全文获取类型
收费全文 | 461篇 |
免费 | 48篇 |
国内免费 | 5篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 18篇 |
妇产科学 | 4篇 |
基础医学 | 70篇 |
口腔科学 | 1篇 |
临床医学 | 50篇 |
内科学 | 116篇 |
皮肤病学 | 18篇 |
神经病学 | 47篇 |
特种医学 | 21篇 |
外科学 | 48篇 |
综合类 | 1篇 |
预防医学 | 42篇 |
眼科学 | 2篇 |
药学 | 29篇 |
肿瘤学 | 46篇 |
出版年
2024年 | 2篇 |
2023年 | 7篇 |
2022年 | 18篇 |
2021年 | 37篇 |
2020年 | 24篇 |
2019年 | 33篇 |
2018年 | 42篇 |
2017年 | 27篇 |
2016年 | 24篇 |
2015年 | 22篇 |
2014年 | 33篇 |
2013年 | 38篇 |
2012年 | 50篇 |
2011年 | 47篇 |
2010年 | 20篇 |
2009年 | 25篇 |
2008年 | 18篇 |
2007年 | 13篇 |
2006年 | 10篇 |
2005年 | 6篇 |
2004年 | 8篇 |
2003年 | 3篇 |
2002年 | 5篇 |
1973年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有514条查询结果,搜索用时 15 毫秒
1.
Cromb Amandine Le Loarer Franois Sitbon Maxime Italiano Antoine Stoeckle Eberhard Buy Xavier Kind Michle 《European radiology》2020,30(5):2413-2424
European Radiology - The strongest adverse prognostic factor in myxoid/round cell liposarcomas (MRC-LPS) is the presence of a round cell component above 5% within the tumor bulk. Its identification... 相似文献
2.
3.
Barriers and Facilitators to Participation in Health Screening: an Umbrella Review Across Conditions
Le Bonniec Alice Sun Sophie Andrin Amandine Dima Alexandra L. Letrilliart Laurent 《Prevention science》2022,23(7):1115-1142
Prevention Science - Screening is an essential prevention practice for a number of health conditions. However, screening coverage remains generally low. Studies that investigate determinants of... 相似文献
4.
5.
6.
7.
Maxence Meyer MD Lidia Calabrese MD Anita Meyer MD Florentin Constancias PhD Louise F. Porter MD PhD Marion Muller Manon Leitner Amandine Leitner Antonin Michaud Georges Kaltenbach MD PhD Elise Schmitt MD PhD Patrick Karcher MD Erik Sauleau MD PhD Saïd Chayer PhD HDR Floriane Zeyons MD Marianne Riou MD Soraya El Ghannudi Abdo MD Frédéric Blanc MD PhD Samira Fafi-Kremer PharmD PhD Aurélie Velay PharmD PhD Thomas Vogel MD PhD 《Journal of the American Geriatrics Society》2021,69(5):1167-1170
8.
9.
Michelle L. Parker Diana M. Penarete-Vargas Phineas T. Hamilton Amandine Guérin Jitender P. Dubey Steve J. Perlman Furio Spano Maryse Lebrun Martin J. Boulanger 《Proceedings of the National Academy of Sciences of the United States of America》2016,113(2):398-403
Plasmodium falciparum and Toxoplasma gondii are widely studied parasites in phylum Apicomplexa and the etiological agents of severe human malaria and toxoplasmosis, respectively. These intracellular pathogens have evolved a sophisticated invasion strategy that relies on delivery of proteins into the host cell, where parasite-derived rhoptry neck protein 2 (RON2) family members localize to the host outer membrane and serve as ligands for apical membrane antigen (AMA) family surface proteins displayed on the parasite. Recently, we showed that T. gondii harbors a novel AMA designated as TgAMA4 that shows extreme sequence divergence from all characterized AMA family members. Here we show that sporozoite-expressed TgAMA4 clusters in a distinct phylogenetic clade with Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) proteins and forms a high-affinity, functional complex with its coevolved partner, TgRON2L1. High-resolution crystal structures of TgAMA4 in the apo and TgRON2L1-bound forms complemented with alanine scanning mutagenesis data reveal an unexpected architecture and assembly mechanism relative to previously characterized AMA–RON2 complexes. Principally, TgAMA4 lacks both a deep surface groove and a key surface loop that have been established to govern RON2 ligand binding selectivity in other AMAs. Our study reveals a previously underappreciated level of molecular diversity at the parasite–host-cell interface and offers intriguing insight into the adaptation strategies underlying sporozoite invasion. Moreover, our data offer the potential for improved design of neutralizing therapeutics targeting a broad range of AMA–RON2 pairs and apicomplexan invasive stages.Phylum Apicomplexa comprises >5,000 parasitic protozoan species, many of which cause devastating diseases on a global scale. Two of the most prevalent species are Toxoplasma gondii and Plasmodium falciparum, the causative agents of toxoplasmosis and severe human malaria, respectively (1, 2). The obligate intracellular apicomplexan parasites lead complex and diverse lifestyles that require invasion of many different cell types. Despite this diversity of target host cells, most apicomplexans maintain a generally conserved mechanism for active invasion (3). The parasite initially glides over the surface of a host cell and then reorients to place its apical end in close contact to the host-cell membrane. After this initial attachment, a circumferential ring of adhesion (termed the moving or tight junction) is formed, through which the parasite actively propels itself while concurrently depressing the host-cell membrane to create a nascent protective vacuole (4).Formation of the moving junction relies on a pair of highly conserved parasite proteins: rhoptry neck protein 2 (RON2) and apical membrane antigen 1 (AMA1). Initially, parasites discharge RON2 into the host cell membrane where an extracellular portion (domain 3; D3) serves as a ligand for AMA1 displayed on the parasite surface (5–8). Intriguingly, recent studies have shown that the AMA1–RON2 complex is an attractive target for therapeutic intervention (9–12). The importance of the AMA1–RON2 pairing is also reflected in the observation that many apicomplexan parasites encode functional paralogs that are generally expressed in a stage-specific manner (13–15). We recently showed that, in addition to AMA1 and RON2, T. gondii harbors three additional AMA paralogs and two additional RON2 paralogs (14, 15): TgAMA2 forms a functional invasion complex with TgRON2 (15), TgAMA3 (also annotated as SporoAMA1) selectively coordinates TgRON2L2 (14), and TgAMA4 binds TgRON2L1 (15). Despite substantial sequence divergence, structural characterization of all AMA–RON2D3 complexes solved to date [TgAMA1–TgRON2D3 (16), PfAMA1–PfRON2D3 (17), and TgAMA3–TgRON2L2D3 (14)] reveal a largely conserved architecture and binding paradigm. Intriguingly, however, sequence analysis indicates that TgAMA4 and TgRON2L1 are likely to adopt substantially divergent structures with an atypical assembly mechanism.To investigate the functional implications of the AMA4–RON2L1 complex in T. gondii, we first established that TgAMA4 is part of a highly divergent AMA clade that includes the functionally important malaria vaccine candidate Plasmodium merozoite apical erythrocyte-binding ligand (MAEBL) (18–20) and that TgRON2L1 displays a similar divergence consistent with coevolution of receptor and ligand. We then show that TgAMA4 and TgRON2L1 form a high-affinity binary complex and probe its overall architecture and underlying mechanism of assembly using crystal structures of TgAMA4 in the apo and TgRON2L1D3 bound forms. Finally, we show proof of principle that TgAMA4 and TgRON2L1 form a functional pairing capable of supporting host-cell invasion. Collectively, our study reveals exceptional molecular diversity at the parasite–host-cell interface that we discuss in the context of the unique invasion barriers encountered by the sporozoite. 相似文献
10.
Aliya Ishmukhametova Jian‐Min Chen Rafaëlle Bernard Bernard de Massy Frédéric Baudat Amandine Boyer Déborah Méchin Delphine Thorel Brigitte Chabrol Marie‐Claire Vincent Mireille Claustres Sylvie Tuffery‐Giraud 《Human mutation》2013,34(8):1080-1084
Pathogenic complex genomic rearrangements are being increasingly characterized at the nucleotide level, providing unprecedented opportunities to evaluate the complexities of mutational mechanisms. Here, we report the molecular characterization of a complex duplication–triplication rearrangement involving exons 45–60 of the DMD gene. Inverted repeats facilitated this complex rearrangement, which shares common genomic organization with the recently described duplication‐inverted triplication–duplication (DUP–TRP/INV‐DUP) events; specifically, a 690‐kb region comprising DMD exons from 45 to 60 was duplicated in tandem, and another 46‐kb segment containing exon 51 was inserted inversely in between them. Taking into consideration (1) the presence of a predicted PRDM9 binding site in the near vicinity of the junction involving two inverted L1 elements and (2) the inherent properties of X–Y chromosome recombination during male meiosis, we proposed an alternative two‐step model for the generation of this X‐linked DMD DUP–TRP/INV‐DUP event. 相似文献