全文获取类型
收费全文 | 931篇 |
免费 | 106篇 |
专业分类
1037篇 |
出版年
2023年 | 11篇 |
2022年 | 17篇 |
2021年 | 34篇 |
2020年 | 18篇 |
2019年 | 21篇 |
2018年 | 31篇 |
2017年 | 27篇 |
2016年 | 43篇 |
2015年 | 56篇 |
2014年 | 63篇 |
2013年 | 57篇 |
2012年 | 104篇 |
2011年 | 82篇 |
2010年 | 42篇 |
2009年 | 41篇 |
2008年 | 50篇 |
2007年 | 56篇 |
2006年 | 47篇 |
2005年 | 42篇 |
2004年 | 32篇 |
2003年 | 32篇 |
2002年 | 27篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 11篇 |
1998年 | 13篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 5篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1985年 | 3篇 |
1981年 | 3篇 |
1978年 | 2篇 |
1937年 | 3篇 |
1935年 | 2篇 |
1933年 | 2篇 |
1932年 | 2篇 |
1929年 | 1篇 |
1928年 | 1篇 |
1927年 | 1篇 |
1926年 | 3篇 |
1925年 | 1篇 |
1903年 | 1篇 |
1902年 | 1篇 |
1897年 | 1篇 |
1875年 | 1篇 |
排序方式: 共有1037条查询结果,搜索用时 0 毫秒
91.
Speed N Saunders C Davis AR Owens WA Matthies HJ Saadat S Kennedy JP Vaughan RA Neve RL Lindsley CW Russo SJ Daws LC Niswender KD Galli A 《PloS one》2011,6(9):e25169
Background
The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.Methodology/Principal Findings
We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Conclusions/Significance
Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity. 相似文献92.
93.
Potential aposematism in an insular tree species: are signals dishonest early in ontogeny? 下载免费PDF全文
Patrick H. Kavanagh Rachael C. Shaw Kevin C. Burns 《Biological journal of the Linnean Society. Linnean Society of London》2016,118(4):951-958
Recent investigations have suggested that some plants are aposematic. Our understanding of how aposematism varies through plant ontogeny, however, is incomplete. Furthermore, the potential for lower leaf surfaces to signal to vertebrate herbivores that are viewing leaves from below has not been investigated. Here, we investigate ontogenetic changes in leaf colour in Pseudopanax crassifolius (Araliaceae), a tree species that is endemic to New Zealand. We demonstrate that P. crassifolius produces lateral leaf spines that peak in size during the sapling stage of development. Spots of brightly coloured tissues on the upper leaf surfaces may be warning signals. The intensity of these signals, however, peaked at the seedling stage, providing a dishonest signal of defence. Conversely, signals on lower leaf surfaces peaked in the sapling stage, providing an honest defensive signal later in ontogeny. Lateral leaf spines and all potential warning colours were absent in adults, after they grow above the reach of the largest known native megaherbivores (moa – Aves: Dinornithiformes). Overall, these results suggest that aposematism may vary predictably through plant ontogeny in response to the changing perspective of herbivores as plants grow vertically. 相似文献
94.
95.
There is an enormous initiative to establish the genetic basis for disorders of brain function. Unfortunately, genetic intervention is not accomplished easily in the nervous system. One strategy is to engineer and deliver to neurons specialized viral vectors that carry a gene (or genes) of interest, thereby exploiting the natural ability of viruses to insert genetic material into cells. When delivered to brain cells, these vectors cause infected cells to increase the expression of the genes of interest. The ability to deliver genes into neurons in vitro and in vivo with herpes simplex virus (HSV) amplicon vectors has made it possible to carry out exactly these sorts of experiments. This technology has the potential to offer new insights into the etiology of a wide variety of neuropsychiatric disorders. We describe the use of HSV amplicon vectors to study Alzheimer disease, drug addiction, and depression, and discuss the considerations that enter into the use of these vectors both in vitro and in vivo. The HSV amplicon virus is a user-friendly vector for the delivery of genes into neurons that has come of age for the study of brain function. 相似文献
96.
Development of ToxA and ToxB promoter-driven fluorescent protein expression vectors for use in filamentous ascomycetes 总被引:3,自引:0,他引:3
The green fluorescent protein (GFP) has been established as the premier in vivo reporter for investigations of gene expression, protein localization, and cell and organism dynamics. The fungal transformation vector pCT74, with sGFP under the control of the ToxA promoter from Pyrenophora tritici-repentis, effectively expresses GFP in a diverse group of filamentous ascomycetes. Due to the versatility of ToxA promoter-driven expression of GFP, we constructed an additional set of fluorescent protein expression vectors to expand the color palette of fluorescent markers for use in filamentous fungi. EYFP, ECFP and mRFP1 were successfully expressed from the ToxA promoter in its fungus of origin, P. tritici-repentis, and a distant relative, Verticillium dahliae. Additionally the ToxB promoter from P. tritici-repentis drove expression of sGFP in V. dahliae, suggesting a similar potential to the ToxA promoter for heterologous expression in ascomycetes. The suite of fungal transformation vectors presented here promise to be useful for a variety of fungal research applications. 相似文献
97.
Peters N Domchek SM Domcheck SM Rose A Polis R Stopfer J Armstrong K 《Genetic testing》2005,9(1):48-53
A total of 2,400 questionnaires were mailed to members of two mid-Atlantic breast cancer awareness/support groups to investigate the association between attitudes, knowledge, and use of BRCA1/2 testing among women with early-onset breast cancer. Of the 493 (21%) questionnaires returned, 406 respondents had a diagnosis of breast cancer, of whom 248 were diagnosed prior to age 50 and included in the analyses. Eighty-three percent (206/248) of these women had heard of BRCA1/2 testing and 12.5% (31/248) had undergone BRCA1/2 testing. Among women who had heard of BRCA1/2 testing, women who had been tested were younger (p = 0.03), more likely to have a college education (p = 0.03), more likely to have a family member who had undergone BRCA1/2 testing (p = 0.005), and had greater knowledge, more positive attitudes, and fewer negative attitudes about BRCA1/2 testing (p = 0.02, p = 0.004, and p = 0.004, respectively). In this sample, knowledge regarding BRCA1/2 testing is high, but uptake of genetic testing is low. Lack of information regarding how genetic testing might alter health-care decisions and fear about the genetic testing procedure, its costs, and possible false-positive results are associated with low uptake of genetic testing. Further education regarding these specific points may enhance the use of genetic testing. 相似文献
98.
99.
We examine the efficiency of a number of schemes to select cases from nuclear families for case-control association analysis using the Genetic Analysis Workshop 14 simulated dataset. We show that with this simulated dataset comparing all affected siblings with unrelated controls is considerably more powerful than all of the other approaches considered. We find that the test statistic is increased by almost 3-fold compared to the next best sampling schemes of selecting all affected sibs only from families with affected parents (AF aff), one affected sib with most evidence of allele-sharing from each family (SF), and all affected sibs from families with evidence for linkage (AF L). We consider accounting for biological relatedness of samples in the association analysis to maintain the correct type I error. We also discuss the relative efficiencies of increasing the ratio of unrelated cases to controls, methods to confirm associations and issues to consider when applying our conclusions to other complex disease datasets. 相似文献
100.
Murray RZ Wylie FG Khromykh T Hume DA Stow JL 《The Journal of biological chemistry》2005,280(11):10478-10483
A key function of activated macrophages is to secrete proinflammatory cytokines such as TNFalpha; however, the intracellular pathway and machinery responsible for cytokine trafficking and secretion is largely undefined. Here we show that individual SNARE proteins involved in vesicle docking and fusion are regulated at both gene and protein expression upon stimulation with the bacterial cell wall component lipopolysaccharide. Focusing on two intracellular SNARE proteins, Vti1b and syntaxin 6 (Stx6), we show that they are up-regulated in conjunction with increasing cytokine secretion in activated macrophages and that their levels are selectively titrated to accommodate the volume and timing of post-Golgi cytokine trafficking. In macrophages, Vti1b and syntaxin 6 are localized on intracellular membranes and are present on isolated Golgi membranes and on Golgi-derived TNFalpha vesicles budded in vitro. By immunoprecipitation, we find that Vti1b and syntaxin 6 interact to form a novel intracellular Q-SNARE complex. Functional studies using overexpression of full-length and truncated proteins show that both Vti1b and syntaxin 6 function and have rate-limiting roles in TNFalpha trafficking and secretion. This study shows how macrophages have uniquely adapted a novel Golgi-associated SNARE complex to accommodate their requirement for increased cytokine secretion. 相似文献