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81.
82.
Adalbert Krawczyk Miriam Dirks Maren Kasper Anna Buch Ulf Dittmer Bernd Giebel Lena Wildschütz Martin Busch Andre Goergens Karl E. Schneweis Anna M. Eis-Hübinger Beate Sodeik Arnd Heiligenhaus Michael Roggendorf Dirk Bauer 《PloS one》2015,10(1)
The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans. 相似文献
83.
Frederike J?rg Johan Ormel Sijmen A. Reijneveld Dani?lle E. M. C. Jansen Frank C. Verhulst Albertine J. Oldehinkel 《PloS one》2012,7(9)
Background
The increased use and costs of specialist child and adolescent mental health services (MHS) urge us to assess the effectiveness of these services. The aim of this paper is to compare the course of emotional and behavioural problems in adolescents with and without MHS use in a naturalistic setting.Method and Findings
Participants are 2230 (pre)adolescents that enrolled in a prospective cohort study, the TRacking Adolescents'' Individual Lives Survey (TRAILS). Response rate was 76%, mean age at baseline 11.09 (SD 0.56), 50.8% girls. We used data from the first three assessment waves, covering a six year period. Multiple linear regression analysis, propensity score matching, and data validation were used to compare the course of emotional and behavioural problems of adolescents with and without MHS use. The association between MHS and follow-up problem score (β 0.20, SE 0.03, p-value<0.001) was not confounded by baseline severity, markers of adolescent vulnerability or resilience nor stressful life events. The propensity score matching strategy revealed that follow-up problem scores of non-MHS-users decreased while the problem scores of MHS users remained high. When taking into account future MHS (non)use, it appeared that problem scores decreased with limited MHS use, albeit not as much as without any MHS use, and that problem scores with continuous MHS use remained high. Data validation showed that using a different outcome measure, multiple assessment waves and multiple imputation of missing values did not alter the results. A limitation of the study is that, although we know what type of MHS participants used, and during which period, we lack information on the duration of the treatment.Conclusions
The benefits of MHS are questionable. Replication studies should reveal whether a critical examination of everyday care is necessary or an artefact is responsible for these results. 相似文献84.
Cátia Fernandes-Cerqueira Elena Ossipova Sunithi Gunasekera Monika Hansson Linda Mathsson Anca I. Catrina Yngve Sommarin Lars Klareskog Karin Lundberg Johan R?nnelid Ulf G?ransson Per-Johan Jakobsson 《Arthritis research & therapy》2015,17(1)
IntroductionWe have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA).MethodsThe autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC® system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP)2 using the CCPlus® ELISA kit.ResultsTwo peptides derived from the fibrinogen α chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen β chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65 %, 15 %, 35 %, and 53 % of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5 % (Cit573), 6 % (Cit591), 8 % (Cit72), and 4 % (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84 % and 63 % respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency.ConclusionsHere we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA. 相似文献
85.
Quantitative trait locus (QTL) isogenic recombinant analysis: a method for high-resolution mapping of QTL within a single population 总被引:3,自引:0,他引:3 下载免费PDF全文
Peleman JD Wye C Zethof J Sørensen AP Verbakel H van Oeveren J Gerats T van der Voort JR 《Genetics》2005,171(3):1341-1352
In the quest for fine mapping quantitative trait loci (QTL) at a subcentimorgan scale, several methods that involve the construction of inbred lines and the generation of large progenies of such inbred lines have been developed (Complex Trait Consortium 2003). Here we present an alternative method that significantly speeds up QTL fine mapping by using one segregating population. As a first step, a rough mapping analysis is performed on a small part of the population. Once the QTL have been mapped to a chromosomal interval by standard procedures, a large population of 1000 plants or more is analyzed with markers flanking the defined QTL to select QTL isogenic recombinants (QIRs). QIRs bear a recombination event in the QTL interval of interest, while other QTL have the same homozygous genotype. Only these QIRs are subsequently phenotyped to fine map the QTL. By focusing at an early stage on the informative individuals in the population only, the efforts in population genotyping and phenotyping are significantly reduced as compared to prior methods. The principles of this approach are demonstrated by fine mapping an erucic acid QTL of rapeseed at a subcentimorgan scale. 相似文献
86.
87.
Background
Understanding the adaptive changes that alter the function of proteins during evolution is an important question for biology and medicine. The increasing number of completely sequenced genomes from closely related organisms, as well as individuals within species, facilitates systematic detection of recent selection events by means of comparative genomics. 相似文献88.
Jennifer L. Green Matthieu Bauer Kyu Won Yum Yao-Cheng Li Miranda L. Cox Karl Willert Geoffrey M. Wahl 《PloS one》2013,8(3)
Functional and mechanistic studies of Wnt signaling have been severely hindered by the inaccessibility of bioactive proteins. To overcome this long-standing barrier, we engineered and characterized a panel of Chinese hamster ovary (CHO) cell lines with inducible transgenes encoding tagged and un-tagged human WNT1, WNT3A, WNT5A, WNT7A, WNT11, WNT16 or the soluble Wnt antagonist Fzd8CRD, all integrated into an identical genomic locus. Using a quantitative real-time bioluminescence assay, we show that cells expressing WNT1, 3A and 7A stimulate Wnt/beta-catenin reporter activity, while the other WNT expressing cell lines interfere with this activation. Additionally, in contrast to WNT3A, WNT1 only exhibits activity when cell-associated, and thus only signals to neighboring cells. The reporter assay also revealed a rapid decline of Wnt activity at 37°C, indicating that Wnt activity is highly labile. These engineered cell lines will reduce the cost of making and purifying Wnt proteins and serve as a continuous, reliable and regulatable source of Wnts to research laboratories around the world. 相似文献
89.
Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype 下载免费PDF全文
Kalb R Neveling K Hoehn H Schneider H Linka Y Batish SD Hunt C Berwick M Callen E Surralles J Casado JA Bueren J Dasi A Soulier J Gluckman E Zwaan CM van Spaendonk R Pals G de Winter JP Joenje H Grompe M Auerbach AD Hanenberg H Schindler D 《American journal of human genetics》2007,80(5):895-910
FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA. 相似文献
90.
Facilitation in plant communities: the past, the present, and the future 总被引:24,自引:11,他引:24
Rob W. Brooker Fernando T. Maestre Ragan M. Callaway Christopher L. Lortie Lohengrin A. Cavieres Georges Kunstler Pierre Liancourt Katja Tielbörger Justin M. J. Travis Fabien Anthelme Cristina Armas Lluis Coll Emmanuel Corcket Sylvain Delzon Estelle Forey Zaal Kikvidze Johan Olofsson Francisco Pugnaire Constanza L. Quiroz Patrick Saccone Katja Schiffers Merav Seifan Blaize Touzard Richard Michalet 《Journal of Ecology》2008,96(1):18-34