全文获取类型
收费全文 | 5468篇 |
免费 | 543篇 |
出版年
2022年 | 41篇 |
2021年 | 87篇 |
2020年 | 49篇 |
2019年 | 57篇 |
2018年 | 58篇 |
2017年 | 60篇 |
2016年 | 128篇 |
2015年 | 238篇 |
2014年 | 255篇 |
2013年 | 299篇 |
2012年 | 415篇 |
2011年 | 401篇 |
2010年 | 232篇 |
2009年 | 224篇 |
2008年 | 339篇 |
2007年 | 287篇 |
2006年 | 294篇 |
2005年 | 294篇 |
2004年 | 293篇 |
2003年 | 261篇 |
2002年 | 297篇 |
2001年 | 70篇 |
2000年 | 45篇 |
1999年 | 62篇 |
1998年 | 80篇 |
1997年 | 48篇 |
1996年 | 49篇 |
1995年 | 54篇 |
1994年 | 52篇 |
1993年 | 47篇 |
1992年 | 36篇 |
1991年 | 39篇 |
1990年 | 52篇 |
1989年 | 34篇 |
1988年 | 38篇 |
1987年 | 32篇 |
1986年 | 32篇 |
1985年 | 42篇 |
1984年 | 48篇 |
1983年 | 48篇 |
1982年 | 35篇 |
1981年 | 56篇 |
1980年 | 40篇 |
1979年 | 36篇 |
1978年 | 28篇 |
1977年 | 41篇 |
1976年 | 31篇 |
1974年 | 30篇 |
1973年 | 29篇 |
1972年 | 28篇 |
排序方式: 共有6011条查询结果,搜索用时 31 毫秒
991.
Atkin JD Farg MA Turner BJ Tomas D Lysaght JA Nunan J Rembach A Nagley P Beart PM Cheema SS Horne MK 《The Journal of biological chemistry》2006,281(40):30152-30165
Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study. 相似文献
992.
During metamorphic development, bullfrogs (Rana catesbeiana) undergo substantial morphological, anatomical, and physiological changes as the animals prepare for the transition from a fully-aquatic to a semi-terrestrial existence. Using BrdU incorporation and immunohistochemistry, we quantify changes in cell proliferation in two key auditory brainstem nuclei, the dorsolateral nucleus and the superior olivary nucleus, over the course of larval and early postmetamorphic development. From hatchling through early larval stages, numbers of proliferating cells increase in both nuclei, paralleling the overall increase in total numbers of cells available for labeling. Numbers of proliferating cells in the superior olivary nucleus decrease during the late larval and deaf periods, and significantly increase during metamorphic climax. Proliferating cells in the dorsolateral nucleus increase in number from hatchling to late larval stages, decrease during the deaf period, and increase during climax. In both nuclei, numbers of proliferating cells decrease during the postmetamorphic froglet stage, despite increases in the number of cells available for label. Newly generated cells express either glial- or neural-specific phenotypes beginning between 1 week and 1 month post-BrdU injection, respectively, while some new cells express gamma-aminobutyric acid within 2 days of mitosis. Our data show that these auditory nuclei dramatically up-regulate mitosis immediately prior to establishment of a transduction system based on atmospheric hearing. 相似文献
993.
Sarah W. Read Mary DeGrezia Emily J. Ciccone Rebecca DerSimonian Jeanette Higgins Joseph W. Adelsberger Judith M. Starling Catherine Rehm Irini Sereti 《PloS one》2010,5(8)
Background
The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.Methodology
A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit.Findings
Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation.Conclusions
Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy.Trial Registration
ClinicalTrials.gov NCT00101374相似文献994.
Latisha D. Heinlen Micah T. McClain Lauren L. Ritterhouse Benjamin F. Bruner Colin C. Edgerton Michael P. Keith Judith A. James John B. Harley 《PloS one》2010,5(3)
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns. 相似文献
995.
Lau JY Oliver BG Baraket M Beckett EL Hansbro NG Moir LM Wilton SD Williams C Foster PS Hansbro PM Black JL Burgess JK 《PloS one》2010,5(10):e13360
Background
The extracellular matrix is a dynamic and complex network of macromolecules responsible for maintaining and influencing cellular functions of the airway. The role of fibronectin, an extracellular matrix protein, is well documented in asthma. However, the expression and function of fibulin-1, a secreted glycoprotein which interacts with fibronectin, has not been reported. Fibulin-1 is widely expressed in basement membranes in many organs including the lung. There are four isoforms in humans (A–D) of which fibulin-1C and 1D predominate. The objective of this study was to study the expression of fibulin-1 in volunteers with and without asthma, and to examine its function in vitro.Methodology/Principal Findings
We used immunohistochemistry and dot-blots to examine fibulin-1 levels in bronchial biopsies, bronchoalveolar lavage fluid and serum. Real-time PCR for fibulin-1C and 1D, and ELISA and western blotting for fibulin-1 were used to study the levels in airway smooth muscle cells. The function of fibulin-1C was determined by assessing its role, using an antisense oligonucleotide, in cell proliferation, migration and wound healing. A murine model of airway hyperresponsiveness (AHR) was used to explore the biological significance of fibulin-1. Levels of fibulin-1 were significantly increased in the serum and bronchoalveolar lavage fluid of 21 asthmatics compared with 11 healthy volunteers. In addition fibulin-1 was increased in asthma derived airway smooth muscle cells and fibulin-1C contributed to the enhanced proliferation and wound repair in these cells. These features were reversed when fibulin-1C was suppressed using an antisense oligomer. In a mouse model of AHR, treatment with an AO inhibited the development of AHR to methacholine.Conclusions
Our data collectively suggest fibulin-1C may be worthy of further investigation as a target for airway remodeling in asthma. 相似文献996.
Koen Peeters Grietens Sabine Gies Sheick Oumar Coulibaly Clotilde Ky Judith Somda Elizabeth Toomer Joan Muela Ribera Umberto D'Alessandro 《PloS one》2010,5(8)
Background
While IPTp-SP is currently being scaled up in sub-Saharan Africa (SSA), the coverage with the required ≥2 doses of SP remains considerably short of the Roll Back Malaria (RBM) goal of 80%, not to mention of the recently advocated universal coverage.Methods
The study triangulates quantitative data from a health center randomized community-based trial on IPTp-SP effectiveness and the additional benefit of a promotional campaign with qualitative data from focused ethnography.Findings
In rural Burkina Faso, despite the significantly higher risk of malaria infection among adolescent primigravidae (PG) (OR 2.44 95%CI 1.81–3.28, p<0.001), making them primary target beneficiaries of IPTp-SP, adolescents adhered to the required three or more ANC visits significantly less (PG: 46.6%; SG 43.7%) than adults (PG: 61.9%; SG 54.9%) and had lower SP uptake during the malaria transmission season, further showing the difficulty of reaching this age group. Adolescents'' structural constraints (such as their social position and household labor requirements) and needs (such as anonymity in the health encounter) leave them highly vulnerable during their pregnancies and, especially, during the high malaria transmission season.Conclusion
Our study shows that adolescents need to be targeted specifically, prior to their first pregnancy and with measures adapted to their social context, addressing their structural constraints and needs and going beyond standard health promotion campaigns. Unless such specific measures are taken, adolescents'' social vulnerability will present a serious bottleneck for the effectiveness of IPTi-SP. 相似文献997.
Judith L. Stella Candace C. Croney C. Tony Buffington 《Journal of applied animal welfare science : JAAWS》2017,20(3):296-312
The effect of providing additional floor space on cat behavior and welfare is not well documented. This study involved replication of an investigation of cats’ responses to enhanced cage and room environments using cages of 0.56 m2 with the same methodology but an increased space allowance of 1.1 m2. Singly housed adult cats (n = 59) were randomly assigned to a treatment group that was a combination of a managed or unmanaged room and an enriched or unenriched cage environment. Cats were observed for 2 days for maintenance, affiliative, and avoidant behaviors using scan sampling and 5-min, continuous focal sampling. At the end of Day 2, cats’ reactions to the approach of an unfamiliar person were assessed. Cats housed in enriched/managed environments exhibited more maintenance and affiliative behaviors and fewer avoidant behaviors than cats in unmanaged/unenriched environments, suggesting that macro and micro environments may be equally relevant to the cat. Increased space did not enhance the cats’ welfare outcomes, suggesting that the provision of additional cage space may not be as important to the cat as a managed housing environment. 相似文献
998.
The Cercopithecini, or African guenon monkeys, are one of the most diverse clades of living primates and comprise the most species‐rich clade of Catarrhini. Species identity is announced by flamboyant coloration of the facial and genital regions and, more cryptically, by vigorous chromosomal rearrangements among taxa. Beneath the skin, however, these animals are skeletally conservative and show low levels of genetic sequence divergence consonant with recent divergence between congeneric species. The guenons clearly demonstrate that morphological, cytogenetic, and reproductive differentiation proceed at different rates during speciation. We review diverse kinds of data in an effort to understand this conundrum. 相似文献
999.
1000.