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排序方式: 共有1315条查询结果,搜索用时 15 毫秒
121.
Passley Hargrove-Grimes Lucie A Low Danilo A Tagle 《Experimental biology and medicine (Maywood, N.J.)》2021,246(12):1435
Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools. 相似文献
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Naylor SW Nart P Sales J Flockhart A Gally DL Low JC 《Applied and environmental microbiology》2007,73(5):1493-1500
Enterohemorrhagic Escherichia coli O157:H7 is an important intestinal pathogen of humans with a main reservoir of domesticated ruminants, particularly cattle. It is anticipated that the risk of human infection can be reduced by controlling the organism within its reservoir hosts. Several options for the control of E. coli O157:H7 in cattle have been proposed, but none have been demonstrated to be successful in the field. Here we describe a novel experimental method, based on the terminal-rectum-restricted colonization described previously, to eliminate fecal carriage of E. coli O157:H7. In experimentally challenged calves, direct application to the rectal mucosa of either of two therapeutic agents, polymyxin B or chlorhexidine, greatly reduced bacterial shedding levels in the immediate posttreatment period. The most efficacious therapeutic agent, chlorhexidine, was compared in orally and rectally challenged calves. The treatment eliminated high-level shedding and reduced low-level shedding by killing bacteria at the terminal rectum. A rapid-detection system based on the ability to identify E. coli O157:H7 from swabs of the rectal mucosa was also assessed. This test was sufficiently sensitive to identify high-level bacterial carriage. Thus, a combination of the detection method and treatment regimens could be used in the field to eliminate high-level fecal excretion of E. coli O157:H7, so greatly reducing its prevalence within this host and the risk of human infection. 相似文献
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Yingjuan Lu Nikki Parker Paul J Kleindl Vicky A Cross Kristin Wollak Elaine Westrick Torian W Stinnette Mark A Gehrke Kevin Wang Hari Krishna R Santhapuram Fei You Spencer J Hahn Jeremy F Vaughn Patrick J Klein Iontcho R Vlahov Philip S Low Christopher P Leamon 《Molecular medicine (Cambridge, Mass.)》2015,21(1):584-596
Folate receptor (FR)-β has been identified as a promising target for antimacrophage and antiinflammatory therapies. In the present study, we investigated EC0565, a folic acid–derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Because of its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture and FR-binding specificity. Using FR-expressing macrophages, the effect of EC0565 on mTOR signaling and cellular proliferation was studied. The pharmacokinetics, metabolism and bioavailability of EC0565 were studied in normal rats. The in vivo activity of EC0565 was assessed in rats with adjuvant arthritis, a “macrophage-rich” model with close resemblance to rheumatoid arthritis. EC0565 forms micellar aggregates in physiological buffers and demonstrates good water solubility as well as strong multivalent FR-binding capacity. EC0565 inhibited mTOR signaling in rat macrophages at nanomolar concentrations and induced G0/G1 cell cycle arrest in serum-starved RAW264.7 cells. Subcutaneously administered EC0565 in rats displayed good bioavailability and a relatively long half-life (~12 h). When given at 250 nmol/kg, EC0565 selectively inhibited proliferating cell nuclear antigen expression in thioglycollate-stimulated rat peritoneal cells. With limited dosing regimens, the antiarthritic activity of EC0565 was found superior to that of etanercept, everolimus and a nontargeted everolimus analog. The in vivo activity of EC0565 was also comparable to that of a folate-targeted aminopterin. Folate-targeted mTOR inhibition may be an effective way of suppressing activated macrophages in sites of inflammation, especially in nutrient-deprived conditions, such as in the arthritic joints. Further investigation and improvement upon the physical and biochemical properties of EC0565 are warranted. 相似文献
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Low E Kim B Francavilla C Shiau TP Turtle ED O'Mahony DJ Alvarez N Houchin A Xu P Zuck M Celeri C Anderson MB Najafi RR Jain RK 《Bioorganic & medicinal chemistry letters》2011,21(12):3682-3685
Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion. 相似文献
129.
Variation in morphological traits along latitudinal gradients often manifests as size clines. In insects, both positive and negative correlations are seen, and the mechanism behind the response is unclear. We studied variation in seven morphological traits of Roesel's bush cricket, Metrioptera roeselii, sampled from seven latitude-matched-pair populations that were either geographically isolated from or connected to the species continuous distribution range. The aim was to examine whether morphological traits differed between isolated and continuous populations, and whether latitudinal variation was apparent. The data were used to indicate whether variation in trait means originates from plastic responses to the environment or genetic adaptation to local conditions. To evaluate the influence of gene flow on trait means, we analysed the genetic variation in seven microsatellites. Data showed that individuals from isolated populations display a positive relationship between latitude and body size, whereas individuals from continuous populations show little or no such relationship. The combined morphological and genetic data suggest that the isolated populations have adapted to local optima, while gene flow between continuous populations appears to counteract this process. 相似文献
130.
Previously, a dominant role of the adaptive immune system in the pathogenesis of Sj?gren's syndrome was suspected. Recent
advances, however, have revealed a major role of the type I IFN pathway, documented by an increased circulating type I IFN
activity and an IFN 'signature' in peripheral blood mononuclear cells and minor salivary gland biopsies from the patients.
Polymorphisms in the genes IRF5 and STAT4 leading to increased IFN activation are associated with disease susceptibility. In the pathogenesis of Sj?gren's syndrome,
the activation of salivary gland epithelial cells appears to be the initial event. Once intrinsically activated, they express
costimulatory and Toll-like receptors (TLRs) and MHC class I and II molecules, can present autoantigens and produce proinflammatory
cytokines. The subsequent activation of plasmacytoid dendritic cells induces the production of high levels of proinflammatory
cytokines in individuals with the risk alleles of the susceptibility genes IRF5 and STAT4. Under the influence of the high IFN concentration in the glands and through TLR ligation, B-cell activating factor is produced
by epithelial cells and, together with autoantigen presentation on salivary gland epithelial cells, stimulates the adaptive
immune system. In view of the central role of IFNalpha in at least the initiation of the pathogenesis of Sj?gren's syndrome,
blockade of this cytokine may be a rational therapeutic approach. 相似文献