全文获取类型
收费全文 | 1545篇 |
免费 | 89篇 |
国内免费 | 2篇 |
出版年
2022年 | 21篇 |
2021年 | 22篇 |
2020年 | 11篇 |
2019年 | 24篇 |
2018年 | 21篇 |
2017年 | 21篇 |
2016年 | 36篇 |
2015年 | 92篇 |
2014年 | 67篇 |
2013年 | 88篇 |
2012年 | 147篇 |
2011年 | 125篇 |
2010年 | 81篇 |
2009年 | 68篇 |
2008年 | 102篇 |
2007年 | 100篇 |
2006年 | 102篇 |
2005年 | 108篇 |
2004年 | 88篇 |
2003年 | 64篇 |
2002年 | 67篇 |
2001年 | 18篇 |
2000年 | 20篇 |
1999年 | 11篇 |
1998年 | 20篇 |
1997年 | 9篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 6篇 |
1993年 | 6篇 |
1992年 | 16篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 9篇 |
1988年 | 3篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 6篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1978年 | 6篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1973年 | 2篇 |
1966年 | 1篇 |
1965年 | 2篇 |
1964年 | 1篇 |
1929年 | 1篇 |
排序方式: 共有1636条查询结果,搜索用时 187 毫秒
121.
Popa C Netea MG Barrera P Radstake TR van Riel PL Kullberg BJ Van der Meer JW 《Cytokine》2005,30(2):72-77
Patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) strategies have an increased susceptibility to infections, especially those caused by intracellular pathogens. In this study we assessed the cytokine production capacity in patients with RA and we further investigated whether anti-TNF therapy modulates the production of pro-inflammatory cytokines involved in the resistance against infections. Whole blood cultures from 10 RA patients and 10 healthy controls were stimulated with heat-killed Candida albicans, Salmonella typhimurium, Staphyloccocus aureus, Aspergillus fumigatus or Mycobacterium tuberculosis and production of interleukin (IL)-1beta, IL-6, IL-10, interferon (IFN)-gamma and TNF-alpha was measured. Before anti-TNF therapy, whole blood cultures from RA patients released significantly less IFN-gamma than healthy controls after stimulation with all tested microorganisms. Short-term anti-TNF therapy did not have an inhibitory effect on the release of the cytokines tested. We conclude that cells of patients with RA have a strongly reduced production capacity of IFN-gamma after bacterial challenge. Although short-term therapy with anti-TNF agents did not further decrease the release of other proinflammatory cytokines, the combination of defective IFN-gamma production in basal conditions and TNF neutralization during anti-TNF therapy is likely to be responsible for the higher susceptibility to infections in patients with RA. 相似文献
122.
123.
Leslie?G?Cleland Michael?J?JamesEmail author Susanna?M?Proudman 《Arthritis research & therapy》2005,8(1):202
There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory
drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis
of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs
has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with
NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of
these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through
multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis,
in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory
diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective
dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors
and patients who may choose to prescribe or take fish oil. 相似文献
124.
Cogoi S Codognotto A Rapozzi V Xodo LE 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):971-974
Peptide nucleic acid (PNA) is a DNA mimic with antigene properties. To enhance its capacity to enter in the cell and internalize in the nucleus, PNA has been conjugated to the nuclear localization signal (NLS) peptide, PKKKRKV PNA-NLS conjugates form stable hybrids with complementary DNA strands and poorly tolerate mismatched base pairing. Employed against cancer-associated genes, PNA-NLS exhibited a potent and specific antigene activity, suggesting exciting therapeutic approaches to cancer. 相似文献
125.
9-Fluorenemethyl H-phosphonoselenoate monoester has been used to produce thymidine 3'-O-phosphoroselenoate monoester from which various P(V) derivatives containing multiple modifications at phosphorus were obtained; e.g., thymidine 3'-O-phosphoroselenofluoridate, 3'-O-phosphoroselenothioate, or 3'-O-phosphorodiselenoate monoesters. 相似文献
126.
127.
K. Susanna S. Hall 《Journal of Ornithology》2005,146(2):121-126
The number of primary feathers in a birds wing has been used as a systematic character since the first half of the nineteenth century. During the years, though, the definition of which feathers to count as a primary has changed and today the species historically denoted as having only nine primaries are instead said to have, for example, nine functional primaries. In this study, I investigated the borderline between nine-primaried and ten-primaried birds to search for a proper definition of the term nine-primaried. A total of 161 specimens of 104 bird species, mainly passerines, were examined. All species examined had ten primaries although the nine-primaried species had primary ten more or less concealed under primary covert nine. The number of primary coverts has decreased over time, with ten primary coverts as the ancestral state within Passeriformes and nine primary coverts among most oscine species. In conclusion, a proper definition of nine-primaried might be with primary ten concealed by primary covert nine. This definition includes all taxa historically denoted nine-primaried, i.e. systematically it is a definition of a paraphyletic group. The term nine-primaried is thus too inclusive to be of more than very limited systemtic value and, consequently, the New World nine-primaried oscines group might gain from a new denotation.Electronic Supplementary Material Supplementary material is available for this article at 相似文献
128.
129.
Wilson R Freddi S Chan D Cheah KS Bateman JF 《The Journal of biological chemistry》2005,280(16):15544-15552
Collagen X is a short chain collagen expressed specifically by the hypertrophic chondrocytes of the cartilage growth plate during endochondral bone formation. Accordingly, COL10A1 mutations disrupt growth plate function and cause Schmid metaphyseal chondrodysplasia (SMCD). SMCD mutations are almost exclusively located in the NC1 domain, which is crucial for both trimer formation and extracellular assembly. Several mutations are expected to reduce the level of functional collagen X due to NC1 domain misfolding or exclusion from stable trimer formation. However, other mutations may be tolerated within the structure of the assembled NC1 trimer, allowing mutant chains to exert a dominant-negative impact within the extracellular matrix. To address this, we engineered SMCD mutations that are predicted either to prohibit subunit folding and assembly (NC1del10 and Y598D, respectively) or to allow trimerization (N617K and G618V) and transfected these constructs into 293-EBNA and SaOS-2 cells. Although expected to form stable trimers, G618V and N617K chains (like Y598D and NC1del10 chains) were secreted very poorly compared with wild-type collagen X. Interestingly, all mutations resulted in formation of an unusual SDS-stable dimer, which dissociated upon reduction. As the NC1 domain sulfhydryl group is not solvent-exposed in the correctly folded NC1 monomer, disulfide bond formation would result only from a dramatic conformational change. In cells expressing mutant collagen X, we detected significantly increased amounts of the spliced form of X-box DNA-binding protein mRNA and up-regulation of BiP, two key markers for the unfolded protein response. Our data provide the first clear evidence for misfolding of SMCD collagen X mutants, and we propose that solvent exposure of the NC1 thiol may trigger the recognition and degradation of mutant collagen X chains. 相似文献
130.
Tempera I Cipriani R Campagna G Mancini P Gatti A Guidobaldi L Pantellini F Mandosi E Sensi M Quesada P Mario UD D'Erme M Morano S 《Journal of cellular physiology》2005,205(3):387-392
Poly(ADP-ribose)polymerase (PARP-1), a nuclear enzyme activated by DNA strand breaks, is involved in DNA repair, aging, inflammation, and neoplastic transformation. In diabetes, reactive oxygen and nitrogen species occurring in response to hyperglycemia cause DNA damages and PARP-1 activation. Because circulating mononuclear cells (MNCs) are involved in inflammation mechanisms, these cells were chosen as the experimental model to evaluate PARP-1 levels and activity in patients with type 2 diabetes. MNCs were isolated from 25 diabetic patients (18 M, 7 F, age, 63.5 +/- 10.2 years, disease duration 17.7 +/- 8.2 years) and 11 age and sex matched healthy controls. PARP-1 expression and activity were analyzed by semi-quantitative PCR, Western and activity blot, and immunofluorescence microscopy. PARP-1-mRNA expression was increased in MNCs from all diabetic patients versus controls (P < 0.01), whereas PARP-1 content and activity were significantly lower in diabetic patients (P < 0.0001). To verify whether low PARP-1 levels and activity were due to a proteolytic effect of caspase-3 like, the latter activation was measured by a fluorimetric assay. Caspase-3 activity in MNCs was significantly higher in diabetic patients versus control subjects (P < 0.0001). The different PARP-1 behavior in MNCs from patients with type 2 diabetes could therefore be responsible for the abnormal inflammation and infection responses in diabetes. 相似文献