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101.
Advances in the field of targeted proteomics and mass spectrometry have significantly improved assay sensitivity and multiplexing capacity. The high-throughput nature of targeted proteomics experiments has increased the rate of data production, which requires development of novel analytical tools to keep up with data processing demand. Currently, development and validation of targeted mass spectrometry assays require manual inspection of chromatographic peaks from large datasets to ensure quality, a process that is time consuming, prone to inter- and intra-operator variability and limits the efficiency of data interpretation from targeted proteomics analyses. To address this challenge, we have developed TargetedMSQC, an R package that facilitates quality control and verification of chromatographic peaks from targeted proteomics datasets. This tool calculates metrics to quantify several quality aspects of a chromatographic peak, e.g. symmetry, jaggedness and modality, co-elution and shape similarity of monitored transitions in a peak group, as well as the consistency of transitions’ ratios between endogenous analytes and isotopically labeled internal standards and consistency of retention time across multiple runs. The algorithm takes advantage of supervised machine learning to identify peaks with interference or poor chromatography based on a set of peaks that have been annotated by an expert analyst. Using TargetedMSQC to analyze targeted proteomics data reduces the time spent on manual inspection of peaks and improves both speed and accuracy of interference detection. Additionally, by allowing the analysts to customize the tool for application on different datasets, TargetedMSQC gives the users the flexibility to define the acceptable quality for specific datasets. Furthermore, automated and quantitative assessment of peak quality offers a more objective and systematic framework for high throughput analysis of targeted mass spectrometry assay datasets and is a step towards more robust and faster assay implementation.  相似文献   
102.
In this paper, we develop a 3D-individual-based model (IBM) to understand effect of various small-scale mechanisms in phytoplankton cells, on the cellular aggregation process. These mechanisms are: spatial interactions between cells due to their chemosensory abilities (chemotaxis), a molecular diffusion and a demographical process. The latter is considered as a branching process with a density-dependent death rate to take into account the local competition on resources. We implement the IBM and simulate various scenarios under real parameter values for phytoplankton cells. To quantify the effects of the different processes quoted above on the spatial and temporal distribution of phytoplankton, we used two spatial statistics: the Clark–Evans index and the group belonging percentage. Our simulation study highlights the role of the branching process with a weak-to-medium competition in reinforcing the aggregating structure that forms from attraction mechanisms (under suitable conditions for diffusion and attraction forces), and shows by contrast that aggregations cannot form when competition is high.  相似文献   
103.
The aim of this work is to propose methods to test mechanism of synergy of toxic agents in bees. A synergy between prochloraz, an imidazole fungicide, and deltamethrin, a pyrethroid insecticide, was demonstrated experimentally. The hypothesis is that prochloraz modifies the penetration or the metabolism of deltamethrin. This hypothesis is tested using a pharmacokinetic box model. A previous experimental work showed that bee instantaneous mortalities were higher, from the time t 1 to the time t 2 after spraying, in groups sprayed with deltamethrin at dose D 0 in the presence of prochloraz (+P) than in those sprayed with deltamethrin alone at a dose time as high (). We postulate that accrued mortality is proportional to the cumulated internal deltamethrin (ID 2). ID 2 of treatment (+P) had to be greater than ID 2 of treatment () during the period from t 1 to t 2 so that the hypothesis would be consistent with the experimental data. The limit, for which the hypothesis is conceivable, is the ID 2() = ID 2(+P ) curve. We study, in particular, the asymptotic behaviour of the limit curve when different parameters of the kinetic model tend to 0 or . These limits allow to verify quickly and easily whether a mechanism is conceivable or not As the limits are calculated with algebraic values, the test can be used for other synergies.  相似文献   
104.
The catalyzed coupling reaction of activated alcohol and mercaptan was used for the short and efficient synthesis of 14 thioether compounds. Two types of side chains, the methyl butyl alkylamide related to the pure steroidal antiestrogen ICI 164384 and the dimethylamino ethyloxy phenyl related to the clinically used nonsteroidal antiestrogen tamoxifen, were introduced by a thioether link on two types of nuclei (triphenylethane or estradiol). The new thioether derivatives were tested to assess their relative binding affinity for the estrogen receptor and their estrogenic or antiestrogenic activity in the ZR-75-1 (ER+) cell line. The results indicate that of the three types of compounds studied, only the nonsteroidal derivatives with an alkylamide side chain possess antiestrogenic activity. In the steroidal series, displacement of the alkylamide side chain from the 7 to the 6 position produced compounds with chemical characteristics similar to ICI 164384 or EM-139 but without antiestrogenic activity. In the nonsteroidal series of compounds with an aryl side chain, compounds with estrogenic activity were obtained. One compound, a nonsteroidal derivative with a methyl butyl alkylamide side chain 20, possesses a relative binding affinity for the estrogen receptor identical to EM-139 (1.1 and 1.2%, respectively) and a relatively good antiestrogenic activity that is 10-fold lower than EM-139 (IC50 values of 250 and 25 nM, respectively). This nonsteroidal thioether with an alkylamide side chain is free of estrogenic activity.  相似文献   
105.
Summary Several studies have recently been conducted on cultured skin equivalent (SE), prepared using human keratinocytes seeded on various types of dermal equivalents (DE). We previously showed the advantages of our anchorage method in preventing the severe surface reduction of DE due to fibroblast contractile properties in vitro. A new anchored human SE was established in our laboratory in order to obtain a bioengineered tissue that would possess the appropriate histological and biological properties. In order to compare the effects of different collagen origins on the evolution of SE in vitro, human keratinocytes were seeded on three types of anchored DE. A comparative study was carried out between bovine SE (bSE), human SE (hSE), and human skin equivalent containing additional dermal matrix components (hSE +). Immunohistological analysis showed that hSE and hSE+ presented good structural organization, including the deposition of several basement membrane constituents. Higher amounts of transglutaminase, ceramides, and keratin 1 were detected in the epidermal layers of all SE when cultured at the air-liquid interface. However, a 92 kDa gelatinase activity was higher in bovine skin equivalent (bSE) compared to hSE cultures. The use of human collagens comparatively to bovine collagen as SE matricial component delayed the degradation of the dermal layer in culture.  相似文献   
106.
Computer-aided sperm analysis (CASA) was developed in the last decade to overcome the problems related to the inherent subjectivity of manual semen analysis. A typical CASA system includes a video camera, a microscope equiped with phase optics and a warming stage, a microcomputer with hardware and software dedicated to motion analysis, a monitor and a printer. The image of the sperm cells under the microscope is transformed into discrete pixels producing a voltage proportional to the intensity of the light as light strikes the camera’s CCD array. In standard video technology, the first field (set of rows; odd lines) is scanned in one sixtieth of a second and remains illuminated, then the alternate set of rows (even lines) is scanned in the next one sixtieth of a second to display the complete video frame which requires one thirthieth of a second. The first step called digitization is the encoding of video pixels as numbers following a gray level scale between white and black. From this process the detection of the sperm heads in the field is performed and repeated on a field by field basis. The centroïd coordinates of the sperm heads in the field are calculated and sequentially transmitted to the hard disk. A path finder algorithm connects the centroïds through time allowing the reconstruction of trajectories and the calculation of various parameters. Many factors modulating CASA measurements can invalidate the results of analysis. Consequently, a standardization of CASA is necessary. Various guidelines for accurate analysis are proposed. In summary, basic knowledge on sperm physiology, CASA technology and rigorous standardized conditions of analysis are required for providing reliable and accurate results because CASA systems are not ready-to-use “robots”. CASA is useful for routine semen analysis and essential for the measurement of sperm kinematics for clinical as well as for research purposes.  相似文献   
107.
-Dihydroheptaprenyl-pyrophosphoryl- N-acetylmuramoyl-L-Ala--D-Glu- meso-diaminopimeloyl(N-dansyl)-D-Ala-D-Ala ( 1), an analogue of lipid I ofpeptidoglycan biosynthesis, was synthesized from natural UDP-N-acetylmuramoyl-pentapeptide in three steps. Compound 1 was shown to be asubstrate for the MurG transferase from Escherichia coli, even in theabsence of membranes. When membranes were present, dansylated peptidoglycanwas also formed.  相似文献   
108.
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles. Here, we show that FUS disrupts the VAPB–PTPIP51 interaction and ER–mitochondria associations. These disruptions are accompanied by perturbation of Ca2+ uptake by mitochondria following its release from ER stores, which is a physiological read‐out of ER–mitochondria contacts. We also demonstrate that mitochondrial ATP production is impaired in FUS‐expressing cells; mitochondrial ATP production is linked to Ca2+ levels. Finally, we demonstrate that the FUS‐induced reductions to ER–mitochondria associations and are linked to activation of glycogen synthase kinase‐3β (GSK‐3β), a kinase already strongly associated with ALS/FTD.  相似文献   
109.
A low molecular weight compound, which inhibits the G1-S transition in rat hepatocytes, was obtained by tryptic hydrolysis of human alpha 2-macroglobulin followed by ultrafiltration at pH 10. It was purified by high-performance liquid chromatography on mu Bondapak C18 and mu Bondapak NH2 with a practically quantitative yield; from 5.1 g of alpha 2-macroglobulin, 2.8 micrograms of purified compound were recovered. Inactivation by specific enzymes and chemical analyses showed that the inhibitor is a sialylated glycopeptide whose peptide moiety contains a pyroglutamyl residue. Its molecular mass, estimated by gel permeation chromatography, would be in the interval 3,500-4,600. However, amino acid analyses indicated that it is not yet pure. All these data suggest that alpha 2-macroglobulin could be the carrier of the precursor form of the glycopeptide.  相似文献   
110.
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