全文获取类型
收费全文 | 2693篇 |
免费 | 210篇 |
国内免费 | 1篇 |
专业分类
2904篇 |
出版年
2023年 | 10篇 |
2022年 | 22篇 |
2021年 | 43篇 |
2020年 | 17篇 |
2019年 | 24篇 |
2018年 | 28篇 |
2017年 | 36篇 |
2016年 | 63篇 |
2015年 | 109篇 |
2014年 | 114篇 |
2013年 | 148篇 |
2012年 | 231篇 |
2011年 | 178篇 |
2010年 | 117篇 |
2009年 | 121篇 |
2008年 | 225篇 |
2007年 | 155篇 |
2006年 | 167篇 |
2005年 | 150篇 |
2004年 | 153篇 |
2003年 | 134篇 |
2002年 | 137篇 |
2001年 | 23篇 |
2000年 | 17篇 |
1999年 | 31篇 |
1998年 | 45篇 |
1997年 | 25篇 |
1996年 | 20篇 |
1995年 | 31篇 |
1994年 | 23篇 |
1993年 | 17篇 |
1992年 | 21篇 |
1991年 | 17篇 |
1990年 | 13篇 |
1989年 | 13篇 |
1988年 | 16篇 |
1987年 | 13篇 |
1986年 | 13篇 |
1985年 | 18篇 |
1984年 | 12篇 |
1983年 | 13篇 |
1982年 | 15篇 |
1981年 | 21篇 |
1980年 | 17篇 |
1978年 | 15篇 |
1977年 | 12篇 |
1976年 | 7篇 |
1974年 | 10篇 |
1973年 | 10篇 |
1968年 | 6篇 |
排序方式: 共有2904条查询结果,搜索用时 0 毫秒
91.
92.
Adrianna Z. Herskovits Joseph J. Locascio Elaine R. Peskind Ge Li Bradley T. Hyman 《PloS one》2013,8(7)
Amyloid beta (aβ) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer’s disease (AD) and there is increasing evidence that soluble aβ oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased aβ42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric aβ in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized aβ42 and sAPPα fragments. We evaluated oligomeric aβ reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and aβ42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated aβ oligomers compared to control subjects (p < 0.05) and the ratio of aβ oligomers to aβ42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric aβ becomes a routine diagnostic assay for the evaluation of late onset AD patients. 相似文献
93.
Anna Nolan Elaine Fajardo Maryann L. Huie Rany Condos Anil Pooran Rodney Dawson Keertan Dheda Eric Bateman William N. Rom Michael D. Weiden 《PloS one》2013,8(3)
Background
Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness.Methods
We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.50 C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model.Conclusion
Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness. 相似文献94.
David Mesher Elaine Stanford Joanne White Jamie Findlow Rosalind Warrington Sukamal Das Richard Pebody Ray Borrow Kate Soldan 《PloS one》2016,11(3)
Background
Reported human papillomavirus (HPV) vaccination coverage in England is high, particularly in girls offered routine immunisation at age 12 years. Serological surveillance can be used to validate reported coverage and explore variations within it and changes in serological markers over time.Methods
Residual serum specimens collected from females aged 15–19 years in 2010–2011 were tested for anti-HPV16 and HPV18 IgG by ELISA. Based on these results, females were classified as follows: seronegative, probable natural infection, probable vaccine-induced seropositivity, or possible natural infection/possible vaccine-induced seropositivity. The proportion of females with vaccine-induced seropositivity was compared to the reported vaccination coverage.Results
Of 2146 specimens tested, 1380 (64%) were seropositive for both types HPV16 and HPV18 and 159 (7.4%) positive for only one HPV type. The IgG concentrations were far higher for those positive for both HPV types than those positive for only one HPV type. 1320 (62%) females were considered to have probable vaccine-induced seropositivity. Among vaccine-induced seropositives, antibody concentrations declined with increasing age at vaccination and increasing time since vaccination.Conclusions
The proportion of females with vaccine-induced seropositivity was closest to the reported 3-dose coverage in those offered the vaccination at younger ages, with a greater discrepancy in the older females. This suggests either some under-reporting of immunisations of older females and/or that partial vaccination (i.e. one- or two-doses) has provided high antibody responses in 13–17 year olds. 相似文献95.
Laleh Khodaparast Ladan Khodaparast Mohammad Shahrooei Benoit Stijlemans Rita Merckx Pieter Baatsen James P. O’Gara Elaine Waters Lieve Van Mellaert Johan Van Eldere 《PloS one》2016,11(1)
Staphylococcus epidermidis is the most common cause of device-associated infections. It has been shown that active and passive immunization in an animal model against protein SesC significantly reduces S. epidermidis biofilm-associated infections. In order to elucidate its role, knock-out of sesC or isolation of S. epidermidis sesC-negative mutants were attempted, however, without success. As an alternative strategy, sesC was introduced into Staphylococcus aureus 8325–4 and its isogenic icaADBC and srtA mutants, into the clinical methicillin-sensitive S. aureus isolate MSSA4 and the MRSA S. aureus isolate BH1CC, which all lack sesC. Transformation of these strains with sesC i) changed the biofilm phenotype of strains 8325–4 and MSSA4 from PIA-dependent to proteinaceous even though PIA synthesis was not affected, ii) converted the non-biofilm-forming strain 8325–4 ica::tet to a proteinaceous biofilm-forming strain, iii) impaired PIA-dependent biofilm formation by 8325–4 srtA::tet, iv) had no impact on protein-mediated biofilm formation of BH1CC and v) increased in vivo catheter and organ colonization by strain 8325–4. Furthermore, treatment with anti-SesC antibodies significantly reduced in vitro biofilm formation and in vivo colonization by these transformants expressing sesC. These findings strongly suggest that SesC is involved in S. epidermidis attachment to and subsequent biofilm formation on a substrate. 相似文献
96.
Karen Einsfeldt Isis Cavalcante Baptista Juliana Christina Castanheira Vicente Pereira Roberta Eitler Bruno Fabiana Vieira Mello Isabele Campos Costa-Amaral Elaine Sobral da Costa Maria Cecília Menks Ribeiro Marcelo Gerardin Poirot Land Tito Lívio Moitinho Alves Ariane Leites Larentis Rodrigo Volcan Almeida 《PloS one》2016,11(9)
97.
Cavin K. Ward-Caviness Lucas M. Neas Colette Blach Carol S. Haynes Karen LaRocque-Abramson Elizabeth Grass Elaine Dowdy Robert B. Devlin David Diaz-Sanchez Wayne E. Cascio Marie Lynn Miranda Simon G. Gregory Svati H. Shah William E. Kraus Elizabeth R. Hauser 《PloS one》2016,11(4)
There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic (“traffic exposure”)—a recognized vascular disease risk factor—on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10-8) in European-Americans. Rs755249 is located in the 3’ untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10-6) and rs1180341 (tibial artery, eQTL P = 5.3x10-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes. 相似文献
98.
Nikele Nadur-Andrade Camila Squarzoni Dale Victoria Regina da Silva Oliveira Elaine Flamia Toniolo Regiane dos Santos Feliciano José Antonio da Silva Jr. Stella Regina Zamuner 《PLoS neglected tropical diseases》2016,10(10)
BackgroundEnvenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv), as well as the mechanisms involved was investigated.Conclusion/SignificanceThese data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites. 相似文献
99.
100.
Aviva Breuer Christeene G. Haj Manoela V. Foga?a Felipe V. Gomes Nicole Rodrigues Silva Jo?o Francisco Pedrazzi Elaine A. Del Bel Jaime C. Hallak José A. Crippa Antonio W. Zuardi Raphael Mechoulam Francisco S. Guimar?es 《PloS one》2016,11(7)
Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4''-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors. 相似文献