年 | 13篇 |
1966年 | 11篇 |
排序方式: 共有1863条查询结果,搜索用时 406 毫秒
291.
Housley WJ Adams CO Nichols FC Puddington L Lingenheld EG Zhu L Rajan TV Clark RB 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(12):6779-6787
TNF-α has a multifunctional role in autoimmune diseases as reflected in the variable responses of different human diseases to anti-TNF-α therapy. Recent studies have suggested that TNF-α modulates autoimmunity partially via effects on regulatory T cells (Tregs) and that these effects are mediated through the type II TNFR (TNFR2). We have investigated the requirement for TNFR2-expression on murine natural Tregs (nTregs) and induced Tregs (iTregs) in mediating suppression of colitis. Surprisingly, we find that TNFR2-expression is required for both spleen- and thymus-derived nTreg-mediated suppression, but is not required for iTreg-mediated suppression. Abnormal TNFR2(-/-) nTreg function was not associated with an in vivo decrease in accumulation, stability, or expression of markers known to be relevant in Treg function. Because iTregs are generated in the presence of TGF-β, we investigated whether activation in the presence of TGF-β could overcome the functional defect in TNFR2(-/-) nTregs. Although preactivation alone did not restore suppressive function of nTregs, preactivation in the presence of TGF-β did. These results identify potentially critical differences in activation requirements for nTregs versus iTregs. Furthermore, our findings are consistent with reports suggesting that nTregs are activated in sites of inflammation while iTregs are activated in lymph nodes. Finally, by demonstrating that nTregs require TNF-α for optimal function whereas iTregs do not, our results suggest that the enigma of variable responses of different human diseases to anti-TNF-α therapy may relate to whether nTregs or iTregs have the predominant regulatory role in a given disease. 相似文献
292.
James D. Nichols Mark D. Koneff Patricia J. Heglund Melinda G. Knutson Mark E. Seamans James E. Lyons John M. Morton Malcolm T. Jones G. Scott Boomer Byron K. Williams 《The Journal of wildlife management》2011,75(1):6-18
Climate change and its associated uncertainties are of concern to natural resource managers. Although aspects of climate change may be novel (e.g., system change and nonstationarity), natural resource managers have long dealt with uncertainties and have developed corresponding approaches to decision-making. Adaptive resource management is an application of structured decision-making for recurrent decision problems with uncertainty, focusing on management objectives, and the reduction of uncertainty over time. We identified 4 types of uncertainty that characterize problems in natural resource management. We examined ways in which climate change is expected to exacerbate these uncertainties, as well as potential approaches to dealing with them. As a case study, we examined North American waterfowl harvest management and considered problems anticipated to result from climate change and potential solutions. Despite challenges expected to accompany the use of adaptive resource management to address problems associated with climate change, we conclude that adaptive resource management approaches will be the methods of choice for managers trying to deal with the uncertainties of climate change. © 2010 The Wildlife Society. 相似文献
293.
Design and synthesis of potent,orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase 总被引:3,自引:0,他引:3
Stelmach JE Liu L Patel SB Pivnichny JV Scapin G Singh S Hop CE Wang Z Strauss JR Cameron PM Nichols EA O'Keefe SJ O'Neill EA Schmatz DM Schwartz CD Thompson CM Zaller DM Doherty JB 《Bioorganic & medicinal chemistry letters》2003,13(2):277-280
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h). 相似文献
294.
Laban U Kurrasch-Orbaugh D Marona-Lewicka D Nichols DE 《Bioorganic & medicinal chemistry letters》2001,11(6):793-795
Synthesis and biological evaluation of a novel fluorinated tryptamine analogue are described. This new compound 1-(4-fluoro-5-methoxyindol-3-yl)pyrrolidine (2) was found to be a potent serotonin 5-HT1A agonist. 相似文献
295.
296.
二甲基亚砜毒性研究 总被引:1,自引:0,他引:1
二甲基亚砜(Dimethyl sulfoxide DMSO)是一种含硫有机化合物,被誉为"万能溶剂",广泛用作溶剂和反应试剂。在医药工业中,DMSO可直接用作某些药物的原料及载体。DMSO本身有消炎止痛,利尿,镇静等作用,亦誉为"万灵药",常作为止痛药物的活性组分添加于药物之中。DMSO也是一种渗透性保护剂,能够降低细胞冰点,减少冰晶的形成,减轻自由基对细胞损害,改变生物膜对电解质、药物、毒物和代谢产物的通透性。DMSO作为组蛋白去乙酰化酶抑制剂(Histone Deacetylases-inhibitor HDACi)的一种,同样具有恢复组蛋白的乙酰化与去乙酰化平衡,抑制细胞程序性死亡,修复DNA双螺旋结构,抗放射性损伤,抗炎症反应及抗癌作用。鉴于其应用广泛,本文就其物理特性及毒性研究做一综述。 相似文献
297.
Insulator function and topological domain border strength scale with architectural protein occupancy
Kevin Van Bortle Michael H Nichols Li Li Chin-Tong Ong Naomi Takenaka Zhaohui S Qin Victor G Corces 《Genome biology》2014,15(5):R82
Background
Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions.Results
By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals.Conclusions
We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains. 相似文献298.
Hlack Mohammed Jan Arp Frank Chambers Mark Copley Volker Glaab Mark Hammond Derek Solomon Kerry Bradford Theresa Russell Yvonne Sizer Steven C. Nichols Daryl L. Roberts Christopher Shelton Roland Greguletz Jolyon P. Mitchell 《AAPS PharmSciTech》2014,15(5):1126-1137
Compendial methods determining dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distribution (APSD) collect a 4-L air sample containing the aerosol bolus, where the flow, which propagates through the cascade impactor (CI) measurement system from the vacuum source, is used to actuate the inhaler. A previous article described outcomes with two CIs (Andersen eight-stage cascade impactor (ACI) and Next-Generation Pharmaceutical Impactor (NGI)) when the air sample volume was ≤4 L with moderate-resistance DPIs. This article extends that work, examining the hypothesis that DPI flow resistance may be a factor in determining outcomes. APSD measurements were made using the same CI systems with inhalers representing low and high flow resistance extremes (Cyclohaler® and HandiHaler® DPIs, respectively). The ratio of sample volume to internal dead space (normalized volume (V*)) was varied from 0.25 to 1.98 (NGI) and from 0.43 to 3.46 (ACI). Inhaler resistance was a contributing factor to the rate of bolus transfer; the higher resistance DPI completing bolus relocation to the NGI pre-separator via the inlet when V* was as small as 0.25, whereas only ca. 50% of the bolus mass was collected at this condition with the Cyclohaler® DPI. Size fractionation of the bolus from either DPI was completed within the ACI at smaller values of V* than within the NGI. Bolus transfer from the Cyclohaler® capsule and from the HandiHaler® to the ACI system were unaffected by the different flow rise time observed in the two different flow controller systems, and the effects the ACI-based on APSD measurements were marginal. 相似文献
299.
The cavins are a family of proteins associated with caveolae, cavin-1, -2 and -3 being widely expressed while cavin-4 is restricted to striated muscle. Deletion of cavin-1 results in phenotypes including metabolic changes consistent with adipocyte dysfunction, and caveolae are completely absent. Deletion of cavin-2 causes tissue-specific loss of caveolae. The consequences of cavin-3 deletion are less clear, as there are divergent data on the abundance of caveolae in cavin-3 null mice. Here we examine the consequences of cavin-3 deficiency in vivo by making cavin-3 knockout mice. We find that loss of cavin-3 has minimal or no effects on the levels of other caveolar proteins, does not appear to play a major role in formation of protein complexes important for caveolar morphogenesis, and has no significant effect on caveolae abundance. Cavin-3 null mice have the same body weight and fat mass as wild type animals at ages 8 through 30 weeks on both normal chow and high fat diets. Likewise, the two mouse strains exhibit identical glucose tolerance tests on both diets. Microarray analysis from adipose tissue shows that the changes in mRNA expression between cavin-3 null and wild type mouse are minimal. We conclude that cavin-3 is not absolutely required for making caveolae, and suggest that the mechanistic link between cavin-3 and metabolic regulation remains uncertain. 相似文献