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151.
Rawson DJ Ballard S Barber C Barker L Beaumont K Bunnage M Cole S Corless M Denton S Ellis D Floc'h M Foster L Gosset J Holmwood F Lane C Leahy D Mathias J Maw G Million W Poinsard C Price J Russel R Street S Watson L 《Bioorganic & medicinal chemistry》2012,20(1):498-509
This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published. 相似文献
152.
153.
154.
Furtado GC Piña B Tacke F Gaupp S van Rooijen N Moran TM Randolph GJ Ransohoff RM Chensue SW Raine CS Lira SA 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):6871-6879
Local inflammation may be a precipitating event in autoimmune processes. In this study, we demonstrate that regulated influx of monocytes and dendritic cells (DC) into the CNS causes an acute neurological syndrome that results in a demyelinating encephalomyelitis. Expansion of monocytes and DC by conditional expression of Flt3 ligand in animals expressing CCL2 in the CNS promoted parenchymal cell infiltration and ascending paralysis in 100% of the mice within 9 days of Flt3 ligand induction. Depletion of circulating monocytes and DC reduced disease incidence and severity. Unlike the classical models of experimental autoimmune encephalomyelitis, depletion of CD4+ and CD8+ T cells did not affect disease induction. T cells and demyelinating lesions were observed in the CNS at a later stage as a result of organ-specific inflammation. We propose that alterations in the numbers or function of monocytes and DC coupled to dysregulated expression of chemokines in the neural tissues, favors development of CNS autoimmune disease. 相似文献
155.
Dridi S Ververken C Hillgartner FB Arckens L Lutgarde A Van der Gucht E Cnops L Decuypere E Buyse J 《American journal of physiology. Regulatory, integrative and comparative physiology》2006,291(1):R138-R147
Cerulenin, a natural fatty acid synthase (FAS) inhibitor, and its synthetic analog C75 are hypothesized to alter the metabolism of neurons in the hypothalamus that regulate ingestive behavior to cause a profound decrease of food intake and an increase in metabolic rate, leading to body weight loss. The bulk of data exclusively originates from mammals (rodents); however, such effects are currently lacking in nonmammalian species. We have, therefore, addressed this issue in broiler chickens because this species is selected for high growth rate and high food intake and is prone to obesity. First, we demonstrate that FAS messenger and protein are expressed in the hypothalamus of chickens. FAS immunoreactivity was detected in a number of brain regions, including the nucleus paraventricularis magnocellularis and the nucleus infundibuli hypothalami, the avian equivalent of the mammalian arcuate nucleus, suggesting that FAS may be involved in the regulation of food intake. Second, we show that hypothalamic FAS gene expression was significantly (P < 0.05) decreased by overnight fasting similar to that in liver, indicating that hypothalamic FAS gene is regulated by energy status in chickens. Finally, to investigate the physiological consequences of in vivo inhibition of fatty acid synthesis on food intake, we administered cerulenin by intravenous injections (15 mg/kg) to 2-wk-old broiler chickens. Cerulenin administration significantly reduced food intake by 23 to 34% (P < 0.05 to P < 0.0001) and downregulated FAS and melanocortin receptors 1, 4, and 5 gene expression (P < 0.05). However, the known orexigenic (neuropeptide Y, agouti gene-related peptide, orexin, and orexin receptor) and anorexigenic (pro-opiomelanocortin and corticotropin-releasing hormone) neuropeptide mRNA levels remained unchanged after cerulenin treatment. These results suggest that the catabolic effect of cerulenin in chickens may be mediated through the melanocortin system rather than the other neuropeptides known to be involved in food intake regulation. 相似文献
156.
The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells 总被引:1,自引:0,他引:1
Eljaschewitsch E Witting A Mawrin C Lee T Schmidt PM Wolf S Hoertnagl H Raine CS Schneider-Stock R Nitsch R Ullrich O 《Neuron》2006,49(1):67-79
Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB(1) receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage. 相似文献
157.
William B. Grant Heide S. Cross Cedric F. Garland Edward D. Gorham Johan Moan Meinrad Peterlik Alina C. Porojnicu Jrg Reichrath Armin Zittermann 《Progress in biophysics and molecular biology》2009,99(2-3):104-113
Vitamin D has important benefits in reducing the risk of many conditions and diseases. Those diseases for which the benefits are well supported and that have large economic effects include many types of cancer, cardiovascular diseases, diabetes mellitus, several bacterial and viral infections, and autoimmune diseases such as multiple sclerosis. Europeans generally have low serum 25-hydroxyvitamin D [25(OH)D] levels owing to the high latitudes, largely indoor living, low natural dietary sources of vitamin D such as cold-water ocean fish, and lack of effective vitamin D fortification of food in most countries. Vitamin D dose–disease response relations were estimated from observational studies and randomized controlled trials. The reduction in direct plus indirect economic burden of disease was based on increasing the mean serum 25(OH)D level to 40 ng/mL, which could be achieved by a daily intake of 2000–3000 IU of vitamin D. For 2007, the reduction is estimated at €187,000 million/year. The estimated cost of 2000–3000 IU of vitamin D3/day along with ancillary costs such as education and testing might be about €10,000 million/year. Sources of vitamin D could include a combination of food fortification, supplements, and natural and artificial UVB irradiation, if properly acquired. Additional randomized controlled trials are warranted to evaluate the benefits and risks of vitamin D supplementation. However, steps to increase serum 25(OH)D levels can be implemented now based on what is already known. 相似文献
158.
Gerardo Corzo Cedric Bernard Herlinda Clement Elba Villegas Frank Bosmans Jan Tytgat Lourival D. Possani Herve Darbon Alejandro Alagón 《Biochimica et Biophysica Acta - Proteins and Proteomics》2009,1794(8):1190-1196
Soluble venom and purified fractions of the theraposid spider Brachypelma albiceps were screened for insecticidal peptides based on toxicity to crickets. Two insecticidal peptides, named Ba1 and Ba2, were obtained after the soluble venom was separated by high performance liquid chromatography and cation exchange chromatography. The two insecticidal peptides contain 39 amino acid residues and three disulfide bonds, and based on their amino acid sequence, they are highly identical to the insecticidal peptides from the theraposid spiders Aphonopelma sp. from the USA and Haplopelma huwenum from China indicating a relationship among these genera. Although Ba1 and Ba2 were not able to modify currents in insect and vertebrate cloned voltage-gated sodium ion channels, they have noteworthy insecticidal activities compared to classical arachnid insecticidal toxins indicating that they might target unknown receptors in insect species. The most abundant insecticidal peptide Ba2 was submitted to NMR spectroscopy to determine its 3-D structure; a remarkable characteristic of Ba2 is a cluster of basic residues, which might be important for receptor recognition. 相似文献
159.
Ellen AF Albers SV Huibers W Pitcher A Hobel CF Schwarz H Folea M Schouten S Boekema EJ Poolman B Driessen AJ 《Extremophiles : life under extreme conditions》2009,13(1):67-79
The crenarchaea Sulfolobus acidocaldarius, S. solfataricus and S. tokodaii, release membrane vesicles into the medium. These membrane vesicles consist of tetraether lipids and are coated with an S-layer.
A proteomic analysis reveals the presence of proteins homologous to subunits of the eukaryotic endosomal sorting complex required
for transport (ESCRT). Immunodetection of one of these homologs suggest a cell surface localization in intact cells. These
data suggest that the membrane vesicles in Sulfolobus sp. emerge from a specific budding process with similarity to the endosomal sorting pathway. 相似文献
160.
Taratra Andrée Fenoradosoa Ghina Ali Cedric Delattre Celine Laroche Emmanuel Petit Anne Wadouachi Philippe Michaud 《Journal of applied phycology》2010,22(2):131-137
Matrix polysaccharide from the brown algae Sargassum turbinarioides collected in the coastal waters of Nosy Be (Madagascar) in the Indian Ocean was isolated and its structure was studied by
1H-NMR spectroscopy, FT-IR, SEC-MALLS and HPAEC. An alginate with a molecular weight of 5.528 × 105 g mol−1 was identified as sole polysaccharide. Values of the M/G ratio, F
GG, F
MM and F
GM (or F
GM) blocks were measured at respectively 0.94, 0.39, 0.36 and 0.25 and compared with those of alginates from other Sargassum species. This sodium alginate appeared similar to some of the other Sargassum alginates with M/G < 1, high values of homopolymeric blocks (η < 1) and significant polyguluronic block content. 相似文献