全文获取类型
收费全文 | 418篇 |
免费 | 55篇 |
出版年
2022年 | 1篇 |
2021年 | 2篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 8篇 |
2016年 | 9篇 |
2015年 | 18篇 |
2014年 | 23篇 |
2013年 | 29篇 |
2012年 | 31篇 |
2011年 | 29篇 |
2010年 | 33篇 |
2009年 | 19篇 |
2008年 | 31篇 |
2007年 | 31篇 |
2006年 | 21篇 |
2005年 | 36篇 |
2004年 | 24篇 |
2003年 | 34篇 |
2002年 | 23篇 |
2001年 | 4篇 |
2000年 | 4篇 |
1999年 | 8篇 |
1998年 | 4篇 |
1997年 | 1篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1978年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有473条查询结果,搜索用时 15 毫秒
201.
Meredith H. Shaffer Yanping Huang Evann Corbo Gregory F. Wu Marielena Velez John K. Choi Ichiko Saotome Judy L. Cannon Andrea I. McClatchey Anne I. Sperling Jonathan S. Maltzman Paula M. Oliver Avinash Bhandoola Terri M. Laufer Janis K. Burkhardt 《PloS one》2010,5(8)
Background
Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored.Methodology/Principal Findings
We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin−/− mice likely arise as a consequence of nutritional stress.Conclusions/Significance
We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin. 相似文献202.
Salmon Verity G. Brice Deanne J. Bridgham Scott Childs Joanne Graham Jake Griffiths Natalie A. Hofmockel Kirsten Iversen Colleen M. Jicha Terri M. Kolka Randy K. Kostka Joel E. Malhotra Avni Norby Richard J. Phillips Jana R. Ricciuto Daniel Schadt Christopher W. Sebestyen Stephen D. Shi Xiaoying Walker Anthony P. Warren Jeffrey M. Weston David J. Yang Xiaojuan Hanson Paul J. 《Plant and Soil》2021,466(1-2):649-674
Plant and Soil - Slow decomposition and isolation from groundwater mean that ombrotrophic peatlands store a large amount of soil carbon (C) but have low availability of nitrogen (N) and phosphorus... 相似文献
203.
204.
205.
Ondrej Kuda Terri A. Pietka Zuzana Demianova Eva Kudova Josef Cvacka Jan Kopecky Nada A. Abumrad 《The Journal of biological chemistry》2013,288(22):15547-15555
FAT/CD36 is a multifunctional glycoprotein that facilitates long-chain fatty acid (FA) uptake by cardiomyocytes and adipocytes and uptake of oxidized low density lipoproteins (oxLDL) by macrophages. CD36 also mediates FA-induced signaling to increase intracellular calcium in various cell types. The membrane-impermeable sulfo-N-hydroxysuccinimidyl (NHS) ester of oleate (SSO) irreversibly binds CD36 and has been widely used to inhibit CD36-dependent FA uptake and signaling to calcium. The inhibition mechanism and whether SSO modification of CD36 involves the FA-binding site remain unexplored. CHO cells expressing human CD36 were SSO-treated, and the protein was pulled down, deglycosylated, and resolved by electrophoresis. The CD36 band was extracted from the gel and digested for analysis by mass spectrometry. NHS derivatives react with primary or secondary amines on proteins to yield stable amide or imide bonds. Two oleoylated peptides, found only in SSO-treated samples, were identified with high contribution and confidence scores as carrying oleate modification of Lys-164. Lysine 164 lies within a predicted CD36 binding domain for FA and oxLDL. CHO cells expressing CD36 with mutated Lys-164 had impaired CD36 function in FA uptake and FA-induced calcium release from the endoplasmic reticulum, supporting the importance of Lys-164 for both FA effects. Furthermore, consistent with the importance of Lys-164 for oxLDL binding, SSO inhibited oxLDL uptake by macrophages. In conclusion, SSO accesses Lys-164 in the FA-binding site on CD36, and initial modeling of this site is presented. The data suggest competition between FA and oxLDL for access to the CD36 binding pocket. 相似文献
206.
Antoine Chaillon Gabriel A. Wagner N. Lance Hepler Susan J. Little Sergei L. Kosakovsky Pond Gemma Caballero Mary E. Pacold Pham Phung Terri Wrin Douglas D. Richman Joel O. Wertheim Davey M. Smith 《Journal of virology》2013,87(23):12737-12744
Investigating the incidence and prevalence of HIV-1 superinfection is challenging due to the complex dynamics of two infecting strains. The superinfecting strain can replace the initial strain, be transiently expressed, or persist along with the initial strain in distinct or in recombined forms. Various selective pressures influence these alternative scenarios in different HIV-1 coding regions. We hypothesized that the potency of the neutralizing antibody (NAb) response to autologous viruses would modulate viral dynamics in env following superinfection in a limited set of superinfection cases. HIV-1 env pyrosequencing data were generated from blood plasma collected from 7 individuals with evidence of superinfection. Viral variants within each patient were screened for recombination, and viral dynamics were evaluated using nucleotide diversity. NAb responses to autologous viruses were evaluated before and after superinfection. In 4 individuals, the superinfecting strain replaced the original strain. In 2 individuals, both initial and superinfecting strains continued to cocirculate. In the final individual, the surviving lineage was the product of interstrain recombination. NAb responses to autologous viruses that were detected within the first 2 years of HIV-1 infection were weak or absent for 6 of the 7 recently infected individuals at the time of and shortly following superinfection. These 6 individuals had detectable on-going viral replication of distinct superinfecting virus in the env coding region. In the remaining case, there was an early and strong autologous NAb response, which was associated with extensive recombination in env between initial and superinfecting strains. This extensive recombination made superinfection more difficult to identify and may explain why the detection of superinfection has typically been associated with low autologous NAb titers. 相似文献
207.
Hochheiser H Aronow BJ Artinger K Beaty TH Brinkley JF Chai Y Clouthier D Cunningham ML Dixon M Donahue LR Fraser SE Hallgrimsson B Iwata J Klein O Marazita ML Murray JC Murray S de Villena FP Postlethwait J Potter S Shapiro L Spritz R Visel A Weinberg SM Trainor PA 《Developmental biology》2011,(2):175-182
The FaceBase Consortium consists of ten interlinked research and technology projects whose goal is to generate craniofacial research data and technology for use by the research community through a central data management and integrated bioinformatics hub. Funded by the National Institute of Dental and Craniofacial Research (NIDCR) and currently focused on studying the development of the middle region of the face, the Consortium will produce comprehensive datasets of global gene expression patterns, regulatory elements and sequencing; will generate anatomical and molecular atlases; will provide human normative facial data and other phenotypes; conduct follow up studies of a completed genome-wide association study; generate independent data on the genetics of craniofacial development, build repositories of animal models and of human samples and data for community access and analysis; and will develop software tools and animal models for analyzing and functionally testing and integrating these data. The FaceBase website (http://www.facebase.org) will serve as a web home for these efforts, providing interactive tools for exploring these datasets, together with discussion forums and other services to support and foster collaboration within the craniofacial research community. 相似文献
208.
The 5-hydroxytryptamine 3 (5-HT(3)) receptor is a pentameric ligand-gated ion channel with potential molecular isoforms arising from different subunit combinations and/or different post-translational modifications of the individual subunits. Since N-glycosylation of the 5-HT3A subunit impacts cell surface trafficking, the presence of N-glycosylation of the human (h) 5-HT3B subunit and the influence upon cell membrane expression was investigated. Following transient expression of the h5-HT3B subunit by human embryonic kidney cells (HEK293 cells) stably expressing the h5-HT3A subunit, the N-glycosylation inhibitor tunicamycin reduced the size of the predominant h5-HT3B-immunoreactive protein (~ 55 kDa reduced to ~ 40 kDa). Disruption of each consensus N-glycosylation sequences in the h5-HT3B subunit (N31S, N75S, N117S, N147S and N182S) resulted in a reduced molecular weight (by ~ 2-4 kDa) of each mutant when expressed by HEK293 cells stably expressing the h5-HT3A subunit. Immunocytochemical studies demonstrated that disruption of each of the N-glycosylation sequences (individually or combined) reduced the expression of the mutant h5-HT3B subunit protein in the cell membrane when co-expressed with the h5-HT3A subunit. The present study has identified utilised N-glycosylation sites of the h5-HT3B subunit and demonstrated that they promote subunit expression in the cell membrane; a prerequisite for 5-HT(3) receptor function. 相似文献
209.
Delano MJ Kelly-Scumpia KM Thayer TC Winfield RD Scumpia PO Cuenca AG Harrington PB O'Malley KA Warner E Gabrilovich S Mathews CE Laface D Heyworth PG Ramphal R Strieter RM Moldawer LL Efron PA 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(2):911-918
Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few studies have investigated the mechanisms responsible for neutrophil mobilization from the bone marrow during polymicrobial sepsis. Using a cecal ligation and puncture model of polymicrobial sepsis, we demonstrated that neutrophil mobilization from the bone marrow is not dependent on TLR4, MyD88, TRIF, IFNARα/β, or CXCR2 pathway signaling during sepsis. In contrast, we observed that bone marrow CXCL12 mRNA abundance and specific CXCL12 levels are sharply reduced, whereas splenic CXCR4 mRNA and cell surface expression are increased during sepsis. Blocking CXCL12 activity significantly reduced blood neutrophilia by inhibiting bone marrow release of granulocytes during sepsis. However, CXCL12 inhibition had no impact on the expansion of bone marrow neutrophil precursors and hematopoietic progenitors. Bone marrow neutrophil retention by CXCL12 blockade prevented blood neutrophilia, inhibited peritoneal neutrophil accumulation, allowed significant peritoneal bacterial invasion, and increased polymicrobial sepsis mortality. We concluded that changes in the pattern of CXCL12 signaling during sepsis are essential for neutrophil bone marrow mobilization and host survival but have little impact on bone marrow granulopoiesis. 相似文献
210.
Molitoris JK McColl KS Swerdlow S Matsuyama M Lam M Finkel TH Matsuyama S Distelhorst CW 《The Journal of biological chemistry》2011,286(34):30181-30189
Glucocorticoid hormones, including dexamethasone, induce apoptosis in lymphocytes and consequently are used clinically as chemotherapeutic agents in many hematologic malignancies. Dexamethasone also induces autophagy in lymphocytes, although the mechanism is not fully elucidated. Through gene expression analysis, we found that dexamethasone induces the expression of a gene encoding a stress response protein variously referred to as Dig2, RTP801, or REDD1. This protein is reported to inhibit mammalian target of rapamycin (mTOR) signaling. Because autophagy is one outcome of mTOR inhibition, we investigated the hypothesis that Dig2/RTP801/REDD1 elevation contributes to autophagy induction in dexamethasone-treated lymphocytes. In support of this hypothesis, RNAi-mediated suppression of Dig2/RTP801/REDD1 reduces mTOR inhibition and autophagy in glucocorticoid-treated lymphocytes. We observed similar results in Dig2/Rtp801/Redd1 knock-out murine thymocytes treated with dexamethasone. Dig2/RTP801/REDD1 knockdown also leads to increased levels of dexamethasone-induced cell death, suggesting that Dig2/RTP801/REDD1-mediated autophagy promotes cell survival. Collectively, these findings demonstrate for the first time that elevation of Dig2/RTP801/REDD1 contributes to the induction of autophagy. 相似文献