全文获取类型
收费全文 | 18269篇 |
免费 | 1260篇 |
国内免费 | 72篇 |
学科分类
医药卫生 | 19601篇 |
出版年
2023年 | 116篇 |
2022年 | 98篇 |
2021年 | 462篇 |
2020年 | 306篇 |
2019年 | 446篇 |
2018年 | 515篇 |
2017年 | 342篇 |
2016年 | 364篇 |
2015年 | 450篇 |
2014年 | 619篇 |
2013年 | 839篇 |
2012年 | 1332篇 |
2011年 | 1347篇 |
2010年 | 776篇 |
2009年 | 665篇 |
2008年 | 1126篇 |
2007年 | 1194篇 |
2006年 | 1176篇 |
2005年 | 1106篇 |
2004年 | 1008篇 |
2003年 | 959篇 |
2002年 | 952篇 |
2001年 | 138篇 |
2000年 | 118篇 |
1999年 | 154篇 |
1998年 | 165篇 |
1997年 | 132篇 |
1996年 | 129篇 |
1995年 | 117篇 |
1994年 | 115篇 |
1993年 | 97篇 |
1992年 | 97篇 |
1991年 | 99篇 |
1990年 | 85篇 |
1989年 | 70篇 |
1988年 | 80篇 |
1987年 | 86篇 |
1986年 | 67篇 |
1985年 | 97篇 |
1984年 | 98篇 |
1983年 | 94篇 |
1982年 | 110篇 |
1981年 | 121篇 |
1980年 | 106篇 |
1979年 | 61篇 |
1978年 | 75篇 |
1977年 | 87篇 |
1976年 | 59篇 |
1975年 | 48篇 |
1974年 | 52篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
1.
Dongbing Lai Emma C. Johnson Sarah Colbert Gayathri Pandey Grace Chan Lance Bauer Meredith W. Francis Victor Hesselbrock Chella Kamarajan John Kramer Weipeng Kuang Sally Kuo Samuel Kuperman Yunlong Liu Vivia McCutcheon Zhiping Pang Martin H. Plawecki Marc Schuckit Jay Tischfield Leah Wetherill Yong Zang Howard J. Edenberg Bernice Porjesz Arpana Agrawal Tatiana Foroud 《Alcoholism, clinical and experimental research》2022,46(3):374-383
2.
Penelas Alice Gonçalves da Silva Eduardo Moreira Fedozzi Julia Mattos Alves Amanda Cypriano Orem Paulo Roberto Barros Poskus Laiza Tatiana Feitosa Victor Pinheiro Guimarães José Guilherme Antunes 《Odontology / the Society of the Nippon Dental University》2022,110(3):569-576
Odontology - This study aimed at evaluating the influence of glass-fiber post (GFP) relining with composites of different opacities on resin cement layer thickness (CLT), bond strength (BS) to root... 相似文献
3.
Glutathione S-transferase Polymorphisms in Head and Neck Squamous Cell Carcinoma Treated with Chemotherapy and/or Radiotherapy 下载免费PDF全文
Mauricio Pereira ManigliaAnelise RussoPatrícia Matos Biselli-ChicoteJuliana Garcia de Oliveira-CucoloGabriela Helena Rodrigues-Flemingjosé Victor -ManigliaÉrika Cristina PavarinoEny Maria Goloni-Bertollo 《Asian Pacific journal of cancer prevention》2020,21(6):1637-1644
Background/Aim: The Glutathione S-transferases (GSTs) are important carcinogen-metabolizing enzymes. Polymorphisms involved in these enzymes can modulate the development and treatment of head and neck cancer. To investigate the association of GSTs polymorphisms with head and neck cancer and risk factors, clinical-pathological features, and survival time of the patients treated with chemotherapy and/or radiotherapy. Methods: The GST gene polymorphisms were evaluated in 197 cases and 514 controls by PCR-RFLP-Polymerase Chain Reaction Restriction Fragment Length Polymorphism. Results: The GSTP-313 was associated with a decreased risk for HNSCC (p=0.050). The GSTP1 haplotype analysis revealed a higher frequency of the AC and AT haplotypes in the case group than in the control group (p=0.013 and p=0.019, respectively), and the opposite for G-C haplotype (p = 0.015). Yet, the different combinations between the genotypes were associated with an increased risk of cancer. The study showed no association between the polymorphisms and primary tumor site, clinical-pathological characteristics, treatment (chemotherapy and/or radiotherapy) and survival time of the patients. Conclusion: The GST polymorphisms combination showed an increased risk for carcinogenesis, and studies with larger casuistry can contribute to the clarification of the role in individual patient differences for the response to chemotherapy and/or radiotherapy and identify biomarkers of susceptibility. 相似文献
4.
5.
6.
7.
8.
Lorena Martin-Morales Sara Manzano Maria Rodrigo-Faus Adrian Vicente-Barrueco Victor Lorca Gonzalo Núñez-Moreno Paloma Bragado Almudena Porras Trinidad Caldes Pilar Garre Alvaro Gutierrez-Uzquiza 《International journal of cancer. Journal international du cancer》2023,152(2):283-297
Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future. 相似文献
9.
Rebecca K. Papas Benson N. Gakinya Michael M. Mwaniki Hana Lee Alfred K. Keter Steve Martino Debra A. Klein Tao Liu Michelle P. Loxley John E. Sidle Kathryn Schlaudt Tobista Nafula Victor M. Omodi Joyce B. Baliddawa Daniel W. Kinyanjui Stephen A. Maisto 《Addiction (Abingdon, England)》2021,116(2):305-318
10.
Yan Zhang Xiaoyun Pang Jian Li Jiashu Xu Victor W. Hsu Fei Sun 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(10)
The sorting nexin (SNX) family of proteins deform the membrane to generate transport carriers in endosomal pathways. Here, we elucidate how a prototypic member, SNX1, acts in this process. Performing cryoelectron microscopy, we find that SNX1 assembles into a protein lattice that consists of helical rows of SNX1 dimers wrapped around tubular membranes in a crosslinked fashion. We also visualize the details of this structure, which provides a molecular understanding of how various parts of SNX1 contribute to its ability to deform the membrane. Moreover, we have compared the SNX1 structure with a previously elucidated structure of an endosomal coat complex formed by retromer coupled to a SNX, which reveals how the molecular organization of the SNX in this coat complex is affected by retromer. The comparison also suggests insight into intermediary stages of assembly that results in the formation of the retromer-SNX coat complex on the membrane.Sorting nexins (SNXs) exist as a large family of proteins defined by the presence of a PX (phox homology) domain (1, 2). Members of this family have been found to act as coat proteins in endosomal pathways that include recycling from endosomes to the plasma membrane and retrieval from endosomes to the Golgi complex (3, 4). Defects in these transport processes is associated with various neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and Down’s syndrome (5, 6).Coat proteins assemble into complexes on the membrane to initiate intracellular transport pathways by coupling two main functions: bending the membrane to generate transport carriers and binding to cargoes for their sorting into these carriers (7). Retromer, a trimeric complex consisting of Vps26, Vps29, and Vps35, has been found to couple with different SNXs to form multiple endosomal coat complexes, in which select members of the SNX family act in membrane deformation while retromer acts in cargo recognition (8–17). Recently, a detailed molecular view of this functional cooperation has been achieved by elucidating the structure of a retromer-SNX complex on the membrane (18).Notably, it has been further discovered recently that an endosomal coat complex can be formed with only SNX members. SNX1/2 have been found to heterodimerize with SNX5/6 to form the endosomal SNX–BAR sorting complex for promoting exit 1 (ESCPE-1) complex, in which SNX1/2 are proposed to act in membrane deformation while SNX5/6 act in cargo recognition (19). As such, a key question has become whether SNX that acts in membrane deformation in this type of coat complex would be organized similarly on the membrane, as previously elucidated for SNX in the context of a retromer-SNX complex (18).One of the best characterized mechanisms of membrane deformation involves proteins that possess the BAR (Bin/Amphiphysin/Rvs) domain. This domain has been shown to undergo homodimerization to form a banana-shaped structure, which can impart membrane curvature through a scaffolding mechanism that involves electrostatic interactions between the positive charges lining the concave side of the curved BAR dimer and the negative charges that line the surface of the membrane bilayer. In some cases, the BAR domain can deform the membrane through a second mechanism, which involves the formation of an amphipathic helix that inserts into one leaflet of the membrane bilayer to generate bilayer asymmetry in driving membrane curvature (20, 21).Besides the PX domain, SNX1 also possesses a BAR domain. However, studies have found that its BAR domain is not sufficient in driving membrane deformation. Instead, the PX domain as well as the linker region between the BAR and PX domains are also needed (22, 23). As such, a key goal has been to achieve a better understanding of how the various parts of SNX1 contribute to its ability to deform the membrane.Structural studies, such as those involving crystallography and single-particle electron microscopy (EM), have been advancing a molecular understanding of coat proteins (24), including components of endosomal coats (17, 19, 22, 25–27). Notably, however, these approaches solve protein structures in solution, but the functional form of coat proteins involves their association with the membrane. In this study, we have pursued cryo-EM to reveal how SNX1 is organized on the membrane to explain its ability to deform the membrane. The result advances a molecular understanding of how an endosomal coat that contains only SNXs generates transport carriers. Moreover, by comparing our SNX1 structure to the previously solved retromer-SNX structure (18), we delineate the extent to which the molecular organization of SNX on the membrane is affected by the presence of retromer. This comparison also suggests insight into intermediary stages of coat assembly that form the retromer-SNX complex on the membrane. 相似文献