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91.
Billam P Bonaparte KL Liu J Ruckwardt TJ Chen M Ryder AB Wang R Dash P Thomas PG Graham BS 《The Journal of biological chemistry》2011,286(6):4829-4841
CD8+ T cell responses are important for recognizing and resolving viral infections. To better understand the selection and hierarchy of virus-specific T cell responses, we compared the T cell receptor (TCR) clonotype in parent and hybrid strains of respiratory syncytial virus-infected mice. K(d)M2(82-90) (SYIGSINNI) in BALB/c and D(b)M(187-195) (NAITNAKII) in C57Bl/6 are both dominant epitopes in parent strains but assume a distinct hierarchy, with K(d)M2(82-90) dominant to D(b)M(187-195) in hybrid CB6F1/J mice. The dominant K(d)M2(82-90) response is relatively public and is restricted primarily to the highly prevalent Vβ13.2 in BALB/c and hybrid mice, whereas D(b)M(187-195) responses in C57BL/6 mice are relatively private and involve multiple Vβ subtypes, some of which are lost in hybrids. A significant frequency of TCR CDR3 sequences in the D(b)M(187-195) response have a distinct "(D/E)WG" motif formed by a limited number of recombination strategies. Modeling of the dominant epitope suggested a flat, featureless structure, but D(b)M(187-195) showed a distinctive structure formed by Lys(7). The data suggest that common recombination events in prevalent Vβ genes may provide a numerical advantage in the T cell response and that distinct epitope structures may impose more limited options for successful TCR selection. Defining how epitope structure is interpreted to inform T cell function will improve the design of future gene-based vaccines. 相似文献
92.
Ratish Gambhira Brandon F. Keele John B. Schell Meredith J. Hunter Jason P. Dufour David C. Montefiori Haili Tang John K. Rose Nina Rose Preston A. Marx 《PloS one》2014,9(10)
Identification of transmitted/founder simian immunodeficiency virus (SIV) envelope sequences responsible for infection may prove critical for understanding HIV/SIV mucosal transmission. We used single genome amplification and phylogenetic analyses to characterize transmitted/founder SIVs both in the inoculum and in immunized-infected rhesus monkeys. Single genome amplification of the SIVsmE660 inoculum revealed a maximum diversity of 1.4%. We also noted that the consensus sequence of the challenge stock differed from the vaccine construct in 10 amino acids including 3 changes in the V4 loop. Viral env was prepared from rhesus plasma in 3 groups of 6 immunized with vesicular stomatitis virus (VSV) vectors and boosted with Semliki forest virus (SFV) replicons expressing (a) SIVsmE660 gag-env (b) SIVsmE660 gag-env plus rhesus GM-CSF and (c) control influenza hemagglutinin protein. Macaques were immunized twice with VSV-vectors and once with SFV vector and challenged intrarectally with 4000 TCID50. Single genome amplification characterized the infections of 2 unprotected animals in the gag-env immunized group, both of which had reduced acute plasma viral loads that ended as transient infections indicating partial immune control. Four of 6 rhesus were infected in the gag-env + GM-CSF group which demonstrated that GM-CSF abrogated protection. All 6 animals from the control group were infected having high plasma viral loads. We obtained 246 full-length envelope sequences from SIVsmE660 infected macaques at the peak of infection and determined the number of transmitted/founder variants per animal. Our analysis found that 2 of 2 gag-env vaccinated but infected macaques exhibited single but distinct virus envelope lineages whereas rhesus vaccinated with gag-env-GM-CSF or HA control exhibited both single and multiple env lineages. Because there were only 2 infected animals in the gag-env vaccinated rhesus compared to 10 infected rhesus in the other 2 groups, the significance of finding single env variants in the gag-env vaccinated group could not be established. 相似文献
93.
Jhumka Gupta Kathryn L. Falb Hannah Carliner Mazeda Hossain Denise Kpebo Jeannie Annan 《PloS one》2014,9(5)
Background
Objectives were to assess associations between intimate partner violence (IPV), violence during armed conflict (i.e. crisis violence), and probable post-traumatic stress disorder (PTSD).Methods
Using a sample of 950 women in rural Côte d’Ivoire, logistic generalized estimating equations assessed associations between IPV and crisis violence exposures with past-week probable PTSD.Results
Over one in 5 (23.4%) women reported past-year IPV, and over one in 4 women (26.5%) reported experiencing IPV prior to the past year (i.e. remote IPV). Crisis violence was experienced by 72.6% of women. In adjusted models including demographics, crisis violence (overall and specific forms), and IPV (remote and past-year), women who reported past-year IPV had 3.1 times the odds of reporting probable past-week PTSD (95%CI: 1.8–5.3) and those who reported remote IPV had 1.6 times the odds (95%CI: 0.9–2.7). Violent exposures during the crisis were not significantly associated with probable PTSD (any crisis violence: aOR: 1.04 (0.7–1.5); displacement: aOR: 0.9 (95%CI: 0.5–1.7); family victimization during crisis: aOR: 1.1 (95%CI: 0.8–1.7); personal victimization during crisis: aOR: 1.7 (95%CI: 0.7–3.7)).Conclusion
Past-year IPV was more strongly associated with past-week probable PTSD than remote IPV and violence directly related to the crisis. IPV must be considered within humanitarian mental health and psychosocial programming. 相似文献94.
Erin G. Worrall Bartosz Wawrzynow Liam Worrall Malcolm Walkinshaw Kathryn L. Ball Ted R. Hupp 《Journal of chemical biology》2009,2(3):113-129
The tumor suppressor p53 has evolved a MDM2-dependent feedback loop that promotes p53 protein degradation through the ubiquitin–proteasome
system. MDM2 is an E3-RING containing ubiquitin ligase that catalyzes p53 ubiquitination by a dual-site mechanism requiring
ligand occupation of its N-terminal hydrophobic pocket, which then stabilizes MDM2 binding to the ubiquitination signal in
the DNA-binding domain of p53. A unique pseudo-substrate motif or “lid” in MDM2 is adjacent to its N-terminal hydrophobic
pocket, and we have evaluated the effects of the flexible lid on the dual-site ubiquitination reaction mechanism catalyzed
by MDM2. Deletion of this pseudo-substrate motif promotes MDM2 protein thermoinstability, indicating that the site can function
as a positive regulatory element. Phospho-mimetic mutation in the pseudo-substrate motif at codon 17 (MDM2S17D) stabilizes the binding of MDM2 towards two distinct peptide docking sites within the p53 tetramer and enhances p53 ubiquitination.
Molecular modeling orientates the phospho-mimetic pseudo-substrate motif in equilibrium over a charged surface patch on the
MDM2 at Arg97/Lys98, and mutation of these residues to the MDM4 equivalent reverses the activating effect of the phospho-mimetic mutation on
MDM2 function. These data highlight the ability of the pseudo-substrate motif to regulate the allosteric interaction between
the N-terminal hydrophobic pocket of MDM2 and its central acidic domain, which stimulates the E3 ubiquitin ligase function
of MDM2. This model of MDM2 regulation implicates an as yet undefined lid-kinase as a component of pro-oncogenic pathways
that stimulate the E3 ubiquitin ligase function of MDM2 in cells. 相似文献
95.
Amino acid residues in the cytoplasmic domain of the Mason-Pfizer monkey virus glycoprotein critical for its incorporation into virions 下载免费PDF全文
Assembly of an infectious retrovirus requires the incorporation of the envelope glycoprotein complex during the process of particle budding. We have recently demonstrated that amino acid substitutions of a tyrosine residue in the cytoplasmic domain block glycoprotein incorporation into budding Mason-Pfizer monkey virus (M-PMV) particles and abrogate infectivity (C. Song, S. R. Dubay, and E. Hunter, J. Virol. 77:5192-5200, 2003). To investigate the contribution of other amino acids in the cytoplasmic domain to the process of glycoprotein incorporation, we introduced alanine-scanning mutations into this region of the transmembrane protein. The effects of the mutations on glycoprotein biosynthesis and function, as well as on virus infectivity, have been examined. Mutation of two cytoplasmic residues, valine 20 and histidine 21, inhibits viral protease-mediated cleavage of the cytoplasmic domain that is observed during virion maturation, but the mutant virions show only moderately reduced infectivity. We also demonstrate that the cytoplasmic domain of the M-PMV contains three amino acid residues that are absolutely essential for incorporation of glycoprotein into virions. In addition to the previously identified tyrosine at residue 22, an isoleucine at position 18 and a leucine at position 25 each mediate the process of incorporation and efficient release of virions. While isoleucine 18 may be involved in direct interactions with immature capsids, antibody uptake studies showed that leucine 25 and tyrosine 22 are part of an efficient internalization signal in the cytoplasmic domain of the M-PMV glycoprotein. These results demonstrate that the cytoplasmic domain of M-PMV Env, in part through its YXXL-mediated endocytosis and intracellular trafficking signals, plays a critical role in the incorporation of glycoprotein into virions. 相似文献
96.
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98.
Maria L. N. Moura Kathryn M. Dupnik Gabriel A. A. Sampaio Priscilla F. C. Nóbrega Ana K. Jeronimo Jose M. do Nascimento-Filho Roberta L. Miranda Dantas Jose W. Queiroz James D. Barbosa Gutemberg Dias Selma M. B. Jeronimo Marcia C. F. Souza Maurício L. Nobre 《PLoS neglected tropical diseases》2013,7(3)
Hansen''s disease (leprosy) remains an important health problem in Brazil, where 34,894 new cases were diagnosed in 2010, corresponding to 15.3% of the world''s new cases detected in that year. The purpose of this study was to use home visits as a tool for surveillance of Hansen''s disease in a hyperendemic area in Brazil. A total of 258 residences were visited with 719 individuals examined. Of these, 82 individuals had had a previous history of Hansen''s disease, 209 were their household contacts and 428 lived in neighboring residences. Fifteen new Hansen''s disease cases were confirmed, yielding a detection rate of 2.0% of people examined. There was no difference in the detection rate between household and neighbor contacts (p = 0.615). The two groups had the same background in relation to education (p = 0.510), household income (p = 0.582), and the number of people living in the residence (p = 0.188). Spatial analysis showed clustering of newly diagnosed cases and association with residential coordinates of previously diagnosed multibacillary cases. Active case finding is an important tool for Hansen''s disease control in hyperendemic areas, enabling earlier diagnosis, treatment, decrease in disability from Hansen''s disease and potentially less spread of Mycobacterium leprae. 相似文献
99.
Eric Dumonteil Pierre Nouvellet Kathryn Rosecrans Maria Jesus Ramirez-Sierra Rubi Gamboa-León Vladimir Cruz-Chan Miguel Rosado-Vallado Sébastien Gourbière 《PLoS neglected tropical diseases》2013,7(9)