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71.
While the general blueprint of ribosome biogenesis is evolutionarily conserved, most details have diverged considerably. A striking exception to this divergence is the universally conserved KsgA/Dim1p enzyme family, which modifies two adjacent adenosines in the terminal helix of small subunit ribosomal RNA (rRNA). While localization of KsgA on 30S subunits [small ribosomal subunits (SSUs)] and genetic interaction data have suggested that KsgA acts as a ribosome biogenesis factor, mechanistic details and a rationale for its extreme conservation are still lacking. To begin to address these questions we have characterized the function of Escherichia coli KsgA in vivo using both a ksgA deletion strain and a methyltransferase-deficient form of this protein. Our data reveal cold sensitivity and altered ribosomal profiles are associated with a DeltaksgA genotype in E. coli. Our work also indicates that loss of KsgA alters 16S rRNA processing. These findings allow KsgAs role in SSU biogenesis to be integrated into the network of other identified factors. Moreover, a methyltransferase-inactive form of KsgA, which we show to be deleterious to cell growth, profoundly impairs ribosome biogenesis-prompting discussion of KsgA as a possible antimicrobial drug target. These unexpected data suggest that methylation is a second layer of function for KsgA and that its critical role is as a supervisor of biogenesis of SSUs in vivo. These new findings and this proposed regulatory role offer a mechanistic explanation for the extreme conservation of the KsgA/Dim1p enzyme family. 相似文献
72.
Yuxin Wu Lei Wang Chen Lin Yan Lin Mei Zhou Liang Chen Brian Connolly Yingqi Zhang Tianbao Chen Chris Shaw 《PloS one》2013,8(2)
The defensive skin secretions of amphibians are a rich resource for the discovery of novel, bioactive peptides. Here we report the identification of a novel vascular smooth muscle-relaxing peptide, named vasorelaxin, from the skin secretion of the Chinese piebald odorous frog, Odorrana schmackeri. Vasorelaxin consists of 20 amino acid residues, SRVVKCSGFRPGSPDSREFC, with a disulfide-bridge between Cys-6 and Cys-20. The structure of its biosynthetic precursor was deduced from cloned skin cDNA and consists of 67 amino acid residues encoding a single copy of vasorelaxin (vasorelaxin, accession number: ). Synthetic vasorelaxin caused a profound relaxation of rat arterial smooth muscle with an EC50 of 6.76 nM. HE860494相似文献
73.
Herpesviruses are double-stranded DNA, enveloped viruses that infect host cells through fusion with either the host cell plasma membrane or endocytic vesicle membranes. Efficient infection of host cells by herpesviruses is remarkably more complex than infection by other viruses, as it requires the concerted effort of multiple glycoproteins and involves multiple host receptors. The structures of the major viral glycoproteins and a number of host receptors involved in the entry of the prototypical herpesviruses, the herpes simplex viruses (HSVs) and Epstein-Barr virus (EBV), are now known. These structural studies have accelerated our understanding of HSV and EBV binding and fusion by revealing the conformational changes that occur on virus-receptor binding, depicting potential sites of functional protein and lipid interactions, and identifying the probable viral fusogen. 相似文献
74.
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
75.
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
76.
John H. Connolly 《BMJ (Clinical research ed.)》1961,1(5229):877-878
77.
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78.
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
79.
80.
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