全文获取类型
收费全文 | 1045篇 |
免费 | 128篇 |
出版年
2023年 | 12篇 |
2022年 | 14篇 |
2021年 | 22篇 |
2020年 | 16篇 |
2019年 | 14篇 |
2018年 | 19篇 |
2017年 | 12篇 |
2016年 | 23篇 |
2015年 | 43篇 |
2014年 | 26篇 |
2013年 | 42篇 |
2012年 | 45篇 |
2011年 | 50篇 |
2010年 | 33篇 |
2009年 | 32篇 |
2008年 | 37篇 |
2007年 | 30篇 |
2006年 | 40篇 |
2005年 | 38篇 |
2004年 | 31篇 |
2003年 | 34篇 |
2002年 | 30篇 |
2001年 | 25篇 |
2000年 | 26篇 |
1999年 | 30篇 |
1998年 | 20篇 |
1997年 | 10篇 |
1996年 | 18篇 |
1995年 | 14篇 |
1994年 | 10篇 |
1993年 | 15篇 |
1992年 | 16篇 |
1991年 | 19篇 |
1990年 | 13篇 |
1988年 | 14篇 |
1987年 | 18篇 |
1986年 | 19篇 |
1985年 | 13篇 |
1983年 | 17篇 |
1980年 | 9篇 |
1979年 | 12篇 |
1977年 | 15篇 |
1975年 | 12篇 |
1974年 | 13篇 |
1972年 | 9篇 |
1970年 | 13篇 |
1969年 | 16篇 |
1968年 | 8篇 |
1967年 | 11篇 |
1966年 | 8篇 |
排序方式: 共有1173条查询结果,搜索用时 15 毫秒
91.
Laure Civeyrel Annick Le Thomas Keith Ferguson Mark W. Chase 《Molecular phylogenetics and evolution》1998,9(3):517-527
The family Asclepiadaceae (Dicotyledones) was created by Brown in 1810 by splitting in two the family Apocynaceae of Jussieu established in 1789. The morphological characters used to make this distinction were mainly palynological, such as presence of tetrads or pollinia and number and orientation of pollinia. Those characters, still used in higher taxonomic delimitation (families, subfamilies, and tribes), are here critically reexamined and compared to a molecular phylogeny obtained with one of the more variable plastid genes (matK) of 46 species in the order Gentianales. In this molecular phylogeny, Asclepiadaceae form a monophyletic group derived from within Apocynaceae. Each of the subfamilies of Asclepiadaceae is monophyletic and based on reliable palynological characters, but palynological characters are not useful to delimit tribes of the subfamily Asclepiadoideae. Based on the molecular data, these tribes have undergone parallelisms in several reproductive traits. 相似文献
92.
The packed‐bed adsorption and elution of aqueous solutions of whey concentrate powders were investigated at pH 3.7 using a 5‐mL SP Sepharose FF column to separate and isolate two major proteins namely, α‐lactalbumin (ALA) and β‐lactoglobulin (BLG) from these solutions. ALA displaced and eluted BLG from the column in a pure form. Pure ALA could then be eluted with good recovery. A novel consecutive two‐stage separation process was developed to separate ALA and BLG from whey concentrate mixtures. Almost all of the BLG in the feed was recovered, with 78% being recovered at 95% purity and a further 20% at 86% purity. In addition, 67% of ALA was recovered, 48% at 54% purity and 19% at 60% purity. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 相似文献
93.
Chase W. Kessinger Jin Won Kim Peter K. Henke Brian Thompson Jason R. McCarthy Tetsuya Hara Martin Sillesen Ronan J. P. Margey Peter Libby Ralph Weissleder Charles P. Lin Farouc A. Jaffer 《PloS one》2015,10(2)
Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. 相似文献
94.
95.
William D. Pearse Mark W. Chase Michael J. Crawley Konrad Dolphin Michael F. Fay Jeffrey A. Joseph Gary Powney Chris D. Preston Giovanni Rapacciuolo David B. Roy Andy Purvis 《PloS one》2015,10(5)
Conservation biologists have only finite resources, and so must prioritise some species over others. The EDGE-listing approach ranks species according to their combined evolutionary distinctiveness and degree of threat, but ignores the uncertainty surrounding both threat and evolutionary distinctiveness. We develop a new family of measures for species, which we name EDAM, that incorporates evolutionary distinctiveness, the magnitude of decline, and the accuracy with which decline can be predicted. Further, we show how the method can be extended to explore phyogenetic uncertainty. Using the vascular plants of Britain as a case study, we find that the various EDAM measures emphasise different species and parts of Britain, and that phylogenetic uncertainty can strongly affect the prioritisation scores of some species. 相似文献
96.
Narayana PB Fazolini André LS Cruz Miriam BF Werneck Jo?o PB Viola Clarissa M Maya-Monteiro Patrícia T Bozza 《Cell cycle (Georgetown, Tex.)》2015,14(16):2667-2676
Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway-dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-β production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF-β production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma. 相似文献
97.
Pinyi Lu Raquel Hontecillas Vida Abedi Shiv Kale Andrew Leber Chase Heltzel Mark Langowski Victoria Godfrey Casandra Philipson Nuria Tubau-Juni Adria Carbo Stephen Girardin Aykut Uren Josep Bassaganya-Riera 《PloS one》2015,10(12)
Nucleotide-binding domain and leucine-rich repeat containing (NLR) family are intracellular sentinels of cytosolic homeostasis that orchestrate immune and inflammatory responses in infectious and immune-mediated diseases. NLRX1 is a mitochondrial-associated NOD-like receptor involved in the modulation of immune and metabolic responses. This study utilizes molecular docking approaches to investigate the structure of NLRX1 and experimentally assesses binding to naturally occurring compounds from several natural product and lipid databases. Screening of compound libraries predicts targeting of NLRX1 by conjugated trienes, polyketides, prenol lipids, sterol lipids, and coenzyme A-containing fatty acids for activating the NLRX1 pathway. The ligands of NLRX1 were identified by docking punicic acid (PUA), eleostearic acid (ESA), and docosahexaenoic acid (DHA) to the C-terminal fragment of the human NLRX1 (cNLRX1). Their binding and that of positive control RNA to cNLRX1 were experimentally determined by surface plasmon resonance (SPR) spectroscopy. In addition, the ligand binding sites of cNLRX1 were predicted in silico and validated experimentally. Target mutagenesis studies demonstrate that mutation of 4 critical residues ASP677, PHE680, PHE681, and GLU684 to alanine resulted in diminished affinity of PUA, ESA, and DHA to NLRX1. Consistent with the regulatory actions of NLRX1 on the NF-κB pathway, treatment of bone marrow derived macrophages (BMDM)s with PUA and DHA suppressed NF-κB activity in a NLRX1 dependent mechanism. In addition, a series of pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the regulatory function of PUA on colitis is NLRX1 dependent. Thus, we identified novel small molecules that bind to NLRX1 and exert anti-inflammatory actions. 相似文献
98.
Freddy A. Medina Giselle Torres-Malavé Amanda J. Chase Gilberto A. Santiago Juan F. Medina Luis M. Santiago Jorge L. Mu?oz-Jordán 《PLoS neglected tropical diseases》2015,9(3)
Background/ObjectivesIn vitro studies have shown that dengue virus (DENV) can thwart the actions of interferon (IFN)-α/β and prevent the development of an antiviral state in infected cells. Clinical studies looking at gene expression in patients with severe dengue show a reduced expression of interferon stimulated genes compared to patients with dengue fever. Interestingly, there are conflicting reports as to the ability of DENV or other flaviviruses to inhibit IFN-α/β signaling.ConclusionsThe ability of DENVs to inhibit IFN-α/β signaling is conserved. Although some variation in the inhibition was observed, the moderate differences may be difficult to correlate with clinical outcomes. DENVs were unable to inhibit pSTAT1 in NHP cell lines, but their ability to inhibit pSTAT1 in primary Rhesus macaque dendritic cells suggests that this may be a cell specific phenomena or due to the transformed nature of the cell lines. 相似文献
99.
Lead is a neurotoxin that has been documented to affect many forms of wildlife, and has been identified as a limiting factor in a population of California Condors in Northern Arizona. The Arizona Game and Fish Department provides vouchers for free nonlead ammunition to hunters selected to hunt within the distribution of California Condors, with the intention of having fewer lead-laden offal piles available to California Condors. Although wildlife agencies may reasonably assume voucher programs motivate hunters into choosing nonlead ammunition, the lead reduction efforts attributable to the voucher program has not been empirically quantified. Our intention was to compare a control group of hunters to a treatment group of hunters within California Condor occupied areas. Both groups received educational materials regarding the deleterious effects of lead, but the treatment group also received a voucher for a free initial box of ammunition. About half of the control group used nonlead ammunition, compared to about three-fourths of the treatment group. Prominent barriers to adoption of nonlead ammunition included a general difficulty of obtaining it, obtaining it in the desired caliber, and its costliness. Frequently mentioned motivations for using nonlead was the exhortation to use it by the Department, and the desire to aid California Condor recovery by hunters. The disparate compliance rates found herein confirm and quantify the success of nonlead ammunition voucher programs, but underscore the importance of working to increase the supply of nonlead ammunition with the end of facilitating its procurement and reducing its cost. 相似文献
100.
Mao H Graziano JJ Chase TM Bentley CA Bazirgan OA Reddy NP Song BD Smider VV 《Nature biotechnology》2010,28(11):1195-1202
Antibody discovery typically uses hybridoma- or display-based selection approaches, which lack the advantages of directly screening spatially addressed compound libraries as in small-molecule discovery. Here we apply the latter strategy to antibody discovery, using a library of ~10,000 human germline antibody Fabs created by de novo DNA synthesis and automated protein expression and purification. In multiplexed screening assays, we obtained specific hits against seven of nine antigens. Using sequence-activity relationships and iterative mutagenesis, we optimized the binding affinities of two hits to the low nanomolar range. The matured Fabs showed full and partial antagonism activities in cell-based assays. Thus, protein drug leads can be discovered using surprisingly small libraries of proteins with known sequences, questioning the requirement for billions of members in an antibody discovery library. This methodology also provides sequence, expression and specificity information at the first step of the discovery process, and could enable novel antibody discovery in functional screens. 相似文献