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101.
102.
103.
Discovery of potent,selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors
Meizhong Jin Jing Wang Andrew Kleinberg Mridula Kadalbajoo Kam W. Siu Andrew Cooke Mark A. Bittner Yan Yao April Thelemann Qunsheng Ji Shripad Bhagwat Kristen M. Mulvihill Josef A. Rechka Jonathan A. Pachter Andrew P. Crew David Epstein Mark J. Mulvihill 《Bioorganic & medicinal chemistry letters》2013,23(4):979-984
This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure–activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors. 相似文献
104.
Two unicellular cyanobacteria Synechocystis sp. PCC 6803 and Synechococcus elongatus PCC 7942 showed contrasting responses to chromate stress with EC50 of 12 ± 2 and 150 ± 15 μM potassium dichromate respectively. There was no depletion of chromate in growth medium in both the cases. Using labeled chromate, very low accumulation (<1 nmol/108 cells) was observed in Synechocystis after incubation for 24 h in light. No accumulation of chromate could be observed in Synechococcus under these conditions. Chromate oxyanion is known to enter the cells using sulfate uptake channels. Therefore, inhibition of sulfate uptake caused by chromate was monitored using 35S labeled sulfate. IC50 values of chromate for 35sulfate uptake were higher in Synechococcus as compared to Synechocystis. The results suggested that the sulfate transporters in Synechococcus have lower affinity to chromate than those from Synechocystis possibly due to differences in affinity of sulfate receptors for chromate. Bioinformatic analyses revealed presence of sulfate and chromate transporters with considerable similarity; however, minor differences in these may play a role in their differential response to chromate. In both cases the IC50 values decreased when sulfate concentration was reduced in the medium indicating competitive inhibition of sulfate uptake by chromate. Interestingly, Synechococcus showed stimulation of growth at concentrations of chromate less than 100 μM, which affected its cell size without disturbing the ultrastructure and thylakoid organization. In Synechocystis, growth with 12 μM potassium dichromate damaged the ultrastructure and thylakoid organization with slight elongation of the cells. The results suggested that Synechococcus possesses efficient strategies to prevent entry and to remove chromate from the cell as compared to Synechocystis. This is the first time a differential response of Synechococcus 7942 and Synechocystis 6803 to chromate is reported. The contrasting characteristics observed in the two cyanobacteria will be useful in understanding the basis of resistance or susceptibility to chromate. 相似文献
105.
Abraham S Hadd MJ Tran L Vickers T Sindac J Milanov ZV Holladay MW Bhagwat SS Hua H Ford Pulido JM Cramer MD Gitnick D James J Dao A Belli B Armstrong RC Treiber DK Liu G 《Bioorganic & medicinal chemistry letters》2011,21(18):5296-5300
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model. 相似文献
106.
ANTONIO HERNÁNDEZ‐MATÍAS JOAN REAL ROGER PRADEL ALAIN RAVAYROL NICOLAS VINCENT‐MARTIN 《Ibis》2011,153(4):846-857
Survival typically contributes most to population trends in long‐lived birds and its accurate estimation is therefore vital for population management and conservation. We evaluated the effects of age, territoriality and reproduction on survival in Bonelli’s Eagle Aquila fasciata through multistate capture‐mark‐recapture analyses on a long‐term dataset. Monitoring was carried out in southeast France (1990–2008) and involved the surveying of territorial Eagles, the marking of fledged chicks, and the recording of resightings and recoveries of marked non‐territorial and territorial birds. Survival improved with age, but territoriality was not retained in the best model; yearly survival was estimated at 0.479 for fledglings (to 1 year of age), 0.570 for 1‐ and 2‐year‐olds, and 0.870 for 3‐year‐old and older individuals. The second best model supported a further increase in survival from 3‐year‐olds (0.821) to older individuals (0.880). In the third best supported model, territoriality enhanced survival, but only in 2‐year‐olds (0.632 vs. 0.562 for non‐territorial). We found no correlation between the previous breeding stage and future survival, consistent with the long lifespan of the study species. Nevertheless, 4‐year‐old and older successful breeders were more likely to breed the following year than failed adult breeders (0.869 vs. 0.582), suggesting that the cost of reproduction is small in comparison with the variation in quality among individuals or their territories. 相似文献
107.
Aruna C Bhagwat VR Madhusudhana R Sharma V Hussain T Ghorade RB Khandalkar HG Audilakshmi S Seetharama N 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2011,122(8):1617-1630
Shoot fly is one of the most important pests affecting the sorghum production. The identification of quantitative trait loci
(QTL) affecting shoot fly resistance enables to understand the underlying genetic mechanisms and genetic basis of complex
interactions among the component traits. The aim of the present study was to detect QTL for shoot fly resistance and the associated
traits using a population of 210 RILs of the cross 27B (susceptible) × IS2122 (resistant). RIL population was phenotyped in
eight environments for shoot fly resistance (deadheart percentage), and in three environments for the component traits, such
as glossiness, seedling vigor and trichome density. Linkage map was constructed with 149 marker loci comprising 127 genomic-microsatellite,
21 genic-microsatellite and one morphological marker. QTL analysis was performed by using MQM approach. 25 QTL (five each
for leaf glossiness and seedling vigor, 10 for deadhearts, two for adaxial trichome density and three for abaxial trichome
density) were detected in individual and across environments. The LOD and R
2 (%) values of QTL ranged from 2.44 to 24.1 and 4.3 to 44.1%, respectively. For most of the QTLs, the resistant parent, IS2122
contributed alleles for resistance; while at two QTL regions, the susceptible parent 27B also contributed for resistance traits.
Three genomic regions affected multiple traits, suggesting the phenomenon of pleiotrophy or tight linkage. Stable QTL were
identified for the traits across different environments, and genetic backgrounds by comparing the QTL in the study with previously
reported QTL in sorghum. For majority of the QTLs, possible candidate genes were identified. The QTLs identified will enable
marker assisted breeding for shoot fly resistance in sorghum. 相似文献
108.
Abstract: The Jurassic was an important period in the evolution of Testudinata and encompasses the origin of many clades, and this is especially true of Jurassic turtles from Western Europe. A new genus and species of Late Jurassic turtle, Hispaniachelys prebetica gen. et sp. nov. from the upper Oxfordian of the Prebetic (Southern Spain), is described on the basis of postcranial material. The specimen is the only known tetrapod from the Mesozoic of the Prebetic and the oldest turtle from southern Europe. A mosaic of characters indicates this is a new genus: it displays basal features including dorsal epiplastral processes/reduced cleithra, no medial contact of the extragulars and a long first thoracic rib, alongside derived characters including an absence of mesoplastra and the vertebral 3/4 sulcus crossing neural 5. The phylogenetic position of the new taxon is hard to resolve, and it might be either a paracryptodire or a basal testudine, but it is distinct from Plesiochelys. A complex taphonomic history is shown by a range of overlying grazing traces and bioerosion on the carapace. The carapace was subsequently overturned and buried ventrally up, terminating grazing activity, and was then bored by sponges before final burial. Scanning electron microscopy reveals phosphatic microspheroids associated with bacterial decay in the vascular cavities of the cancellous bone, suggesting the carapace may have acted as a closed microenvironment in which decay‐derived authigenic minerals formed. 相似文献
109.
Sharma M Kniel KE Derevianko A Ling J Bhagwat AA 《Applied and environmental microbiology》2007,73(13):4351-4353
Escherichia albertii is a potential food-borne pathogen because of its documented ability to cause diarrheal disease by producing attachment and effacement lesions. Its tolerances to heat (56 degrees C), acid (pH 3.0), and pressure (500 MPa [5 min]) were evaluated and found to be significantly less than those of wild-type E. coli O157:H7. 相似文献
110.
Mistianne Feeney Basdeo Bhagwat Jeremy S. Mitchell W. David Lane 《Plant Cell, Tissue and Organ Culture》2007,90(2):201-214
A complete method to regenerate adventitious shoots and to produce field-ready trees from three commercial cultivars of sweet
cherry (Prunus avium L.) is described. The effects of explant types, pre-treatments, basal media, and phloroglucinol on cultivars Bing, Sweetheart,
and Lapins were investigated. Callus developed on four explant types: apical shoot tips isolated from orchard trees; and punctured
shoot tips, stem sections, and shoot bases of in vitro shoot cultures. Callus formed on Bing (5%), Sweetheart (8%), and Lapins
(20%) shoot tips from orchard trees after 4 months on Murashige and Skoog medium (MS) at half-strength with 3 μM benzylaminopurine
(BA). In vitro-derived explants formed callus after 3 months on Woody Plant Medium with 3 μM BA (W3B): punctured shoot tips
(Sweetheart and Lapins 67%), stem sections (Sweetheart 31%, Lapins 27%), and shoot bases (Sweetheart 10%, Lapins 17%). Pre-treatment
of shoot cultures on MS with 3 μM BA and 1 mM phloroglucinol increased callus formation three-fold on shoot base explants.
Callus was separated from parental explants and maintained on MS with 3 μM BA. Shooting was induced by transferring callus
to W3B. At 2 weeks, shoot development approached 100%. By 4 weeks, 7–17 shoots had formed on each explant. Callus was maintained
for 1.5 years with no decrease in shoot production. Shoots were grafted onto Mazzard (P. avium) rootstocks with 54% (Sweetheart), 57% (Lapins), and 21% (Bing) success after 5 weeks. 相似文献