全文获取类型
收费全文 | 1149篇 |
免费 | 102篇 |
国内免费 | 3篇 |
出版年
2021年 | 17篇 |
2020年 | 9篇 |
2017年 | 13篇 |
2016年 | 21篇 |
2015年 | 46篇 |
2014年 | 51篇 |
2013年 | 57篇 |
2012年 | 77篇 |
2011年 | 81篇 |
2010年 | 45篇 |
2009年 | 29篇 |
2008年 | 54篇 |
2007年 | 61篇 |
2006年 | 51篇 |
2005年 | 47篇 |
2004年 | 52篇 |
2003年 | 47篇 |
2002年 | 46篇 |
2001年 | 10篇 |
1999年 | 14篇 |
1998年 | 18篇 |
1997年 | 7篇 |
1996年 | 13篇 |
1995年 | 7篇 |
1994年 | 15篇 |
1993年 | 16篇 |
1991年 | 12篇 |
1990年 | 15篇 |
1989年 | 16篇 |
1988年 | 6篇 |
1987年 | 7篇 |
1986年 | 6篇 |
1985年 | 9篇 |
1984年 | 12篇 |
1983年 | 8篇 |
1981年 | 10篇 |
1980年 | 18篇 |
1978年 | 10篇 |
1977年 | 13篇 |
1976年 | 9篇 |
1975年 | 12篇 |
1973年 | 19篇 |
1972年 | 9篇 |
1971年 | 8篇 |
1969年 | 13篇 |
1968年 | 10篇 |
1967年 | 8篇 |
1966年 | 6篇 |
1965年 | 7篇 |
1964年 | 9篇 |
排序方式: 共有1254条查询结果,搜索用时 218 毫秒
991.
Tai ES Sim XL Ong TH Wong TY Saw SM Aung T Kathiresan S Orho-Melander M Ordovas JM Tan JT Seielstad M 《Journal of lipid research》2009,50(3):514-520
We conducted a cross-sectional study of Malay participants aged 40-80 years (n = 2,932) to examine the associations between polymorphisms at newly identified, lipid-associated loci with blood lipid levels and prevalent cardiovascular disease (CVD) in a Malay population in Asia. A polymorphism adjacent to the TRIB1 locus (rs17321515) was associated with elevated total cholesterol and LDL-cholesterol (LDL-C) after adjustment for age and sex (both P values <0.007) and with increased risk of coronary heart disease and CVD [odds ratio (OR) 1.23, 95% confidence interval (95% CI) 1.03-1.46; and OR 1.2, 95% CI 1.02-1.42, respectively] under an additive model of inheritance. In addition, using recessive models of inheritance, polymorphisms on chromosome 19 adjacent to the CILP2 and PBX4 loci (rs16996148) and on chromosome 1 at the GALNT2 locus (rs4846914) were associated with elevated HDL-C (P = 0.005) and lower LDL-C (P = 0.048), respectively. Although novel, the former is consistent with the association between this polymorphism and lower blood triglycerides observed in the initial studies conducted in populations of European ancestry. Neither showed statistically significant association with CVD. These observations should form the basis of further investigation to identify the causative polymorphisms at this locus, and also to understand the mechanistic roles that this protein may play in lipoprotein metabolism in Asians and other populations. 相似文献
992.
As the earliest divergent land plants, bryophytes (mosses, hornworts, and liverworts) provide insight into the evolution of
the unique plant process of sporogenesis by which meiosis results in heavy walled spores. New immunohistochemical data on
microtubules and γ-tubulin in four genera of complex thalloid liverworts combined with previously published data on another
four genera demonstrate grades in the evolution of spindle organization in meiosis. We have discovered that all recognized
forms of microtubule organizing centers (MTOCs) in plant cells (plastid MTOCs, spheroid cytoplasmic MTOCs, polar organizers,
and nuclear envelope MTOCs) occur in organization of the meiotic spindle of complex thalloid liverworts. In addition, all
aspects of pre-meiotic preparation for quadripartitioning of the sporocyte into a tetrad of spores occur, with the exception
of pre-meiotic wall precursors found in certain simple thalloids. The preparation includes morphogenetic plastid migration,
cortical bands of microtubules that mark future cytokinetic planes in pre-meiosis, quadrilobing of the cytoplasm during meiotic
prophase, and quadripolar microtubule systems that are transformed into functionally bipolar metaphase I spindles. Quadripolar
spindle origin is typical of bryophyte sporogenesis even though the MTOCs involved may differ. However, in certain crown taxa
of complex thalloids the spindle develops with no traces of quadripolarity and placement of intersporal walls is determined
after meiosis, as is typical of higher plants. 相似文献
993.
Andrew E. Dellinger Seang-Mei Saw Liang K. Goh Mark Seielstad Terri L. Young Yi-Ju Li 《Nucleic acids research》2010,38(9):e105
Determination of copy number variants (CNVs) inferred in genome wide single nucleotide polymorphism arrays has shown increasing utility in genetic variant disease associations. Several CNV detection methods are available, but differences in CNV call thresholds and characteristics exist. We evaluated the relative performance of seven methods: circular binary segmentation, CNVFinder, cnvPartition, gain and loss of DNA, Nexus algorithms, PennCNV and QuantiSNP. Tested data included real and simulated Illumina HumHap 550 data from the Singapore cohort study of the risk factors for Myopia (SCORM) and simulated data from Affymetrix 6.0 and platform-independent distributions. The normalized singleton ratio (NSR) is proposed as a metric for parameter optimization before enacting full analysis. We used 10 SCORM samples for optimizing parameter settings for each method and then evaluated method performance at optimal parameters using 100 SCORM samples. The statistical power, false positive rates, and receiver operating characteristic (ROC) curve residuals were evaluated by simulation studies. Optimal parameters, as determined by NSR and ROC curve residuals, were consistent across datasets. QuantiSNP outperformed other methods based on ROC curve residuals over most datasets. Nexus Rank and SNPRank have low specificity and high power. Nexus Rank calls oversized CNVs. PennCNV detects one of the fewest numbers of CNVs. 相似文献
994.
Ilan Ben-Zvi Cynthia Aranow Meggan Mackay Anfisa Stanevsky Diane L. Kamen L. Manuela Marinescu Christopher E. Collins Gary S. Gilkeson Betty Diamond John A. Hardin 《PloS one》2010,5(2)
Background
Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNα amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNα-regulated genes in vitro.Methodology/Principal Findings
In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = −.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNα-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma.Conclusions/Significance
We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNα activity in vivo and, most importantly, improves clinical outcome. 相似文献995.
Thomasco LM Gadwood RC Weaver EA Ochoada JM Ford CW Zurenko GE Hamel JC Stapert D Moerman JK Schaadt RD Yagi BH 《Bioorganic & medicinal chemistry letters》2003,13(23):4193-4196
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4-thiadiazolyl ring leads to oxazolidinone analogues 5 having potent antibacterial activity against both gram-positive and gram-negative organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds. 相似文献
996.
Chen JP Lu HL Lai SL Campanella GS Sung JM Lu MY Wu-Hsieh BA Lin YL Lane TE Luster AD Liao F 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(5):3185-3192
Dengue virus is an arthropod-borne flavivirus that causes a mild febrile illness, dengue fever, or a potentially fatal syndrome, dengue hemorrhagic fever/dengue shock syndrome. Chemokines primarily orchestrate leukocyte recruitment to the areas of viral infection, which makes them critical mediators of immune and inflammatory responses. In the present study, we investigated the induction and function of chemokines in mice early after infection with dengue virus in vivo. We found that CXCL10/IFN-gamma-inducible protein 10 (IP-10) expression was rapidly and transiently induced in liver following infection. The expressed CXCL10/IP-10 likely mediates the recruitment of activated NK cells, given that anti-CXCL10/IP-10-treated mice showed diminished NK cell infiltration and reduced hepatic expression of effector molecules in activated NK cells after dengue virus infection. Of particular interest, we found that CXCL10/IP-10 also was able to inhibit viral binding to target cells in vitro. Further investigation revealed that various CXCL10/IP-10 mutants, in which the residues that mediate the interaction between the chemokine and heparan sulfate were substituted, failed to exert the inhibitory effect on dengue binding, which suggests that CXCL10/IP-10 competes with dengue virus for binding to heparan sulfate on the cell surface. Moreover, subsequent plaque assays showed that this inhibition of dengue binding blocked viral uptake and replication. The inhibitory effect of CXCL10/IP-10 on the binding of dengue virus to cells may represent a novel contribution of this chemokine to the host defense against viral infection. 相似文献
997.
I-HmuI and I-BasI are two highly similar nicking DNA endonucleases, which are each encoded by a group I intron inserted into homologous sites within the DNA polymerase genes of Bacillus phages SPO1 and Bastille, respectively. Here, we present a comparison of the DNA specificities and cleavage activities of these enconucleases with homologous target sites. I-BasI has properties that are typical of homing endonucleases, nicking the intron-minus polymerase genes in either host genome, three nucleotides downstream of the intron insertion site. In contrast, I-HmuI nicks both the intron-plus and intron-minus site in its own host genome, but does not act on the target from Bastille phage. Although the enzymes have distinct DNA substrate specificities, both bind to an identical 25bp region of their respective intron-minus DNA polymerase genes surrounding the intron insertion site. The endonucleases appear to interact with the DNA substrates in the downstream exon 2 in a similar manner. However, whereas I-HmuI is known to make its only base-specific contacts within this exon region, structural modeling analyses predict that I-BasI might make specific base contacts both upstream and downstream of the site of intron insertion. The predicted requirement for base-specific contacts in exon 1 for cleavage by I-BasI was confirmed experimentally. This explains the difference in substrate specificities between the two enzymes, including the observation that the former enzyme is relatively insensitive to the presence of an intron upstream of exon 2. These differences are likely a consequence of divergent evolutionary constraints. 相似文献
998.
999.
Betty Y. L. Hsu John W. Foreman Susan M. Corcoran Kristina Ginkinger Stanton Segal 《The Journal of membrane biology》1984,80(2):167-173
Summary The role of the enzyme, gamma-glutamyl transpeptidase on the uptake of amino acids by the brushborder membrane of the rat proximal tubule was examined by inhibiting it with AT-125 (l-[S, 5S]--amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid). AT-125 inhibited 98% of the activity of gamma-glutamyl transpeptidase when incubated for 20 min at 37°C with rat brushborder membrane vesicles. AT-125 given to ratsin vivo inhibited 90% of the activity of gamma-glutamyl transpeptidase in subsequently isolated brushborder membrane vesicles from these animals. AT-125 inhibition of gamma-glutamyl transpeptidase bothin vivo andin vitro had no effect on the brushborder membrane uptake of cystine. Similarly, there was no effect of gamma-glutamyl transpeptidase inhibition by AT-125 on glutamine, proline, glycine, methionine, leucine or lysine uptake by brushborder membrane vesicles. Furthermore, the uptake of cystine by isolated rat renal cortical tubule fragments, in which the complete gamma-glutamyl cycle is present, was unaffected by AT-125 inhibition of gamma-glutamyl transpeptidase. Therefore, in the two model systems studied, gamma-glutamyl transpeptidase did not appear to play a role in the transport of amino acids by the renal brushborder membrane. 相似文献
1000.
Daniel P. Rossignol Betty J. Earles Glenn L. Decker William J. Lennarz 《Developmental biology》1984,104(2):308-321
Eggs of the sea urchins Strongylocentrotus purpuratus and Arbacia punctulata bind sperm with a high degree of species specificity. By use of an in vitro assay that utilizes bindin (the protein from sperm that mediates sperm-egg binding) egg surface-derived glycoconjugates that function as receptors in this adhesion process have been identified and purified. These glycoconjugates are of extraordinarily high molecular weight and exhibit some properties expected for a proteoglycan. The isolated receptors from both species bind to sperm and inhibit fertilization species specifically. Both receptors contain active carbohydrate-rich fragments that can be liberated by proteolytic digestion. The carbohydrate-rich receptor fragment from S. purpuratus is a very high-molecular-weight (>106), negatively charged glycosaminoglycan-like polymer containing fucose, galactosamine, iduronic acid, and sulfate esters. By contrast, the carbohydrate-rich fragment derived from the A. punctulata receptor is of defined molecular weight (6000) and has no net charge. Incubation of acrosome-reacted sperm with nanomolar amounts of the carbohydrate-rich fragments from either species results in inhibition of fertilization, indicating that these receptor fragments retain sperm binding activity. However, studies utilizing heterologous gametes show that the carbohydrate-rich receptor fragments are not species specific in binding. Thus, it appears that although the carbohydrate chains of the receptor are an adhesive element of the receptor, the intact glycoconjugate is required for species-specific binding. 相似文献