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Preparation of novel 9-pyrrolo-9-deoxoerythromycin A analogs from 9-(S) and (R, erythromycylamines by the Clauson-Kass and Wasserman reactions is described. The biological activities of these novel analogs are also reported. 相似文献
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Catherine A. Blizzard Katherine A. Southam Edgar Dawkins Katherine E. Lewis Anna E. King Jayden A. Clark Tracey C. Dickson 《Disease models & mechanisms》2015,8(3):215-224
There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.KEY WORDS: Motor neuron disease, Amyotrophic lateral sclerosis, Excitotoxicity, Lower motor neuron, Excitotoxin exposure 相似文献
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Tan Van Bui Christopher Leigh Blizzard Khue Ngoc Luong Ngoc Le Van Truong Bao Quoc Tran Petr Otahal Velandai Srikanth Mark Raymond Nelson Thuy Bich Au Son Thai Ha Hai Ngoc Phung Mai Hoang Tran Michele Callisaya Seana Gall 《PloS one》2015,10(10)
IntroductionOur aims were to provide the first national estimates of physical activity (PA) for Vietnam, and to investigate issues affecting their accuracy.MethodsMeasurements were made using the Global Physical Activity Questionnaire (GPAQ) on a nationally-representative sample of 14706 participants (46.5% males, response 64.1%) aged 25−64 years selected by multi-stage stratified cluster sampling.ResultsApproximately 20% of Vietnamese people had no measureable PA during a typical week, but 72.9% (men) and 69.1% (women) met WHO recommendations for PA by adults for their age. On average, 52.0 (men) and 28.0 (women) Metabolic Equivalent Task (MET)-hours/week (largely from work activities) were reported. Work and total PA were higher in rural areas and varied by season. Less than 2% of respondents provided incomplete information, but an additional one-in-six provided unrealistically high values of PA. Those responsible for reporting errors included persons from rural areas and all those with unstable work patterns. Box-Cox transformation (with an appropriate constant added) was the most successful method of reducing the influence of large values, but energy-scaled values were most strongly associated with pathophysiological outcomes.ConclusionsAround seven-in-ten Vietnamese people aged 25–64 years met WHO recommendations for total PA, which was mainly from work activities and higher in rural areas. Nearly all respondents were able to report their activity using the GPAQ, but with some exaggerated values and seasonal variation in reporting. Data transformation provided plausible summary values, but energy-scaling fared best in association analyses. 相似文献
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1. The increase of species richness with the area of the habitat sampled, that is the species–area relationship, and its temporal analogue, the species–time relationship (STR), are among the few general laws in ecology with strong conservation implications. However, these two scale‐dependent phenomena have rarely been considered together in biodiversity assessment, especially in freshwater systems. 2. We examined how the spatial scale of sampling influences STRs for a Central‐European stream fish assemblage (second‐order Bernecei stream, Hungary) using field survey data in two simulation‐based experiments. 3. In experiment one, we examined how increasing the number of channel units, such as riffles and pools (13 altogether), and the number of field surveys involved in the analyses (12 sampling occasions during 3 years), influence species richness. Complete nested curves were constructed to quantify how many species one observes in the community on average for a given number of sampling occasions at a given spatial scale. 4. In experiment two, we examined STRs for the Bernecei fish assemblage from a landscape perspective. Here, we evaluated a 10‐year reach level data set (2000–09) for the Bernecei stream and its recipient watercourse (third‐order Kemence stream) to complement results on experiment one and to explore the mechanisms behind the observed patterns in more detail. 5. Experiment one indicated the strong influence of the spatial scale of sampling on the accumulation of species richness, although time clearly had an additional effect. The simulation methodology advocated here helped to estimate the number of species in a diverse combination of spatial and temporal scale and, therefore, to determine how different scale combinations influence sampling sufficiency. 6. Experiment two revealed differences in STRs between the upstream (Bernecei) and downstream (Kemence) sites, with steeper curves for the downstream site. Equations of STR curves were within the range observed in other studies, predominantly from terrestrial systems. Assemblage composition data suggested that extinction–colonisation dynamics of rare, non‐resident (i.e. satellite) species influenced patterns in STRs. 7. Our results highlight that the determination of species richness can benefit from the joint consideration of spatial and temporal scales in biodiversity inventory surveys. Additionally, we reveal how our randomisation‐based methodology may help to quantify the scale dependency of diversity components (α, β, γ) in both space and time, which have critical importance in the applied context. 相似文献
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An estimate of the risk or prevalence ratio, adjusted for confounders, can be obtained from a log binomial model (binomial errors, log link) fitted to binary outcome data. We propose a modification of the log binomial model to obtain relative risk estimates for nominal outcomes with more than two attributes (the "log multinomial model"). Extensive data simulations were undertaken to compare the performance of the log multinomial model with that of an expanded data multinomial logistic regression method based on the approach proposed by Schouten et al. (1993) for binary data, and with that of separate fits of a Poisson regression model based on the approach proposed by Zou (2004) and Carter, Lipsitz and Tilley (2005) for binary data. Log multinomial regression resulted in "inadmissable" solutions (out-of-bounds probabilities) exceeding 50% in some data settings. Coefficient estimates by the alternative methods produced out-of-bounds probabilities for the log multinomial model in up to 27% of samples to which a log multinomial model had been successfully fitted. The log multinomial coefficient estimates generally had lesser relative bias and mean squared error than the alternative methods. The practical utility of the log multinomial regression model was demonstrated with a real data example. The log multinomial model offers a practical solution to the problem of obtaining adjusted estimates of the risk ratio in the multinomial setting, but must be used with some care and attention to detail. 相似文献
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Michael D Kennedy Mark J Haykowsky Carol A Boliek Ben TA Esch Jessica M Scott Darren ER Warburton 《Dynamic medicine : DM》2006,5(1):8