全文获取类型
收费全文 | 3250篇 |
免费 | 272篇 |
国内免费 | 2篇 |
出版年
2023年 | 11篇 |
2022年 | 37篇 |
2021年 | 65篇 |
2020年 | 34篇 |
2019年 | 50篇 |
2018年 | 82篇 |
2017年 | 55篇 |
2016年 | 121篇 |
2015年 | 177篇 |
2014年 | 183篇 |
2013年 | 216篇 |
2012年 | 293篇 |
2011年 | 269篇 |
2010年 | 172篇 |
2009年 | 164篇 |
2008年 | 194篇 |
2007年 | 215篇 |
2006年 | 172篇 |
2005年 | 170篇 |
2004年 | 132篇 |
2003年 | 124篇 |
2002年 | 134篇 |
2001年 | 30篇 |
2000年 | 15篇 |
1999年 | 29篇 |
1998年 | 30篇 |
1997年 | 29篇 |
1996年 | 15篇 |
1995年 | 15篇 |
1994年 | 19篇 |
1993年 | 18篇 |
1992年 | 20篇 |
1991年 | 20篇 |
1990年 | 13篇 |
1989年 | 8篇 |
1988年 | 8篇 |
1987年 | 7篇 |
1985年 | 17篇 |
1984年 | 11篇 |
1983年 | 7篇 |
1982年 | 12篇 |
1981年 | 6篇 |
1980年 | 10篇 |
1979年 | 6篇 |
1978年 | 7篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1957年 | 5篇 |
1953年 | 4篇 |
1946年 | 4篇 |
排序方式: 共有3524条查询结果,搜索用时 93 毫秒
91.
Esther Sastre Laura Caracuel Fabiano E. Xavier Gloria Balfagón Javier Blanco-Rivero 《PloS one》2013,8(8)
Objectives
We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries.Methods
Electrical field stimulation (EFS)-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L), and 3-hour tranilast incubated (0.1 mmol/L). To assess the possible participation of nitrergic or sympathetic innervation, EFS contraction was analyzed in the presence of non-selective nitric oxide synthase (NOS) inhibitor L-NAME (0.1 mmol/L), α-adrenergic receptor antagonist phentolamine (0.1 µmol/L), or the neurotoxin 6-hydroxydopamine (6-OHDA, 1.46 mmol/L). Nitric oxide (NO) and superoxide anion (O2 .-) levels were measured, as were vasomotor responses to noradrenaline (NA) and to NO donor DEA-NO, in the presence and absence of 0.1 mmol/L tempol. Phosphorylated neuronal NOS (P-nNOS) expression was also analyzed.Results
EFS-induced contraction was increased by ketotifen and decreased by tranilast. L-NAME increased the vasoconstrictor response to EFS only in control segments. The vasodilator response to DEA-NO was higher in ketotifen- and tranilast-incubated segments, while tempol increased vasodilator response to DEA-NO only in control segments. Both NO and O2 - release, and P-nNOS expression were diminished by ketotifen and by tranilast treatment. The decrease in EFS-induced contraction produced by phentolamine was lower in tranilast-incubated segments. NA vasomotor response was decreased only by tranilast. The remnant vasoconstriction observed in control and ketotifen-incubated segments was abolished by 6-OHDA.Conclusion
While both ketotifen and tranilast diminish nitrergic innervation function, only tranilast diminishes sympathetic innnervation function, thus they alter the vasoconstrictor response to EFS in opposing manners. 相似文献92.
Andrew J. Atkin Kirsten Corder Ulf Ekelund Katrien Wijndaele Simon J. Griffin Esther M. F. van Sluijs 《PloS one》2013,8(6)
Background
Understanding the determinants of sedentary time during childhood contributes to the development of effective intervention programmes.Purpose
To examine family and home-environmental determinants of 1-year change in objectively measured sedentary time after-school and at the weekend.Methods
Participants wore accelerometers at baseline and 1 year later. Longitudinal data for after-school and weekend analyses were available for 854 (41.5%male, mean±SD age 10.2±0.3years) and 718 (41.8%male, age 10.2±0.3years) participants. Information on 26 candidate determinants, including socioeconomic status (SES), availability of electronic media and parental rules for sedentary behaviours was self-reported by children or their parents at baseline. Change in the proportion of registered time spent sedentary was used as the outcome variable in multi-level linear regression models, adjusted for age, sex, body mass index and baseline sedentary time. Simple and multiple models were run and interactions with sex explored.Results
Children from higher socioeconomic status families exhibited greater increases in after-school (beta; 95% CI for change in % time spent sedentary 1.02; 0.37, 1.66) and weekend (1.42; 0.65, 2.18) sedentary time. Smaller increases in after-school sedentary time were observed in children with more siblings (−1.00; −1.69, −0.30), greater availability of electronic media (−0.81; −1.29, −0.33) and, for boys, more frequent family visits to the park (−1.89; −3.28, −0.51) and family participation in sport (−1.28; −2.54, −0.02). Greater maternal weekend screen-time (0.45; 0.08, 0.83) and, in girls, greater parental restriction on playing outside (0.91; 0.08, 1.74) were associated with larger increases in weekend sedentary time. The analytical sample was younger, more likely to be female, had lower BMI and was of higher SES than the original baseline sample.Conclusions
Intervention strategies aimed at reducing parents’ weekend screen-time, increasing family participation in sports or recreation (boys) and promoting freedom to play outside (girls) may contribute towards preventing the age-related increase in sedentary time. 相似文献93.
94.
Masaru K Nobu Jeremy A Dodsworth Senthil K Murugapiran Christian Rinke Esther A Gies Gordon Webster Patrick Schwientek Peter Kille R John Parkes Henrik Sass Bo B J?rgensen Andrew J Weightman Wen-Tso Liu Steven J Hallam George Tsiamis Tanja Woyke Brian P Hedlund 《The ISME journal》2016,10(2):273-286
The ‘Atribacteria'' is a candidate phylum in the Bacteria recently proposed to include members of the OP9 and JS1 lineages. OP9 and JS1 are globally distributed, and in some cases abundant, in anaerobic marine sediments, geothermal environments, anaerobic digesters and reactors and petroleum reservoirs. However, the monophyly of OP9 and JS1 has been questioned and their physiology and ecology remain largely enigmatic due to a lack of cultivated representatives. Here cultivation-independent genomic approaches were used to provide a first comprehensive view of the phylogeny, conserved genomic features and metabolic potential of members of this ubiquitous candidate phylum. Previously available and heretofore unpublished OP9 and JS1 single-cell genomic data sets were used as recruitment platforms for the reconstruction of atribacterial metagenome bins from a terephthalate-degrading reactor biofilm and from the monimolimnion of meromictic Sakinaw Lake. The single-cell genomes and metagenome bins together comprise six species- to genus-level groups that represent most major lineages within OP9 and JS1. Phylogenomic analyses of these combined data sets confirmed the monophyly of the ‘Atribacteria'' inclusive of OP9 and JS1. Additional conserved features within the ‘Atribacteria'' were identified, including a gene cluster encoding putative bacterial microcompartments that may be involved in aldehyde and sugar metabolism, energy conservation and carbon storage. Comparative analysis of the metabolic potential inferred from these data sets revealed that members of the ‘Atribacteria'' are likely to be heterotrophic anaerobes that lack respiratory capacity, with some lineages predicted to specialize in either primary fermentation of carbohydrates or secondary fermentation of organic acids, such as propionate. 相似文献
95.
Jorge Lizandra José Devís-Devís Esther Pérez-Gimeno Alexandra Valencia-Peris Carmen Peiró-Velert 《PloS one》2016,11(4)
This study examined whether adolescents’ time spent on sedentary behaviors (academic, technological-based and social-based activities) was a better predictor of academic performance than the reverse. A cohort of 755 adolescents participated in a three-year period study. Structural Equation Modeling techniques were used to test plausible causal hypotheses. Four competing models were analyzed to determine which model best fitted the data. The Best Model was separately tested by gender. The Best Model showed that academic performance was a better predictor of sedentary behaviors than the other way round. It also indicated that students who obtained excellent academic results were more likely to succeed academically three years later. Moreover, adolescents who spent more time in the three different types of sedentary behaviors were more likely to engage longer in those sedentary behaviors after the three-year period. The better the adolescents performed academically, the less time they devoted to social-based activities and more to academic activities. An inverse relationship emerged between time dedicated to technological-based activities and academic sedentary activities. A moderating auto-regressive effect by gender indicated that boys were more likely to spend more time on technological-based activities three years later than girls. To conclude, previous academic performance predicts better sedentary behaviors three years later than the reverse. The positive longitudinal auto-regressive effects on the four variables under study reinforce the ‘success breeds success’ hypothesis, with academic performance and social-based activities emerging as the strongest ones. Technological-based activities showed a moderating effect by gender and a negative longitudinal association with academic activities that supports a displacement hypothesis. Other longitudinal and covariate effects reflect the complex relationships among sedentary behaviors and academic performance and the need to explore these relationships in depth. Theoretical and practical implications for school health are outlined. 相似文献
96.
Cyclolipopeptides derived from the antimicrobial peptide c(Lys-Lys-Leu-Lys-Lys-Phe-Lys-Lys-Leu-Gln) (BPC194) were prepared on solid-phase and screened against four plant pathogens. The incorporation at Lys5 of fatty acids of 4 to 9 carbon atoms led to active cyclolipopeptides. The influence on the antimicrobial activity of the Lys residue that is derivatized was also evaluated. In general, acylation of Lys1, Lys2 or Lys5 rendered the sequences with the highest activity. Incorporation of a D-amino acid maintained the antimicrobial activity while significantly reduced the hemolysis. Replacement of Phe with a His also yielded cyclolipopeptides with low hemolytic activity. Derivatives exhibiting low phytotoxicity in tobacco leaves were also found. Interestingly, sequences with or without significant activity against phytopathogenic bacteria and fungi, but with differential hemolysis and phytotoxicity were identified. Therefore, this study represents an approach to the development of bioactive peptides with selective activity against microbial, plant and animal cell targets. These selective cyclolipopeptides are candidates useful not only to combat plant pathogens but also to be applied in other fields. 相似文献
97.
Emily E. I. M. Mouser Georgios Pollakis Maria Yazdanbakhsh William Harnett Esther C. de Jong William A. Paxton 《PloS one》2016,11(1)
One of the hallmarks of HIV-1 disease is the association of heightened CD4+ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4+ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4+ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4+ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4+ Th-cells induced by exposed DCs. 相似文献
98.
Kavitha Kothur Louise Wienholt Esther M Tantsis John Earl Sushil Bandodkar Kristina Prelog Fiona Tea Sudarshini Ramanathan Fabienne Brilot Russell C. Dale 《PloS one》2016,11(2)
Background
Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.Aim
To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups.Methods
We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.Results
The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Conclusion
Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets. 相似文献99.
Verónica García-Alonso Esther Titos Jose Alcaraz-Quiles Bibiana Rius Aritz Lopategi Cristina López-Vicario Per-Johan Jakobsson Salvadora Delgado Juanjo Lozano Joan Clària 《PloS one》2016,11(4)
Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT. 相似文献
100.
Pak Hei Chan Jo Jo Hai Esther W. Chan Wen Hua Li Hung Fat Tse Ian C. K. Wong Gregory Y. H. Lip Chung Wah Siu 《PloS one》2016,11(3)