全文获取类型
收费全文 | 10579篇 |
免费 | 899篇 |
出版年
2023年 | 33篇 |
2022年 | 77篇 |
2021年 | 156篇 |
2020年 | 115篇 |
2019年 | 156篇 |
2018年 | 198篇 |
2017年 | 170篇 |
2016年 | 266篇 |
2015年 | 432篇 |
2014年 | 440篇 |
2013年 | 632篇 |
2012年 | 723篇 |
2011年 | 678篇 |
2010年 | 469篇 |
2009年 | 429篇 |
2008年 | 578篇 |
2007年 | 628篇 |
2006年 | 548篇 |
2005年 | 556篇 |
2004年 | 560篇 |
2003年 | 553篇 |
2002年 | 629篇 |
2001年 | 128篇 |
2000年 | 91篇 |
1999年 | 138篇 |
1998年 | 155篇 |
1997年 | 144篇 |
1996年 | 128篇 |
1995年 | 109篇 |
1994年 | 100篇 |
1993年 | 102篇 |
1992年 | 104篇 |
1991年 | 80篇 |
1990年 | 70篇 |
1989年 | 64篇 |
1988年 | 50篇 |
1987年 | 49篇 |
1986年 | 40篇 |
1985年 | 53篇 |
1984年 | 68篇 |
1983年 | 59篇 |
1982年 | 95篇 |
1981年 | 84篇 |
1980年 | 63篇 |
1979年 | 57篇 |
1978年 | 52篇 |
1977年 | 51篇 |
1976年 | 51篇 |
1975年 | 35篇 |
1973年 | 40篇 |
排序方式: 共有10000条查询结果,搜索用时 46 毫秒
951.
D Dudley Williams Sarah E MacKay Ralf C M Verdonschot Pierre J P Tacchino 《Journal of vector ecology》2007,32(2):328-335
Ochlerotatus triseriatus, the eastern treehole mosquito, reaches its northernmost range limit in the extreme southeast of Canada. As a known vector of West Nile and La Crosse encephalitis viruses and a potential vector of eastern equine encephalitis, its population biology is of interest. In southern Ontario, high larval densities occur in urban woodlots within sugar maple and American beech treehole communities comprising rotifers, nematode worms, mites, other dipterans, and scirtid beetles. Treehole water was characterized by low dissolved oxygen levels and seasonally variable pH and temperature, with the latter being most influential on local populations. Densities were significantly higher (up to 503 larvae 100 ml(-1)) in tree holes close to the forest floor (<1 m) and in experimental tree holes seeded with autumn-shed maple leaves as opposed to leaves of black oak and beech. In this locality, weekly sampling showed Oc. triseriatus to be multivoltine, with mass egg hatching beginning under coldwater (<10 degrees C) conditions in March/April, and thereafter producing three successful generations with a possible, less successful fourth in late summer. Some 1st instar larvae were present in water as cold as 0.7 degree C. Compared with larval psychodids living in the same tree hole, population losses of Oc. triseriatus due to washout during major rainfall events were negligible despite high flowthrough of water derived from stemflow. 相似文献
952.
CD16 promotes Escherichia coli sepsis through an FcR gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation 总被引:3,自引:0,他引:3
Pinheiro da Silva F Aloulou M Skurnik D Benhamou M Andremont A Velasco IT Chiamolera M Verbeek JS Launay P Monteiro RC 《Nature medicine》2007,13(11):1368-1374
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion. 相似文献
953.
Orchard S Salwinski L Kerrien S Montecchi-Palazzi L Oesterheld M Stümpflen V Ceol A Chatr-aryamontri A Armstrong J Woollard P Salama JJ Moore S Wojcik J Bader GD Vidal M Cusick ME Gerstein M Gavin AC Superti-Furga G Greenblatt J Bader J Uetz P Tyers M Legrain P Fields S Mulder N Gilson M Niepmann M Burgoon L De Las Rivas J Prieto C Perreau VM Hogue C Mewes HW Apweiler R Xenarios I Eisenberg D Cesareni G Hermjakob H 《Nature biotechnology》2007,25(8):894-898
A wealth of molecular interaction data is available in the literature, ranging from large-scale datasets to a single interaction confirmed by several different techniques. These data are all too often reported either as free text or in tables of variable format, and are often missing key pieces of information essential for a full understanding of the experiment. Here we propose MIMIx, the minimum information required for reporting a molecular interaction experiment. Adherence to these reporting guidelines will result in publications of increased clarity and usefulness to the scientific community and will support the rapid, systematic capture of molecular interaction data in public databases, thereby improving access to valuable interaction data. 相似文献
954.
955.
956.
Lamarche F Mével M Montier T Burel-Deschamps L Giamarchi P Tripier R Delépine P Le Gall T Cartier D Lehn P Jaffrès PA Clément JC 《Bioconjugate chemistry》2007,18(5):1575-1582
The DNA compacting properties of polyamines (especially spermine) are well-known, hence the use of spermine as the cationic part in several synthetic DNA carriers. Here, we describe the synthesis of modified spermines, with a "lipophosphoramidate" as the lipidic part, and their use for efficient in vitro transfection. Physicochemical measurements (particle size, zeta potentials, pKa determination) and gel retardation assays were also performed. Theoretical membrane-disrupting ability was established by FRET. Taken together, our results indicate that lipophosphoramidates constitute an interesting alternative to "classical" lipidic parts of cationic lipids used as DNA carriers. 相似文献
957.
Javelle A Lupo D Li XD Merrick M Chami M Ripoche P Winkler FK 《Journal of structural biology》2007,159(2):243-252
Amt/Rh proteins, which mediate movement of ammonium across cell membranes, are spread throughout the three kingdoms of life. Most functional studies on various members of the family have been performed using cellular assays in heterologous expression systems, which are, however, not very well suited for detailed mechanistic studies. Although now generally considered to be ammonia conducting channels, based on a number of experimental studies and structural insights, the possibility remains that some plant Amts facilitate net ammonium ion transport. The Escherichia coli channel AmtB has become the model system of choice for analysis of the mechanism of ammonia conductance, increasingly also through molecular dynamics simulations. Further progress in a more detailed mechanistic understanding of these proteins requires a reliable in vitro assay using purified protein, allowing quantitative kinetic measurements under a variety of experimental conditions for different Amt/Rh proteins, including mutants. Here, we critically review the existing functional data in the context of the most interesting and unresolved mechanistic questions and we present our results, obtained using an in vitro assay set up with the purified E. coli channel AmtB. 相似文献
958.
Vignal C Singer E Peyrin-Biroulet L Desreumaux P Chamaillard M 《Microbes and infection / Institut Pasteur》2007,9(5):658-663
NOD2 mutations are associated with the development of granulomatous inflammatory diseases, such as early-onset sarcoidosis (EOS), Blau syndrome (BS) and Crohn's disease (CD). As a pathogen-recognition molecule for muramyl dipeptide (MDP), NOD2 controls both innate and adaptive immune responses, through the regulation of cytokines, chemokines and antimicrobial peptides production. Notably, Nod2-deficient mice experienced increased susceptibility to enteric infection and to antigen-specific colitis. Furthermore, mutant mice bearing the orthologue of the major CD-associated NOD23020ins allele showed increased susceptibility to DSS-induced colitis. However, many questions remain open. (i) Is antimicrobial function deficiency sufficient to initiate the development of CD? (ii) How impaired and mutant NOD2 might lead to increased adaptive immune response? (iii) How do the other disease-associated NOD2 mutations contribute to the development of chronic intestinal inflammation? Whatever the relevant mechanism(s), it provides a casual link between abnormal bacterial sensing and development of inflammatory disorders. Further work should now focus on restoring abnormal NOD2 function by modulating antimicrobial function and regulatory mechanisms of the adaptive immune system. 相似文献
959.
Natural antibody--complement dependent neutralization of bovine herpesvirus 4 by human serum 总被引:1,自引:0,他引:1
Machiels B Gillet L Nascimento Brito SD Drion P Delforge C Nizet Y Gianello P Bona C Costes B Markine-Goriaynoff N Vanderplasschen A 《Microbes and infection / Institut Pasteur》2007,9(14-15):1530-1537
In contrast to most gammaherpesviruses, Bovine herpesvirus 4 (BoHV-4) has a broad range of host species both in vitro and in vivo. Several in vitro studies demonstrated that some human cell lines are sensitive or even permissive to BoHV-4. These observations led to the hypothesis that cross-species transmission of BoHV-4 could lead to human infections. In the present study, we investigate the sensitivity of BoHV-4 to neutralization by na?ve human sera in order to determine if humans exhibit innate anti-viral activities against this virus. Our results demonstrate that human sera from na?ve individuals, in contrast to the sera of na?ve subjects from various animal species, neutralize BoHV-4 efficiently. A series of complementary experiments were performed to unravel the mechanism(s) of this neutralization. The data obtained in this study demonstrates that human serum neutralizes BoHV-4 in a complement dependent manner activated by natural antibodies raised against the Galalpha1-3Galbeta1-4GlcNAc-R epitope expressed by bovine cells. 相似文献
960.
Rassoulzadegan M Grandjean V Gounon P Cuzin F 《Journal de la Société de Biologie》2007,201(4):397-399
By contrast with a wide definition of the 'epigenetic variation', including all changes in gene expression that do not result from alteration of the gene structure, a more restricted class had been defined, initially in plants, under the name 'paramutation'. It corresponds to epigenetic modifications distinct from the regulatory interactions of the cell differentiation pathways, mitotically stable and sexually transmitted with non-Mendelian patterns. This class of epigenetic changes appeared for some time restricted to the plant world, but examples progressively accumulated of epigenetic inheritance in organisms ranging from mice to humans. Occurrence of paramutation in the mouse and possible mechanisms were then established in the paradigmatic case of a mutant phenotype maintained and hereditarily transmitted by wild type homozygotes. Together with recent findings in plants indicative of a necessary step of RNA amplification in the reference maize paramutation, the mouse studies point to a new role of RNA, as an inducer and hereditary determinant of epigenetic variation. Given the known presence of a wide range of RNAs in human spermatozoa, as well as a number of unexplained cases of familial disease predisposition and transgenerational maintenance, speculations can be extended to possible roles of RNA-mediated inheritance in human biology and pathology.La paramutation est une modification épigénétique héréditaire, découverte chez des plantes et récemment, chez la souris. C'est un changement héréditaire du phénotype associé avec un allèle sauvage à la suite de son passage dans une structure hétérozygote avec un allèle mutant (phénomène quelquefois appelé "conversation interchromosomique"). Souvent il est considéré comme une exception à la base de lois de Mendel, "les allèles sont retrouvés inchangés lors des ségrégations au cours des croisements". Au contraire la paramutation observée chez la souris résulte d'une modification de l'allèle sauvage du gène Kit après transmission à partir d'un hétérozygote avec un allèle mutant "insertion". Le phénotype des taches blanches visibles aisément par la couleur du pelage est transmis en absence de l'allèle inducteur sur plusieurs générations. Il est corrélé avec une diminution du niveau d'ARNm de Kit et une accumulation d'ARN de taille variable de Kit dans les spermatozo?des des souris paramutantes. La micro-injection de l'ARN de l'hétérozygote, ou de l'ARN et des microARN spécifiques de Kit dans l'oeuf fécondé induit le phénotype "taches blanches". Le r?le de l'ARN dans l'établissement et le maintien d'un état épigénétique héréditaire est proposé et discuté. 相似文献