全文获取类型
收费全文 | 18072篇 |
免费 | 1380篇 |
国内免费 | 66篇 |
专业分类
耳鼻咽喉 | 128篇 |
儿科学 | 566篇 |
妇产科学 | 539篇 |
基础医学 | 2553篇 |
口腔科学 | 304篇 |
临床医学 | 2058篇 |
内科学 | 3466篇 |
皮肤病学 | 480篇 |
神经病学 | 1822篇 |
特种医学 | 494篇 |
外科学 | 1898篇 |
综合类 | 116篇 |
一般理论 | 7篇 |
预防医学 | 1959篇 |
眼科学 | 423篇 |
药学 | 1073篇 |
1篇 | |
中国医学 | 19篇 |
肿瘤学 | 1612篇 |
出版年
2024年 | 25篇 |
2023年 | 236篇 |
2022年 | 359篇 |
2021年 | 690篇 |
2020年 | 469篇 |
2019年 | 584篇 |
2018年 | 764篇 |
2017年 | 509篇 |
2016年 | 608篇 |
2015年 | 675篇 |
2014年 | 829篇 |
2013年 | 1116篇 |
2012年 | 1642篇 |
2011年 | 1609篇 |
2010年 | 820篇 |
2009年 | 766篇 |
2008年 | 1168篇 |
2007年 | 1191篇 |
2006年 | 1037篇 |
2005年 | 958篇 |
2004年 | 830篇 |
2003年 | 760篇 |
2002年 | 729篇 |
2001年 | 97篇 |
2000年 | 66篇 |
1999年 | 85篇 |
1998年 | 108篇 |
1997年 | 103篇 |
1996年 | 66篇 |
1995年 | 53篇 |
1994年 | 53篇 |
1993年 | 58篇 |
1992年 | 42篇 |
1991年 | 29篇 |
1990年 | 23篇 |
1989年 | 23篇 |
1988年 | 11篇 |
1987年 | 13篇 |
1986年 | 24篇 |
1985年 | 20篇 |
1984年 | 22篇 |
1983年 | 18篇 |
1982年 | 23篇 |
1981年 | 14篇 |
1980年 | 11篇 |
1978年 | 12篇 |
1977年 | 11篇 |
1932年 | 15篇 |
1931年 | 16篇 |
1930年 | 11篇 |
排序方式: 共有10000条查询结果,搜索用时 13 毫秒
71.
Gunilla Caisander Hannah Park Katarina Frej Jenny Lindqvist Christina Bergh Kersti Lundin Charles Hanson 《Chromosome research》2006,14(2):131-137
There have been recent reports of human embryonic stem cell (hESC) lines developing chromosomal aberrations after long-term
culture, indicating an unstable genomic status due to the in vitro milieu. This raises concern, since it would limit their use in therapeutics. In this study the chromosomal status of five
well-characterized hESC lines, SA002, SA002.5, AS034.1.1, SA121 and SA461, was monitored during long-term in vitro culture. The criteria of defined hESCs were met by all of the five hESC lines (four diploid and one trisomic for chromosome
13). The genomes were screened for chromosomal aberrations and rearrangements using comparative genomic hybridization (CGH),
interphase fluorescence in situ hybridization (FISH) and traditional karyotyping on several occasions while in culture. The genomic integrity was shown to
be maintained after repeated freeze-thaw procedures and continuous culture in vitro for up to 22 months (148 passages). We discuss the most common de novo chromosomal aberrations reported in hESCs, as well as their possible origin. 相似文献
72.
Barbaro G Grisorio B Fruttaldo L Bacca D Babudieri S Torre D Francavilla R Rizzo G Belloni G Lucchini A Annese M Matarazzo F Hazra C Barbarini G 《BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy》2003,17(6):433-439
Background: The differential tolerability profile of various interferon (IFN)-α preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNα-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNα is deemed to have a better safety profile than recombinant IFNα. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNα or with recombinant IFNα-2b in treatment-naive patients with chronic hepatitis C. Study design: We randomised 423 patients to either leucocyte IFNα 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNα-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response. Results: In patients receiving leucocyte IFNα, the total number of adverse events was lower than in the group receiving recombinant IFNα (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNα plus ribavirin and in 44% of patients receiving IFNα-2b plus ribavirin. Conclusions: Both therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNα plus ribavirin was more favourable than that observed with the administration of recombinant IFNα-2b plus ribavirin, suggesting that leucocyte IFNα may be an alternative option in patients with reduced tolerability to other IFNs. 相似文献
73.
Cation channels,cell volume and the death of an erythrocyte 总被引:8,自引:0,他引:8
Lang F Lang KS Wieder T Myssina S Birka C Lang PA Kaiser S Kempe D Duranton C Huber SM 《Pflügers Archiv : European journal of physiology》2003,447(2):121-125
Similar to a variety of nucleated cells, human erythrocytes activate a non-selective cation channel upon osmotic cell shrinkage. Further stimuli of channel activation include oxidative stress, energy depletion and extracellular removal of Cl–. The channel is permeable to Ca2+ and opening of the channel increases cytosolic [Ca2+]. Intriguing evidence points to a role of this channel in the elimination of erythrocytes by apoptosis. Ca2+ entering through the cation channel stimulates a scramblase, leading to breakdown of cell membrane phosphatidylserine asymmetry, and stimulates Ca2+-sensitive K+ channels, thus leading to KCl loss and (further) cell shrinkage. The breakdown of phosphatidylserine asymmetry is evidenced by annexin binding, a typical feature of apoptotic cells. The effects of osmotic shock, oxidative stress and energy depletion on annexin binding are mimicked by the Ca2+ ionophore ionomycin (1 µM) and blunted in the nominal absence of extracellular Ca2+. Nevertheless, the residual annexin binding points to additional mechanisms involved in the triggering of the scramblase. The exposure of phosphatidylserine at the extracellular face of the cell membrane stimulates phagocytes to engulf the apoptotic erythrocytes. Thus, sustained activation of the cation channels eventually leads to clearance of affected erythrocytes from peripheral blood. Susceptibility to annexin binding is enhanced in several genetic disorders affecting erythrocyte function, such as thalassaemia, sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency. The enhanced vulnerability presumably contributes to the shortened life span of the affected erythrocytes. Beyond their role in the limitation of erythrocyte survival, cation channels may contribute to the triggering of apoptosis in nucleated cells exposed to osmotic shock and/or oxidative stress. 相似文献
74.
Shields CM Taylor R Nazarenus T Cheatle J Hou A Tapprich A Haifley A Atkin AL 《Current genetics》2003,44(4):184-194
Saccharomyces cerevisiae ATS1 (-tubulin suppressor 1) was originally identified as a high-copy suppressor of class two -tubulin mutations and was proposed to have a regulatory role in coordinating the microtubule state with the cell cycle. Here, we show that Ats1p interacts with Nap1p, a cytoplasmic protein that regulates the activity of the Cdc28p/Clb2p complex. Loss of Nap1p results in a delayed switch from polar to isotropic bud growth. The delayed switch results in elongated buds. Nap1p and Ats1p interact in two-hybrid and co-immunoprecipitation assays. Both nap1 and ats1 cells have a Clb2p-dependent elongated bud morphology. Deletion of ATS1 partially suppresses the elongated bud morphology and benomyl resistance of nap1 mutants. Our results suggest Ats1p might regulate coordination of the microtubule state with the cell cycle through an interaction with Nap1p.Communicated by S. Hohmann 相似文献
75.
76.
Regulation of activation-induced receptor activator of NF-kappaB ligand (RANKL) expression in T cells 总被引:6,自引:0,他引:6
Wang R Zhang L Zhang X Moreno J Celluzzi C Tondravi M Shi Y 《European journal of immunology》2002,32(4):1090-1098
Receptor activator of NF-kappaB ligand (RANKL) is a type II membrane protein of the TNF family and plays a critical role in the regulation of osteoclastogenesis. RANKL expressed on osteoblastic stromal cells has been shown to support osteoclast differentiation originated from hematopoietic precursors. Interestingly, RANKL is also expressed on cells of the immune system including T cells and dendritic cells. We have shown that anti-CD3 could induce RANKL expression in T cell hybridoma A1.1 cells and splenic T cells. RANKL expressed on T cells could effectively induce osteoclast formation from the whole population of murine splenocytes. Furthermore, we have found that the induction of RANKL expression is solely dependent on TCR activation-induced Ca2+ mobilization since its expression can be blocked by cyclosporine A and TMB-8, a Ca2+ mobilization inhibitor. Additionally, treatment of A1.1 cells with ionomycin alone also strongly induces RANKL expression, while phorbol myristate acetate by itself does not. Moreover, although inhibition of c-myc has significant effects on anti-CD3-induced Fas ligand (FasL) expression, we have found that the anti-CD3-induced RANKL expression is independent of c-myc. Surprisingly, in contrast to its inhibitory effect on FasL expression, TGF-beta dramatically increased the expression of anti-CD3-induced RANKL expression. In addition to its potential role in immune responses, RANKL expressed on activated T lymphocytes may provide a mechanism for the communication between the immune and skeletal systems during immune responses and disease states such as rheumatoid arthritis. 相似文献
77.
Pernille Mathiesen Tørring Martin Jakob Larsen Charlotte Brasch-Andersen Lotte Nylandsted Krogh Maria Kibæk Lone Laulund Niels Illum Ulrike Dunkhase-Heinl Antje Wiesener Bernt Popp Giuseppe Marangi Tina Duelund Hjortshøj Jakob Ek Ida Vogel Naja Becher Laura Roos Marcella Zollino Christina Ringmann Fagerberg 《European journal of medical genetics》2019,62(2):129-136
Introduction
MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients.Materials and methods
In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing.Results
All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations.Conclusions
Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance. 相似文献78.
79.
Characterization of the antibody response to the receptor binding domain of botulinum neurotoxin serotypes A and E
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Baldwin MR Tepp WH Pier CL Bradshaw M Ho M Wilson BA Fritz RB Johnson EA Barbieri JT 《Infection and immunity》2005,73(10):6998-7005
Clostridium botulinum neurotoxins (BoNTs) are the most toxic proteins for humans. The current clostridial-derived vaccines against BoNT intoxication have limitations including production and accessibility. Conditions were established to express the soluble receptor binding domain (heavy-chain receptor [HCR]) of BoNT serotypes A and E in Escherichia coli. Sera isolated from mice and rabbits immunized with recombinant HCR/A1 (rHCR/A1) from the classical type A-Hall strain (ATCC 3502) (BoNT/A1) and rHCR/E from BoNT serotype E Beluga (BoNT/E(B)) neutralized the homologous serotype of BoNT but displayed differences in cross-recognition and cross-protection. Enzyme-linked immunosorbent assay and Western blotting showed that alpha-rHCR/A1 recognized epitopes within the C terminus of the HCR/A and HCR/E, while alpha-rHCR/E recognized epitopes within the N terminus or interface between the N and C termini of the HCR proteins. alpha-rHCR/E(B) sera possessed detectable neutralizing capacity for BoNT/A1, while alpha-rHCR/A1 did not neutralize BoNT/E. rHCR/A was an effective immunogen against BoNT/A1 and the Kyoto F infant strain (BoNT/A2), but not BoNT serotype E Alaska (BoNT/E(A)), while rHCR/E(B) neutralized BoNT/E(A), and under hyperimmunization conditions protected against BoNT/A1 and BoNT/A2. The protection elicited by rHCR/A1 to BoNT/A1 and BoNT/A2 and by rHCR/E(B) to BoNT/E(A) indicate that immunization with receptor binding domains elicit protection within sub-serotypes of BoNT. The protection elicited by hyperimmunization with rHCR/E against BoNT/A suggests the presence of common neutralizing epitopes between the serotypes E and A. These results show that a receptor binding domain subunit vaccine protects against serotype variants of BoNTs. 相似文献
80.
Infantile hemangioma is a proliferation of beta 4-negative endothelial cells adjacent to HLA-DR-positive cells with dendritic cell morphology 总被引:4,自引:0,他引:4
Although hemangioma is referred as to the most common tumor in infancy, the underlying pathogenetic events and the biologic origin of this benign vascular neoplasm have remained obscure. By using immunohistochemistry on frozen sections of infantile hemangiomas, we show here that proliferating endothelial cells abundantly expressed alpha(v)beta(3) but lacked beta(4) integrins. Instead, regressing and involuting infantile hemangiomas due to treatment with IFN-alpha showed positive staining of beta(4) integrin, which might point to the angiogenic significance of beta(4) integrin in infantile hemangiomas. Moreover, immunofluorescence analysis revealed the existence of HLA-DR(+), mostly CD68(+) and partly DC-SIGN/CD209(+) cells with dendritic cell morphology in the intimate vicinity of hemangiomatous vessels. Such cells were also detected in the dermal microvascular unit in normal skin. The coupled occurrence of vascular structures and perivascular cells that were stained positive with markers of monocyte or macrophage or dendritic cells might suggest that the development of infantile hemangioma is a result of vasculogenesis, that is, the formation of primitive blood vessels from angioblasts, rather than of angiogenesis, that is, the sprouting of capillaries from preexisting vessels. 相似文献