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排序方式: 共有200条查询结果,搜索用时 46 毫秒
101.
102.
Daniel G.M. Shore Zachary K. Sweeney Alan Beresford Bryan K. Chan Huifen Chen Jason Drummond Andrew Gill Tracy Kleinheinz Xingrong Liu Andrew D. Medhurst Edward G. McIver John G. Moffat Haitao Zhu Anthony A. Estrada 《Bioorganic & medicinal chemistry letters》2019,29(4):674-680
The discovery of disease-modifying therapies for Parkinson’s Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration. 相似文献
103.
Crout NM Beresford NA Mayes RW MacEachern PJ Barnett CL Lamb CS Howard BJ 《Radiation and environmental biophysics》2000,39(1):59-65
Previously reported models for radioiodine in ruminants cannot account for the effect of variations in stable iodine intake
including large countermeasure doses of stable iodine on the transfer of radioiodine to goat milk. A metabolically based model
of radioiodine transfer in goats has been parameterised using new experimental data on the effect of countermeasure doses
of stable iodine on radioiodine transfer to milk. To account for the effect of dietary stable iodine levels, the model represents
the transfer of iodine from the extracellular fluid to milk with Michaelis-Menten kinetics. The model shows good agreement
with the experimental data, and the estimated parameters compare favourably with values which can be estimated from the literature.
The parameterised model accounts for 95% of the variation in the observed data for milk, faeces, urine and thyroid (n=199). The model has been used to predict the effects of variation in stable iodine intake and the extent of consequent chemical
contamination of milk by stable iodine. The time taken for radio-iodine to reach peak concentrations in milk following a deposition
event is predicted to vary significantly (ca. 2 days) over a range of expected stable iodine intakes. Doses of stable iodine
sufficient to reduce the radioiodine transfer to milk will result in stable iodine concentrations in milk greatly in excess
of internationally advised limits. Therefore, we recommend that stable iodine supplementation not be used as a countermeasure
to reduce radioiodine transfer to milk. Indeed, model predictions suggest that reductions in stable iodine intake would be
a more effective countermeasure. However, this is unlikely to be feasible since the short physical half-life of 131I may not allow adequate time to implement changes in feed manufacture. The model described in this paper is freely available
in ModelMaker 3.0 format (http://www.notingham.ac.uk/environmental-modelling/).
Received: 16 August 1999 / Accepted in revised form: 15 November 1999 相似文献
104.
Time series data are commonly obtained by trapping over a standardized period of time, for example daily or weekly. In this paper we present evidence that such sampling designs are inherently irregularly spaced due to the varying developmental rates and population parameters caused by changing temperatures during a sampling season. We modeled an exponentially growing population based on stable fly population growth rates, and then compare different sampling regimes to determine which produces the best estimate of population growth rate. These results are then compared to field data based on weekly sampling at three dairy farms in Ontario over two summers. Transforming catch numbers (N) to ln(N)/(number of degree days within the sampling period) corrects for the irregular spaced sampling in these data. These results support the use of measuring population parameters such as population growth rates in terms of degree days. 相似文献
105.
106.
David M. Wilson James Apps Nicholas Bailey Mark J. Bamford Isabel J. Beresford Kim Brackenborough Michael A. Briggs Stephen Brough Andrew R. Calver Barry Crook Rebecca K. Davis Robert P. Davis Susannah Davis David K. Dean Leanne Harris Teresa Heslop Vicky Holland Phillip Jeffrey Andrew D. Medhurst 《Bioorganic & medicinal chemistry letters》2013,23(24):6890-6896
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer’s disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties. 相似文献
107.
108.
Chowdhury D Beresford PJ Zhu P Zhang D Sung JS Demple B Perrino FW Lieberman J 《Molecular cell》2006,23(1):133-142
Granzyme A (GzmA) activates a caspase-independent cell death pathway with morphological features of apoptosis. Single-stranded DNA damage is initiated when the endonuclease NM23-H1 becomes activated to nick DNA after granzyme A cleaves its inhibitor, SET. SET and NM23-H1 reside in an endoplasmic reticulum-associated complex (the SET complex) that translocates to the nucleus in response to superoxide generation by granzyme A. We now find the 3'-to-5' exonuclease TREX1, but not its close homolog TREX2, in the SET complex. TREX1 binds to SET and colocalizes and translocates with the SET complex. NM23-H1 and TREX1 work in concert to degrade DNA. Silencing NM23-H1 or TREX1 inhibits DNA damage and death of cells treated with perforin (PFN) and granzyme A, but not of cells treated with perforin and granzyme B (GzmB). After granzyme A activates NM23-H1 to make single-stranded nicks, TREX1 removes nucleotides from the nicked 3' end to reduce the possibility of repair by rejoining the nicked ends. 相似文献
109.
Juvenile roach Rutilus rutilus from seven rivers of varying water quality were examined for evidence of endocrine disruption. The majority of roach from five of these rivers had female‐like reproductive ducts. The results suggest that juvenile, rather than adult, fish could be used in studies of endocrine disruption in wild fish populations. 相似文献
110.