全文获取类型
收费全文 | 2957篇 |
免费 | 199篇 |
出版年
2024年 | 6篇 |
2023年 | 21篇 |
2022年 | 54篇 |
2021年 | 86篇 |
2020年 | 58篇 |
2019年 | 61篇 |
2018年 | 79篇 |
2017年 | 83篇 |
2016年 | 115篇 |
2015年 | 173篇 |
2014年 | 206篇 |
2013年 | 228篇 |
2012年 | 256篇 |
2011年 | 255篇 |
2010年 | 152篇 |
2009年 | 161篇 |
2008年 | 183篇 |
2007年 | 166篇 |
2006年 | 143篇 |
2005年 | 118篇 |
2004年 | 108篇 |
2003年 | 108篇 |
2002年 | 119篇 |
2001年 | 31篇 |
2000年 | 13篇 |
1999年 | 21篇 |
1998年 | 23篇 |
1997年 | 15篇 |
1996年 | 16篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 7篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1985年 | 4篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1969年 | 2篇 |
1961年 | 3篇 |
排序方式: 共有3156条查询结果,搜索用时 15 毫秒
51.
Beatriz Aldaz Ainara Sagardoy Lorena Nogueira Elizabeth Guruceaga Lara Grande Jason T. Huse Maria A. Aznar Ricardo Díez-Valle Sonia Tejada-Solís Marta M. Alonso Jose L. Fernandez-Luna Jose A. Martinez-Climent Raquel Malumbres 《PloS one》2013,8(10)
Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process. 相似文献
52.
Laercio Martins De Stefano Alex Lombardi Barbosa Ferraz Ana Lúcia dos Anjos Ferreira Ana Lúcia Gut Ana Lúcia Cogni Elaine Farah Beatriz Bojikian Matsubara 《PloS one》2013,8(10)
Purpose
To investigate the predictors of intolerance to beta-blockers treatment and the 6-month mortality in hospitalized patients with acute coronary syndrome (ACS).Methods
This was a single-center, prospective, and longitudinal study including 370 consecutive ACS patients in Killip class I or II. BBs were prescribed according to international guidelines and withdrawn if intolerance occurred. The study was approved by the institutional ethics committee of our university. Statistics: the clinical parameters evaluated at admission, and the related intolerance to BBs and death at 6 months were analyzed using logistic regression (p<0.05)in PATIENTS.Results
BB intolerance was observed in 84 patients and was associated with no prior use of statins (OR: 2.16, 95%CI: 1.26–3.69, p= 0.005) and Killip class II (OR: 2.5, 95%CI: 1.30-4.75, p=0.004) in the model adjusted for age, sex, blood pressure, and renal function. There was no association with ST-segment alteration or left anterior descending coronary artery plaque. Intolerance to BB was associated with the greatest risk of death (OR: 4.5, 95%CI: 2.15–9.40, p<0.001).Conclusions
After ACS, intolerance to BBs in the first 48 h of admission was associated to non previous use of statin and Killip class II and had a high risk of death within 6 months. 相似文献53.
Julio Plaza-Diaz Carolina Gomez-Llorente Laura Campa?a-Martin Esther Matencio Inmaculada Ortu?o Rosario Martínez-Silla Carlos Gomez-Gallego Maria Jesús Periago Gaspar Ros Empar Chenoll Salvador Genovés Beatriz Casinos ángela Silva Dolores Corella Olga Portolés Fernando Romero Daniel Ramón Antonio Perez de la Cruz Angel Gil Luis Fontana 《PloS one》2013,8(10)
We previously described the isolation and characterization of three probiotic strains from the feces of exclusively breast-fed newborn infants: Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036. These strains were shown to adhere to intestinal mucus in vitro, to be sensitive to antibiotics and to resist biliary salts and low pH. In the present study, a multicenter, randomized, double-blind, placebo-controlled trial with 100 healthy volunteers in three Spanish cities was carried out to evaluate the tolerance, safety, gut colonization and immunomodulatory effects of these three probiotics. Volunteers underwent a 15-day washout period, after which they were randomly divided into 5 groups that received daily a placebo, a capsule containing one of the 3 strains or a capsule containing a mixture of two strains for 30 days. The intervention was followed by another 15-day washout period. Patients did not consume fermented milk for the entire duration of the study. Gastrointestinal symptoms, defecation frequency and stool consistency were not altered by probiotic intake. No relevant changes in blood and serum, as well as no adverse events occurred during or after treatment. Probiotic administration slightly modified bacterial populations in the volunteers’ feces. Intestinal persistence occurred in volunteers who received L. rhamnosus CNCM I-4036. Administration of B. breve CNCM I-4035 resulted in a significant increase in fecal secretory IgA content. IL-4 and IL-10 increased, whereas IL-12 decreased in the serum of volunteers treated with any of the three strains. These results demonstrate that the consumption of these three bacterial strains was safe and exerted varying degrees of immunomodulatory effects.
Trial Registration
ClinicalTrials.gov NCT01479543 相似文献54.
Sheila K. West Robin Bailey Beatriz Munoz Tansy Edwards Harran Mkocha Charlotte Gaydos Thomas Lietman Travis Porco David Mabey Thomas C. Quinn 《PLoS neglected tropical diseases》2013,7(8)
Background
The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown.Trial Design
2×2 factorial community randomized, double blind, trial.Trial methods
32 communities with prevalence of trachoma ≥20% were randomized to: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. The primary outcome was the community prevalence of infection with C. trachomatis at 36 months.Results
Over the trial''s course, no community met the MDA cessation rule, so all communities had the full 3 rounds of MDA. At 36 months, there was no significant difference in the prevalence of infection, 4.0 versus 5.4 (mean adjusted difference = 1.4%, 95% CI = −1.0% to 3.8%), nor in the prevalence of trachoma, 6.1 versus 9.0 (mean adjusted difference = 2.6%, 95% CI = −0.3% to 5.3%) comparing the usual target to the enhanced target group. There was no difference if analyzed using coverage as a continuous variable.Conclusion
In communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. 相似文献55.
Peter J.K. van Meer Marlous Kooijman Vera Brinks Christine C. Gispen-de Wied Beatriz Silva-Lima Ellen H.M. Moors Huub Schellekens 《MABS-AUSTIN》2013,5(5):810-816
The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies. 相似文献
56.
M. Rosario Darquier Cecilia F. Bessega Mariano Cony Juan C. Vilardi Beatriz O. Saidman 《Tree Genetics & Genomes》2013,9(1):307-320
Prosopis flexuosa is an arboreal Leguminosae that grows in arid and semiarid temperate zones of Argentina, in the Monte eco-region. It is a promising native forest species for recovering arid and semiarid regions because it plays an important role in erosion control as well as in soil fertility. Furthermore, it provides diverse economical resources. The main challenge to the forestry sector is finding a balance between production and forest protection. For this purpose, it is necessary to gather information about genetic parameters. In this study, we measured the distribution of the variation of 14 quantitative traits in an experimental half-sib stand, where families are representative of hierarchically structured populations. We applied a multivariate extension of the classical Q ST –F ST neutrality test to determine the relative importance of drift versus selection in the distribution of genetic variability. We found strong evidence that different selective regimes act on different traits and that selection favors different optima in each sampling site. The selection to different optima is much stronger among than within provenances. This result helps explain the possible causes for the regional variation observed in P. flexuosa and to define the management units and the evolutionarily significant units for this species. 相似文献
57.
58.
Beatriz Grinsztejn Paula M. Luz Antonio G. Pacheco Desiree V. G. Santos Luciane Velasque Ronaldo I. Moreira Maria Regina C. Guimar?es Estev?o P. Nunes Alberto S. Lemos Sayonara R. Ribeiro Dayse P. Campos Marco A. A. Vitoria Valdilea G. Veloso 《PloS one》2013,8(4)
Introduction
We describe temporal trends in the mortality rates and factors associated with AIDS and non-AIDS related mortality at the Evandro Chagas Clinical Research Institute (IPEC), Oswaldo Cruz Foundation (FIOCRUZ).Methods
Adult patients enrolling from 1986 through 2009 with a minimum follow up of 60 days were included. Vital status was exhaustively checked using patients’ medical charts, through active contact with individuals and family members and by linkage with the Rio de Janeiro Mortality database using a previously validated algorithm. The CoDe protocol was used to establish the cause of death. Extended Cox proportional hazards models were used for multivariate modeling.Results
A total of 3530 individuals met the inclusion criteria, out of which 868 (24.6%) deceased; median follow up per patient was 3.9 years (interquartile range 1.7–9.2 years). The dramatic decrease in the overall mortality rates was driven by AIDS-related causes that decreased from 9.19 deaths/100PYs n 1986–1991 to 1.35/100PYs in 2007–2009. Non-AIDS related mortality rates remained stable overtime, at around 1 death/100PYs. Immunodeficiency significantly increased the hazard of both AIDS-related and non-AIDS-related causes of death, while HAART use was strongly associated with a lower hazard of death from either cause.Conclusions
Our results confirm the remarkable decrease in AIDS-related mortality as the HIV epidemic evolved and alerts to the conditions not traditionally related to HIV/AIDS which are now becoming more frequent, needing careful monitoring. 相似文献59.
Alberto Crespo Guardo Carmen álvarez-Fernández Hodei Arberas Javier García-Pérez Felipe García Manuel Enric Bargalló María José Maleno José María Gatell Beatriz Mothe José Alcami Sonsoles Sánchez-Palomino Montserrat Plana 《PloS one》2013,8(3)
Background
Generation of new reagents that can be used to screen or monitor HIV-1-specific responses constituted an interesting field in the development of HIV vaccines to improve their efficacy.Methods
We have evaluated the specific T cell response against different types of NL4-3 virions (including NL4-3 aldrithiol-2 treated, NL4-3/ΔRT and R5 envelopes: NL4-3/ΔRT/ΔEnv[AC10] and NL4-3/ΔRT/ΔEnv[Bal]) and against pools of overlapping peptides (15 mer) encompassing the HIV-1 Gag and Nef regions. Cryopreserved PBMC from a subset of 69 chronic asymptomatic HIV positive individuals have been employed using different techniques including IFN-γ ELISPOT assay, surface activation markers and intracellular cytokine staining (ICS) by flow cytometry.Results
The differential response obtained against NL4-3 aldrithiol-2 treated and NL4-3/ΔRT virions (25% vs 55%, respectively) allow us to divide the population in three groups: “full-responders” (positive response against both viral particles), “partial-responders” (positive response only against NL4-3/ΔRT virions) and “non-responders” (negative responses). There was no difference between X4 and R5 envelopes. The magnitude of the total responses was higher against NL4-3/ΔRT and was positively correlated with gender and inverse correlated with viral load. On the contrary CD4+ T cell count was not associated with this response. In any case responses to the viruses tended to be lower in magnitude than those detected by the overlapping peptides tested. Finally we have found an increased frequency of HLA-B27 allele (23% vs 9%) and a significant reduction in some activation markers (CD69 and CD38) on T cells surface in responders vs non-responders individuals.Conclusions
In summary these virions could be considered as alternative and useful reagents for screening HIV-1-specific T cell responses in HIV exposed uninfected people, HIV infected patients and to assess immunogenicity of new prototypes both in vitro and in vaccine trials, by a feasible, simply, effective and low cost assay. 相似文献60.
Severo Juliana Soares Morais Jennifer Beatriz Silva Beserra Jessica Batista dos Santos Loanne Rocha de Sousa Melo Stéfany Rodrigues de Sousa Gustavo Santos de Matos Neto Emídio Marques Henriques Gilberto Simeone do Nascimento Marreiro Dilina 《Biological trace element research》2020,193(1):81-88
Biological Trace Element Research - Excessive adipose tissue promotes the manifestation of endocrine disorders such as reduction of the secretion of zinc-α2-glycoprotein (ZAG), an adipokine... 相似文献