全文获取类型
收费全文 | 1819篇 |
免费 | 155篇 |
出版年
2019年 | 17篇 |
2018年 | 21篇 |
2017年 | 18篇 |
2016年 | 29篇 |
2015年 | 43篇 |
2014年 | 47篇 |
2013年 | 60篇 |
2012年 | 68篇 |
2011年 | 63篇 |
2010年 | 42篇 |
2009年 | 38篇 |
2008年 | 55篇 |
2007年 | 51篇 |
2006年 | 56篇 |
2005年 | 59篇 |
2004年 | 57篇 |
2003年 | 60篇 |
2002年 | 60篇 |
2001年 | 34篇 |
2000年 | 62篇 |
1999年 | 44篇 |
1998年 | 29篇 |
1997年 | 19篇 |
1996年 | 18篇 |
1995年 | 20篇 |
1993年 | 22篇 |
1992年 | 27篇 |
1991年 | 32篇 |
1990年 | 37篇 |
1989年 | 33篇 |
1988年 | 28篇 |
1987年 | 25篇 |
1986年 | 27篇 |
1985年 | 35篇 |
1984年 | 32篇 |
1983年 | 24篇 |
1982年 | 19篇 |
1980年 | 15篇 |
1979年 | 25篇 |
1977年 | 19篇 |
1976年 | 21篇 |
1975年 | 18篇 |
1974年 | 24篇 |
1973年 | 19篇 |
1972年 | 21篇 |
1971年 | 19篇 |
1970年 | 18篇 |
1969年 | 20篇 |
1968年 | 20篇 |
1961年 | 16篇 |
排序方式: 共有1974条查询结果,搜索用时 31 毫秒
101.
Global warming and excess nitrogen deposition can exert strong impacts on aquatic populations, communities, and ecosystems. However, experimental data to establish clear cause-and-effect relationships in naturally complex field conditions are scarce in aquatic environments. Here, we describe the design and performance of a unique outdoor enclosure facility used to simulate warming, increased nitrogen supply, and both factors combined in a littoral freshwater wetland dominated by common reed, Phragmites australis. The experimental system effectively simulated a 2.8 °C climate warming scenario over an extended period, capturing the natural temperature variations in the wetland at diel and seasonal scales with only small deviations. Excess nitrogen supply enhanced nitrate concentrations especially in winter when it was associated with increased concentration of ammonium and dissolved organic carbon. Nitrogen also reduced dissolved oxygen concentrations, particularly in the summer. Importantly, by stimulating biological activity, warming enhanced the nitrogen uptake capacity of the wetland during the winter, emphasizing the need for multifactorial global change experiments that examine both warming and nitrogen loading in concert. Establishing similar experiments across broad environmental gradients holds great potential to provide robust assessments of the impacts of climate change on shallow aquatic ecosystems. 相似文献
102.
Nathalia Torres Dutra Vanildo Silveira Inga Gonçalves de Azevedo Lupis Ribeiro Gomes‐Neto Arnoldo Rocha Façanha Neusa Steiner Miguel Pedro Guerra Eny Iochevet Segal Floh Claudete Santa‐Catarina 《Physiologia plantarum》2013,148(1):121-132
Polyamines (PAs) are abundant polycationic compounds involved in many physiological processes in plants, including somatic embryogenesis. This study investigates the role of PAs on cellular growth and structure of pro‐embryogenic masses (PEMs), endogenous PA and proton pump activities in embryogenic suspension cultures of Araucaria angustifolia. The embryogenic suspension cultures were incubated with putrescine (Put), spermidine (Spd), spermine (Spm) and the inhibitor methylglyoxal‐bis(guanylhydrazone) (MGBG), respectively (1 mM). After 24 h and 21 days, the cellular growth and structure of PEMs, endogenous PA contents and proton pump activities were analyzed. The addition of Spm reduced the cellular growth and promoted the development of PEMs in embryogenic cultures, which could be associated with a reduction in the activities of proton pumps, such as H+‐ATPase P‐ and V‐types and H+‐PPases, and alterations in the endogenous PA contents. Spm significantly affected the physiology of the A. angustifolia somatic embryogenesis suspension, as it potentially affects cellular growth and structure of PEMs through the modulation of proton pump activities. This work demonstrates the involvement of exogenous PAs in the modulation of cellular growth and structure of PEMs, endogenous PA levels and proton pump activities during somatic embryogenesis. To our knowledge, this study is the first to report a relationship between PAs and proton pump activities in these processes. The results obtained in this study offer new perspectives for studies addressing the role of PAs and proton pump on somatic embryogenesis in this species. 相似文献
103.
104.
Benedikt Kretner Akio Fukumori Peer‐Hendrik Kuhn Blanca Isabel Pérez‐Revuelta Stefan F. Lichtenthaler Christian Haass Harald Steiner 《Journal of neurochemistry》2013,125(1):144-156
γ‐Secretase plays a central role in the generation of the Alzheimer disease‐causing amyloid β‐peptide (Aβ) from the β‐amyloid precursor protein (APP) and is thus a major Alzheimer′s disease drug target. As several other γ‐secretase substrates including Notch1 and CD44 have crucial signaling functions, an understanding of the mechanism of substrate recognition and cleavage is key for the development of APP selective γ‐secretase‐targeting drugs. The γ‐secretase active site domain in its catalytic subunit presenilin (PS) 1 has been implicated in substrate recognition/docking and cleavage. Highly critical in this process is its GxGD active site motif, whose invariant glycine residues cannot be replaced without causing severe functional losses in substrate selection and/or cleavage efficiency. Here, we have investigated the contribution of the less well characterized residue x of the motif (L383 in PS1) to this function. Extensive mutational analysis showed that processing of APP was overall well‐tolerated over a wide range of hydrophobic and hydrophilic mutations. Interestingly, however, most L383 mutants gave rise to reduced levels of Aβ37–39 species, and several increased the pathogenic Aβ42/43 species. Several of the Aβ42/43‐increasing mutants severely impaired the cleavages of Notch1 and CD44 substrates, which were not affected by any other L383 mutation. Our data thus establish an important, but compared with the glycine residues of the motif, overall less critical functional role for L383. We suggest that L383 and the flanking glycine residues form a spatial arrangement in PS1 that is critical for docking and/or cleavage of different γ‐secretase substrates. 相似文献
105.
Ryan P. P. Shugg Ashley Thomson Natsuko Tanabe Adam Kashishian Bart H. Steiner Kamal D. Puri Alexey Pereverzev Brian J. Lannutti Frank R. Jirik S. Jeffrey Dixon Stephen M. Sims 《The Journal of biological chemistry》2013,288(49):35346-35357
Phosphatidylinositol 3-kinases (PI3K) participate in numerous signaling pathways, and control distinct biological functions. Studies using pan-PI3K inhibitors suggest roles for PI3K in osteoclasts, but little is known about specific PI3K isoforms in these cells. Our objective was to determine effects of isoform-selective PI3K inhibitors on osteoclasts. The following inhibitors were investigated (targets in parentheses): wortmannin and (pan-p110), PIK75 (α), GDC0941 (α, δ), TGX221 (β), AS252424 (γ), and IC87114 (δ). In addition, we characterized a new potent and selective PI3Kδ inhibitor, GS-9820, and explored roles of PI3K isoforms in regulating osteoclast function. Osteoclasts were isolated from long bones of neonatal rats and rabbits. Wortmannin, LY294002, GDC0941, IC87114, and GS-9820 induced a dramatic retraction of osteoclasts within 15–20 min to 65–75% of the initial area. In contrast, there was no significant retraction in response to vehicle, PIK75, TGX221, or AS252424. Moreover, wortmannin and GS-9820, but not PIK75 or TGX221, disrupted actin belts. We examined effects of PI3K inhibitors on osteoclast survival. Whereas PIK75, TGX221, and GS-9820 had no significant effect on basal survival, all blocked RANKL-stimulated survival. When studied on resorbable substrates, osteoclastic resorption was suppressed by wortmannin and inhibitors of PI3Kβ and PI3Kδ, but not other isoforms. These data are consistent with a critical role for PI3Kδ in regulating osteoclast cytoskeleton and resorptive activity. In contrast, multiple PI3K isoforms contribute to the control of osteoclast survival. Thus, the PI3Kδ isoform, which is predominantly expressed in cells of hematopoietic origin, is an attractive target for anti-resorptive therapeutics. LY294002相似文献
106.
107.
Ellen?M?Unterwald Michelle?E?Page Timothy?B?Brown Jonathan?S?Miller Marta?Ruiz Karen?A?Pescatore Baoji?Xu Louis?French?Reichardt Joel?Beverley Bin?Tang Heinz?Steiner Elizabeth?A?Thomas Michelle?E?EhrlichEmail author 《Molecular neurodegeneration》2013,8(1):47
Background
The high affinity tyrosine kinase receptor, TrkB, is the primary receptor for brain derived neurotrophic factor (BDNF) and plays an important role in development, maintenance and plasticity of the striatal output medium size spiny neuron. The striatal BDNF/TrkB system is thereby implicated in many physiologic and pathophysiologic processes, the latter including mood disorders, addiction, and Huntington’s disease. We crossed a mouse harboring a transgene directing cre-recombinase expression primarily to postnatal, dorsal striatal medium spiny neurons, to a mouse containing a floxed TrkB allele (fB) mouse designed for deletion of TrkB to determine its role in the adult striatum.Results
We found that there were sexually dimorphic alterations in behaviors in response to stressful situations and drugs of abuse. Significant sex and/or genotype differences were found in the forced swim test of depression-like behaviors, anxiety-like behaviors on the elevated plus maze, and cocaine conditioned reward. Microarray analysis of dorsal striatum revealed significant dysregulation in individual and groups of genes that may contribute to the observed behavioral responses and in some cases, represent previously unidentified downstream targets of TrkB.Conclusions
The data point to a set of behaviors and changes in gene expression following postnatal deletion of TrkB in the dorsal striatum distinct from those in other brain regions.108.
Tamara Dubowitz Madhumita Ghosh‐Dastidar Elizabeth Steiner José J. Escarce Rebecca L. Collins 《Obesity (Silver Spring, Md.)》2013,21(3):419-420
Recent debate about the role of food deserts in the United States (i.e., places that lack access to healthy foods) has prompted discussion on policies being enacted, including efforts that encourage the placement of full‐service supermarkets into food deserts. Other initiatives to address obesogenic neighborhood features include land use zoning and parks renovations. Yet, there is little evidence to demonstrate that such policies effect change. While we suspect most researchers and policymakers would agree that effective neighborhood change could be a powerful tool in combating obesity, we desperately need strong and sound evidence to guide decisions about where and how to invest. 相似文献
109.
Lucia Vernerova Frantisek Spoutil Miroslav Vlcek Katarina Krskova Adela Penesova Milada Meskova Andrea Marko Katarina Raslova Branislav Vohnout Jozef Rovensky Zdenko Killinger Ivana Jochmanova Ivica Lazurova Guenter Steiner Josef Smolen Richard Imrich 《PloS one》2016,11(4)
IntroductionThe aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA).MethodsA total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti–citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA.ResultsHLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA.ConclusionsThe association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA. 相似文献
110.
Ruth R. Miller Miguel Uyaguari-Diaz Mark N. McCabe Vincent Montoya Jennifer L. Gardy Shoshana Parker Theodore Steiner William Hsiao Matthew J. Nesbitt Patrick Tang David M. Patrick for the CCD Study Group 《PloS one》2016,11(11)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease causing indefinite fatigue. ME/CFS has long been hypothesised to have an infectious cause; however, no specific infectious agent has been identified. We used metagenomics to analyse the RNA from plasma samples from 25 individuals with ME/CFS and compare their microbial content to technical controls as well as three control groups: individuals with alternatively diagnosed chronic Lyme syndrome (N = 13), systemic lupus erythematosus (N = 11), and healthy controls (N = 25). We found that the majority of sequencing reads were removed during host subtraction, thus there was very low microbial RNA content in the plasma. The effects of sample batching and contamination during sample processing proved to outweigh the effects of study group on microbial RNA content, as the few differences in bacterial or viral RNA abundance we did observe between study groups were most likely caused by contamination and batch effects. Our results highlight the importance of including negative controls in all metagenomic analyses, since there was considerable overlap between bacterial content identified in study samples and control samples. For example, Proteobacteria, Firmicutes, Actinobacteria, and Bacteriodes were found in both study samples and plasma-free negative controls. Many of the taxonomic groups we saw in our plasma-free negative control samples have previously been associated with diseases, including ME/CFS, demonstrating how incorrect conclusions may arise if controls are not used and batch effects not accounted for. 相似文献