全文获取类型
收费全文 | 910篇 |
免费 | 101篇 |
国内免费 | 2篇 |
出版年
2021年 | 18篇 |
2020年 | 8篇 |
2019年 | 13篇 |
2018年 | 14篇 |
2017年 | 15篇 |
2016年 | 23篇 |
2015年 | 47篇 |
2014年 | 40篇 |
2013年 | 54篇 |
2012年 | 50篇 |
2011年 | 53篇 |
2010年 | 24篇 |
2009年 | 27篇 |
2008年 | 39篇 |
2007年 | 26篇 |
2006年 | 48篇 |
2005年 | 31篇 |
2004年 | 30篇 |
2003年 | 30篇 |
2002年 | 27篇 |
2001年 | 19篇 |
2000年 | 13篇 |
1999年 | 12篇 |
1998年 | 8篇 |
1992年 | 10篇 |
1991年 | 10篇 |
1990年 | 11篇 |
1989年 | 17篇 |
1988年 | 14篇 |
1987年 | 13篇 |
1986年 | 17篇 |
1985年 | 14篇 |
1984年 | 13篇 |
1983年 | 9篇 |
1982年 | 14篇 |
1980年 | 9篇 |
1979年 | 8篇 |
1978年 | 12篇 |
1977年 | 15篇 |
1976年 | 7篇 |
1975年 | 7篇 |
1974年 | 14篇 |
1973年 | 11篇 |
1972年 | 10篇 |
1971年 | 9篇 |
1970年 | 6篇 |
1969年 | 9篇 |
1968年 | 8篇 |
1967年 | 10篇 |
1966年 | 6篇 |
排序方式: 共有1013条查询结果,搜索用时 46 毫秒
51.
52.
Brett D. Welch Ping Yuan Sayantan Bose Christopher A. Kors Robert A. Lamb Theodore S. Jardetzky 《PLoS pathogens》2013,9(8)
Paramyxoviruses cause a wide variety of human and animal diseases. They infect host cells using the coordinated action of two surface glycoproteins, the receptor binding protein (HN, H, or G) and the fusion protein (F). HN binds sialic acid on host cells (hemagglutinin activity) and hydrolyzes these receptors during viral egress (neuraminidase activity, NA). Additionally, receptor binding is thought to induce a conformational change in HN that subsequently triggers major refolding in homotypic F, resulting in fusion of virus and target cell membranes. HN is an oligomeric type II transmembrane protein with a short cytoplasmic domain and a large ectodomain comprising a long helical stalk and large globular head domain containing the enzymatic functions (NA domain). Extensive biochemical characterization has revealed that HN-stalk residues determine F specificity and activation. However, the F/HN interaction and the mechanisms whereby receptor binding regulates F activation are poorly defined. Recently, a structure of Newcastle disease virus (NDV) HN ectodomain revealed the heads (NA domains) in a “4-heads-down” conformation whereby two of the heads form a symmetrical interaction with two sides of the stalk. The interface includes stalk residues implicated in triggering F, and the heads sterically shield these residues from interaction with F (at least on two sides). Here we report the x-ray crystal structure of parainfluenza virus 5 (PIV5) HN ectodomain in a “2-heads-up/2-heads-down” conformation where two heads (covalent dimers) are in the “down position,” forming a similar interface as observed in the NDV HN ectodomain structure, and two heads are in an “up position.” The structure supports a model in which the heads of HN transition from down to up upon receptor binding thereby releasing steric constraints and facilitating the interaction between critical HN-stalk residues and F. 相似文献
53.
Chana Borjigin Rhiannon K. Schilling Jayakumar Bose Maria Hrmova Jiaen Qiu Stefanie Wege Apriadi Situmorang Caitlin Byrt Chris Brien Bettina Berger Matthew Gilliham Allison S. Pearson Stuart J. Roy 《Plant, cell & environment》2020,43(9):2158-2171
Improving salinity tolerance in the most widely cultivated cereal, bread wheat (Triticum aestivum L.), is essential to increase grain yields on saline agricultural lands. A Portuguese landrace, Mocho de Espiga Branca accumulates up to sixfold greater leaf and sheath sodium (Na+) than two Australian cultivars, Gladius and Scout, under salt stress in hydroponics. Despite high leaf and sheath Na+ concentrations, Mocho de Espiga Branca maintained similar salinity tolerance compared to Gladius and Scout. A naturally occurring single nucleotide substitution was identified in the gene encoding a major Na+ transporter TaHKT1;5-D in Mocho de Espiga Branca, which resulted in a L190P amino acid residue variation. This variant prevents Mocho de Espiga Branca from retrieving Na+ from the root xylem leading to a high shoot Na+ concentration. The identification of the tissue-tolerant Mocho de Espiga Branca will accelerate the development of more elite salt-tolerant bread wheat cultivars. 相似文献
54.
55.
56.
Sayantan Bose Carissa M. Heath Priya A. Shah Maher Alayyoubi Theodore S. Jardetzky Robert A. Lamb 《Journal of virology》2013,87(24):13520-13531
Paramyxovirus membrane glycoproteins F (fusion protein) and HN, H, or G (attachment protein) are critical for virus entry, which occurs through fusion of viral and cellular envelopes. The F protein folds into a homotrimeric, metastable prefusion form that can be triggered by the attachment protein to undergo a series of structural rearrangements, ultimately folding into a stable postfusion form. In paramyxovirus-infected cells, the F protein is activated in the Golgi apparatus by cleavage adjacent to a hydrophobic fusion peptide that inserts into the target membrane, eventually bringing the membranes together by F refolding. However, it is not clear how the attachment protein, known as HN in parainfluenza virus 5 (PIV5), interacts with F and triggers F to initiate fusion. To understand the roles of various F protein domains in fusion triggering and metastability, single point mutations were introduced into the PIV5 F protein. By extensive study of F protein cleavage activation, surface expression, and energetics of fusion triggering, we found a role for an immunoglobulin-like (Ig-like) domain, where multiple hydrophobic residues on the PIV5 F protein may mediate F-HN interactions. Additionally, destabilizing mutations of PIV5 F that resulted in HN trigger-independent mutant F proteins were identified in a region along the border of F trimer subunits. The positions of the potential HN-interacting region and the region important for F stability in the lower part of the PIV5 F prefusion structure provide clues to the receptor-binding initiated, HN-mediated F trigger. 相似文献
57.
Annalisa Cavallini Suzanne Brewerton Amanda Bell Samantha Sargent Sarah Glover Clare Hardy Roger Moore John Calley Devaki Ramachandran Michael Poidinger Eric Karran Peter Davies Michael Hutton Philip Szekeres Suchira Bose 《The Journal of biological chemistry》2013,288(32):23331-23347
Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies. 相似文献
58.
59.
SpoIIIE directionally pumps DNA across membranes during Bacillus subtilis sporulation and vegetative growth. The sequence-reading domain (γ domain) is required for directional DNA transport, and its deletion severely impairs sporulation. We selected suppressors of the spoIIIEΔγ sporulation defect. Unexpectedly, many suppressors were intragenic missense mutants, and some restore sporulation to near-wild-type levels. The mutant proteins are likely not more abundant, faster at translocating DNA, or sequence-sensitive, and rescue does not involve the SpoIIIE homolog SftA. Some mutants behave differently when co-expressed with spoIIIEΔγ, consistent with the idea that some, but not all, variants may form mixed oligomers. In full-length spoIIIE, these mutations do not affect sporulation, and yet the corresponding residues are rarely found in other SpoIIIE/FtsK family members. The suppressors do not rescue chromosome translocation defects during vegetative growth, indicating that the role of the γ domain cannot be fully replaced by these mutations. We present two models consistent with our findings: that the suppressors commit to transport in one arbitrarily-determined direction or delay spore development. It is surprising that missense mutations somehow rescue loss of an entire domain with a complex function, and this raises new questions about the mechanism by which SpoIIIE pumps DNA and the roles SpoIIIE plays in vivo. 相似文献
60.
Ahtesham Hussain Mukesh Kumar Yadav Shambhunath Bose Jing-Hua Wang Dongwoo Lim Yun-Kyung Song Seong-Gyu Ko Hojun Kim 《PloS one》2016,11(11)
BackgroundObesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer.