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971.
Fang Y Banner D Kelvin AA Huang SS Paige CJ Corfe SA Kane KP Bleackley RC Rowe T Leon AJ Kelvin DJ 《Journal of virology》2012,86(4):2229-2238
During the 2009 H1N1 influenza virus pandemic (pdmH1N1) outbreak, it was found that most individuals lacked antibodies against the new pdmH1N1 virus, and only the elderly showed anti-hemagglutinin (anti-HA) antibodies that were cross-reactive with the new strains. Different studies have demonstrated that prior contact with the virus can confer protection against strains with some degree of dissimilarity; however, this has not been sufficiently explored within the context of a pdmH1N1 virus infection. In this study, we have found that a first infection with the A/Brisbane/59/2007 virus strain confers heterologous protection in ferrets and mice against a subsequent pdmH1N1 (A/Mexico/4108/2009) virus infection through a cross-reactive but non-neutralizing antibody mechanism. Heterologous immunity is abrogated in B cell-deficient mice but maintained in CD8(-/-) and perforin-1(-/-) mice. We identified cross-reactive antibodies from A/Brisbane/59/2007 sera that recognize non-HA epitopes in pdmH1N1 virus. Passive serum transfer showed that cross-reactive sH1N1-induced antibodies conferred protection in naive recipient mice during pdmH1N1 virus challenge. The presence or absence of anti-HA antibodies, therefore, is not the sole indicator of the effectiveness of protective cross-reactive antibody immunity. Measurement of additional antibody repertoires targeting the non-HA antigens of influenza virus should be taken into consideration in assessing protection and immunization strategies. We propose that preexisting cross-protective non-HA antibody immunity may have had an overall protective effect during the 2009 pdmH1N1 outbreak, thereby reducing disease severity in human infections. 相似文献
972.
Stephen S. H. Huang David Banner Norbert Degousee Alberto J. Leon Louling Xu Stephane G. Paquette Thirumagal Kanagasabai Yuan Fang Salvatore Rubino Barry Rubin David J. Kelvin Alyson A. Kelvin 《Journal of virology》2012,86(24):13187-13201
Young children are typically considered a high-risk group for disease associated with influenza virus infection. Interestingly, recent clinical reports suggested that young children were the smallest group of cases with severe pandemic 2009 H1N1 (H1N1pdm) influenza virus infection. Here we established a newly weaned ferret model for the investigation of H1N1pdm infection in young age groups compared to adults. We found that young ferrets had a significantly milder fever and less weight loss than adult ferrets, which paralleled the mild clinical symptoms in the younger humans. Although there was no significant difference in viral clearance, disease severity was associated with pulmonary pathology, where newly weaned ferrets had an earlier pathology improvement. We examined the immune responses associated with protection of the young age group during H1N1pdm infection. We found that interferon and regulatory interleukin-10 responses were more robust in the lungs of young ferrets. In contrast, myeloperoxidase and major histocompatibility complex responses were persistently higher in the adult lungs; as well, the numbers of inflammation-prone granulocytes were highly elevated in the adult peripheral blood. Importantly, we observed that H1N1pdm infection triggered formation of lung structures that resembled inducible bronchus-associated lymphoid tissues (iBALTs) in young ferrets which were associated with high levels of homeostatic chemokines CCL19 and CXCL13, but these were not seen in the adult ferrets with severe disease. These results may be extrapolated to a model of the mild disease seen in human children. Furthermore, these mechanistic analyses provide significant new insight into the developing immune system and effective strategies for intervention and vaccination against respiratory viruses. 相似文献
973.
Chang SY Hudon-Miller SE Yang SH Jung HJ Lee JM Farber E Subramanian T Andres DA Spielmann HP Hrycyna CA Young SG Fong LG 《Journal of lipid research》2012,53(6):1176-1182
Protein farnesyltransferase (FTase) inhibitors, generally called "FTIs," block the farnesylation of prelamin A, inhibiting the biogenesis of mature lamin A and leading to an accumulation of prelamin A within cells. A recent report found that a GGTI, an inhibitor of protein geranylgeranyltransferase-I (GGTase-I), caused an exaggerated accumulation of prelamin A in the presence of low amounts of an FTI. This finding was interpreted as indicating that prelamin A can be alternately prenylated by GGTase-I and that inhibiting both protein prenyltransferases leads to more prelamin A accumulation than blocking FTase alone. Here, we tested an alternative hypothesis-GGTIs are not specific for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesyl-prelamin A to mature lamin A). In our studies, commonly used GGTIs caused prelamin A accumulation in human fibroblasts, but the prelamin A in GGTI-treated cells exhibited a more rapid electrophoretic mobility than prelamin A from FTI-treated cells. The latter finding suggested that the prelamin A in GGTI-treated cells might be farnesylated (which would be consistent with the notion that GGTIs inhibit ZMPSTE24). Indeed, metabolic labeling studies revealed that the prelamin A in GGTI-treated fibroblasts is farnesylated. Moreover, biochemical assays of ZMPSTE24 activity showed that ZMPSTE24 is potently inhibited by a GGTI. Our studies show that GGTIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. Thus, caution is required when interpreting the effects of GGTIs on prelamin A processing. 相似文献
974.
Virginia M. Tanis Genesis M. Bacani Jonathan M. Blevitt Christa C. Chrovian Shelby Crawford Aimee De Leon Anne M. Fourie Laurent Gomez Cheryl A. Grice Krystal Herman Aaron M. Kearney Adrienne M. Landry-Bayle Alice Lee-Dutra Jay Nelson Jason P. Riley Alejandro Santillán John J.M. Wiener Xiaohua Xue Arlene L. Young 《Bioorganic & medicinal chemistry letters》2012,22(24):7504-7511
Previously, benzthiazole containing LTA4H inhibitors were discovered that were potent (1–3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering c Log D) a new benzthiazole series was designed, congeners of 1–3, which led to compounds 7a, 7c, 12a–d which exhibited LTA4H IC50 = 3–6 nM and hERG Dofetilide Binding IC50 = 8.9–> >10 μM. 相似文献
975.
976.
977.
Miguel Muñoz Ana González-Ortega Marisa Rosso María José Robles-Frias Andres Carranza Manuel Vicente Salinas-Martín Rafael Coveñas 《Peptides》2012
The last decades have seen no significant progress in extending the survival of lung cancer patients and there is an urgent need to improve current therapies. The substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in the development of cancer: SP and NK-1R antagonists respectively induce cell proliferation and inhibition in human cancer cell lines. No study of the involvement of this system in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells has been carried out in depth. Here, we demonstrate the involvement of the SP/NK-1R system in human H-69 (SCLC) and COR-L23 (NSCLC) cell lines: (1) they express isoforms of the NK-1R and mRNA for the NK-1R; (2) they overexpress the tachykinin 1 gene; (3) the NK-1R is involved in their viability; (4) SP induces their proliferation; (5) NK-1R antagonists (Aprepitant (Emend), L-733,060, L-732,138) inhibit the growth of both cell lines in a concentration-dependent manner; (6) the specific antitumor action of these antagonists against such cells occurs through the NK-1R; and (7) lung cancer cell death is due to apoptosis. We also demonstrate the presence of NK-1Rs and SP in all the human SCLC and NSCLC samples studied. Our findings indicate that the NK-1R may be a promising new target in the treatment of lung cancer and that NK-1R antagonists could be new candidate antitumor drugs in the treatment of SCLC and NSCLC. 相似文献
978.
Endo A Futagawa-Endo Y Schumann P Pukall R Dicks LM 《Systematic and applied microbiology》2012,35(2):92-97
Five strains of bifidobacteria were isolated from faeces of a common marmoset (Callithrix jacchus) and a red-handed tamarin (Saguinus midas). The five isolates clustered inside the phylogenetic group of the genus Bifidobacterium but did not show high sequence similarities between the isolates and to known species in the genus by phylogenetic analysis based on 16S rRNA gene sequences. Sequence analyses of dnaJ1 and hsp60 also indicated their independent phylogenetic positions to each other in the Bifidobacterium cluster. DNA G+C contents of the species ranged from 57.3 to 66.3 mol%, which is within the values recorded for Bifidobacterium species. All isolates showed fructose-6-phosphate phosphoketolase activity. Based on the data provided, the five isolates represent five novel species, for which the names Bifidobacterium reuteri sp. nov. (type strain: AFB22-1(T) = JCM 17295(T) = DSM 23975(T)), Bifidobacterium callitrichos sp. nov. (type strain: AFB22-5(T) = JCM 17296(T) = DSM 23973(T)), Bifidobacterium saguini sp. nov. (type strain: AFB23-1(T) = JCM 17297(T) = DSM 23967(T)), Bifidobacterium stellenboschense sp. nov. (type strain: AFB23-3(T) = JCM 17298(T) = DSM 23968(T)) and Bifidobacterium biavatii sp. nov. (type strain: AFB23-4(T) = JCM 17299(T) = DSM 23969(T)) are proposed. 相似文献
979.
Isabel Mendizabal Oscar Lao Urko M. Marigorta Andreas Wollstein Leonor Gusmão Vladimir Ferak Mihai Ioana Albena Jordanova Radka Kaneva Anastasia Kouvatsi Vaidutis Kučinskas Halyna Makukh Andres Metspalu Mihai G. Netea Rosario de Pablo Horolma Pamjav Dragica Radojkovic Sarah J.H. Rolleston Jadranka Sertic Milan Macek Manfred Kayser 《Current biology : CB》2012,22(24):2342-2349
980.
Kershenbaum A Ilany A Blaustein L Geffen E 《Proceedings. Biological sciences / The Royal Society》2012,279(1740):2974-2981
Few mammalian species produce vocalizations that are as richly structured as bird songs, and this greatly restricts the capacity for information transfer. Syntactically complex mammalian vocalizations have been previously studied only in primates, cetaceans and bats. We provide evidence of complex syntactic vocalizations in a small social mammal: the rock hyrax (Procavia capensis: Hyracoidea). We adopted three algorithms, commonly used in genetic sequence analysis and information theory, to examine the order of syllables in hyrax calls. Syntactic dialects exist, and the syntax of hyrax calls is significantly different between different regions in Israel. Call syntax difference is positively correlated to geographical distance over short distances. No correlation is found over long distances, which may reflect limited dispersal movement. These findings indicate that rich syntactic structure is more common in the vocalizations of mammalian taxa than previously thought and suggest the possibility of vocal production learning in the hyrax. 相似文献