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排序方式: 共有267条查询结果,搜索用时 15 毫秒
31.
James Mu Sajjad A. Qureshi Edward J. Brady Eric S. Muise Mari Rios Candelore Guoqiang Jiang Zhihua Li Margaret S. Wu Xiaodong Yang Qing Dallas-Yang Corey Miller Yusheng Xiong Ronald B. Langdon Emma R. Parmee Bei B. Zhang 《PloS one》2012,7(11)
Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism. 相似文献
32.
Marie-José Gaillard Shinya Sugita M. Jane Bunting Richard Middleton Anna Broström Christopher Caseldine Thomas Giesecke Sophie E. V. Hellman Sheila Hicks Kari Hjelle Catherine Langdon Anne-Birgitte Nielsen Anneli Poska Henrik von Stedingk Sim Veski 《Vegetation History and Archaeobotany》2008,17(5):419-443
Information on past land cover in terms of absolute areas of different landscape units (forest, open land, pasture land, cultivated
land, etc.) at local to regional scales is needed to test hypotheses and answer questions related to climate change (e.g.
feedbacks effects of land-cover change), archaeological research, and nature conservancy (e.g. management strategy). The palaeoecological
technique best suited to achieve quantitative reconstruction of past vegetation is pollen analysis. A simulation approach
developed by Sugita (the computer model POLLSCAPE) which uses models based on the theory of pollen analysis is presented together
with examples of application. POLLSCAPE has been adopted as the central tool for POLLANDCAL (POLlen/LANdscape CALibration),
an international research network focusing on this topic. The theory behind models of the pollen–vegetation relationship and
POLLSCAPE is reviewed. The two model outputs which receive greatest attention in this paper are the relevant source area of
pollen (RSAP) and pollen loading in mires and lakes. Six examples of application of POLLSCAPE are presented, each of which
explores a possible use of the POLLANDCAL tools and a means of validating or evaluating the models with empirical data. The
landscape and vegetation factors influencing the size of the RSAP, the importance of pollen productivity estimates (PPEs)
for the model outputs, the detection of small and rare patches of plant taxa in pollen records, and quantitative reconstructions
of past vegetation and landscapes are discussed on the basis of these examples. The simulation approach is seen to be useful
both for exploring different vegetation/landscape scenarios and for refuting hypotheses. 相似文献
33.
Nicki J. Whitehouse Peter G. Langdon Richard Bustin Sarah Galsworthy 《Biodiversity and Conservation》2008,17(9):2055-2078
We review the uses of fossil insects, particularly Coleoptera (beetles) and Chironomidae (non-biting midges) from ancient
deposits to inform the study of wetland ecosystems and their ecological and restoration processes. In particular, we focus
on two contrasting ecosystems, drawing upon research undertaken by us on British raised mire peats and shallow lake systems,
one an essentially terrestrial ecosystem, the other aquatic, but in which wetland insects play an important and integral part.
The study of raised mire peats suggests that faunal stability is a characteristic of these wetland systems, over what appear
to be extensive periods of time (up to several millennia), whilst studies of shallow lake ecosystems over recent timescales
indicates that faunal instability appears to be more common, usually driven by increasing eutrophication. Drawing upon a series
of fossil Coleoptera records spanning several thousand years from Hatfield Moors, south Yorkshire, we reconstruct in some
detail the mire’s ontogeny and fluctuations in site hydrology and vegetation cover, illustrating the intimate association
between substrate, topography and peat development. A comparison between fossil and modern beetle populations indicates that
the faunal characteristics of this mire and its adjacent neighbour, Thorne Moors, become established during the early phases
of peat development, including its rare endemics, and that the faunal biodiversity on the sites today is dictated by complex
site histories. The over-riding characteristic of these faunas is of stability over several thousand years, which has important
implications for the restoration of degraded sites, especially those where refugial areas are limited. In contrast, analyses
of fossil Chironomidae from shallow lakes allow researchers to track changes in limnological status and while attempts have
been made to reconstruct changes in nutrient levels quantitatively, the chironomids respond indirectly to such changes, typically
mediated through complex ecosystem dynamics such as changes in fish and/or macrophyte communities. These changes are illustrated
via historic chironomid stratigraphies and diversity indices from a range of shallow lakes located across Britain: Slapton
Ley, Frensham Great Pond, Fleet Pond, Kyre Pool and Barnes Loch. These sites have shown varying degrees of eutrophication
over recent timescales which tends to be associated with a decline in chironomid diversity. While complex functional processes
exist within these ecosystems, our evidence suggests that one of the key drivers in the loss of shallow lake chironomid diversity
appears to be the loss of aquatic macrophytes. Overall, while chironomids do show a clear response to altered nutrient regimes,
multi-proxy reconstructions are recommended for a clear interpretation of past change. We conclude that if we are to have
a better understanding of biota at the ecosystem level we need to know more of the complex interactions between different
insect groups as well as with other animal and plant communities. A palaeoecological approach is thus crucial in order to
assess the role of insect groups in ecosystem processes, both in the recent past and over long time scales, and is essential
for wetland managers and conservation organisations involved in long term management and restoration of wetland systems 相似文献
34.
T R Thomas K E Horner M M Langdon J Q Zhang E S Krul G Y Sun R H Cox 《Journal of applied physiology》2001,90(4):1239-1246
The purpose of this study was to evaluate the effect of medium-chain triglycerides (MCT) with and without exercise on postprandial lipemia (PPL). Subjects were 25 young men and women. Each subject performed three trials: 1) control (fat meal only, 1.5 g fat/kg) 2) MCT (substitution of MCT oil, 30% of fat calories), and 3) MCT + Ex (exercise 12 h before the MCT meal). Before each trial, the subject underwent consistent dietary preparation. Blood was collected on 2 separate days for baseline measurements of postheparin lipases and, in each trial, at 0 h (premeal), at 2, 4, 6, and 8 h after the fat meal for triglycerides and cholesterol ester transfer protein (CETP), and at 8 h for postheparin lipoprotein lipase (LPL) and hepatic lipase activities (HL). ANOVA indicated that the partial substitution of MCT oil to the fat meal did not affect the PPL response. However, the PPL was significantly lower after the MCT + Ex trial vs. the other trials. LPL activity was significantly elevated after all trials compared with baseline, whereas HL was lower in the MCT + Ex trial only. CETP mass was significantly lower at 4 and 8 h than 0 h during all trials but relatively higher in the MCT + Ex trial vs. the nonexercise trials. These results suggest that MCT does not affect the TG response to a fat meal. LPL and CETP are affected by a fat meal with or without exercise, but HL is affected only when exercise is included. 相似文献
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36.
Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. 总被引:31,自引:0,他引:31
R Feng C Rampon Y P Tang D Shrom J Jin M Kyin B Sopher M W Miller C B Ware G M Martin S H Kim R B Langdon S S Sisodia J Z Tsien 《Neuron》2001,32(5):911-926
To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain. 相似文献
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