全文获取类型
收费全文 | 3590篇 |
免费 | 257篇 |
专业分类
3847篇 |
出版年
2023年 | 27篇 |
2022年 | 50篇 |
2021年 | 116篇 |
2020年 | 81篇 |
2019年 | 70篇 |
2018年 | 96篇 |
2017年 | 94篇 |
2016年 | 134篇 |
2015年 | 181篇 |
2014年 | 196篇 |
2013年 | 245篇 |
2012年 | 316篇 |
2011年 | 261篇 |
2010年 | 178篇 |
2009年 | 126篇 |
2008年 | 181篇 |
2007年 | 171篇 |
2006年 | 165篇 |
2005年 | 150篇 |
2004年 | 143篇 |
2003年 | 109篇 |
2002年 | 101篇 |
2001年 | 59篇 |
2000年 | 76篇 |
1999年 | 48篇 |
1998年 | 21篇 |
1997年 | 17篇 |
1996年 | 18篇 |
1995年 | 27篇 |
1994年 | 8篇 |
1993年 | 16篇 |
1992年 | 25篇 |
1991年 | 35篇 |
1990年 | 16篇 |
1989年 | 33篇 |
1988年 | 15篇 |
1987年 | 17篇 |
1986年 | 12篇 |
1985年 | 26篇 |
1984年 | 16篇 |
1983年 | 11篇 |
1980年 | 13篇 |
1979年 | 10篇 |
1978年 | 9篇 |
1975年 | 14篇 |
1974年 | 9篇 |
1973年 | 10篇 |
1972年 | 9篇 |
1971年 | 9篇 |
1970年 | 7篇 |
排序方式: 共有3847条查询结果,搜索用时 15 毫秒
51.
Maria E. Merlin Rocha Brian Bandy Cristine A. Costa Marcelo P. de Barros Adriana M.P. Pinto Etelvino J.H. Bechara 《Free radical research》2013,47(4):343-353
Accumulation of 5-aminolevulinic acid (ALA) is an event characteristic of porphyrias that may contribute to their pathological manifestations. To investigate effects of ALA independent of porphyrin accumulation we treated rats with the methyl ester of succinylacetone, an inhibitor of 5-aminolevulinic acid dehydratase that accumulates in the porphyric-like syndrome hereditary tyrosinemia. Acute 2-day treatment of fasted rats with succinylacetone methyl ester (SAME) promoted a 27% increase in plasma ALA. This increase in plasma ALA was accompanied by augmentation of the level of total nonheme iron in liver (37%) and brain (20%). Mobilization of iron was also indicated by 49% increase in plasma iron and a 77% increase in plasma transferrin saturation. Liver responded with a mild (12%) increase in ferritin. Under these acute conditions, some indications of oxidative stress were evident: a 15% increase in liver reactive protein carbonyls, and a 42% increase in brain subcellular membrane TBARS. Brain also showed a 44% increase in CuZnSOD activity, consistent with observations in treatment with ALA. Overall, the data indicate that SAME promotes ALA-driven changes in iron metabolism that could lead to increased production of free radicals. The findings support other evidence that accumulation of ALA in porphyrias and hereditary tyrosinemia may induce iron-dependent biological damage that contributes to neuropathy and hepatoma. 相似文献
52.
Mauro C. X. Pinto Betania B. Cota Michele A. Rodrigues Maria F. Leite Elaine M. de Souza‐Fagundes 《Journal of biochemical and molecular toxicology》2013,27(11):479-485
Hypnophilin (HNP) is a sesquiterpene that is isolated from Lentinus cf. strigosus and has cytotoxic activities. Here, we studied the calcium signaling and cytotoxic effects of HNP in UACC‐62 cells, a human skin melanoma cell line. HNP was able to increase the intracellular calcium concentration in UACC‐62 cells, which was blocked in cells stimulated in Ca2+‐free media. HNP treatment with BAPTA‐AM, an intracellular Ca2+ chelator, caused an increase in calcium signals. HNP showed cytotoxicity against UACC‐62 cells in which it induced DNA fragmentation and morphological alterations, including changes in the nuclear chromatin profile and increased cytoplasmatic vacuolization, but it had no effect on the plasma membrane integrity. These data suggest that cytotoxicity in UACC‐62 cells, after treatment with HNP, is associated with Ca2+ influx. Together, these findings suggest that HNP is a relevant tool for the further investigation of new anticancer approaches. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:479‐485, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21507 相似文献
53.
M. L. Gonçalves F. Pinto J. A. Ribeiro 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1161-1163
Abstract The effect of adenosine on 45Ca uptake by rat brain synaptosomes electrically stimulated was studied as function of time of stimulation (10, 30, 120 s). Inhibition of 45Ca uptake was more evident for 120 s. 相似文献
54.
Olga Martinho Filipe Pinto Sara Granja Vera Miranda-Gon?alves Marise A. R. Moreira Luis F. J. Ribeiro Celso di Loreto Marsha R. Rosner Adhemar Longatto-Filho Rui Manuel Reis 《PloS one》2013,8(3)
Cervical cancer is one of the most common cancers in women worldwide, being high-risk group the HPV infected, the leading etiological factor. The raf kinase inhibitory protein (RKIP) has been associated with tumor progression and metastasis in several human neoplasms, however its role on cervical cancer is unclear. In the present study, 259 uterine cervix tissues, including cervicitis, cervical intraepithelial lesions and carcinomas, were analyzed for RKIP expression by immunohistochemistry. We found that RKIP expression was significantly decreased during malignant progression, being highly expressed in non-neoplastic tissues (54% of the samples; 73/135), and expressed at low levels in the cervix invasive carcinomas (∼15% (19/124). Following in vitro downregulation of RKIP, we observed a viability and proliferative advantage of RKIP-inhibited cells over time, which was associated with an altered cell cycle distribution and higher colony number in a colony formation assay. An in vitro wound healing assay showed that RKIP abrogation is associated with increased migratory capability. RKIP downregulation was also associated with an increased vascularization of the tumors in vivo using a CAM assay. Furthermore, RKIP inhibition induced cervical cancer cells apoptotic resistance to cisplatin treatment. In conclusion, we described that RKIP protein is significantly depleted during the malignant progression of cervical tumors. Despite the lack of association with patient clinical outcome, we demonstrate, in vitro and in vivo, that loss of RKIP expression can be one of the factors that are behind the aggressiveness, malignant progression and chemotherapy resistance of cervical cancer. 相似文献
55.
Camila Fernandes Heitor Sá Gon?alves Paula Brito Cabral Helena Camara Pinto Maria Isabel Moraes Pinto Lilia Maria Carneiro Camara 《PloS one》2013,8(11)
Background
Leprosy is a chronic disease, caused by Mycobacterium leprae, which poses a serious public health problem worldwide. Its high incidence in people under 15 years old in Ceará state, Brazil, reflects the difficulty of its control. The spectrum of clinical manifestations is associated with the immune response developed, with the Th1 and Th2 responses being related to the paucibacillary and multibacillary forms, respectively. Regulatory T cells (Treg), which can suppress Th1 and Th2 response, have received special attention in the literature and have been associated with development of chronic infections. However, their role in leprosy in individuals under 15 years old has not yet been elucidated. We evaluated the frequency of CD4+/CD8+CD25highFOXP3+ and CD4+/CD8+CD25highFOXP3high cells in leprosy patients and household contacts, in both cases under 15 years old.Methodology/Principal Findings
PBMC from 12 patients and 17 contacts were cultured for 72 hours with anti-CD3 and anti-CD28 (activators) or with activators associated with total sonicated fraction of M. leprae. After culture, the frequency of CD4+/CD8+ Treg was identified by flow cytometry. Cells stimulated by activators and antigen from multibacillary patients showed Treg frequencies almost two times that of the contacts: CD4+FOXP3+ (21.93±8.43 vs. 13.79±8.19%, p = 0.0500), CD4+FOXP3high (10.33±5.69 vs. 5.57±4.03%, p = 0.0362), CD8+FOXP3+ (13.88±9.19 vs. 6.18±5.56%, p = 0.0230) and CD8+FOXP3high (5.36±4.17 vs. 2.23±2.68%, p = 0.0461). Furthermore, the mean fluorescence intensity of FOXP3 in Treg was higher in multibacillary patients than in the contacts. Interestingly, there was a positive correlation of the bacillary index and number of lesions with the frequency of all Treg evaluated in patients.Conclusions/Significance
We have demonstrated for the first time that multibacillary leprosy patients under 15 years old have greater CD4+ and CD8+ Treg frequencies and these correlate with clinical and laboratorial aspects of disease. These findings suggest the involvement of these cells in the perpetuation of M. leprae infection. 相似文献56.
Mónica Costa Eugénia Cruz James C. Barton Ketil Thorstensen Sandra Morais Berta M. da Silva Jorge P. Pinto Cristina P. Vieira Jorge Vieira Ronald T. Acton Gra?a Porto 《PloS one》2013,8(11)
Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8+T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8+ T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8+ T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01–B*08 or A*03–B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8+ T-lymphocyte numbers. 相似文献
57.
58.
Jorge Almarza Luis Rincón Alí Bahsas María Angela Pinto Francisco Brito 《The protein journal》2013,32(2):118-125
Understanding of protein–urea interactions is one of the greatest challenges to modern structural protein chemistry. Based in enzyme kinetics experiments and 1H NMR spectroscopic analysis we proposed that urea, at low concentrations, directly interacts with the protonated histidines of the active center of RNase A, following a simple model of competitive inhibition. These results were supported by theoretical analysis based on the frontier molecular orbital theory and suggest that urea might establish a favorable interaction with the cationic amino acids. Our experimental evidence and theoretical analysis indicate that the initials steps of the molecular mechanism of Urea–RNase A interaction passes through the establishment of a three center four electron adduct. Also, our results would explain the observed disruption of the 1H NMR signals corresponding to H12 and H119 (involved in catalysis) of the RNase A studied in the presence of urea. Our interaction model of urea–amino acids (cationic) can be extended to explain the inactivation of other enzymes with cationic amino acids at the active site. 相似文献
59.
Objectives
It is unclear whether sedentary behaviour, and the domain in which it occurs, is related to body mass index (BMI) change. We aim to elucidate whether sedentary behaviour is prospectively related to BMI change using markers from three domains (leisure, work and commuting).Methods
Among employed 1958 British birth cohort members (n = 6,562), we analysed whether TV-viewing, work sitting (six categories: 0 h/d to >4 h/d) and motorised commuting (at 45 y) were related to BMI (at 45 y and 50 y) and BMI change 45–50 y, after adjusting for lifestyle and socioeconomic factors.Results
Per category higher TV-viewing, 45 y and 50 y BMI were higher by 0.69 kg/m2 (95% CI: 0.59,0.80) and 0.75 kg/m2 (0.64,0.86) respectively. A category higher TV-viewing was associated with 0.11 kg/m2 (0.06,0.17) increased BMI 45–50 y, attenuating to 0.06 kg/m2 (0.01,0.12) after adjustment. There was no trend for work sitting with 45 y or 50 y BMI, nor, after adjustment, for BMI change. However, those sitting 2–3 h/d had greater BMI gain by 0.33 kg/m2 (0.10,0.56) compared to those sitting 0–1 h/d. Associations between TV-viewing and BMI change were independent of work sitting. Motorised commuting was associated with 45 y, but not 50 y BMI or change.Conclusions
TV-viewing is associated with BMI gain in mid-adulthood; evidence is weaker for other sedentary behaviours. 相似文献60.
Lorenzo Maria Donini Eleonora Poggiogalle Veronica Mosca Alessandro Pinto Amelia Brunani Paolo Capodaglio 《PloS one》2013,8(10)