全文获取类型
收费全文 | 1649篇 |
免费 | 245篇 |
专业分类
1894篇 |
出版年
2021年 | 18篇 |
2017年 | 13篇 |
2016年 | 24篇 |
2015年 | 34篇 |
2014年 | 47篇 |
2013年 | 78篇 |
2012年 | 62篇 |
2011年 | 56篇 |
2010年 | 48篇 |
2009年 | 46篇 |
2008年 | 56篇 |
2007年 | 70篇 |
2006年 | 60篇 |
2005年 | 46篇 |
2004年 | 58篇 |
2003年 | 54篇 |
2002年 | 40篇 |
2001年 | 45篇 |
2000年 | 45篇 |
1999年 | 43篇 |
1998年 | 24篇 |
1997年 | 18篇 |
1996年 | 22篇 |
1995年 | 18篇 |
1994年 | 14篇 |
1993年 | 26篇 |
1992年 | 54篇 |
1991年 | 40篇 |
1990年 | 48篇 |
1989年 | 51篇 |
1988年 | 30篇 |
1987年 | 36篇 |
1986年 | 32篇 |
1985年 | 38篇 |
1984年 | 20篇 |
1983年 | 24篇 |
1982年 | 33篇 |
1981年 | 14篇 |
1980年 | 15篇 |
1979年 | 31篇 |
1978年 | 21篇 |
1977年 | 29篇 |
1976年 | 15篇 |
1975年 | 20篇 |
1974年 | 28篇 |
1973年 | 29篇 |
1972年 | 25篇 |
1971年 | 18篇 |
1970年 | 26篇 |
1968年 | 18篇 |
排序方式: 共有1894条查询结果,搜索用时 15 毫秒
61.
Inna G. Ovsyannikova Iana H. Haralambieva Richard B. Kennedy V. Shane Pankratz Robert A. Vierkant Robert M. Jacobson Gregory A. Poland 《Gene》2012
We explored associations between SNPs in cytokine/cytokine receptor genes and cellular immunity in subjects following primary smallpox vaccination. We also analyzed the genotype–phenotype associations discovered in the Caucasian subjects among a cohort of African-Americans. In Caucasians we found 277 associations (p < 0.05) between gene SNPs and inter-individual variations in IFN-α, IL-12p40, IL-1β, IL-2, and TNF-α secretion levels. A collection of SNPs in the IL1RN, IL2RB, IL4R, IL6, IL10RB, IL12A, and IL12RB2 genes had consistent associations among both Caucasians and African-Americans. A regulatory SNP (rs452204) in the IL1RN gene was significantly associated with higher levels of IL-2 secretion in an allele dose-dependent manner in both race groups (p = 0.05 for Caucasians and p = 0.002 for African-Americans). IL12RB2 polymorphism rs3790567 was associated with a dose-related decrease in IL-1β secretion (p = 0.009 for Caucasians and p = 0.01 for African-Americans). Our results demonstrate that variations in smallpox vaccine-induced cytokine responses are modulated by genetic polymorphisms in cytokine and cytokine receptor genes. 相似文献
62.
Hyuk Woo Lee Hea Ok Kim Won Jun Choi Sun Choi Jin Hee Lee Seul-gi Park Lena Yoo Kenneth A. Jacobson Lak Shin Jeong 《Bioorganic & medicinal chemistry》2010,18(19):7015-7021
We synthesized homologated truncated 4′-thioadenosine analogues 3 in which a methylene (CH2) group was inserted in place of the glycosidic bond of a potent and selective A3 adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A3 adenosine receptor. However, all homologated nucleosides were devoid of binding affinity at all subtypes of adenosine receptors, indicating that free rotation through the single bond allowed the compound to adopt an indefinite number of conformations, disrupting the favorable binding interaction essential for receptor recognition. 相似文献
63.
T O Yeates D H Jacobson A Martin C Wychowski M Girard D J Filman J M Hogle 《The EMBO journal》1991,10(9):2331-2341
The crystal structure of V510, a chimeric type 2/type 1 poliovirus, has been determined at 2.6 A resolution. Unlike the parental Mahoney strain of type 1 poliovirus, V510 is able to replicate in the mouse central nervous system, due entirely to the replacement of six amino acids in the exposed BC loop of capsid protein VP1. Significant structural differences between the two strains cluster in a major antigenic site of the virus, located at the apex of the radial projection which surrounds the viral five-fold axis. Residues implicated in the mouse-virulence of poliovirus by genetic studies are located in this area, and include the residues which are responsible for stabilizing the conformation of the BC loop in V510. Despite evidence that this area is not involved in receptor binding in cultured primate cells, the genetic and structural observations suggest that this area plays a critical role in receptor interactions in the mouse central nervous system. These results provide a structural framework for further investigation of the molecular determinants of host and tissue tropism in viruses. 相似文献
64.
Attempts to eliminate Sarcoptes scabiei var. suis were made in 2 piglet producing herds by intramuscular injections with doramectin (Dectomax™, Pfizer inc., New York, USA). No hygienic measures of the environments were undertaken. In herd A, all animals were treated twice at a 14-day interval. Theoretically it should be possible to eliminate the mite with a single injection and therefore the animals in herd B were treated only once. The results were measured by attempts to demonstrate S. scabiei by skin scrapings, by recording skin lesions, by establishing rubbing indexes, and by measuring serum antibodies to S. scabiei. All adult animals greater than 8 months of age and 15 weaned piglets 8–16 weeks of age per herd were investigated prior to treatments and every fourth month for a total of 20 months following administration of the treatments. Live S. scabiei were demonstrated prior to treatments in both herds, but no further. Skin lesion scores, rubbing indexes and serum antibody levels remained low throughout the study. It is possible to eliminate S. scabiei from a herd with one single injection of doramectin. Precautions must be taken to ensure that all animals get a correct dose and that the drug is properly administered. 相似文献
65.
Amanda D. Melin Brooke E. Crowley Shaun T. Brown Patrick V. Wheatley Gillian L. Moritz Fred Tuh Yit Yu Henry Bernard Donald J. DePaolo Andrew D. Jacobson Nathaniel J. Dominy 《American journal of physical anthropology》2014,154(4):633-643
Calcium stable isotope ratios are hypothesized to vary as a function of trophic level. This premise raises the possibility of using calcium stable isotope ratios to study the dietary behaviors of fossil taxa and to test competing hypotheses on the adaptive origins of euprimates. To explore this concept, we measured the stable isotope composition of contemporary mammals in northern Borneo and northwestern Costa Rica, two communities with functional or phylogenetic relevance to primate origins. We found that bone collagen δ13C and δ15N values could differentiate trophic levels in each assemblage, a result that justifies the use of these systems to test the predicted inverse relationship between bioapatite δ13C and δ44Ca values. As expected, taxonomic carnivores (felids) showed a combination of high δ13C and low δ44Ca values; however, the δ44Ca values of other faunivores were indistinguishable from those of primary consumers. We suggest that the trophic insensitivity of most bioapatite δ44Ca values is attributable to the negligible calcium content of arthropod prey. Although the present results are inconclusive, the tandem analysis of δ44Ca and δ13C values in fossils continues to hold promise for informing paleodietary studies and we highlight this potential by drawing attention to the stable isotope composition of the Early Eocene primate Cantius. Am J Phys Anthropol 154:633–643, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
66.
Simultaneous determination of histamine and N tau-methylhistamine with high-performance liquid chromatography using electrochemical detection 总被引:1,自引:0,他引:1
We have developed a liquid chromatographic method which uses electrochemical detection for the simultaneous quantitation of histamine and N tau-methylhistamine in rat brain. The amines are derivatized with the water-soluble Bolton-Hunter reagent (sulfo B-H). Perchloric acid extracts of rat brains are chromatographed on a strong cation-exchange resin. The eluate is evaporated and allowed to react with sulfo B-H at pH 9.8 at room temperature. The derivatization is complete after 30 s vortexing. The derivatives are purified using a cellulose-phosphate fibrous cation exchanger. They are quantified with an electrochemical detector at a potential of 0.56 V after preoxidizing the sample at 0.47 V. The derivatives of histamine, N tau-methylhistamine, and N alpha-methylhistamine are completely separated without interfering peaks. Since no N alpha-methylhistamine was detected in rat brain it was used as an internal standard. The detection limits are 0.1 pmol of histamine and 0.2 pmol of N tau-methylhistamine. The precision of this method is high, with within-run and between-run coefficients of variation of 2-7% and linearity of 0.999. Both histamine and N tau-methylhistamine peak heights increased significantly and selectively after treatment with pargyline. Because of the high sensitivity, accuracy, and precision, the histamine and N tau-methylhistamine contents of single nuclei of the rat hypothalamus can be routinely quantified. 相似文献
67.
Joshua Herbeck Suvankar Ghorai Lennie Chen Charles R. Rinaldo Joseph B. Margolick Roger Detels Lisa Jacobson Steven Wolinsky James I. Mullins 《PloS one》2015,10(3)
Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R2 = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1. 相似文献
68.
M. D. Weston P. M. Kelley L. D. Overbeck M. Wagenaar D. J. Orten T. Hasson Z. Y. Chen D. Corey M. Mooseker J. Sumegi C. Cremers C. Moller S. G. Jacobson M. B. Gorin W. J. Kimberling 《American journal of human genetics》1996,59(5):1074-1083
Usher syndrome type 1b (USH1B) is an autosomal recessive disorder characterized by congenital profound hearing loss, vestibular abnormalities, and retinitis pigmentosa. The disorder has recently been shown to be caused by mutations in the myosin VIIa gene (MYO7A) located on 11q14. In the current study, a panel of 189 genetically independent Usher I cases were screened for the presence of mutations in the N-terminal coding portion of the motor domain of MYO7A by heteroduplex analysis of 14 exons. Twenty-three mutations were found segregating with the disease in 20 families. Of the 23 mutations, 13 were unique, and 2 of the 13 unique mutations (Arg212His and Arg212Cys) accounted for the greatest percentage of observed mutant alleles (8/23, 31%). Six of the 13 mutations caused premature stop codons, 6 caused changes in the amino acid sequence of the myosin VIIa protein, and 1 resulted in a splicing defect. Three patients were homozygotes or compound heterozygotes for mutant alleles; these three cases were Tyr333Stop/Tyr333Stop, Arg212His-Arg302His/Arg212His-Arg302His, and IVS13nt-8c-->g/Glu450Gln. All the other USH1B mutations observed were simple heterozygotes, and it is presumed that the mutation on the other allele is present in the unscreened regions of the gene. None of the mutations reported here were observed in 96 unrelated control samples, although several polymorphisms were detected. These results add three patients to single case reported previously where mutations have been found in both alleles and raises the total number of unique mutations in MYO7A to 16. 相似文献
69.
Cyclical inactivation of B-type cyclins has been proposed to be required for alternating DNA replication and mitosis. Destruction box-dependent Clb5p degradation is strongly increased in mitotic cells, and constitutive overexpression of Clb5p lacking the destruction box resulted in rapid accumulation of inviable cells, frequently multiply budded, with DNA contents ranging from unreplicated to apparently fully replicated. Loss of viability correlated with retention of nuclear Clb5p at the time of nuclear division. CLB2-Deltadb overexpression that was quantitatively comparable to CLB5-Deltadb overexpression with respect to Clb protein production and Clb-associated kinase activity resulted in a distinct phenotype: reversible mitotic arrest with uniformly replicated DNA. Simultaneous overexpression of CLB2-Deltadb and CLB5-Deltadb overexpressers similarly resulted in a uniform arrest with replicated DNA, and this arrest was significantly more reversible than that observed with CLB5-Deltadb overexpression alone. These results suggest that Clb2p and not Clb5p can efficiently block mitotic completion. We speculate that CLB5-Deltadb overexpression may be lethal, because persistence of high nuclear Clb5p-associated kinase throughout mitosis leads to failure to load origins of replication, thus preventing DNA replication in the succeeding cell cycle. 相似文献