全文获取类型
收费全文 | 2641篇 |
免费 | 187篇 |
出版年
2023年 | 16篇 |
2022年 | 29篇 |
2021年 | 68篇 |
2020年 | 32篇 |
2019年 | 42篇 |
2018年 | 46篇 |
2017年 | 47篇 |
2016年 | 93篇 |
2015年 | 168篇 |
2014年 | 168篇 |
2013年 | 185篇 |
2012年 | 259篇 |
2011年 | 204篇 |
2010年 | 130篇 |
2009年 | 113篇 |
2008年 | 151篇 |
2007年 | 153篇 |
2006年 | 124篇 |
2005年 | 141篇 |
2004年 | 131篇 |
2003年 | 112篇 |
2002年 | 77篇 |
2001年 | 14篇 |
2000年 | 17篇 |
1999年 | 28篇 |
1998年 | 20篇 |
1997年 | 15篇 |
1996年 | 20篇 |
1995年 | 14篇 |
1994年 | 8篇 |
1993年 | 15篇 |
1992年 | 14篇 |
1991年 | 11篇 |
1990年 | 16篇 |
1989年 | 8篇 |
1988年 | 12篇 |
1987年 | 7篇 |
1986年 | 10篇 |
1985年 | 10篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1979年 | 11篇 |
1976年 | 7篇 |
1975年 | 8篇 |
1974年 | 3篇 |
1972年 | 5篇 |
1966年 | 5篇 |
1931年 | 3篇 |
排序方式: 共有2828条查询结果,搜索用时 187 毫秒
911.
Multiple roles of biosurfactants in structural biofilm development by Pseudomonas aeruginosa 下载免费PDF全文
Recent studies have indicated that biosurfactants produced by Pseudomonas aeruginosa play a role both in maintaining channels between multicellular structures in biofilms and in dispersal of cells from biofilms. Through the use of flow cell technology and enhanced confocal laser scanning microscopy, we have obtained results which suggest that the biosurfactants produced by P. aeruginosa play additional roles in structural biofilm development. We present genetic evidence that during biofilm development by P. aeruginosa, biosurfactants promote microcolony formation in the initial phase and facilitate migration-dependent structural development in the later phase. P. aeruginosa rhlA mutants, deficient in synthesis of biosurfactants, were not capable of forming microcolonies in the initial phase of biofilm formation. Experiments involving two-color-coded mixed-strain biofilms showed that P. aeruginosa rhlA mutants were defective in migration-dependent development of mushroom-shaped multicellular structures in the later phase of biofilm formation. Experiments involving three-color-coded mixed-strain P. aeruginosa biofilms demonstrated that the wild-type and rhlA and pilA mutant strains formed distinct subpopulations on top of each other dependent on their ability to migrate and produce biosurfactants. 相似文献
912.
Takaluoma K Hyry M Lantto J Sormunen R Bank RA Kivirikko KI Myllyharju J Soininen R 《The Journal of biological chemistry》2007,282(9):6588-6596
We have generated mice with targeted inactivation of the Plod1 gene for lysyl hydroxylase 1 (LH1). Its human mutations cause Ehlers-Danlos syndrome VIA (EDS VIA) characterized by muscular hypotonia, joint laxity, and kyphoscoliosis. The Plod1(-/-) mice are flaccid and have gait abnormalities. About 15% of them died because of aortic rupture and smooth muscle cells in non-ruptured Plod1(-/-) aortas showed degenerative changes. Collagen fibrils in the Plod1(-/-) aorta and skin had an abnormal morphology. The LH activity level in the Plod1(-/-) skin and aorta samples was 35-45% of that in the wild type. The hydroxylysine content was decreased in all the Plod1(-/-) tissues, ranging from 22% of that in the wild type in the skin to 75 and 86% in the femur and lung. The hydroxylysylpyridinoline crosslinks likewise showed decreases in all the Plod1(-/-) tissues, ranging from 28 and 33% of that in the wild type in the aorta and cornea to 47 and 59% in femur and tendon, while lysylpyridinolines were increased. The hydroxylysines found in the Plod1(-/-) collagens and their cross-links were evidently synthesized by the other two LH isoenzymes. Few data are available on abnormalities in EDS VIA tissues other than the skin. Plod1(-/-) mice offer an in vivo model for systematic analysis of the tissue-specific consequences of the lack of LH1 activity and may also provide a tool for analyzing the roles of connective tissue in muscle function and the complex interactions occurring in the proper assembly of the extracellular matrix. 相似文献
913.
Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia 总被引:1,自引:0,他引:1
Knecht W Cottrell GS Amadesi S Mohlin J Skåregärde A Gedda K Peterson A Chapman K Hollenberg MD Vergnolle N Bunnett NW 《The Journal of biological chemistry》2007,282(36):26089-26100
Although principally produced by the pancreas to degrade dietary proteins in the intestine, trypsins are also expressed in the nervous system and in epithelial tissues, where they have diverse actions that could be mediated by protease-activated receptors (PARs). We examined the biological actions of human trypsin IV (or mesotrypsin) and rat p23, inhibitor-resistant forms of trypsin. The zymogens trypsinogen IV and pro-p23 were expressed in Escherichia coli and purified to apparent homogeneity. Enteropeptidase cleaved both zymogens, liberating active trypsin IV and p23, which were resistant to soybean trypsin inhibitor and aprotinin. Trypsin IV cleaved N-terminal fragments of PAR(1), PAR(2), and PAR(4) at sites that would expose the tethered ligand (PAR(1) = PAR(4) > PAR(2)). Trypsin IV increased [Ca(2+)](i) in transfected cells expressing human PAR(1) and PAR(2) with similar potencies (PAR(1), 0.5 microm; PAR(2), 0.6 microm). p23 also cleaved fragments of PAR(1) and PAR(2) and signaled to cells expressing these receptors. Trypsin IV and p23 increased [Ca(2+)](i) in rat dorsal root ganglion neurons that responded to capsaicin and which thus mediate neurogenic inflammation and nociception. Intraplantar injection of trypsin IV and p23 in mice induced edema and granulocyte infiltration, which were not observed in PAR (-/-)(1)(trypsin IV) and PAR (-/-)(2) (trypsin IV and p23) mice. Trypsin IV and p23 caused thermal hyperalgesia and mechanical allodynia and hyperalgesia in mice, and these effects were absent in PAR (-/-)(2) mice but maintained in PAR (-/-)(1) mice. Thus, trypsin IV and p23 are inhibitor-resistant trypsins that can cleave and activate PARs, causing PAR(1)- and PAR(2)-dependent inflammation and PAR(2)-dependent hyperalgesia. 相似文献
914.
915.
Pakkanen S Baffoe-Bonnie AB Matikainen MP Koivisto PA Tammela TL Deshmukh S Ou L Bailey-Wilson JE Schleutker J 《Human genetics》2007,121(2):257-267
Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide and is likely to be caused by a number of genes
with different modes of inheritance, population frequencies and penetrance. The objective of this study was to assess the
familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during
1988–1993, from the unique, founder population-based resource of the Finnish Cancer Registry. Segregation analysis was performed
for two cohorts of 557 early-onset and 989 late-onset families evaluating residual paternal effects and assuming that age
at diagnosis followed a logistic distribution after log-transformation. The results did not support an autosomal dominant
inheritance as has been reported in many of the hospital-based prostatectomy series. Instead, it confirmed the existence of
hereditary PCa in the Finnish population under a complex model that included a major susceptibility locus with Mendelian recessive
inheritance and a significant paternal regressive coefficient that is indicative of a polygenic/multifactorial component.
The strengths of our study are the homogenous Finnish population, large epidemiological population-based data, histologically
confirmed cancer diagnosis done before the PSA-era in Finland and registry based approach. Our results support the evidence
that the inheritance of PCa is controlled by major genes and are in line with the previous linkage studies. Moreover, this
is the first time a recessive inheritance is suggested to fit PCa in all data even when divided to early and late-onset cohorts.
Sanna Pakkanen and Agnes B Baffoe-Bonnie equally contributed to this work. 相似文献
916.
Herling AW Gossel M Haschke G Stengelin S Kuhlmann J Müller G Schmoll D Kramer W 《American journal of physiology. Endocrinology and metabolism》2007,293(3):E826-E832
The objective of the present study was to investigate in fed Wistar rats whether the cannabinoid-1 (CB1) receptor antagonist AVE1625 causes primary effects on metabolic blood and tissue parameters as well as metabolic rate, which are independent of reduced caloric intake. After single administration to rats postprandially, AVE1625 caused a slight dose-dependent increase in basal lipolysis. Six hours after single administration, liver glycogen content was dose-dependently reduced to approximately 60% of that of untreated controls. These findings demonstrate a primary acute effect of AVE1625 on induction of 1) lipolysis from fat tissue (increased FFA) and 2) glycogenolysis from the liver (reduced hepatic glycogen). Measured by indirect calorimetry, AVE1625 caused an immediate increase in total energy expenditure, a long-lasting increase of fat oxidation, and a transient increase of glucose oxidation, which were consistent with the acute findings on metabolic blood and tissue parameters. We conclude that, in addition to the well-investigated effects of CB1 receptor antagonists to reduce caloric intake and subsequently body weight, this pharmacological approach is additionally linked to inherently increased lipid oxidation. This oxidation is driven by persistently increased lipolysis from fat tissues, independently of reduced caloric intake, and might significantly contribute to the weight-reducing effect. 相似文献
917.
918.
Sabater-Vilar M Malekinejad H Selman MH van der Doelen MA Fink-Gremmels J 《Mycopathologia》2007,163(2):81-90
The high prevalence of the Fusarium mycotoxins, deoxynivalenol (DON) and zearalenone (ZON) in animal feeds in mild climatic
zones of Europe and North America results in considerable economic losses, as these toxins affect health and productivity
particularly of pigs from all age groups. The use of mycotoxin adsorbents as feed additives is one of the most prominent approaches
to reduce the risk for mycotoxicoses in farm animals, and to minimise carry-over of mycotoxins from contaminated feeds into
foods of animal origin. Successful aflatoxin adsorption by means of different substances (phyllosilicate minerals, zeolites,
activated charcoal, synthetic resins or yeast cell-wall-derived products) has been demonstrated in vivo and in vitro. However, attempts to adsorb DON and ZON have been less encouraging. Here we describe the adsorption capacity of a variety
of potential binders, including compounds that have not been evaluated before, such as humic acids. All compounds were tested
at realistic inclusion levels for their capacity to bind ZON and DON, using an in vitro method that resembles the different pH conditions in the gastro-intestinal tract of pigs. Mycotoxin adsorption was assessed
by chemical methods and distinct bioassays, using specific markers of toxicity as endpoints of toxicity in cytological assays.
Whereas none of the tested substances was able to bind DON in an appreciable percentage, some of the selected smectite clays,
humic substances and yeast-wall derived products efficiently adsorbed ZON (>70%). Binding efficiency was indirectly confirmed
by the reduction of toxicity in the in vitro bioassays. In conclusion, the presented test protocol allows the rapid screening of potential mycotoxin binders. Like other
in vitro assays, the presented protocol combining chemical and biological assays cannot completely simulate the conditions of the
gastro-intestinal tract, and hence in vivo experiments remain mandatory to assess the efficacy of mycotoxin binders under practical conditions. 相似文献
919.
920.
Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea 总被引:5,自引:0,他引:5
Huang LC Thorne PR Housley GD Montgomery JM 《Development (Cambridge, England)》2007,134(16):2925-2933
The adult mammalian cochlea receives dual afferent innervation: the inner sensory hair cells are innervated exclusively by type I spiral ganglion neurons (SGN), whereas the sensory outer hair cells are innervated by type II SGN. We have characterized the spatiotemporal reorganization of the dual afferent innervation pattern as it is established in the developing mouse cochlea. This reorganization occurs during the first postnatal week just before the onset of hearing. Our data reveal three distinct phases in the development of the afferent innervation of the organ of Corti: (1) neurite growth and extension of both classes of afferents to all hair cells (E18-P0); (2) neurite refinement, with formation of the outer spiral bundles innervating outer hair cells (P0-P3); (3) neurite retraction and synaptic pruning to eliminate type I SGN innervation of outer hair cells, while retaining their innervation of inner hair cells (P3-P6). The characterization of this developmental innervation pattern was made possible by the finding that tetramethylrhodamine-conjugated dextran (TMRD) specifically labeled type I SGN. Peripherin and choline-acetyltransferase immunofluorescence confirmed the type II and efferent innervation patterns, respectively, and verified the specificity of the type I SGN neurites labeled by TMRD. These findings define the precise spatiotemporal neurite reorganization of the two afferent nerve fiber populations in the cochlea, which is crucial for auditory neurotransmission. This reorganization also establishes the cochlea as a model system for studying CNS synapse development, plasticity and elimination. 相似文献