全文获取类型
收费全文 | 1156篇 |
免费 | 64篇 |
国内免费 | 8篇 |
专业分类
儿科学 | 16篇 |
妇产科学 | 2篇 |
基础医学 | 750篇 |
口腔科学 | 4篇 |
临床医学 | 41篇 |
内科学 | 185篇 |
皮肤病学 | 18篇 |
神经病学 | 22篇 |
特种医学 | 5篇 |
外科学 | 17篇 |
综合类 | 35篇 |
预防医学 | 21篇 |
眼科学 | 1篇 |
药学 | 50篇 |
中国医学 | 6篇 |
肿瘤学 | 55篇 |
出版年
2024年 | 2篇 |
2023年 | 19篇 |
2022年 | 9篇 |
2021年 | 46篇 |
2020年 | 22篇 |
2019年 | 42篇 |
2018年 | 56篇 |
2017年 | 27篇 |
2016年 | 22篇 |
2015年 | 25篇 |
2014年 | 56篇 |
2013年 | 85篇 |
2012年 | 52篇 |
2011年 | 59篇 |
2010年 | 35篇 |
2009年 | 45篇 |
2008年 | 50篇 |
2007年 | 51篇 |
2006年 | 41篇 |
2005年 | 48篇 |
2004年 | 54篇 |
2003年 | 63篇 |
2002年 | 41篇 |
2001年 | 30篇 |
2000年 | 41篇 |
1999年 | 37篇 |
1998年 | 41篇 |
1997年 | 15篇 |
1996年 | 32篇 |
1995年 | 25篇 |
1994年 | 22篇 |
1993年 | 18篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1989年 | 2篇 |
排序方式: 共有1228条查询结果,搜索用时 406 毫秒
1.
《Cancer cell》2021,39(11):1497-1518.e11
2.
In recent years, a growing interest in the study of peptide antigenicity in relation to the role of flanking sequences and protein topology in processing, presentation, and recognition has been observed. However, the information available on the antigenicity of recombinant fusion proteins and their effect on the selection of antigen receptor repertoires is limited. To analyze the role of molecular topology of T epitopes in a system relevant to human pathology, we have used the bacterially expressed Schistosoma japonicum glutathione S transferase (GST) to construct recombinant antigens containing HIV-1 derived T cell determinants, and human T cell clones specific for these determinants. We found that antigenicity of a given GST—peptide combination was not the same when T cells and antigen presenting cells from different individuals were tested. Our results show that differences in processing and presentation of chimeric proteins are not dictated by the use of diverse restriction elements. We also found that the context in which an antigenic peptide is delivered affects the recruited repertoire as defined according to T cell receptor Vβ usage and fine specificities of selected T cells. 相似文献
3.
In the not-so-distant past the skin was generally viewed as a passive target for immune-mediated injury. Over the last decade, however, concepts of a previously unrecognized role for the skin have unfolded, whereby resident bone marrow-derived leukocytes (e.g. Langerhans cells and T cells) initiate and regulate the immune responses that protect it. Their combination with other immunomodulatory resident cells (e.g. keratinocytes, melanocytes, endothelial cells, fibroblasts) led to the idea that the skin may function as a self-sustaining lymphoid tissue. Although T lymphocytes or, at least, certain subpopulations thereof have the general propensity to populate epithelial tissues, there exist major species differences regarding the phenotype of intraepidermal T cells. The purpose of this review is to fill gaps in our understanding of the relationship of rodent skin T cells to T cells identified in human skin and the normal physiologic and pathologic role(s) of these cells. 相似文献
4.
Immunoglobulin mimicry by Hepatitis C Virus envelope protein E2 总被引:4,自引:0,他引:4
Hu YW Rocheleau L Larke B Chui L Lee B Ma M Liu S Omlin T Pelchat M Brown EG 《Virology》2005,332(2):538-549
Hepatitis C virus (HCV) establishes persistent infection in the majority of infected individuals. The currently accepted hypothesis of immune evasion by antigenic variation in hypervariable region 1 (HVR1) of glycoprotein E2 does not however, explain the lack of subsequent immune recognition. Here, we show that the N-terminal region of E2 is antigenically and structurally similar to human immunoglobulin (Ig) variable domains. E2 is recognized by anti-human IgG antibodies and also possesses common amino acid (aa) sequence features of the conserved v-gene framework regions of human Ig light chains in particular but also heavy chains and T cell receptors. Using a position specific scoring system, the degree of similarity of HVR1 to Ig types correlated with immune escape and persistence in humans and experimentally infected chimpanzees. We propose a unique role for threshold levels of Ig molecular mimicry in HCV biology that not only advances our concept of viral immune escape and persistent infection but also provides insight into host-dependent disease patterns. 相似文献
5.
Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer 总被引:6,自引:0,他引:6
Scholten KB Schreurs MW Ruizendaal JJ Kueter EW Kramer D Veenbergen S Meijer CJ Hooijberg E 《Clinical immunology (Orlando, Fla.)》2005,114(2):119-129
Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies. 相似文献
6.
Palermo B Garbelli S Mantovani S Scoccia E Da Prada GA Bernabei P Avanzini MA Brazzelli V Borroni G Giachino C 《European journal of immunology》2005,35(11):3153-3162
Vitiligo is a skin disorder characterized by depigmented macules secondary to melanocyte loss. An unusual facet is its relation to melanoma: cytotoxic T lymphocytes directed to melanocyte antigens are found in both conditions and imply a breakdown of tolerance, yet the resulting immune reaction is the opposite. The mechanisms at the basis of these opposite effects are not known. Here, we performed a direct comparison of whole melanocyte-specific T cell populations in the two diseases. We demonstrate that neither precursor frequencies of Melan-A/MART-1-specific T lymphocytes nor their status of activation differ significantly. However, by using a tetramer-based T cell receptor down-regulation assay, we documented a higher affinity of vitiligo T cells. We calculated that the peptide concentration required for 50% of maximal receptor down-regulation differed by 6.5-fold between the two diseases. Moreover, only vitiligo T cells were capable of efficient receptor down-regulation and IFN-gamma production in response to HLA-matched melanoma cells, suggesting that this difference in receptor affinity is physiologically relevant. The differences in receptor affinity and tumor reactivity were confirmed by analyzing Melan-A/MART-1-specific clones established from the two diseases. Our results suggest that the quality, and not the quantity, of the melanocyte-specific cytotoxic responses differs between the two pathologies. 相似文献
7.
Clio Mamalaki Marianna Murdjeva Mauro Tolaini Trisha Norton Phillip Chandler Alain Townsend Elizabeth Simpson Dimitris Kioussis 《Clinical & developmental immunology》1995,4(4):299-315
Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed
with transgenic mice expressing the cognate antigenic protein under the control of the H-
2Kb promoter. Double-transgenic mice show negative selection of thymocytes at the
CD4+8+TCR10 to CD4+8+TCRhi transition stage. A few CD8 T cells, however, escape clonal
deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of
the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do
not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can
develop low but detectable levels of antigen-specific cytotoxic function after stimulation
in vitro in the presence of IL-2. 相似文献
8.
The use of HLA transgenic mice in models of immunity and diseaseassumes that human MHC molecules are able to contribute towardthe positive selection of the mouse TCR repertoire. As an initialstep towards analysis of this we have compared the relativeability of DR/Eß or E/Eß complexes to induceT cell receptor (TCR) positive selection in H-2Ea and HLA-DRAtransgenic mice lacking endogenous E. The results show that,like E/Eß, the hybrid DR/ß complexes arecapable of mediating positive selection of Vß2+;,Vß6+, and Vß10+ cells. However, differenceswere found between the effects of the two transgenes. Thus,while Vß6+ cells were efficiently selected in bothH-2Ea and DRA transgenic mice, positive selection of Vß10+cells was less apparent in the DRA transgenic mice. Variationbetween Ea and DRA transgenic mice is consistent with the notionthat this process is dependent on differential binding of endogenouspeptides to the E/Eß and DR/Eß complexes.Furthermore, contrary to expectations, in neither set of micewas positive selection limited solely to the CD4+ subset. Thus,examples were found in which Vß-specific positiveselection was confined to either the CD4+ or CD8+ subsets, andothers in which both subpopulations were concomltantly increased.In the case of Vß2 positive selection, H-2Ea transgenicmice showed expansion of these cells in both the CD4+ and CD8+subpopulations whlle in DRA transgenic mice this occurred predominantlyin the CD8+ subpopulatlon. 相似文献
9.
TCR repertoire in early fetal mouse thymus 总被引:1,自引:0,他引:1
Ohki-Hamazaki Hiroko; Makino Yasuhiko; Kanno Masamoto; Koseki Haruhiko; Akasaka Takeshi; Taniguchi Masaru 《International immunology》1995,7(3):493-499
We investigated the rearrangement and expression of TCR genesin mouse fetal thymus organ culture, a system that avoids subsequententry of hematopoietic precursor cells. The first observablerearranged TCR gene was homogeneous V2-J2, detectable as earlyas fetal day 11 (d11) in the thymic primordla. The productiveTCR was homogeneous V5-J1, first detectable in d13 thymocytes,followed by adult-type TCR (V4 and V7). Sequence analysis ofTCR revealed five types of V-J junctional sequences. In thevery early stage, a homogeneous V-J junction is generated viaa short homology sequence in the coding region (Type I), whilea short homology sequence in the P-nucleotlde rather than thecoding region is used in the following stage (Type II). In thelater embryonic stages, diverse V-J junctions are generatedby well-known mechanisms, such as P-nucleotide (Type III), N-regioninsertion (Type IV) or trimming of the coding ends (Type V).These findings suggest that the generation of homogeneous TCR (V2 and V5) in the early fetal stages is due to the intrinsicrearrangement mechanisms and is in stage specific manner. 相似文献