全文获取类型
收费全文 | 1555篇 |
免费 | 131篇 |
出版年
2023年 | 4篇 |
2022年 | 6篇 |
2021年 | 25篇 |
2020年 | 18篇 |
2019年 | 20篇 |
2018年 | 25篇 |
2017年 | 25篇 |
2016年 | 35篇 |
2015年 | 77篇 |
2014年 | 93篇 |
2013年 | 107篇 |
2012年 | 124篇 |
2011年 | 109篇 |
2010年 | 89篇 |
2009年 | 75篇 |
2008年 | 117篇 |
2007年 | 100篇 |
2006年 | 94篇 |
2005年 | 93篇 |
2004年 | 86篇 |
2003年 | 78篇 |
2002年 | 95篇 |
2001年 | 16篇 |
2000年 | 10篇 |
1999年 | 25篇 |
1998年 | 17篇 |
1997年 | 14篇 |
1996年 | 17篇 |
1995年 | 11篇 |
1994年 | 15篇 |
1993年 | 11篇 |
1992年 | 9篇 |
1991年 | 10篇 |
1990年 | 7篇 |
1989年 | 2篇 |
1987年 | 6篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1957年 | 1篇 |
1921年 | 1篇 |
排序方式: 共有1686条查询结果,搜索用时 281 毫秒
151.
Kinzel O Alfieri A Altamura S Brunetti M Bufali S Colaceci F Ferrigno F Filocamo G Fonsi M Gallinari P Malancona S Hernando JI Monteagudo E Orsale MV Palumbi MC Pucci V Rowley M Sasso R Scarpelli R Steinkühler C Jones P 《Bioorganic & medicinal chemistry letters》2011,21(15):4429-4435
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development. 相似文献
152.
Lin F Sherris D Beijnen JH Van Tellingen O 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2011,879(32):3823-3831
Palomid 529 (8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one), is a novel non-steroidal small-molecule drug, which inhibits both mTORC1 and mTORC2 assembly, and elicits both anti-angiogenic and direct anti-tumor effects in vivo. We have developed and validated a sensitive and selective method for the quantification of Palomid 529 in human and mouse plasma and in a range of mouse tissue samples. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether yielding a recovery of >75%. Palomid 529 and the internal standard Palomid 545 were separated using a GraceSmart RP18 column (2.1 mm × 150 mm) packed with 5 μm C-18 material and a mobile phase comprised of 50% (v/v) acetonitrile and 50% (v/v) water delivered at a flow rate of 0.2 ml/min, and were detected by UV absorbance at a wavelength of 315 nm. Within the linear range of the calibration curve (10-10,000 ng/ml), acceptable accuracy and precision was achieved for all tested matrices. The validation results show that the method was selective and reproducible. Palomid 529 was stable in plasma upon 3 repeated freeze-thaw cycles and during storage for up to 24h at ambient temperature. However, pre-treated samples waiting for HPLC analyses need to be kept under dimmed light conditions at ambient temperature since a significant degradation of both Palomid 529 and Palomid 545 was observed when exposed to light. A pilot pharmacokinetic study in mice demonstrated the applicability of this method for pharmacokinetic purposes. Even at a low dose of 5.4 mg/kg this assay was still sensitive enough to determine the drug concentration in plasma samples obtained up to 24h after administration. 相似文献
153.
Climate change is expected to cause changes in precipitation quantity, intensity, frequency and duration, which will subsequently
alter environmental conditions and might increase the risk of waterborne disease. The objective of this study was to describe
the seasonality of and explore associations between weather, water quality and occurrence of infectious gastrointestinal illnesses
(IGI) in two communities in Nunatsiavut, Canada. Weather data were obtained from meteorological stations in Nain (2005–2008)
and Rigolet (2008). Free-chlorine residual levels in drinking water were extracted from municipal records (2005–2008). Raw
surface water was tested weekly for total coliform and E. coli counts. Daily counts of IGI-related clinic visits were obtained from health clinic registries (2005–2008). Analysis of weather
and health variables included seasonal-trend decomposition procedures based on Loess. Multivariable zero-inflated Poisson
regression was used to examine potential associations between weather events (considering 0–4 week lag periods) and IGI-related
clinic visits. In Nain, water volume input (rainfall + snowmelt) peaked in spring and summer and was positively associated
with levels of raw water bacteriological variables. The number of IGI-related clinic visits peaked in the summer and fall
months. Significant positive associations were observed between high levels of water volume input 2 and 4 weeks prior, and
IGI-related clinic visits (P < 0.05). This study is the first to systematically gather, analyse and compare baseline data on weather, water quality and
health in Nunatsiavut, and illustrates the need for high quality temporal baseline information to allow for detection of future
impacts of climate change on regional Inuit human and environmental health. 相似文献
154.
Aldo S. Pacheco Maria Teresa González Julie Bremner Marcelo Oliva Olaf Heilmayer Jürgen Laudien José M. Riascos 《Helgoland Marine Research》2011,65(3):413-424
Benthic communities show changes in composition and structure across different environmental characteristics and habitats.
However, incorporating species biological traits into the analysis can provide a better understanding of system functioning
within habitats. We compare the functional diversity of macrobenthic communities from a contrasting shallow (15 m) and deep
(50 m) sublittoral soft-sediment habitats in northern Chile, using biological traits analysis. Our aim was to highlight the
biological characteristics responsible for differences between habitats and the implications for ecosystem functioning. Trait
analysis showed that the deep habitat was restricted in providing functionally important biogenic structure and bioturbation
and supports less diverse feeding-related energy pathways. The shallow habitat is characterized by more diverse energy pathways
and a higher potential for matter exchange through bioturbation. We provide support to the predictions of transfer of energy
from the benthos to upper trophic levels in the shallow, which is characterized mainly by normoxia and little organic matter
content in the sediment. In the deep habitat, characterized by hypoxia and more organic matter, energy appears to be transferred
to microbial components. We suggest that trait analysis should be added to the traditional approaches based on species diversity,
because it provides indicators of ecosystem stress. 相似文献
155.
Architects at the bacterial surface - sortases and the assembly of pili with isopeptide bonds 总被引:1,自引:0,他引:1
The cell wall envelope of Gram-positive bacteria can be thought of as a surface organelle for the assembly of macromolecular structures that enable the unique lifestyle of each microorganism. Sortases - enzymes that cleave the sorting signals of secreted proteins to form isopeptide (amide) bonds between the secreted proteins and peptidoglycan or polypeptides - function as the principal architects of the bacterial surface. Acting alone or with other sortase enzymes, sortase construction leads to the anchoring of surface proteins at specific sites in the envelope or to the assembly of pili, which are fibrous structures formed from many protein subunits. The catalysis of intermolecular isopeptide bonds between pilin subunits is intertwined with the assembly of intramolecular isopeptide bonds within pilin subunits. Together, these isopeptide bonds endow these sortase products with adhesive properties and resistance to host proteases. 相似文献
156.
Merrifield CA Lewis M Claus SP Beckonert OP Dumas ME Duncker S Kochhar S Rezzi S Lindon JC Bailey M Holmes E Nicholson JK 《Molecular bioSystems》2011,7(9):2577-2588
The pig is a single-stomached omnivorous mammal and is an important model of human disease and nutrition. As such, it is necessary to establish a metabolic framework from which pathology-based variation can be compared. Here, a combination of one and two-dimensional (1)H and (13)C nuclear magnetic resonance spectroscopy (NMR) and high-resolution magic angle spinning (HR-MAS) NMR was used to provide a systems overview of porcine metabolism via characterisation of the urine, serum, liver and kidney metabolomes. The metabolites observed in each of these biological compartments were found to be qualitatively comparable to the metabolic signature of the same biological matrices in humans and rodents. The data were modelled using a combination of principal components analysis and Venn diagram mapping. Urine represented the most metabolically distinct biological compartment studied, with a relatively greater number of NMR detectable metabolites present, many of which are implicated in gut-microbial co-metabolic processes. The major inter-species differences observed were in the phase II conjugation of extra-genomic metabolites; the pig was observed to conjugate p-cresol, a gut microbial metabolite of tyrosine, with glucuronide rather than sulfate as seen in man. These observations are important to note when considering the translatability of experimental data derived from porcine models. 相似文献
157.
Maurizio Scarpa Zsuzsanna Almássy Michael Beck Olaf Bodamer Iain A Bruce Linda De Meirleir Nathalie Guffon Encarna Guillén-Navarro Pauline Hensman Simon Jones Wolfgang Kamin Christoph Kampmann Christina Lampe Christine A Lavery Elisa Leão Teles Bianca Link Allan M Lund Gunilla Malm Susanne Pitz Michael Rothera Catherine Stewart Anna Tylki-Szymańska Ans van der Ploeg Robert Walker Jiri Zeman James E Wraith 《Orphanet journal of rare diseases》2011,6(1):1-18
?
Mucopolysaccharidosis type II (MPS II) is a rare, life-limiting, X-linked recessive disease characterised by deficiency of the lysosomal enzyme iduronate-2-sulfatase. Consequent accumulation of glycosaminoglycans leads to pathological changes in multiple body systems. Age at onset, signs and symptoms, and disease progression are heterogeneous, and patients may present with many different manifestations to a wide range of specialists. Expertise in diagnosing and managing MPS II varies widely between countries, and substantial delays between disease onset and diagnosis can occur. In recent years, disease-specific treatments such as enzyme replacement therapy and stem cell transplantation have helped to address the underlying enzyme deficiency in patients with MPS II. However, the multisystem nature of this disorder and the irreversibility of some manifestations mean that most patients require substantial medical support from many different specialists, even if they are receiving treatment. This article presents an overview of how to recognise, diagnose, and care for patients with MPS II. Particular focus is given to the multidisciplinary nature of patient management, which requires input from paediatricians, specialist nurses, otorhinolaryngologists, orthopaedic surgeons, ophthalmologists, cardiologists, pneumologists, anaesthesiologists, neurologists, physiotherapists, occupational therapists, speech therapists, psychologists, social workers, homecare companies and patient societies.Take-home message
Expertise in recognising and treating patients with MPS II varies widely between countries. This article presents pan-European recommendations for the diagnosis and management of this life-limiting disease. 相似文献158.
Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNF(R2) specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNF(R2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes. 相似文献
159.
160.