全文获取类型
收费全文 | 2397篇 |
免费 | 210篇 |
国内免费 | 1篇 |
专业分类
2608篇 |
出版年
2023年 | 12篇 |
2022年 | 31篇 |
2021年 | 70篇 |
2020年 | 28篇 |
2019年 | 56篇 |
2018年 | 51篇 |
2017年 | 45篇 |
2016年 | 70篇 |
2015年 | 115篇 |
2014年 | 124篇 |
2013年 | 192篇 |
2012年 | 215篇 |
2011年 | 211篇 |
2010年 | 145篇 |
2009年 | 99篇 |
2008年 | 152篇 |
2007年 | 140篇 |
2006年 | 133篇 |
2005年 | 127篇 |
2004年 | 116篇 |
2003年 | 105篇 |
2002年 | 97篇 |
2001年 | 14篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 13篇 |
1997年 | 10篇 |
1996年 | 13篇 |
1995年 | 16篇 |
1994年 | 9篇 |
1993年 | 20篇 |
1990年 | 4篇 |
1988年 | 3篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 11篇 |
1984年 | 6篇 |
1983年 | 12篇 |
1982年 | 11篇 |
1981年 | 4篇 |
1980年 | 9篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 7篇 |
1976年 | 9篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1971年 | 5篇 |
1966年 | 3篇 |
1965年 | 5篇 |
排序方式: 共有2608条查询结果,搜索用时 11 毫秒
91.
Athman R Fernandez MI Gounon P Sansonetti P Louvard D Philpott D Robine S 《Cellular microbiology》2005,7(8):1109-1116
Villin is an actin-binding protein present in intestinal and kidney brush borders. Villin has been shown to present in vitro Ca(2+)-dependent bundling and severing F-actin properties. The study of villin knock-out mice allowed us to show that while bundling of F-actin microfilaments is unaffected, this protein is important for the reorganization of the actin cytoskeleton elicited by various signals during both physiological and pathological conditions. Here, we studied the role of villin during infection by Shigella flexneri, the causative agent of bacillary dysentery. This bacterium induces the reorganization of the host actin cytoskeleton to penetrate into epithelial cells and spread from cell to cell. In vivo, we show that unlike newborn vil+/+ mice, which are sensitive to Shigella invasion, resulting in a destructive inflammatory response of the intestinal mucosa following intragastric inoculation, newborn vil-/- mice appear fully resistant to infection. Using primary cultures of intestinal epithelial cells derived from vil+/+ or vil -/- mice, we demonstrate that villin plays an essential role in S. flexneri entry and cell-to-cell dissemination. Villin expression is thus critical for Shigella infection through its ability to remodel the actin cytoskeleton. 相似文献
92.
Thorsten Klampfl Jelena D. Milosevic Ana Puda Andreas Sch?negger Klaudia Bagienski Tiina Berg Ashot S. Harutyunyan Bettina Gisslinger Elisa Rumi Luca Malcovati Daniela Pietra Chiara Elena Matteo Giovanni Della Porta Lisa Pieri Paola Guglielmelli Christoph Bock Michael Doubek Dana Dvorakova Nada Suvajdzic Dragica Tomin Natasa Tosic Zdenek Racil Michael Steurer Sonja Pavlovic Alessandro M. Vannucchi Mario Cazzola Heinz Gisslinger Robert Kralovics 《PloS one》2013,8(10)
Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized. 相似文献
93.
Georgios Ioannis Karras Marco Fumasoni Grzegorz Sienski Fabio Vanoli Dana Branzei Stefan Jentsch 《Molecular cell》2013,49(3):536-546
Highlights? 9-1-1 and Exo1 are components of the error-free RAD6 pathway ? 9-1-1 promotes postreplicative template switching ? Polyubiquitylated PCNA and 9-1-1 cooperate in the error-free RAD6 pathway ? 9-1-1’s role in the error-free RAD6 pathway is uncoupled from checkpoint functions 相似文献
94.
Noa Rappaport Simon Fishilevich Ron Nudel Michal Twik Frida Belinky Inbar Plaschkes Tsippi Iny Stein Dana Cohen Danit Oz-Levi Marilyn Safran Doron Lancet 《Biomedical engineering online》2017,16(1):72
Background
A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant-harboring genes are associated with a patient’s disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include GeneCards (human genes), MalaCards (human diseases) and PathCards (human pathways) together with additional tools, are presented with the focus on MalaCards utility for NGS interpretation as well as for large scale bioinformatic analyses.Results
VarElect, our NGS interpretation tool, leverages the broad information in the GeneCards suite databases. MalaCards algorithms unify disease-related terms and annotations from 69 sources. Further, MalaCards defines hierarchical relatedness—aliases, disease families, a related diseases network, categories and ontological classifications. GeneCards and MalaCards delineate and share a multi-tiered, scored gene-disease network, with stringency levels, including the definition of elite status—high quality gene-disease pairs, coming from manually curated trustworthy sources, that includes 4500 genes for 8000 diseases. This unique resource is key to NGS interpretation by VarElect. VarElect, a comprehensive search tool that helps infer both direct and indirect links between genes and user-supplied disease/phenotype terms, is robustly strengthened by the information found in MalaCards. The indirect mode benefits from GeneCards’ diverse gene-to-gene relationships, including SuperPaths—integrated biological pathways from 12 information sources. We are currently adding an important information layer in the form of “disease SuperPaths”, generated from the gene-disease matrix by an algorithm similar to that previously employed for biological pathway unification. This allows the discovery of novel gene-disease and disease–disease relationships. The advent of whole genome sequencing necessitates capacities to go beyond protein coding genes. GeneCards is highly useful in this respect, as it also addresses 101,976 non-protein-coding RNA genes. In a more recent development, we are currently adding an inclusive map of regulatory elements and their inferred target genes, generated by integration from 4 resources.Conclusions
MalaCards provides a rich big-data scaffold for in silico biomedical discovery within the gene-disease universe. VarElect, which depends significantly on both GeneCards and MalaCards power, is a potent tool for supporting the interpretation of wet-lab experiments, notably NGS analyses of disease. The GeneCards suite has thus transcended its 2-decade role in biomedical research, maturing into a key player in clinical investigation.95.
Teresa Sadras Mickaël Martin Kohei Kume Mark E. Robinson Supraja Saravanakumar Gal Lenz Zhengshan Chen Joo Y. Song Tanya Siddiqi Laura Oksa Anne Marie Knapp Jevon Cutler Kadriye Nehir Cosgun Lars Klemm Veronika Ecker Janet Winchester Dana Ghergus Pauline Soulas-Sprauel Markus Müschen 《Molecular cell》2021,81(10):2094-2111.e9
96.
97.
David I. Shapiro-Ilan George N. Mbata Khuong B. Nguyen Scott M. Peat Dana Blackburn Byron J. Adams 《Biological Control》2009,51(3):377-387
Our objective was to estimate the biocontrol potential of the recently discovered entomopathogenic nematode species Heterorhabditis georgiana (Kesha strain). Additionally, we conducted a phylogenetic characterization of the nematode’s symbiotic bacterium. In laboratory experiments, we compared H. georgiana to other entomopathogenic nematodes for virulence, environmental tolerance (to heat, desiccation, and cold), and host seeking ability. Virulence assays targeted Acheta domesticus, Agrotis ipsilon, Diaprepes abbreviatus, Musca domestica, Plodia interpunctella, Solenopsis invicta, and Tenebrio molitor. Each assay included H. georgiana and five or six of the following species: Heterorhabditis floridensis, Heterorhabditis indica, Heterorhabditis mexicana, Steinernema carpocapsae, Steinernema feltiae, Steinernema rarum, and Steinernema riobrave. Environmental tolerance assays included Heterorhabditis bacteriophora, H. georgiana, H. indica, S. carpocapsae, S. feltiae, and S. riobrave (except cold tolerance did not include S. carpocapsae or S. riobrave). Host seeking ability was assessed in H. bacteriophora, H. georgiana, S. carpocapsae, and Steinernema glaseri, all of which showed positive orientation to the host with S. glaseri having greater movement toward the host than S. carpocapsae (and the heterorhabditids being intermediate). Temperature range data (tested at 10, 13, 17, 25, 30 and 35 °C) indicated that H. georgiana can infect Galleria mellonella between 13 and 35 °C (with higher infection at 17–30 °C), and could reproduce between 17 and 30 °C (with higher nematode yields at 25 °C). Compared with other nematode species, H. georgiana expressed low or intermediate capabilities in all virulence and environmental tolerance assays indicating a relatively low biocontrol potential. Some novel observations resulted from comparisons among other species tested. In virulence assays, H. indica caused the highest mortality in P. interpunctella followed by S. riobrave; S. carpocapsae caused the highest mortality in A. domesticus followed by H. indica; and S. riobrave was the most virulent nematode to S. invicta. In cold tolerance, S. feltiae exhibited superior ability to cause mortality in G. mellonella (100%) at 10 °C, yet H. bacteriophora and H. georgiana exhibited the ability to produce attenuated infections at 10 °C, i.e., the infections resumed and produced mortality at 25 °C. In contrast, H. indica did not show an ability to cause attenuated infections. Based on the phylogenetic analysis, the bacterium associated with H. georgiana was identified as Photorhabdus luminescens akhurstii. 相似文献
98.
Sreedevi Lalithambika Landon Peterson Karl Dana Paul Blum 《Applied and environmental microbiology》2012,78(22):7931-7938
Extremely thermoacidophilic microbes, such as Sulfolobus solfataricus, are strict chemoheterotrophs despite their geologic niche. To clarify their ecophysiology, the overlapping roles of endoglucanases and carbohydrate transporters were examined during growth on soluble cellodextrins as the sole carbon and energy source. Strain-specific differences in genome structure implied a unique role for one of three endogenous endoglucanases. Plasmid-based endoglucanase expression promoted the consumption of oligosaccharides, including cellohexaose (G6) through cellonanaose (G9). Protein transporters required for cellodextrin uptake were identified through mutagenesis and complementation of an ABC transporter cassette, including a putative oligosaccharide binding protein. In addition, ablation of the binding protein compromised growth on glucose and alpha-linked oligosaccharides while inactivation of a previously described glucose transporter had no apparent impact. These data demonstrate that S. solfataricus employs a redundant mechanism for soluble cellodextrin catabolism having both substrate uptake and extracytoplasmic hydrolytic components. 相似文献
99.
Susanne Pahlow Anne März Barbara Seise Katharina Hartmann Isabel Freitag Evelyn Kämmer René Böhme Volker Deckert Karina Weber Dana Cialla Jürgen Popp 《Engineering in Life Science》2012,12(2):131-143
Due to its fingerprint specificity and trace‐level sensitivity, surface‐enhanced Raman spectroscopy (SERS) is an attractive tool in bioanalytics. This review reflects the research in this highly interesting topic of the last 3–4 years. The detection of the SERS signature of biomolecules up to microorganisms and cells is introduced. Labeling using modified nanoparticles (SERS tags) is also introduced. In order to establish biomedical applications, SERS analysis is performed in complex matrices such as body fluids. Furthermore, the SERS technique is combined with other methods such as microfluidic devices for online monitoring and scanning probe microscopy (i.e. tip‐enhanced Raman spectroscopy, TERS) to investigate nanoscaled features. The present review illustrates the broad application fields of SERS and TERS in bioanalytics and shows the great potential of these methods for biomedical diagnostics. 相似文献
100.
Bowen DG Shoukry NH Grakoui A Fuller MJ Cawthon AG Dong C Hasselschwert DL Brasky KM Freeman GJ Seth NP Wucherpfennig KW Houghton M Walker CM 《Journal of virology》2008,82(10):5109-5114
The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function. This animal model should facilitate studies of whether PD-1 differentially influences effector and memory T-cell function in resolved versus persistent human infections. 相似文献