全文获取类型
收费全文 | 931篇 |
免费 | 94篇 |
国内免费 | 1篇 |
专业分类
1026篇 |
出版年
2021年 | 6篇 |
2020年 | 7篇 |
2019年 | 10篇 |
2018年 | 9篇 |
2017年 | 10篇 |
2016年 | 11篇 |
2015年 | 25篇 |
2014年 | 29篇 |
2013年 | 38篇 |
2012年 | 37篇 |
2011年 | 44篇 |
2010年 | 26篇 |
2009年 | 32篇 |
2008年 | 52篇 |
2007年 | 48篇 |
2006年 | 36篇 |
2005年 | 45篇 |
2004年 | 50篇 |
2003年 | 33篇 |
2002年 | 33篇 |
2001年 | 27篇 |
2000年 | 34篇 |
1999年 | 22篇 |
1998年 | 6篇 |
1997年 | 13篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 16篇 |
1991年 | 12篇 |
1990年 | 21篇 |
1989年 | 26篇 |
1988年 | 14篇 |
1987年 | 15篇 |
1986年 | 19篇 |
1985年 | 25篇 |
1984年 | 16篇 |
1983年 | 11篇 |
1982年 | 7篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 7篇 |
1978年 | 9篇 |
1977年 | 7篇 |
1975年 | 7篇 |
1973年 | 6篇 |
1971年 | 9篇 |
1967年 | 5篇 |
1960年 | 8篇 |
排序方式: 共有1026条查询结果,搜索用时 15 毫秒
101.
Andreeva V Connolly MH Stewart-Swift C Fraher D Burt J Cardarelli J Yelick PC 《Genesis (New York, N.Y. : 2000)》2011,49(4):360-366
Zebrafish craniofacial, skeletal, and tooth development closely resembles that of higher vertebrates. Our goal is to identify viable adult zebrafish mutants that can be used as models for human mineralized craniofacial, dental, and skeletal system disorders. We used a large-scale forward-genetic chemical N-ethyl-nitroso-urea mutagenesis screen to identify 17 early lethal homozygous recessive mutants with defects in craniofacial cartilage elements, and 7 adult homozygous recessive mutants with mineralized tissue phenotypes including craniofacial shape defects, fused sutures, dysmorphic or missing skeletal elements, scoliosis, and neural arch defects. One mutant displayed both an early lethal homozygous phenotype and an adult heterozygous phenotype. These results extend the utility of the zebrafish model beyond the embryo to study human bone and cartilage disorders. 相似文献
102.
Estimating larval retention at individual reefs by local scale three-dimensional flows is a significant problem for understanding,
and predicting, larval dispersal. Determining larval dispersal commonly involves the use of computationally demanding and
expensively calibrated/validated hydrodynamic models that resolve reef wake eddies. This study models variation in larval
retention times for a range of reef shapes and circulation regimes, using a reef-scale three-dimensional hydrodynamic model.
It also explores how well larval retention time can be estimated based on the “Island Wake Parameter”, a measure of the degree
of flow turbulence in the wake of reefs that is a simple function of flow speed, reef dimension, and vertical diffusion. The
mean residence times found in the present study (0.48–5.64 days) indicate substantial potential for self-recruitment of species
whose larvae are passive, or weak swimmers, for the first several days after release. Results also reveal strong and significant
relationships between the Island Wake Parameter and mean residence time, explaining 81–92% of the variability in retention
among reefs across a range of unidirectional flow speeds and tidal regimes. These findings suggest that good estimates of
larval retention may be obtained from relatively coarse-scale characteristics of the flow, and basic features of reef geomorphology.
Such approximations may be a valuable tool for modeling connectivity and meta-population dynamics over large spatial scales,
where explicitly characterizing fine-scale flows around reef requires a prohibitive amount of computation and extensive model
calibration. 相似文献
103.
John H. Connolly 《BMJ (Clinical research ed.)》1961,1(5229):877-878
104.
Richard Whitlock Jeff S. Healey Stuart J. Connolly Julie Wang Matthew R. Danter Jack V. Tu Richard Novick Stephen Fremes Kevin Teoh Vikas Khera Salim Yusuf 《CMAJ》2014,186(12):905-911
Background:
Much is known about the short-term risks of stroke following cardiac surgery. We examined the rate and predictors of long-term stroke in a cohort of patients who underwent cardiac surgery.Methods:
We obtained linked data for patients who underwent cardiac surgery in the province of Ontario between 1996 and 2006. We analyzed the incidence of stroke and death up to 2 years postoperatively.Results:
Of 108 711 patients, 1.8% (95% confidence interval [CI] 1.7%–1.9%) had a stroke perioperatively, and 3.6% (95% CI 3.5%–3.7%) had a stroke within the ensuing 2 years. The strongest predictors of both early and late stroke were advanced age (≥ 65 year; adjusted hazard ratio [HR] for all stroke 1.9, 95% CI 1.8–2.0), a history of stroke or transient ischemic attack (adjusted HR 2.1, 95% CI 1.9–2.3), peripheral vascular disease (adjusted HR 1.6, 95% CI 1.5–1.7), combined coronary bypass grafting and valve surgery (adjusted HR 1.7, 95% CI 1.5–1.8) and valve surgery alone (adjusted HR 1.4, 95% CI 1.2–1.5). Preoperative need for dialysis (adjusted odds ratio [OR] 2.1, 95% CI 1.6–2.8) and new-onset postoperative atrial fibrillation (adjusted OR 1.5, 95% CI 1.3–1.6) were predictors of only early stroke. A CHADS2 score of 2 or higher was associated with an increased risk of stroke or death compared with a score of 0 or 1 (19.9% v. 9.3% among patients with a history of atrial fibrillation, 16.8% v. 7.8% among those with new-onset postoperative atrial fibrillation and 14.8% v. 5.8% among those without this condition).Interpretation:
Patients who had cardiac surgery were at highest risk of stroke in the early postoperative period and had continued risk over the ensuing 2 years, with similar risk factors over these periods. New-onset postoperative atrial fibrillation was a predictor of only early stroke. The CHADS2 score predicted stroke risk among patients with and without atrial fibrillation.Stroke remains a devastating complication following cardiac surgery, with substantial functional and economic impact.1–3 Stroke research in cardiac surgery has focused on the immediate postoperative period;4–9 however, most patients undergoing cardiac surgery have conditions such as hypertension, diabetes and atrial fibrillation, which place them at long-term risk of stroke.Early and late outcomes among patients undergoing cardiac surgery could be improved if the risk of postoperative stroke was defined and predictors of stroke identified. With this information, clinicians could optimize medical therapy for stroke risk factors such as hypertension,10,11 improve the evidence-based use of oral anticoagulation in patients with atrial fibrillation and evaluate intraoperative surgical strategies (e.g., removal of the left atrial appendage12) in patients whose clinical characteristics predict an increased risk of stroke. We examined the rate and predictors of long-term stroke within 2 years after cardiac surgery. 相似文献105.
Jennifer K. Dowling Christine E. Becker Nollaig M. Bourke Sinead C. Corr Dympna J. Connolly Susan R. Quinn Paolo P. Pandolfi Ashley Mansell Luke A. J. O'Neill 《The Journal of biological chemistry》2014,289(10):6429-6437
The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus. 相似文献
106.
107.
Huang S Lin R Yu Y Lu Y Connolly PJ Chiu G Li S Emanuel SL Middleton SA 《Bioorganic & medicinal chemistry letters》2007,17(5):1243-1245
The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described. 相似文献
108.
Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening 总被引:14,自引:0,他引:14
Barton ES Connolly JL Forrest JC Chappell JD Dermody TS 《The Journal of biological chemistry》2001,276(3):2200-2211
Many serotype 3 reoviruses bind to two different host cell molecules, sialic acid and an unidentified protein, using discrete receptor-binding domains in viral attachment protein, final sigma1. To determine mechanisms by which these receptor-binding events cooperate to mediate cell attachment, we generated isogenic reovirus strains that differ in the capacity to bind sialic acid. Strain SA+, but not SA-, bound specifically to sialic acid on a biosensor chip with nanomolar avidity. SA+ displayed 5-fold higher avidity for HeLa cells when compared with SA-, although both strains recognized the same proteinaceous receptor. Increased avidity of SA+ binding was mediated by increased k(on). Neuraminidase treatment to remove cell-surface sialic acid decreased the k(on) of SA+ to that of SA-. Increased k(on) of SA+ enhanced an infectious attachment process, since SA+ was 50-100-fold more efficient than SA- at infecting HeLa cells in a kinetic fluorescent focus assay. Sialic acid binding was operant early during SA+ attachment, since the capacity of soluble sialyllactose to inhibit infection decreased rapidly during the first 20 min of adsorption. These results indicate that reovirus binding to sialic acid enhances virus infection through adhesion of virus to the cell surface where access to a proteinaceous receptor is thermodynamically favored. 相似文献
109.
Mason AB Halbrooks PJ Larouche JR Briggs SK Moffett ML Ramsey JE Connolly SA Smith VC MacGillivray RT 《Protein expression and purification》2004,36(2):318-326
Transferrin is a bilobal protein with the ability to bind iron in two binding sites situated at the bottom of a cleft in each lobe. We have previously described the production of recombinant non-glycosylated human serum transferrins (hTF-NG), containing a factor Xa cleavage site and a hexa-His tag at the amino-terminus. Constructs in this background that contain strategic mutations to completely prevent iron binding in each lobe or in both lobes have now been produced. These monoferric hTFs will allow dissection of the contribution of each lobe to transferrin function. In addition, the construct completely lacking in the ability to bind iron in either lobe provides an opportunity to assess whether hTF has any other functions in addition to iron transport. Following insertion of the His-tagged hTF molecules into the pNUT vector, transfection into baby hamster kidney cells and selection with methotrexate, the secreted recombinant proteins were isolated from the tissue culture medium and characterized with regard to their iron binding properties. Significant improvements over our previous protocol include: (1) addition of butyric acid at a level of 1mM which leads to a substantial increase in protein production (as much as a 65% increase compared to control cells); and (2) elimination of an anion exchange column prior to isolation on a Qiagen Ni-NTA column which makes purification of the His-tagged constructs faster and therefore more efficient. These improvements should be applicable to expression of other recombinant proteins in mammalian cells. 相似文献
110.
Junction adhesion molecule is a receptor for reovirus 总被引:32,自引:0,他引:32
Barton ES Forrest JC Connolly JL Chappell JD Liu Y Schnell FJ Nusrat A Parkos CA Dermody TS 《Cell》2001,104(3):441-451
Virus attachment to cells plays an essential role in viral tropism and disease. Reovirus serotypes 1 and 3 differ in the capacity to target distinct cell types in the murine nervous system and in the efficiency to induce apoptosis. The binding of viral attachment protein sigma1 to unidentified receptors controls these phenotypes. We used expression cloning to identify junction adhesion molecule (JAM), an integral tight junction protein, as a reovirus receptor. JAM binds directly to sigma1 and permits reovirus infection of nonpermissive cells. Ligation of JAM is required for reovirus-induced activation of NF-kappaB and apoptosis. Thus, reovirus interaction with cell-surface receptors is a critical determinant of both cell-type specific tropism and virus-induced intracellular signaling events that culminate in cell death. 相似文献