全文获取类型
收费全文 | 1145篇 |
免费 | 65篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 87篇 |
妇产科学 | 10篇 |
基础医学 | 97篇 |
口腔科学 | 26篇 |
临床医学 | 138篇 |
内科学 | 230篇 |
皮肤病学 | 20篇 |
神经病学 | 32篇 |
特种医学 | 305篇 |
外科学 | 68篇 |
综合类 | 11篇 |
预防医学 | 68篇 |
眼科学 | 6篇 |
药学 | 62篇 |
肿瘤学 | 59篇 |
出版年
2021年 | 10篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 14篇 |
2017年 | 5篇 |
2016年 | 8篇 |
2015年 | 18篇 |
2014年 | 19篇 |
2013年 | 23篇 |
2012年 | 17篇 |
2011年 | 19篇 |
2010年 | 31篇 |
2009年 | 32篇 |
2008年 | 16篇 |
2007年 | 31篇 |
2006年 | 24篇 |
2005年 | 31篇 |
2004年 | 26篇 |
2003年 | 11篇 |
2002年 | 13篇 |
2001年 | 13篇 |
2000年 | 10篇 |
1999年 | 24篇 |
1998年 | 95篇 |
1997年 | 69篇 |
1996年 | 76篇 |
1995年 | 52篇 |
1994年 | 54篇 |
1993年 | 61篇 |
1992年 | 11篇 |
1991年 | 9篇 |
1990年 | 14篇 |
1989年 | 40篇 |
1988年 | 25篇 |
1987年 | 40篇 |
1986年 | 25篇 |
1985年 | 29篇 |
1984年 | 25篇 |
1983年 | 17篇 |
1982年 | 22篇 |
1981年 | 25篇 |
1980年 | 29篇 |
1979年 | 8篇 |
1978年 | 16篇 |
1977年 | 19篇 |
1976年 | 20篇 |
1975年 | 13篇 |
1973年 | 3篇 |
1970年 | 3篇 |
1968年 | 2篇 |
排序方式: 共有1221条查询结果,搜索用时 15 毫秒
11.
Guo RJ; Wang Y; Kaneko E; Wang DY; Arai H; Hanai H; Takenoshita S; Hagiwara K; Harris CC; Sugimura H 《Carcinogenesis》1998,19(9):1539-1544
Mutations in the transforming growth factor beta type II receptor
(TGFbetaRII) gene have been detected in several human cancer types
exhibiting microsatellite instability. Using intron primers previously
reported for examination of the entire coding region of the TGFbetaRII
gene, 29 sporadic gastric cancers were screened with non-radioactive single
strand conformation polymorphism and subsequent DNA sequencing analysis.
Mutations of the TGFbetaRII gene were detected in three out of 29 tumors
(10%). Two cases showed deletions in a polyadenine tract in both alleles
and was positively associated with replication error. One case had an
insertion of GA dinucleotide sequence in one allele. Mutations of the
TGFbetaRII gene were restricted to exon 3 and other coding regions were not
affected. Loss of heterozygosity was detected by analyzing a polymorphic
site in intron 2. Three out of nine (33%) informative cases, which were all
of intestinal type and advanced cases, showed loss of heterozygosity but
neither TGFbetaRII mutation nor replication error was found in these cases.
Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different
extent in the gastric cancer with genetically abnormal transforming growth
factor. Although the numbers studied are small, homozygous (A)10 deletion
or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and
progression of at least some part of sporadic gastric cancer.
相似文献
12.
13.
Tumour cell growth may be accelerated by protein kinase C (PKC) agonists
such as phorbol esters and receptor tyrosine kinases, but receptor tyrosine
kinases are in turn desensitized to growth factors by PKC agonists. To
clarify this apparent PKC bifunctionality, we have used phosphoantibodies
to determine the relationship between PKC- dependent phosphorylation events
affecting the ErbB2 oncoprotein in G8/DHFR 3T3 cells. Neither the kinetics
nor the extent of phorbol- induced juxtamembrane domain (Thr686)
phosphorylation vary directly with C-terminal (Tyr1222) dephosphorylation,
with Tyr1222 continuing to be dephosphorylated long after Thr686
phosphorylation has also declined. Platelet-derived growth factor (PDGF)
mimics the short-term effects of phorbol on Thr686 and Tyr1222
phosphorylation, and confocal microscopy reveals that both of these PKC
agonists induce rapid internalization of PKC-modified ErbB2. Phorbol causes
sustained cytoplasmic accumulation of PKC-phosphorylated receptors,
however, whereas PDGF triggers the appearance of this ErbB2 subset only
briefly. Metabolic labelling and co-precipitation studies fail to implicate
heterologous molecules in either the tyrosine dephosphorylation or
internalization of PKC-modified ErbB2. Taken in the context of earlier
juxtamembrane domain mutagenesis studies, these findings indicate that
phorbol-activated PKC may desensitize growth factor receptors to
extracellular ligands solely by triggering sustained receptor
internalization. We submit that PKC-dependent juxtamembrane domain
phosphorylation represents a physiological mechanism for shortening the
duration and enhancing the specificity of growth factor signalling by
promoting internalization of liganded and unliganded receptors,
respectively.
相似文献
14.
15.
Kim J Fernie J Laird Shutt Greg Mayne David Hoffman Robert J Letcher Ken G Drouillard Ian J Ritchie 《Toxicological sciences》2005,88(2):375-383
Polybrominated diphenyl ethers (PBDEs), a class of additive flame retardants, are temporally increasing in wildlife tissues and capable of disrupting normal endocrine function. We determined whether in ovo and post-hatch exposure of captive American kestrels (Falco sparverius) to environmentally relevant PBDEs alter thyroid, retinol, and oxidative stress measures. Control eggs were injected with safflower oil and subsequent nestlings fed the same vehicle; dosed eggs received PBDE congeners (BDE-47, -99, -100, -153), which mainly comprise the Penta-BDE commercial mixture, dissolved in safflower oil at concentrations (1500 ng/g total [Sigma] PBDEs) approximating those in Great Lakes gull eggs. Nestlings hatching from dosed eggs were orally exposed for 29 days to variable SigmaPBDE concentrations that are similar to levels reported in tissues of Great Lakes trout (100 ng/g). Treatment kestrels had lower plasma thyroxine (T(4)), plasma retinol, and hepatic retinol and retinyl palmitate concentrations, but unaltered triiodothyronine (T(3)) concentrations and thyroid glandular structure. BDE-47, -100, and -99 were negatively associated with plasma T(4), plasma retinol (BDE-100, -99) and hepatic retinol (BDE-47). Despite an antioxidant-rich diet, PBDE exposure induced hepatic oxidative stress, particularly in females, with an increased hepatic GSSG:GSH ratio, a marginal increase in lipid peroxidation, and increased oxidized glutathione. Positive associations were found between concentrations of BDE-183 and thiols and, in males, between BDE-99 and reduced GSH, but a negative association occurred between BDE-99 and TBARS. Subsequently, concentrations of PBDE congeners in wild birds may alter thyroid hormone and vitamin A concentrations, glutathione metabolism and oxidative stress. 相似文献
16.
Caroline Egloff Doug Crump Emily Porter Kim L. Williams Robert J. Letcher Lewis T. Gauthier Sean W. Kennedy 《Toxicology and applied pharmacology》2014
The organophosphate flame retardants tris(2-butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP) are used in a wide range of applications to suppress or delay the ignition and spread of fire. Both compounds have been detected in the environment and TBOEP was recently measured in free-living avian species. In this study, TBOEP and TEP were injected into the air cell of chicken embryos at concentrations ranging from 0 to 45,400 ng/g and 0 to 241,500 ng/g egg, respectively. Pipping success, development, hepatic mRNA expression of 9 target genes, thyroid hormone levels, and circulating bile acid concentrations were determined. Exposure to the highest doses of TBOEP and TEP resulted in negligible detection of the parent compounds in embryonic contents at pipping indicating their complete metabolic degradation. TBOEP exposure had limited effects on chicken embryos, with the exception of hepatic CYP3A37 mRNA induction. TEP exposure decreased pipping success to 68%, altered growth, increased liver somatic index (LSI) and plasma bile acids, and modulated genes associated with xenobiotic and lipid metabolism and the thyroid hormone pathway. Plasma thyroxine levels were decreased at all TEP doses, including an environmentally-relevant concentration (8 ng/g), and gallbladder hypotrophy was evident at ≥ 43,200 ng/g. Tarsus length and circulating thyroxine concentration emerged as potential phenotypic anchors for the modulation of transthyretin mRNA. The increase in plasma bile acids and LSI, gallbladder hypotrophy, and discoloration of liver tissue represented potential phenotypic outcomes associated with modulation of hepatic genes involved with xenobiotic and lipid metabolism. 相似文献
17.
18.
D'Andrea RJ; Barry SC; Moretti PA; Jones K; Ellis S; Vadas MA; Goodall GJ 《Blood》1996,87(7):2641-2648
The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c- derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid- specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling. 相似文献
19.
Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease 总被引:7,自引:2,他引:7
Gruss HJ; Hirschstein D; Wright B; Ulrich D; Caligiuri MA; Barcos M; Strockbine L; Armitage RJ; Dower SK 《Blood》1994,84(7):2305-2314
CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD. 相似文献
20.
Factor V and factor VIII are homologous cofactors in the blood coagulation cascade that have the domain structure A1-A2-B-A3-C1-C2, of which the B domain has extensively diverged. In transfected COS-1 monkey cells, expression of factor VIII is approximately 10-fold less efficient than that of factor V, primarily because of inefficient protein secretion and, to a lesser extent, reduced mRNA expression. To study the functional significance and effect of the B domain on expression and activity, chimeric cDNAs were constructed in which the B domains of factor V and factor VIII were exchanged. Expression of a factor VIII chimera harboring the B-domain of factor V yielded a fully functional factor VIII molecule that was expressed twofold more efficiently than wild-type factor VIII because of increased mRNA expression. Thus, sequences within the factor VIII B domain were not responsible for the inefficient secretion of factor VIII compared with factor V. Expression of a factor V chimera harboring the B domain of factor VIII was slightly reduced compared with wild-type factor V, although the secreted molecule had significantly reduced procoagulant activity correlating with dissociated heavy and light chains and resistance to thrombin activation. Interestingly, the factor V chimera containing the factor VIII B domain was efficiently activated by Russell's viper venum (RVV). A factor V B domain deletion (residues 710- 1545) molecule also exhibited significantly reduced procoagulant activity caused by resistance to thrombin cleavage and activation, although this molecule was activatable by RVV. These results show that, in contrast to factor VIII, thrombin activation of factor V requires sequences within the B domain. In addition, thrombin activation of factor V occurs through a different mechanism than activation by RVV. 相似文献