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101.
    
Drug combination trials are increasingly common nowadays in clinical research. However, very few methods have been developed to consider toxicity attributions in the dose escalation process. We are motivated by a trial in which the clinician is able to identify certain toxicities that can be attributed to one of the agents. We present a Bayesian adaptive design in which toxicity attributions are modeled via copula regression and the maximum tolerated dose (MTD) curve is estimated as a function of model parameters. The dose escalation algorithm uses cohorts of two patients, following the continual reassessment method (CRM) scheme, where at each stage of the trial, we search for the dose of one agent given the current dose of the other agent. The performance of the design is studied by evaluating its operating characteristics when the underlying model is either correctly specified or misspecified. We show that this method can be extended to accommodate discrete dose combinations.  相似文献   
102.
    

Maximizing the number of offspring born per female is a key functionality trait in commercial- and/or subsistence-oriented livestock enterprises. Although the number of offspring born is closely associated with female fertility and reproductive success, the genetic control of these traits remains poorly understood in sub-Saharan Africa livestock. Using selection signature analysis performed on Ovine HD BeadChip data from the prolific Bonga sheep in Ethiopia, 41 candidate regions under selection were identified. The analysis revealed one strong selection signature on a candidate region on chromosome X spanning BMP15, suggesting this to be the primary candidate prolificacy gene in the breed. The analysis also identified several candidate regions spanning genes not reported before in prolific sheep but underlying fertility and reproduction in other species. The genes associated with female reproduction traits included SPOCK1 (age at first oestrus), GPR173 (mediator of ovarian cyclicity), HB-EGF (signalling early pregnancy success) and SMARCAL1 and HMGN3a (regulate gene expression during embryogenesis). The genes involved in male reproduction were FOXJ1 (sperm function and successful fertilization) and NME5 (spermatogenesis). We also observed genes such as PKD2L2, MAGED1 and KDM3B, which have been associated with diverse fertility traits in both sexes of other species. The results confirm the complexity of the genetic mechanisms underlying reproduction while suggesting that prolificacy in the Bonga sheep, and possibly African indigenous sheep is partly under the control of BMP15 while other genes that enhance male and female fertility are essential for reproductive fitness.

  相似文献   
103.
    
In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure–activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.  相似文献   
104.
The effect of two different semi-artificial diets (S.A.D1 and S.A.D2) as well as a natural corn diet on the biology and bionomics of the pink stem borer, Sesamia cretica was studied under laboratory conditions. The insect was successfully mass reared for ten successive generations at the conditions of 27 +/- 2 C degrees and 60-80% R.H. In addition, a photoperiod of 0:24 (L:D) for larvae and 12:12 (L:D) in concern to the other stages, respectively. ALong the ten successive generations, there were no significant differences between the larval periods for both the artificial diets. The S.A.D2 induced the shortest (24.0 days) larval period compared with the natural diet (27.5 days) and S.A.D1 (31.5 days). Rearing larvae on the natural diets revealed a pupal period of 11.0 days, while it was 10.0 days and 8.5 days for the artificial diets (S.A.D1) and in (S.A.D2), in respect. Moth longevity (pre-oviposition, oviposition and post-oviposition periods), to a certain extent, was affected by the larval diets. The maximal moth longevity (13.0 days) was observed for larva reared on corn plants (4, 8 and 1 days). On the other hand, the shortest period (10.5 days) of moth longevity was noticed in SAD2 (1, 9 and 0.5 days). S.A.D1 showed 11.0 days moth longevity (3,7 and 1 days). The longest oviposition period (9.0 days) was recorded in the artificial diet S.A.D2, while it was only 7.0 days in the artificial diet S.A.D1 compared with 8.0 days in case of the natural diet. The number of deposited eggs increased with the progress of the 10 successive generations (G1:G10) from 150 to 265 and from 384 eggs to 564 eggs / female for the S.A.D1 and S.A.D2, in sequence. The highest mean number of deposited eggs per female (564) was for the derived females from larvae fed on the artificial diet in G10 of S.A.D2. The rate of the deposited eggs in S.A.D2 was gradually increased (from 9.70 to 61.14% increase) more than those reared on the natural diet throughout the ten generations. The highest significant percent hatchability (92.69%) has been resulted from the artificial diet SAD2. But, it has been decreased to 85.59% in the artificial diet S.A.D1 in comparison to 65.71% in the natural diet. In addition, the significant shortest total generation period was 44.0 days resulted from the artificial diet S.A.D2, while it was 53.5 and 54.0 days for corn plants and the artificial diet S.A.D1, consequently. In short, results indicated that the S.A.D2 could be considered as a suitable artificial diet for a feasible mass rearing of the pink corn borer, Sesamia cretica led. The S.A.D2 showed the shortest larval, pupal and life span for the generation periods. Moreover, it induced the longest oviposition period and the highest mean number of deposited eggs per female and the highest significant percent of eggs hatchability/fertility. The utilization of this artificial diet (S.A.D2) would supply the researchers with high-quality insects in adequate numbers, at specified times and specific stages of development for the bioassay, toxicological and biological studies.  相似文献   
105.
Five tested plant volatile oils and their mixtures were evaluated for controlling the coccid, Saissetia coffeae (Walker) on growing Sago palms Cycas revoluta in Antoniades public gardens, Alexandria, Egypt. The tested volatile oils at concentration rates of 0.5, 1 and 1.5% (v/v) were: Camphor 20%, Dill 20%, Rose 30%, Peppermint 20% and Clove 30% (v/v). Their mixtures were : Camphor/Peppermint, Camphor/Rose at a rate of 1:1, Camphor/Rose/Peppermint at 1:1:2 rate and Camphor/Rose/Dill at 2:1:1 rate. The results, as a general mean of residual reduction percent for the whole inspection intervals of the test lasted 2 days up to 9 days post treatment, indicated that the superior volatile oils in reducing the insect were both Camphor and Rose, followed by Dill, Peppermint and the least efficient one was the Clove oil. The evaluated mixtures of the volatile oils showed that each of Camphor/Rose/Peppermint, Camphor/Rose and Camphor/Peppermint mixtures attained a higher rank of efficiency against that of the assigned soft scale insect.  相似文献   
106.
The authors describe an easy-to-use barcode-based animal tracking system that has improved record keeping and data retrieval and proved instrumental in the containment of an outbreak.  相似文献   
107.
The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCdelta, but not PKCalpha or PKCbeta, is required for collagen-induced phospholipase C-dependent signaling, activation of alpha(IIb)beta(3), and platelet aggregation. Analysis of PKCdelta phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by alpha(IIb)beta(3) outside-in signaling. Moreover, PKCdelta triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A(2), which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCdelta signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A(2).  相似文献   
108.
In plants, nucleobase biochemistry is highly compartmented relying upon a well-regulated and selective membrane transport system. In Arabidopsis two proteins, AtAzg1 and AtAzg2, show substantial amino acid sequence similarity to the adenine-guanine-hypoxanthine transporter AzgA of Aspergillus nidulans. Analysis of single and double mutant lines harboring T-DNA insertion alleles AtAzg1-1 and AtAzg2-1 reveal a marked resistance to growth in the presence of 8-azaadenine and 8-azaguanine but not to other toxic nucleobase analogues. Conversely, yeast strains expressing AtAzg1 and AtAzg2 gain heightened sensitivity to growth on 8-azaadenine and 8-azaguanine. Radio-labeled purine uptake experiments in yeast and in planta confirm the function of AtAzg1 and AtAzg2 as plant adenine-guanine transporters.  相似文献   
109.
Type 1 diabetes (T1D) is an autoimmune disease (AID) with both genetic and environmental components. We aimed to investigate the genetic association of polymorphisms in genes previously linked with other AIDs, namely BANK1, IL15 and IL2/IL21 region.  相似文献   
110.
Amphibia egg jelly coats are formed by components secreted along the oviduct. These secretion products overlay the oocytes as they pass along the different oviducal portions. Mucin type glycoproteins are the major constituents of the egg jelly coats. In this study, the O-linked carbohydrate chains of the jelly coats surrounding the eggs of Rana ridibunda were released by alkaline borohydride treatment. Fractionation of the mixture of O-linked oligosaccharide-alditols was achieved by a combination of chromatographic techniques including gel-permeation chromatography, ion-exchange chromatography and high-performance liquid chromatography using an amino-bonded silica column. The primary structures of these O-glycans were determined by one-dimensional and two-dimensional 1H-NMR spectroscopy and matrix-assisted laser-desorption-ionization-time-of flight mass spectrometry. 25 oligosaccharide structures, possessing a core consisting of Gal(beta1-3)GalNAc-ol with or without branching through a GlcNAc residue linked (beta1-6) to the GalNAc residue (core type 2 or core type 1, respectively) are described. The most representative antennae are: HSO3(6)[Fuc(alpha1-3)]GlcNAc; Gal(beta1-2)Gal; Gal(beta1-2)Gal(alpha1-3)[Fuc(alpha1-2)]Gal; GlcA(beta1-3)-Gal(beta1-3)[Fuc(alpha1-2)]Gal; GalNAc(alpha1-4)Gal(beta1-4)Gal; Gal(beta1-3)GalNAc(alpha1-4)Gal(beta1-4)Gal and GlcA(beta1-3)Gal(beta1-3)GalNAc. These results confirm the species-specific O-glycosylation of Amphibia oviducal mucins. The significance of this observation should be linked to a symbiotic role of carbohydrates involved in host-parasite interactions.  相似文献   
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