全文获取类型
收费全文 | 7502篇 |
免费 | 655篇 |
国内免费 | 4篇 |
出版年
2023年 | 53篇 |
2022年 | 123篇 |
2021年 | 273篇 |
2020年 | 148篇 |
2019年 | 176篇 |
2018年 | 199篇 |
2017年 | 160篇 |
2016年 | 335篇 |
2015年 | 509篇 |
2014年 | 521篇 |
2013年 | 532篇 |
2012年 | 756篇 |
2011年 | 646篇 |
2010年 | 375篇 |
2009年 | 364篇 |
2008年 | 490篇 |
2007年 | 417篇 |
2006年 | 377篇 |
2005年 | 288篇 |
2004年 | 288篇 |
2003年 | 262篇 |
2002年 | 239篇 |
2001年 | 52篇 |
2000年 | 29篇 |
1999年 | 38篇 |
1998年 | 60篇 |
1997年 | 29篇 |
1996年 | 22篇 |
1995年 | 27篇 |
1994年 | 23篇 |
1993年 | 27篇 |
1992年 | 23篇 |
1991年 | 19篇 |
1990年 | 14篇 |
1989年 | 21篇 |
1988年 | 12篇 |
1987年 | 9篇 |
1986年 | 10篇 |
1985年 | 12篇 |
1984年 | 15篇 |
1983年 | 24篇 |
1982年 | 8篇 |
1981年 | 16篇 |
1980年 | 13篇 |
1979年 | 11篇 |
1978年 | 15篇 |
1977年 | 10篇 |
1976年 | 9篇 |
1975年 | 9篇 |
1974年 | 8篇 |
排序方式: 共有8161条查询结果,搜索用时 171 毫秒
981.
Finkel J Guptill V Khaibullina A Spornick N Vasconcelos O Liewehr DJ Steinberg SM Quezado ZM 《Nitric oxide》2012,26(2):81-88
Nitric oxide synthases (NOSs) have been shown to modulate thermal hyperalgesia and mechanical hypersensitivity in inflammatory and neuropathic pain. However, little is known about the effect of NOSs on baseline function of sensory nerve fibers. Using genetic deficiency and pharmacologic inhibition of NOSs, we examined the impact of the three isoforms NOS1, NOS2, and NOS3 on baseline nocifensive behavior by measuring current vocalization threshold in response to electrical stimulation at 5, 250, 2000 Hz that preferentially stimulate C, Aδ, and Aβ fibers. In response to 5, 250 and 2000 Hz, NOS1-deficient animals had significantly higher current vocalization thresholds compared with wild-type. Genetic deficiency of NOS2 was associated with higher current vocalization thresholds in response to 5 Hz (C-fiber) stimulation. In contrast, NOS3-deficient animals had an overall weak trend toward lower current vocalization thresholds at 5 Hz and significantly lower current vocalization threshold compared with wild-type animals at 250 and 2000 Hz. Therefore, NOSs distinctively affect baseline mouse current vocalization threshold and appear to play a role on nocifensive response to electrical stimulation of sensory nerve fibers. 相似文献
982.
983.
Bernasconi R Galli C Noack J Bianchi S de Haan CA Reggiori F Molinari M 《Molecular cell》2012,46(6):809-819
Several regulators of endoplasmic reticulum (ER)-associated degradation (ERAD) have a shorter half-life compared to conventional ER chaperones. At steady state, they are selectively removed from the ER by poorly defined events collectively referred to as ERAD tuning. Here we identify the complex comprising the type-I transmembrane protein SEL1L and the cytosolic protein LC3-I as an ERAD tuning receptor regulating the COPII-independent, vesicle-mediated removal of the lumenal ERAD regulators EDEM1 and OS-9 from the ER. Expression of?folding-defective polypeptides enhances the lumenal content of EDEM1 and OS-9 by inhibiting their SEL1L:LC3-I-mediated segregation. This raises ERAD activity in the absence of UPR-induction. The mouse hepatitis virus (MHV) subverts ERAD tuning for replication. Consistently, SEL1L or LC3 silencing impair the MHV life cycle. Collectively, our data provide new molecular information about the ERAD tuning mechanisms that regulate ERAD in mammalian cells at the post translational level and how these mechanisms are hijacked by a pathogen. 相似文献
984.
NL Gutiérrez SR Valencia TA Branch DJ Agnew JK Baum PL Bianchi J Cornejo-Donoso C Costello O Defeo TE Essington R Hilborn DD Hoggarth AE Larsen C Ninnes K Sainsbury RL Selden S Sistla AD Smith A Stern-Pirlot SJ Teck JT Thorson NE Williams 《PloS one》2012,7(8):e43765
Concerns over fishing impacts on marine populations and ecosystems have intensified the need to improve ocean management. One increasingly popular market-based instrument for ecological stewardship is the use of certification and eco-labeling programs to highlight sustainable fisheries with low environmental impacts. The Marine Stewardship Council (MSC) is the most prominent of these programs. Despite widespread discussions about the rigor of the MSC standards, no comprehensive analysis of the performance of MSC-certified fish stocks has yet been conducted. We compared status and abundance trends of 45 certified stocks with those of 179 uncertified stocks, finding that 74% of certified fisheries were above biomass levels that would produce maximum sustainable yield, compared with only 44% of uncertified fisheries. On average, the biomass of certified stocks increased by 46% over the past 10 years, whereas uncertified fisheries increased by just 9%. As part of the MSC process, fisheries initially go through a confidential pre-assessment process. When certified fisheries are compared with those that decline to pursue full certification after pre-assessment, certified stocks had much lower mean exploitation rates (67% of the rate producing maximum sustainable yield vs. 92% for those declining to pursue certification), allowing for more sustainable harvesting and in many cases biomass rebuilding. From a consumer's point of view this means that MSC-certified seafood is 3-5 times less likely to be subject to harmful fishing than uncertified seafood. Thus, MSC-certification accurately identifies healthy fish stocks and conveys reliable information on stock status to seafood consumers. 相似文献
985.
J Simon-Areces MO Dietrich G Hermes LM Garcia-Segura MA Arevalo TL Horvath 《PloS one》2012,7(8):e42911
Mitochondrial uncoupling protein 2 (UCP2) is induced by cellular stress and is involved in regulation of fuel utilization, mitochondrial bioenergetics, cell proliferation, neuroprotection and synaptogenesis in the adult brain. Here we show that natural birth in mice triggers UCP2 expression in hippocampal neurons. Chemical inhibition or genetic ablation of UCP2 lead to diminished neuronal number and size, dendritic growth and synaptogenezis in vitro and impaired complex behaviors in the adult. These data reveal a critical role for Ucp2 expression in the development of hippocampal neurons and circuits and hippocampus-related adult behaviors. 相似文献
986.
987.
988.
Ulrike Donat Stephanie Weibel Michael Hess Jochen Stritzker Barbara H?rtl Julia B. Sturm Nanhai G. Chen Ivaylo Gentschev Aladar A. Szalay 《PloS one》2012,7(9)
Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a significant therapeutic potential in treating lymph node metastases of human PC-3 prostate carcinoma in tumor xenografts. In this study, underlying mechanisms of the virus-mediated metastases reduction were analyzed. Immunohistochemistry demonstrated that virus-treatment resulted in a drastically decrease of blood and lymph vessels, representing essential routes for PC-3 cell migration, in both tumors and metastases. Thus, GLV-1h68 drastically reduced essential routes for the metastatic spread of PC-3 cells. Furthermore, analysis of viral distribution in GLV-1h68-injected tumor-bearing mice by plaque assays, revealed significantly higher virus titers in metastases compared to solid tumors. To elucidate conditions potentially mediating the preferential viral colonization and eradication of metastases, microenvironmental components of uninfected tumors and metastases were compared by microscopic studies. These analyses revealed that PC-3 lymph node metastases showed increased vascular permeability, higher proliferation status of tumor cells as determined by BrdU- and Ki-67 assays and lesser necrosis of PC-3 cells than solid tumors. Moreover, an increased number of immune cells (MHCII+/CD68+ macrophages, MHCII+/CD19+ B lymphocytes) combined with an up-regulated expression of pro-inflammatory cytokines was observed in metastases in comparison to primary PC-3 tumors. We propose that these microenvironmental components mediated the metastatic tropism of GLV-1h68. Therefore, vaccinia virus-based oncolytic virotherapy might offer a novel treatment of metastatic prostate carcinomas in humans. 相似文献
989.
CW Ip A Kroner J Groh M Huber D Klein I Spahn R Diem SK Williams KA Nave JM Edgar R Martini 《PloS one》2012,7(8):e42554
Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. 相似文献
990.
A Stone F Valdés-Mora JM Gee L Farrow RA McClelland H Fiegl C Dutkowski RA McCloy RL Sutherland EA Musgrove RI Nicholson 《PloS one》2012,7(7):e40466
In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR), were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza), the co-addition of oestradiol (E2) restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15), was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is associated with negative proliferation control. Furthermore, reactivation of such genes using epigenetic drugs could provide a potential therapeutic avenue for the management of tamoxifen-resistant breast cancer. 相似文献