全文获取类型
收费全文 | 368篇 |
免费 | 22篇 |
专业分类
390篇 |
出版年
2022年 | 5篇 |
2021年 | 5篇 |
2020年 | 5篇 |
2018年 | 8篇 |
2017年 | 4篇 |
2016年 | 8篇 |
2015年 | 24篇 |
2014年 | 19篇 |
2013年 | 26篇 |
2012年 | 24篇 |
2011年 | 29篇 |
2010年 | 15篇 |
2009年 | 10篇 |
2008年 | 19篇 |
2007年 | 22篇 |
2006年 | 24篇 |
2005年 | 22篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 7篇 |
2001年 | 2篇 |
1998年 | 4篇 |
1996年 | 7篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1980年 | 3篇 |
1978年 | 3篇 |
1973年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1964年 | 2篇 |
1963年 | 1篇 |
1962年 | 2篇 |
1961年 | 3篇 |
1959年 | 1篇 |
1958年 | 1篇 |
1957年 | 2篇 |
1921年 | 1篇 |
排序方式: 共有390条查询结果,搜索用时 15 毫秒
91.
92.
Ye Han Iredia D. Iyamu Matthew R. Clutter Rama K. Mishra Kyle A. Lyman Chengwen Zhou Ioannis Michailidis Maya Y. Xia Horrick Sharma Chi-Hao Luan Gary E. Schiltz Dane M. Chetkovich 《The Journal of biological chemistry》2022,298(7)
Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide–gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat–containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress. Here, we utilize a high-throughput virtual screen to find small molecules capable of disrupting the TRIP8b–HCN interaction. We found that the hit compound NUCC-0200590 disrupts the TRIP8b–HCN interaction in vitro and in vivo. These results provide a compelling strategy for developing new small molecules capable of disrupting the TRIP8b–HCN interaction. 相似文献
93.
94.
Andrea Beam Dane Goede Andrew Fox Mary Jane McCool Goldlin Wall Charles Haley Robert Morrison 《PloS one》2015,10(12)
This study describes a spring 2013 outbreak of porcine epidemic diarrhea virus (PEDv), using data from 222 swine sites in 14 counties area in 4 contiguous states in the United States. During the outbreak, the premises-level incidence of PEDv was 40.5 percent (90/222 sites). One of the three companies from which data were collected had a lower incidence (19.5 percent) than the other two companies (41.1 and 47.2 percent). Sow sites had the highest incidence of PEDv during the outbreak (80.0 percent). Spatial analysis showed that PEDv was clustered rather than randomly distributed, which suggested that sites near a positive site had increased risk of acquiring PEDv infection. Meteorological data were used to investigate the hypothesis that PEDv was spread by air. If airborne dissemination played a role in this outbreak, we would expect the direction of disease spread to correlate with the predominant wind direction. Two methods were used to determine the direction of disease spread—linear direction mean analysis in ArcGIS and the direction test in ClusterSeer. The former method indicated PEDv spread was south to slightly southwest, and the latter indicated spread was to the southeast. The predominant wind direction during the month of the outbreak was toward the south, with some southeast and southwest winds; the strongest wind gusts were toward the southwest. These findings support the hypothesis that PEDv was spread by air. The results, however, should be interpreted cautiously because we did not have information on direct and indirect contacts between sites, such as movement of trucks, feed, pigs or people. These types of contacts should be evaluated before pathogen spread is attributed to airborne mechanisms. Although this study did not provide a definitive assessment of airborne spread of PEDv, we believe the findings justify additional research to investigate this potential mechanism of transmission. 相似文献
95.
96.
97.
Harald Rouha Adriana Badarau Zehra C Visram Michael B Battles Bianka Prinz Zoltán Magyarics Gábor Nagy Irina Mirkina Lukas Stulik Manuel Zerbs Michaela J?gerhofer Barbara Maierhofer Astrid Teubenbacher Ivana Dolezilkova Karin Gross Srijib Banerjee Gerhild Zauner Stefan Malafa Jakub Zmajkovic Sabine Maier Robert Mabry Eric Krauland K Dane Wittrup Tillman U Gerngross Eszter Nagy 《MABS-AUSTIN》2015,7(1):243-254
Staphylococcus aureus is a major human pathogen associated with high mortality. The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial cytotoxins involved in the pathogenesis of S. aureus call for novel therapeutic approaches, such as passive immunization with monoclonal antibodies (mAbs). The complexity of staphylococcal pathogenesis and past failures with single mAb products represent considerable barriers for antibody-based therapeutics. Over the past few years, efforts have focused on neutralizing α-hemolysin. Recent findings suggest that the concerted actions of several cytotoxins, including the bi-component leukocidins play important roles in staphylococcal pathogenesis. Therefore, we aimed to isolate mAbs that bind to multiple cytolysins by employing high diversity human IgG1 libraries presented on the surface of yeast cells. Here we describe cross-reactive antibodies with picomolar affinity for α-hemolysin and 4 different bi-component leukocidins that share only ∼26% overall amino acid sequence identity. The molecular basis of cross-reactivity is the recognition of a conformational epitope shared by α-hemolysin and F-components of gamma-hemolysin (HlgAB and HlgCB), LukED and LukSF (Panton-Valentine Leukocidin). The amino acids predicted to form the epitope are conserved and known to be important for cytotoxic activity. We found that a single cross-reactive antibody prevented lysis of human phagocytes, epithelial and red blood cells induced by α-hemolysin and leukocidins in vitro, and therefore had superior effectiveness compared to α-hemolysin specific antibodies to protect from the combined cytolytic effect of secreted S. aureus toxins. Such mAb afforded high levels of protection in murine models of pneumonia and sepsis. 相似文献
98.
99.
100.
Selection of highly productive hosts for protein expression is a significant component of bioprocess design. As an alternative to traditional plate, halo, and suppression-based screens, we describe a high-throughput, flow cytometric assay, the Cell Surface Secretion Assay (CeSSA), that can be used to select for improved heterologous protein secretion from a population of S. cerevisiae mutants. A ligand is covalently attached to the cell surface via a PEG linker, and as cells secrete a protein that binds the tethered ligand, the protein is captured on the surface where it can be labeled and the cells sorted using flow cytometry. This report describes three different protein/ligand interactions that have been demonstrated with this system. Single-pass sorting enrichments from 23- to 54-fold have been validated in the separation of a 3-fold higher secretor from a background population of wild-type secretors making this system applicable to large library screening (10(8) clones). A mathematical model was developed to improve the parameters of the assay further. The model was validated with time course data and predicts an optimal screening window. The model also predicts a 60-fold enrichment rate for the validation experiment described above. With the development of this selection system, limitations presented by traditional, particularly plate-based, secretion assays can be overcome so that a larger search space can be examined under conditions closer to the growth physiology experienced by cells in fermentors. 相似文献