全文获取类型
收费全文 | 1181篇 |
免费 | 89篇 |
专业分类
1270篇 |
出版年
2023年 | 11篇 |
2022年 | 20篇 |
2021年 | 45篇 |
2020年 | 27篇 |
2019年 | 26篇 |
2018年 | 30篇 |
2017年 | 34篇 |
2016年 | 38篇 |
2015年 | 76篇 |
2014年 | 75篇 |
2013年 | 71篇 |
2012年 | 122篇 |
2011年 | 88篇 |
2010年 | 57篇 |
2009年 | 54篇 |
2008年 | 69篇 |
2007年 | 62篇 |
2006年 | 44篇 |
2005年 | 36篇 |
2004年 | 44篇 |
2003年 | 42篇 |
2002年 | 40篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 17篇 |
1998年 | 10篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 10篇 |
1994年 | 3篇 |
1993年 | 11篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 5篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1973年 | 2篇 |
1972年 | 4篇 |
1970年 | 2篇 |
排序方式: 共有1270条查询结果,搜索用时 15 毫秒
81.
Anna Meuronen Piia Karisola Marina Leino Terhi Savinko Kristiina Sirola Marja-Leena Majuri P?ivi Piiril? Ismo Virtanen Mika M?kel? Annika Laitinen Lauri A Laitinen Harri Alenius 《Respiratory research》2011,12(1):2
Background
Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity.Methods
Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ in vitro.Results
OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression in vivo. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our in vivo findings.Conclusions
Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice. 相似文献82.
von Ruesten A Steffen A Floegel A van der A DL Masala G Tjønneland A Halkjaer J Palli D Wareham NJ Loos RJ Sørensen TI Boeing H 《PloS one》2011,6(11):e27455
Objective
To investigate trends in obesity prevalence in recent years and to predict the obesity prevalence in 2015 in European populations.Methods
Data of 97 942 participants from seven cohorts involved in the European Prospective Investigation into Cancer and Nutrition (EPIC) study participating in the Diogenes project (named as “Diogenes cohort” in the following) with weight measurements at baseline and follow-up were used to predict future obesity prevalence with logistic linear and non-linear (leveling off) regression models. In addition, linear and leveling off models were fitted to the EPIC-Potsdam dataset with five weight measures during the observation period to find out which of these two models might provide the more realistic prediction.Results
During a mean follow-up period of 6 years, the obesity prevalence in the Diogenes cohort increased from 13% to 17%. The linear prediction model predicted an overall obesity prevalence of about 30% in 2015, whereas the leveling off model predicted a prevalence of about 20%. In the EPIC-Potsdam cohort, the shape of obesity trend favors a leveling off model among men (R2 = 0.98), and a linear model among women (R2 = 0.99).Conclusion
Our data show an increase in obesity prevalence since the 1990ies, and predictions by 2015 suggests a sizeable further increase in European populations. However, the estimates from the leveling off model were considerably lower. 相似文献83.
84.
Adiponectin is an adipokine with insulin-sensitising actions in vertebrates. Its receptors, AdipoR1 and AdipoR2, are PAQR-type proteins with 7-transmembrane domains and topologies reversed that of GPCR's, i.e. their C-termini are extracellular. We identified three adiponectin receptor homologs in the nematode C. elegans, named paqr-1, paqr-2 and paqr-3. These are differently expressed in the intestine (the main fat-storing tissue), hypodermis, muscles, neurons and secretory tissues, from which they could exert systemic effects. Analysis of mutants revealed that paqr-1 and -2 are novel metabolic regulators in C. elegans and that they act redundantly but independently from paqr-3. paqr-2 is the most important of the three paqr genes: mutants grow poorly, fail to adapt to growth at low temperature, and have a very high fat content with an abnormal enrichment in long (C20) poly-unsaturated fatty acids when combined with the paqr-1 mutation. paqr-2 mutants are also synthetic lethal with mutations in nhr-49, sbp-1 and fat-6, which are C. elegans homologs of nuclear hormone receptors, SREBP and FAT-6 (a Δ9 desaturase), respectively. Like paqr-2, paqr-1 is also synthetic lethal with sbp-1. Mutations in aak-2, the C. elegans homolog of AMPK, or nhr-80, another nuclear hormone receptor gene, suppress the growth phenotype of paqr-2 mutants, probably because they restore the balance between energy expenditure and storage. We conclude that paqr-1 and paqr-2 are receptors that regulate fatty acid metabolism and cold adaptation in C. elegans, that their main function is to promote energy utilization rather than storage, and that PAQR class proteins have regulated metabolism in metazoans for at least 700 million years. 相似文献
85.
Parsons CE Young KS Parsons E Dean A Murray L Goodacre T Dalton L Stein A Kringelbach ML 《PloS one》2011,6(10):e25897
Cleft lip and palate is the most common of the congenital conditions affecting the face and cranial bones and is associated with a raised risk of difficulties in infant-caregiver interaction; the reasons for such difficulties are not fully understood. Here, we report two experiments designed to explore how adults respond to infant faces with and without cleft lip, using behavioural measures of attractiveness appraisal ('liking') and willingness to work to view or remove the images ('wanting'). We found that infants with cleft lip were rated as less attractive and were viewed for shorter durations than healthy infants, an effect that was particularly apparent where the cleft lip was severe. Women rated the infant faces as more attractive than men did, but there were no differences in men and women's viewing times of these faces. In a second experiment, we found that the presence of a cleft lip in domestic animals affected adults' 'liking' and 'wanting' responses in a comparable way to that seen for human infants. Adults' responses were also remarkably similar for images of infants and animals with cleft lip, although no gender difference in attractiveness ratings or viewing times emerged for animals. We suggest that the presence of a cleft lip can substantially change the way in which adults respond to human and animal faces. Furthermore, women may respond in different ways to men when asked to appraise infant attractiveness, despite the fact that men and women 'want' to view images of infants for similar durations. 相似文献
86.
Ebru Ercan Sameh Eid Christian Weber Alexandra Kowalski Maria Bichmann Annika Behrendt Frank Matthes Sybille Krauss Peter Reinhardt Simone Fulle Dagmar E. Ehrnhoefer 《Molecular neurodegeneration》2017,12(1):87
Background
Tau is a microtubule-binding protein, which is subject to various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Aberrant PTMs such as hyperphosphorylation result in tau aggregation and the formation of neurofibrillary tangles, which are a hallmark of Alzheimer’s disease (AD). In order to study the importance of PTMs on tau function, antibodies raised against specific modification sites are widely used. However, quality control of these antibodies is lacking and their specificity for particular modifications is often unclear.Methods
In this study, we first designed an online tool called ‘TauPTM’, which enables the visualization of PTMs and their interactions on human tau. Using TauPTM, we next searched for commercially available antibodies against tau PTMs and characterized their specificity by peptide array, immunoblotting, electrochemiluminescence ELISA and immunofluorescence technologies.Results
We demonstrate that commercially available antibodies can show a significant lack of specificity, and PTM-specific antibodies in particular often recognize non-modified versions of the protein. In addition, detection may be hindered by other PTMs in close vicinity, complicating the interpretation of results. Finally, we compiled a panel of specific antibodies and show that they are useful to detect PTM-modified endogenous tau in hiPSC-derived neurons and mouse brains.Conclusion
This study has created a platform to reliably and robustly detect changes in localization and abundance of post-translationally modified tau in health and disease. A web-based version of TauPTM is fully available at http://www.tauptm.org.87.
88.
Ritika Dwivedi Harald Nothaft Jolene Garber Lin Xin Kin Martin Stahl Annika Flint Arnoud H. M. van Vliet Alain Stintzi Christine M. Szymanski 《Molecular microbiology》2016,101(4):575-589
Campylobacter jejuni and Campylobacter coli are zoonotic pathogens once considered asaccharolytic, but are now known to encode pathways for glucose and fucose uptake/metabolism. For C. jejuni, strains with the fuc locus possess a competitive advantage in animal colonization models. We demonstrate that this locus is present in > 50% of genome‐sequenced strains and is prevalent in livestock‐associated isolates of both species. To better understand how these campylobacters sense nutrient availability, we examined biofilm formation and chemotaxis to fucose. C. jejuni NCTC11168 forms less biofilms in the presence of fucose, although its fucose permease mutant (fucP) shows no change. In a newly developed chemotaxis assay, both wild‐type and the fucP mutant are chemotactic towards fucose. C. jejuni 81‐176 naturally lacks the fuc locus and is unable to swim towards fucose. Transfer of the NCTC11168 locus into 81‐176 activated fucose uptake and chemotaxis. Fucose chemotaxis also correlated with possession of the pathway for C. jejuni RM1221 (fuc+) and 81116 (fuc‐). Systematic mutation of the NCTC11168 locus revealed that Cj0485 is necessary for fucose metabolism and chemotaxis. This study suggests that components for fucose chemotaxis are encoded within the fuc locus, but downstream signals only in fuc + strains, are involved in coordinating fucose availability with biofilm development. 相似文献
89.
Hanage WP Kaijalainen T Herva E Saukkoriipi A Syrjänen R Spratt BG 《Journal of bacteriology》2005,187(17):6223-6230
We investigated the genetic relationships between serotypeable pneumococci and nonserotypeable presumptive pneumococci using multilocus sequence typing (MLST) and partial sequencing of the pneumolysin gene (ply). Among 121 nonserotypeable presumptive pneumococci from Finland, we identified isolates of three classes: those with sequence types (STs) identical to those of serotypeable pneumococci, suggesting authentic pneumococci in which capsular expression had been downregulated or lost; isolates that clustered among serotypeable pneumococci on a tree based on the concatenated sequences of the MLST loci but which had STs that differed from those of serotypeable pneumococci in the MLST database; and a more diverse collection of isolates that did not cluster with serotypeable pneumococci. The latter isolates typically had sequences at all seven MLST loci that were 5 to 10% divergent from those of authentic pneumococci and also had distinct and divergent ply alleles. These isolates are proposed to be distinct from pneumococci but cannot be resolved from them by optochin susceptibility, bile solubility, or the presence of the ply gene. Complete resolution of pneumococci from the related but distinct population is problematic, as recombination between them was evident, and a few isolates of each population possessed alleles at one or occasionally more MLST loci from the other population. However, a tree based on the concatenated sequences of the MLST loci in most cases unambiguously distinguished whether a nonserotypeable isolate was or was not a pneumococcus, and the sequence of the ply gene fragment was found to be useful to resolve difficult cases. 相似文献
90.
IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria 总被引:4,自引:0,他引:4
Brustoski K Möller U Kramer M Petelski A Brenner S Palmer DR Bongartz M Kremsner PG Luty AJ Krzych U 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(3):1738-1745
Available evidence suggests that immune cells from neonates born to mothers with placental Plasmodium falciparum (Pf) infection are sensitized to parasite Ag in utero but have reduced ability to generate protective Th1 responses. In this study, we detected Pf Ag-specific IFN-gamma(+) T cells in cord blood from human neonates whose mothers had received treatment for malaria or who had active placental Pf infection at delivery, with responses being significantly reduced in the latter group. Active placental malaria at delivery was also associated with reduced expression of monocyte MHC class I and II in vivo and following short term in vitro coculture with Pf Ag compared with levels seen in neonates whose mothers had received treatment during pregnancy. Given that APC activation and Th1 responses are driven in part by IFN-gamma and down-regulated by IL-10, we examined the role of these cytokines in modulating the Pf Ag-specific immune responses in cord blood samples. Exogenous recombinant human IFN-gamma and neutralizing anti-human IL-10 enhanced T cell IFN-gamma production, whereas recombinant human IFN-gamma also restored MHC class I and II expression on monocytes from cord blood mononuclear cells cocultured with Pf Ag. Accordingly, active placental malaria at delivery was associated with increased frequencies of Pf Ag-specific IL-10(+)CD4(+) T cells in cord blood mononuclear cell cultures from these neonates. Generation and maintenance of IL-10(+) T cells in utero may thus contribute to suppression of APC function and Pf Ag-induced Th1 responses in newborns born to mothers with placental malaria at delivery, which may increase susceptibility to infection later in life. 相似文献