全文获取类型
收费全文 | 286篇 |
免费 | 42篇 |
出版年
2021年 | 3篇 |
2020年 | 5篇 |
2019年 | 2篇 |
2018年 | 6篇 |
2017年 | 3篇 |
2016年 | 5篇 |
2015年 | 9篇 |
2014年 | 9篇 |
2013年 | 10篇 |
2012年 | 18篇 |
2011年 | 12篇 |
2010年 | 16篇 |
2009年 | 4篇 |
2008年 | 5篇 |
2007年 | 15篇 |
2006年 | 10篇 |
2005年 | 11篇 |
2004年 | 10篇 |
2003年 | 12篇 |
2002年 | 9篇 |
2001年 | 14篇 |
2000年 | 11篇 |
1999年 | 13篇 |
1998年 | 7篇 |
1996年 | 3篇 |
1995年 | 11篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 7篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1981年 | 4篇 |
1980年 | 6篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1975年 | 3篇 |
1973年 | 2篇 |
1969年 | 2篇 |
1967年 | 1篇 |
1965年 | 2篇 |
1947年 | 1篇 |
1921年 | 1篇 |
1909年 | 1篇 |
1903年 | 1篇 |
1902年 | 11篇 |
排序方式: 共有328条查询结果,搜索用时 250 毫秒
71.
Emily B. Blackman Christopher S. Deperno Ron W. Heiniger Matthew J. Krachey Christopher E. Moorman M. Nils Peterson 《The Journal of wildlife management》2012,76(3):528-533
Since the late 1960s, American woodcock (Scolopax minor) have undergone population declines because of habitat loss. Previous research suggested ridge and furrow topography in conventionally tilled soybean fields provided critical nocturnal cover as birds foraged on earthworms. However, the use of no-till technology has increased and many fields now lack ridge and furrow topography. We assessed woodcock winter nocturnal foraging habitat use given recent changes in agricultural technology, and investigated how field treatment, earthworm abundance, and environmental variables affect the selection of nocturnal foraging sites. We counted woodcock along transects in 5 field treatments twice in each of 67 fields during December–March 2008–2009 and 72 fields during December–March 2009–2010. During both seasons, we collected earthworm and soil samples from a subset of fields of each field treatment. Woodcock densities were at least twice as high in no-till soybean fields planted after corn and in undisked corn fields with mowed stalks than in other field treatments. No-till soybean planted after corn and undisked corn fields contained ridge and furrow topography, whereas other crops did not, and earthworms were at least 1.5 times more abundant in no-till soybean fields than other field treatments. Ridges and furrows in no-till soybean fields planted after corn and undisked corn fields may provide wintering woodcock with thermal protection and concealment from predators. No-till soybean fields planted after corn offered the additional benefit of relatively high food availability. The presence of ridge and furrow topography can be used to predict woodcock field use on the wintering grounds in agricultural areas. Farmers can provide nocturnal winter foraging sites for woodcock by delaying field disking and leaving ridge and furrow topography in crop fields. © 2011 The Wildlife Society. 相似文献
72.
S Gemma S Giovani M Brindisi P Tripaldi S Brogi L Savini I Fiorini E Novellino S Butini G Campiani M Penzo MJ Blackman 《Bioorganic & medicinal chemistry letters》2012,22(16):5317-5321
Plasmodium falciparum subtilisin-like protease 1 (PfSUB1) is a serine protease that plays key roles in the egress of the parasite from red blood cells and in preparing the released merozoites for the subsequent invasion of new erythrocytes. The development of potent and selective PfSUB1 inhibitors could pave the way to the discovery of potential antimalarial drugs endowed with an innovative mode of action and consequently able to overcome the current problems of resistance to established chemotherapies. Through the screening of a proprietary library of compounds against PfSUB1, we identified hydrazone 2 as a hit compound. Here we report a preliminary investigation of the structure-activity relationships for a class of PfSUB1 inhibitors related to our identified hit. 相似文献
73.
74.
Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite 下载免费PDF全文
O'Donnell RA Hackett F Howell SA Treeck M Struck N Krnajski Z Withers-Martinez C Gilberger TW Blackman MJ 《The Journal of cell biology》2006,174(7):1023-1033
Apicomplexan pathogens are obligate intracellular parasites. To enter cells, they must bind with high affinity to host cell receptors and then uncouple these interactions to complete invasion. Merozoites of Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria, invade erythrocytes using a family of adhesins called Duffy binding ligand-erythrocyte binding proteins (DBL-EBPs). The best-characterized P. falciparum DBL-EBP is erythrocyte binding antigen 175 (EBA-175), which binds erythrocyte surface glycophorin A. We report that EBA-175 is shed from the merozoite at around the point of invasion. Shedding occurs by proteolytic cleavage within the transmembrane domain (TMD) at a site that is conserved across the DBL-EBP family. We show that EBA-175 is cleaved by PfROM4, a rhomboid protease that localizes to the merozoite plasma membrane, but not by other rhomboids tested. Mutations within the EBA-175 TMD that abolish cleavage by PfROM4 prevent parasite growth. Our results identify a crucial role for intramembrane proteolysis in the life cycle of this pathogen. 相似文献
75.
Ruslan Dorfman Weili Li Lei Sun Fan Lin Yongqian Wang Andrew Sandford Peter D. Paré Karen McKay Hana Kayserova Tereza Piskackova Milan Macek Kamila Czerska Dorota Sands Harm Tiddens Sonia Margarit Gabriela Repetto Marci K. Sontag Frank J. Accurso Scott Blackman Garry R. Cutting Lap-Chee Tsui Mary Corey Peter Durie Julian Zielenski Lisa J. Strug 《Human genetics》2009,126(6):763-778
Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. 相似文献
76.
Christine R. Collins Chrislaine Withers-Martinez Fiona Hackett Michael J. Blackman 《PLoS pathogens》2009,5(1)
Host cell invasion by apicomplexan pathogens such as the malaria parasite Plasmodium spp. and Toxoplasma gondii involves discharge of proteins from secretory organelles called micronemes and rhoptries. In Toxoplasma a protein complex comprising the microneme apical membrane antigen 1 (AMA1), two rhoptry neck proteins, and a protein called Ts4705, localises to the moving junction, a region of close apposition between parasite and host cell during invasion. Antibodies against AMA1 prevent invasion and are protective in vivo, and so AMA1 is of widespread interest as a malaria vaccine candidate. Here we report that the AMA1 complex identified in Toxoplasma is conserved in Plasmodium falciparum. We demonstrate that the invasion-inhibitory monoclonal antibody (mAb) 4G2, which recognises P. falciparum AMA1 (PfAMA1), cannot bind when PfAMA1 is in a complex with its partner proteins. We further show that a single completely conserved PfAMA1 residue, Tyr251, lying within a conserved hydrophobic groove adjacent to the mAb 4G2 epitope, is required for complex formation. We propose that mAb 4G2 inhibits invasion by preventing PfAMA1 from interacting with other components of the invasion complex. Our findings should aid the rational design of subunit malaria vaccines based on PfAMA1. 相似文献
77.
Michael L. Freeman Kathleen G. Lanzer Tres Cookenham Bjoern Peters John Sidney Ting-Ting Wu Ren Sun David L. Woodland Alessandro Sette Marcia A. Blackman 《Journal of virology》2010,84(6):2881-2892
Murine gammaherpesvirus 68 (γHV68) provides an important experimental model for understanding mechanisms of immune control of the latent human gammaherpesviruses. Antiviral CD8 T cells play a key role throughout three separate phases of the infection: clearance of lytic virus, control of the latency amplification stage, and prevention of reactivation of latently infected cells. Previous analyses have shown that T-cell responses to two well-characterized epitopes derived from ORF6 and ORF61 progress with distinct kinetics. ORF6487-specific cells predominate early in infection and then decline rapidly, whereas ORF61524-specific cells continue to expand through early latency, due to sustained epitope expression. However, the paucity of identified epitopes to this virus has limited our understanding of the overall complexities of CD8 T-cell immune control throughout infection. Here we screened 1,383 predicted H-2b-restricted peptides and identified 33 responses, of which 21 have not previously been reported. Kinetic analysis revealed a spectrum of T-cell responses based on the rapidity of their decline after the peak acute response that generally corresponded to the expression patterns of the two previously characterized epitopes. The slowly declining responses that were maintained during latency amplification proliferated more rapidly and underwent maturation of functional avidity over time. Furthermore, the kinetics of decline was accelerated following infection with a latency-null mutant virus. Overall, the data show that γHV68 infection elicits a highly heterogeneous CD8 T-cell response that segregates into two distinctive kinetic patterns controlled by differential epitope expression during the lytic and latency amplification stages of infection.Murine gammaherpesvirus 68 (γHV68) is a mouse pathogen closely related to the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi''s sarcoma-associated herpesvirus (KSHV). Intranasal infection of mice with γHV68 leads to an acute infection in lung epithelial cells that is ultimately cleared and the concurrent establishment of latency in B cells, dendritic cells, and macrophages that undergoes amplification in the spleen and is maintained lifelong (11, 12). Even though γHV68 has the capacity to downregulate major histocompatibility complex class I (MHC-I) molecules (36), CD8 T cells specific for γHV68 are generated and have been shown to proliferate in response to cognate antigen, protect naive mice from γHV68 infection, lyse peptide-pulsed target cells in vivo and in vitro, and maintain the ability to produce antiviral cytokines (5, 6, 13, 27, 35). Until recently, knowledge of the antiviral CD8 T-cell repertoire in C57BL/6 mice was largely limited to two well-characterized epitopes derived from ORF6 and ORF61. T-cell responses to these epitopes have been shown to progress with distinct kinetics, with ORF6487-specific cells predominating early in infection and ORF61524-specific cells continuing to expand through early latency before declining and then persisting at higher levels late in infection (33). The difference in response kinetics correlates with the differential presentation of the epitopes, with the ORF6487 epitope being expressed only during lytic infection and the ORF61524 epitope being expressed both during lytic infection and during the latency amplification phase (22, 28). Additionally, the latency amplification phase is associated with the expansion of CD8 T cells with a Vβ4 T-cell receptor (TCR) component in several mouse strains (17), presumably due to a superantigen-like effect of the γHV68 M1 protein (4, 9).To better understand the breadth of the anti-γHV68 T-cell response, we used an enzyme-linked immunospot (ELISpot) approach to identify new epitopes. We identified a large number of epitopes derived from 26 proteins that drive the acute CD8 T-cell response to γHV68, which then narrowed over time, resulting in a limited antiviral response during latency. We did not observe inflation of any of the responses, as has been demonstrated for some murine cytomegalovirus (MCMV)-specific responses (20, 26). There was no evidence for functional exhaustion, as all detectable CD8 T-cell responses maintained functionality, but the responses declined in numbers over time. The decline in responses occurred over a broad kinetic range, which segregated into two general groups that correlated precisely with those previously described for ORF6 and ORF61. Thus, some responses declined rapidly after the acute phase of infection, while others declined more slowly.We examined two epitope-specific responses from each of the two patterns in detail over time for functional and phenotypic characteristics and found the responses to be highly heterogeneous, differing in TCR affinity, functional avidity, and proliferation rates. Importantly, slowly declining responses were not maintained as efficiently after infection with a latency-deficient virus, consistent with a role for epitope expression in driving the heterogeneous rate of decline in cell number after the acute infection. The data show that the response kinetics seen for the ORF6487 and ORF61524 responses are broadly applicable to multiple CD8 T-cell epitopes. 相似文献
78.
Stéphane L. Bogen Ashok Arasappan Francisco Velazquez Melissa Blackman Regina Huelgas Weidong Pan Elise Siegel Latha G. Nair Srikanth Venkatraman Zhuyan Guo Ronald Doll Neng-Yang Shih F. George Njoroge 《Bioorganic & medicinal chemistry》2010,18(5):1854-1865
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world’s population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P4 pocket by introducing a new sulfonamide moiety and optimization of the P1/P1′ capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P1 residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey. 相似文献
79.
Nikolas Friedrich Joana M. Santos Yan Liu Angelina S. Palma Ester Leon Savvas Saouros Makoto Kiso Michael J. Blackman Stephen Matthews Ten Feizi Dominique Soldati-Favre 《The Journal of biological chemistry》2010,285(3):2064-2076
Numerous intracellular pathogens exploit cell surface glycoconjugates for host cell recognition and entry. Unlike bacteria and viruses, Toxoplasma gondii and other parasites of the phylum Apicomplexa actively invade host cells, and this process critically depends on adhesins (microneme proteins) released onto the parasite surface from intracellular organelles called micronemes (MIC). The microneme adhesive repeat (MAR) domain of T. gondii MIC1 (TgMIC1) recognizes sialic acid (Sia), a key determinant on the host cell surface for invasion by this pathogen. By complementation and invasion assays, we demonstrate that TgMIC1 is one important player in Sia-dependent invasion and that another novel Sia-binding lectin, designated TgMIC13, is also involved. Using BLAST searches, we identify a family of MAR-containing proteins in enteroparasitic coccidians, a subclass of apicomplexans, including T. gondii, suggesting that all these parasites exploit sialylated glycoconjugates on host cells as determinants for enteric invasion. Furthermore, this protein family might provide a basis for the broad host cell range observed for coccidians that form tissue cysts during chronic infection. Carbohydrate microarray analyses, corroborated by structural considerations, show that TgMIC13, TgMIC1, and its homologue Neospora caninum MIC1 (NcMIC1) share a preference for α2–3- over α2–6-linked sialyl-N-acetyllactosamine sequences. However, the three lectins also display differences in binding preferences. Intense binding of TgMIC13 to α2–9-linked disialyl sequence reported on embryonal cells and relatively strong binding to 4-O-acetylated-Sia found on gut epithelium and binding of NcMIC1 to 6′sulfo-sialyl Lewisx might have implications for tissue tropism. 相似文献
80.
Ernkvist M Aase K Ukomadu C Wohlschlegel J Blackman R Veitonmäki N Bratt A Dutta A Holmgren L 《The FEBS journal》2006,273(9):2000-2011
Angiomotin, an 80 kDa protein expressed in endothelial cells, promotes cell migration and invasion, and stabilizes tube formation in vitro. Angiomotin belongs to a new protein family with two additional members, Amotl-1 and Amotl-2, which are characterized by conserved coiled-coil domains and C-terminal PDZ binding motifs. Here, we report the identification of a 130 kDa splice isoform of angiomotin that is expressed in different cell types including vascular endothelial cells, as well as cytotrophoblasts of the placenta. p130-Angiomotin consists of a cytoplasmic N-terminal extension that mediates its association with F-actin. Transfection of p130-angiomotin into endothelial cells induces actin fiber formation and changes cell shape. The p130-angiomotin protein remained associated with actin after destabilization of actin fibers with cytochalasin B. In contrast to p80-angiomotin, p130-angiomotin does not promote cell migration and did not respond to angiostatin. We propose that p80- and p130-angiomotin play coordinating roles in tube formation by affecting cell migration and cell shape, respectively. 相似文献