全文获取类型
收费全文 | 12183篇 |
免费 | 780篇 |
国内免费 | 10篇 |
专业分类
12973篇 |
出版年
2024年 | 22篇 |
2023年 | 49篇 |
2022年 | 152篇 |
2021年 | 232篇 |
2020年 | 133篇 |
2019年 | 205篇 |
2018年 | 295篇 |
2017年 | 245篇 |
2016年 | 426篇 |
2015年 | 619篇 |
2014年 | 748篇 |
2013年 | 801篇 |
2012年 | 1075篇 |
2011年 | 1047篇 |
2010年 | 653篇 |
2009年 | 503篇 |
2008年 | 790篇 |
2007年 | 681篇 |
2006年 | 615篇 |
2005年 | 564篇 |
2004年 | 573篇 |
2003年 | 455篇 |
2002年 | 363篇 |
2001年 | 356篇 |
2000年 | 328篇 |
1999年 | 229篇 |
1998年 | 89篇 |
1997年 | 77篇 |
1996年 | 49篇 |
1995年 | 48篇 |
1994年 | 38篇 |
1993年 | 29篇 |
1992年 | 83篇 |
1991年 | 54篇 |
1990年 | 44篇 |
1989年 | 48篇 |
1988年 | 27篇 |
1987年 | 28篇 |
1986年 | 21篇 |
1985年 | 23篇 |
1984年 | 13篇 |
1983年 | 15篇 |
1982年 | 12篇 |
1981年 | 12篇 |
1980年 | 11篇 |
1979年 | 9篇 |
1978年 | 15篇 |
1975年 | 13篇 |
1974年 | 11篇 |
1970年 | 6篇 |
排序方式: 共有10000条查询结果,搜索用时 13 毫秒
941.
Murali K. Ravoori Masato Nishimura Sheela P. Singh Chunhua Lu Lin Han Brian P. Hobbs Sunila Pradeep Hyun J. Choi James A. Bankson Anil K. Sood Vikas Kundra 《PloS one》2015,10(6)
Purpose
To assess whether T1 relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy. Procedures: 12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6) or PBS (control, n=6) therapy twice a week for two weeks. T1 maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed.Results
Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6), confirming therapeutic efficacy. Tumor T1 relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6). Microvessel density decreased 59% and cell proliferation (Ki67+) decreased 50% in the bevacizumab treatment group (p<.001, n=6), but not apoptosis.Conclusions
Findings suggest that increased tumor T1 relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response. 相似文献942.
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and its targets (TNFα, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels. 相似文献
943.
E-Ryung Choi Boo-Kyung Han Eun Sook Ko Eun Young Ko Ji Soo Choi Eun Yoon Cho Seok Jin Nam 《PloS one》2015,10(12)
Objective
To determine the imaging characteristic of frequent target lesions of wireless ultrasound (US)-guided, vacuum-assisted breast biopsy (Wi-UVAB) and to evaluate diagnostic yield, accuracy and complication of the device in indeterminate breast lesions.Materials and Methods
From March 2013 to October 2014, 114 women (age range, 29–76 years; mean age, 50.0 years) underwent Wi-UVAB using a 13-gauge needle (Mammotome Elite®; Devicor Medical Products, Cincinnati, OH, USA). In 103 lesions of 96 women with surgical (n = 81) or follow-up (n = 22) data, complications, biopsy procedure, imaging findings of biopsy targets and histologic results were reviewed.Results
Mean number of biopsy cores was 10 (range 4–25). Nine patients developed moderate bleeding. All lesions were suspicious on US, and included non-mass lesions (67.0%) and mass lesions (33.0%). Visible calcifications on US were evident in 57.3% of the target lesions. Most of the lesions (93.2%) were nonpalpable. Sixty-six (64.1%) were malignant [ductal carcinoma in situ (DCIS) rate, 61%] and 12 were high-risk lesions (11.7%). Histologic underestimation was identified in 11 of 40 (27.5%). DCIS cases and in 3 of 9 (33.3%) high-risk lesions necessitating surgery. There was no false-negative case.Conclusion
Wi-UVAB is very handy and advantageous for US-unapparent non-mass lesions to diagnose DCIS, especially for calcification cases. Histologic underestimation is unavoidable; still, Wi-UVAB is safe and accurate to diagnose a malignancy. 相似文献944.
Hwang SM Koo NY Jin M Davies AJ Chun GS Choi SY Kim JS Park K 《The Journal of biological chemistry》2011,286(3):1719-1729
The effect of intracellular acidification and subsequent pH recovery in sensory neurons has not been well characterized. We have studied the mechanisms underlying Ca(2+)-induced acidification and subsequent recovery of intracellular pH (pH(i)) in rat trigeminal ganglion neurons and report their effects on neuronal excitability. Glutamate (500 μM) and capsaicin (1 μM) increased intracellular Ca(2+) concentration ([Ca(2+)](i)) with a following decrease in pH(i). The recovery of [Ca(2+)](i) to the prestimulus level was inhibited by LaCl(3) (1 mM) and o-vanadate (10 mM), a plasma membrane Ca(2+)/ATPase (PMCA) inhibitor. Removal of extracellular Ca(2+) also completely inhibited the acidification induced by capsaicin. TRPV1 was expressed only in small and medium sized trigeminal ganglion neurons. mRNAs for Na(+)/H(+) exchanger type 1 (NHE1), pancreatic Na(+)-HCO(3)(-) cotransporter type 1 (pNBC1), NBC3, NBC4, and PMCA types 1-3 were detected by RT-PCR. pH(i) recovery was significantly inhibited by pretreatment with NHE1 or pNBC1 siRNA. We found that the frequency of action potentials (APs) was dependent on pH(i). Application of the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl) amiloride (5 μM) or the pNBC1 inhibitor 4',4'-di-isothiocyanostilbene-2',2'-sulfonic acid (500 μM) delayed pH(i) recovery and decreased AP frequency. Simultaneous application of 5'-(N-ethyl-N-isopropyl) amiloride and 4',4'-di-isothiocyanostilbene-2',2'-sulfonic acid almost completely inhibited APs. In summary, our results demonstrate that the rise in [Ca(2+)](i) in sensory neurons by glutamate and capsaicin causes intracellular acidification by activation of PMCA type 3, that the pH(i) recovery from acidification is mediated by membrane transporters NHE1 and pNBC1 specifically, and that the activity of these transporters has direct consequences for neuronal excitability. 相似文献
945.
In a previous paper, the first ever application of lytic bacteriophage (virus)-mediated biocontrol of biomass bulking in the activated sludge process using Haliscomenobacter hydrossis as a model filamentous bacterium was demonstrated. In this work we extended the biocontrol application to another predominant filamentous bacterium, Sphaerotilus natans, notoriously known to cause filamentous bulking in wastewater treatment systems. Very similar to previous study, one lytic bacteriophage was isolated from wastewater that could infect S. natans and cause lysis. Significant reduction in sludge volume index and turbidity of the supernatant was observed in batches containing S. natans biomass following addition of lytic phages. Microscopic examination confirmed that the isolated lytic phage can trigger the bacteriolysis of S. natans. This extended finding further strengthens our hypothesis of bacteriophage-based biocontrol of overgrowth of filamentous bacteria and the possibility of phage application in activated sludge processes, the world's widely used wastewater treatment processes. 相似文献
946.
Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development 总被引:4,自引:0,他引:4
Dawlaty MM Ganz K Powell BE Hu YC Markoulaki S Cheng AW Gao Q Kim J Choi SW Page DC Jaenisch R 《Cell Stem Cell》2011,9(2):166-175
The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in?vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1(-/-) ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in?vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development. 相似文献
947.
948.
949.
Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts 下载免费PDF全文
Kyeong Eun Yang Hyun‐Jin Jang In‐Hu Hwang Young‐Ho Chung Jong‐Soon Choi Tae‐Hoon Lee Yun‐Jo Chung Min‐Seung Lee Mi Young Lee Eui‐Ju Yeo Ik‐Soon Jang 《Aging cell》2016,15(2):245-255
Phenyl‐2‐pyridyl ketoxime (PPKO) was found to be one of the small molecules enriched in the extracellular matrix of near‐senescent human diploid fibroblasts (HDFs). Treatment of young HDFs with PPKO reduced the viability of young HDFs in a dose‐ and time‐dependent manner and resulted in senescence‐associated β‐galactosidase (SA‐β‐gal) staining and G2/M cell cycle arrest. In addition, the levels of some senescence‐associated proteins, such as phosphorylated ERK1/2, caveolin‐1, p53, p16ink4a, and p21waf1, were elevated in PPKO‐treated cells. To monitor the effect of PPKO on cell stress responses, reactive oxygen species (ROS) production was examined by flow cytometry. After PPKO treatment, ROS levels transiently increased at 30 min but then returned to baseline at 60 min. The levels of some antioxidant enzymes, such as catalase, peroxiredoxin II and glutathione peroxidase I, were transiently induced by PPKO treatment. SOD II levels increased gradually, whereas the SOD I and III levels were biphasic during the experimental periods after PPKO treatment. Cellular senescence induced by PPKO was suppressed by chemical antioxidants, such as N‐acetylcysteine, 2,2,6,6‐tetramethylpiperidinyloxy, and L‐buthionine‐(S,R)‐sulfoximine. Furthermore, PPKO increased nitric oxide (NO) production via inducible NO synthase (iNOS) in HDFs. In the presence of NOS inhibitors, such as L‐NG‐nitroarginine methyl ester and L‐NG‐monomethylarginine, PPKO‐induced transient NO production and SA‐β‐gal staining were abrogated. Taken together, these results suggest that PPKO induces cellular senescence in association with transient ROS and NO production and the subsequent induction of senescence‐associated proteins . 相似文献
950.
Hans Choi Daniel Conole Darcy J. Atkinson Olivia Laita Morgan Jay‐Smith Mario Angelo Pagano Giovanni Ribaudo Maurizio Cavalli Sergio Bova Brian Hopkins Margaret A. Brimble David Rennison 《化学与生物多样性》2016,13(6):762-775
Norbormide [5‐(α‐hydroxy‐α‐2‐pyridylbenzyl)‐7‐(α‐2‐pyridylbenzylidene)‐5‐norbornene‐2,3‐dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB‐derived pro‐toxicants ( 3a – i , 4a – i , and 5a – i ) were prepared in an effort to ‘mask’ this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague–Dawley, wild Norway, and wild ship rats is described. Most notably, pro‐toxicant 3d was revealed to be free of all pre‐cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two‐choice bait‐palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB‐derived toxicants with enhanced palatability and efficacy profiles. 相似文献