全文获取类型
收费全文 | 1237篇 |
免费 | 105篇 |
出版年
2022年 | 21篇 |
2021年 | 28篇 |
2020年 | 6篇 |
2019年 | 13篇 |
2018年 | 23篇 |
2017年 | 21篇 |
2016年 | 32篇 |
2015年 | 50篇 |
2014年 | 66篇 |
2013年 | 75篇 |
2012年 | 92篇 |
2011年 | 103篇 |
2010年 | 46篇 |
2009年 | 46篇 |
2008年 | 71篇 |
2007年 | 75篇 |
2006年 | 58篇 |
2005年 | 51篇 |
2004年 | 63篇 |
2003年 | 53篇 |
2002年 | 40篇 |
2001年 | 21篇 |
2000年 | 26篇 |
1999年 | 15篇 |
1998年 | 10篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 9篇 |
1992年 | 14篇 |
1991年 | 11篇 |
1990年 | 14篇 |
1989年 | 12篇 |
1988年 | 12篇 |
1987年 | 15篇 |
1986年 | 11篇 |
1985年 | 15篇 |
1984年 | 11篇 |
1983年 | 13篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 9篇 |
1978年 | 8篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1974年 | 7篇 |
1971年 | 3篇 |
1968年 | 3篇 |
排序方式: 共有1342条查询结果,搜索用时 15 毫秒
991.
Kim HJ Kwon MS Choi JS Kim BH Yoon JK Kim K Park JS 《Bioorganic & medicinal chemistry》2007,15(4):1708-1715
Many therapeutic carrier materials were exploited for human gene therapy from viral to polymeric vectors. This research describes the evaluation of two biodegradable ester-bonded polymers synthesized by double-monomer polycondensation for a non-viral cationic polymer-based gene delivery system. The backbone was constructed to include inner tertiary amines and outer primary amines. Self-assembly with DNA resulted in the production of regularly nano-sized spherical polyplexes with good transfection efficiency, especially in the presence of serum. The polymers showed a relatively slow degradability for an amine-containing ester polymer, as they maintained DNA/polymer complex for 7 days in physiological buffer conditions. Finally, the low toxicity and slow degradation concluded these polymers reliable for long-term therapeutic applications. 相似文献
992.
Se-Ho Park Seung-Su Lee Myun-Ho Bang Sung Kwan Jo Kwang-Hwan Jhee 《Bioscience, biotechnology, and biochemistry》2019,83(3):551-560
This study was undertaken to determine the effects of enzyme-treated Zizania latifolia (ETZL) and of its major compound tricin on skin photo-aging and to investigate the mechanisms involved. It was found ETZL and tricin suppressed matrix metalloproteinase (MMP) production and increased type I-procollagen production in UVB-irradiated human dermal fibroblasts (HDFs). Furthermore, ETZL and tricin significantly up-regulated the expressions of the antioxidant enzymes HO-1 and SOD1, reduced UVB-induced reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPK) induction by ROS and thereby attenuated activator protein-1 (AP-1) expression. In addition, ETZL and tricin both reduced the phosphorylations of IκBα and IKKα/ß and κB blocked the nuclear translocation of nuclear factor-κB (NF-κB) p65. These results show that ETZL have skin protective effects against UVB and suggest tricin as major efficacious material in ETZL protecting skin photoaging. 相似文献
993.
Vertical vs. horizontal transmission of the microbiome in a key disease vector,Ixodes pacificus
下载免费PDF全文
![点击此处可从《Molecular ecology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jessica Y. Kwan Reid Griggs Betsabel Chicana Caitlin Miller Andrea Swei 《Molecular ecology》2017,26(23):6578-6589
Vector‐borne pathogens are increasingly found to interact with the vector's microbiome, influencing disease transmission dynamics. However, the processes that regulate the formation and development of the microbiome are largely unexplored for most tick species, an emerging group of disease vectors. It is not known how much of the tick microbiome is acquired through vertical transmission vs. horizontally from the environment or interactions with bloodmeal sources. Using 16S rRNA sequencing, we examined the microbiome of Ixodes pacificus, the vector of Lyme disease in the western USA, across life stages and infection status. We also characterized microbiome diversity in field and laboratory‐collected nymphal ticks to determine how the surrounding environment affects microbiome diversity. We found a decrease in both species richness and evenness as the tick matures from larva to adult. When the dominant Rickettsial endosymbiont was computationally removed from the tick microbial community, we found that infected nymphs had lower species evenness than uninfected ticks, suggesting that lower microbiome diversity is associated with pathogen transmission in wild‐type ticks. Furthermore, laboratory‐reared nymph microbiome diversity was found to be compositionally distinct and significantly depauperate relative to field‐collected nymphs. These results highlight unique patterns in the microbial community of I. pacificus that is distinct from other tick species. We provide strong evidence that ticks acquire a significant portion of their microbiome through exposure to their environment despite a loss of overall diversity through life stages. We provide evidence that loss of microbial diversity is at least in part due to elimination of microbial diversity with bloodmeal feeding but other factors may also play a role. 相似文献
994.
Muthukumar Elangovan Hae Kwan Chong Jin Hee Park Eui Ju Yeo Yung Joon Yoo 《Journal of cell communication and signaling》2017,11(3):265-273
The human Ube2j1 and Ube2j2 are the only ubiquitin-conjugating enzymes (E2s) that are localized to endoplasmic reticulum (ER) through its C-terminal transmembrane domains. Ube2j1 is a known substrate of MAPK signalling pathway and it is phosphorylated at serine-184 during ER stress. Here, we demonstrate that Ube2j1, not Ube2j2 is essential for the recovery of cells from transient ER stress. The ectopic expression of wild-type Ube2j1 and phospho-mimic mutant, Ube2j1S184D but not phospho-mutant Ube2j1S184A can recover cells from ER stress. We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome. 相似文献
995.
The hemodynamic force generated by blood flow is considered to be the physiologically most important stimulus for the release of nitric oxide (NO) and prostacyclin (PGI(2)) from vascular endothelial cells (1). NO and PGI(2) then act on the underlying smooth muscle cells, causing vasodilation and thus lowering blood pressure (2, 3). One critical early event occurring in this flow-induced regulation of vascular tone is that blood flow induces Ca(2+) entry into vascular endothelial cells, which in turn leads to the formation of NO (4, 5). Here we report a mechanosensitive Ca(2+)-permeable channel in vascular endothelial cells. The activity of the channel was inhibited by 8-Br-cGMP, a membrane-permeant activator of protein kinase G (PKG), in cell-attached membrane patches. The inhibition could be reversed by PKG inhibitor KT5823 or H-8. A direct application of active PKG in inside-out patches blocked the channel activity. Gd(3+), Ni(2+), or SK&F-96365 also inhibited the channel activity. A study of fluorescent Ca(2+) entry revealed a striking pharmacological similarity between the Ca(2+) entry elicited by flow and the mechanosensitive Ca(2+)-permeable channel we identified, suggesting that this channel is the primary pathway mediating flow-induced Ca(2+) entry into vascular endothelial cells. 相似文献
996.
Ming Yang Michelle Grace Tsui Jessica Kwan Wun Tsang Rajesh Kumar Goit Kwok-Ming Yao Kwok-Fai So Wai-Ching Lam Amy Cheuk Yin Lo 《Cell death & disease》2022,13(5)
Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ10-NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ10/NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ10-NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration.Subject terms: Apoptosis, Neurodegenerative diseases, Experimental models of disease 相似文献
997.
Benjamin C. Blum Weiwei Lin Matthew L. Lawton Qian Liu Julian Kwan Isabella Turcinovic Ryan Hekman Pingzhao Hu Andrew Emili 《Molecular & cellular proteomics : MCP》2022,21(1)
Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings. 相似文献
998.
Epithelial tissues form folded structures during embryonic development and organogenesis. Whereas substantial efforts have been devoted to identifying mechanical and biochemical mechanisms that induce folding, whether and how their interplay synergistically shapes epithelial folds remains poorly understood. Here we propose a mechano–biochemical model for dorsal fold formation in the early Drosophila embryo, an epithelial folding event induced by shifts of cell polarity. Based on experimentally observed apical domain homeostasis, we couple cell mechanics to polarity and find that mechanical changes following the initial polarity shifts alter cell geometry, which in turn influences the reaction-diffusion of polarity proteins, thus forming a feedback loop between cell mechanics and polarity. This model can induce spontaneous fold formation in silico, recapitulate polarity and shape changes observed in vivo, and confer robustness to tissue shape change against small fluctuations in mechanics and polarity. These findings reveal emergent properties of a developing epithelium under control of intracellular mechano–polarity coupling. 相似文献
999.
1000.
Boileau C Tat SK Pelletier JP Cheng S Martel-Pelletier J 《Arthritis research & therapy》2008,10(3):R71