全文获取类型
收费全文 | 1827篇 |
免费 | 234篇 |
国内免费 | 9篇 |
出版年
2022年 | 14篇 |
2021年 | 26篇 |
2020年 | 16篇 |
2019年 | 18篇 |
2018年 | 25篇 |
2017年 | 20篇 |
2016年 | 42篇 |
2015年 | 101篇 |
2014年 | 95篇 |
2013年 | 101篇 |
2012年 | 134篇 |
2011年 | 115篇 |
2010年 | 106篇 |
2009年 | 76篇 |
2008年 | 90篇 |
2007年 | 73篇 |
2006年 | 83篇 |
2005年 | 80篇 |
2004年 | 66篇 |
2003年 | 72篇 |
2002年 | 62篇 |
2001年 | 62篇 |
2000年 | 57篇 |
1999年 | 56篇 |
1998年 | 25篇 |
1997年 | 39篇 |
1996年 | 19篇 |
1995年 | 23篇 |
1994年 | 26篇 |
1993年 | 16篇 |
1992年 | 37篇 |
1991年 | 31篇 |
1990年 | 32篇 |
1989年 | 20篇 |
1988年 | 21篇 |
1987年 | 26篇 |
1986年 | 10篇 |
1985年 | 21篇 |
1984年 | 8篇 |
1983年 | 12篇 |
1982年 | 10篇 |
1980年 | 11篇 |
1979年 | 11篇 |
1978年 | 8篇 |
1977年 | 9篇 |
1975年 | 6篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1972年 | 8篇 |
1968年 | 6篇 |
排序方式: 共有2070条查询结果,搜索用时 31 毫秒
981.
In this work, we introduce a new customized anti-lung cancer peptide, CB1a, with IC(50) of about 25.0±1.6μM on NCI-H460 lung cancer cells. Using a multi-cellular tumor spheroid (MCTS) model, results show that CB1a is potent in preventing the growth of lung cancer tumor-like growths in vitro. Additionally, atomic force microscopy (AFM) was used to examine cell surface damage of a single cancer. The mechanism for cell death under CB1a toxicity was verified as being largely due to cell surface damage. Moreover, with a treatment dosage of CB1a at 25μM, Young's module (E) shows that the elasticity and stiffness of cancer cell decreased with time such that the interaction time for a 50% reduction of E (IT(50)) was about 7.0min. This new single-cell toxicity investigation using IT(50) under AFM assay can be used to separately verify drug efficacy in support of the traditional IC(50) measurement in bulk solution. These results could be of special interest to researchers engaged in new drug development. 相似文献
982.
Kao PM Hsu BM Chen NH Huang KH Huang SW King KL Chiu YC 《Experimental parasitology》2012,130(4):354-358
Acanthamoeba species are free-living amoebae found in a range of environments. Within this genus, a number of species are recognized as human pathogens, potentially causing Acanthamoeba keratitis, granulomatous amoebic encephalitis, and chronic granulomatous lesions. In this study, 60 water samples were taken from four thermal spring recreation areas in southern Taiwan. We detected living Acanthamoeba spp. based on culture-confirmed detection combined with the molecular taxonomic identification method. Living Acanthamoeba spp. were detected in nine (15%) samples. The presence or absence of Acanthamoeba spp. in the water samples depended significantly on the pH value. The most frequently identified living Acanthamoeba genotype was T15 followed by T4, Acanthamoeba spp., and T2. Genotypes T2, T4, and T15 of Acanthamoeba, are responsible for Acanthamoeba keratitis as well as granulomatous amoebic encephalitis, and should therefore be considered a potential health risk associated with human activities in thermal spring environments. 相似文献
983.
Aeromonas aquariorum, a recently described species, is associated with a variety of human diseases. We present here the first genome sequence of A. aquariorum strain AAk1, which was isolated as the sole pathogen from the blood of a patient with septicemia and necrotizing fasciitis. 相似文献
984.
Khurana S Chakraborty S Lam M Liu Y Su YT Zhao X Saleem MA Mathieson PW Bruggeman LA Kao HY 《The Journal of biological chemistry》2012,287(15):12027-12035
985.
Toll-like receptors (TLRs) 3, 7, and 9 are innate immune receptors that recognize nucleic acids from pathogens in endosomes and initiate signaling transductions that lead to cytokine production. Activation of TLR9 for signaling requires proteolytic processing within the ectodomain by endosome-associated proteases. Whether TLR3 requires similar proteolytic processing to become competent for signaling remains unclear. Herein we report that human TLR3 is proteolytically processed to form two fragments in endosomes. Unc93b1 is required for processing by transporting TLR3 through the Golgi complex and to the endosomes. Proteolytic cleavage requires the eight-amino acid Loop1 within leucine-rich repeat 12 of the TLR3 ectodomain. Proteolytic cleavage is not required for TLR3 signaling in response to poly(I:C), although processing could modulate the degree of response toward viral double-stranded RNAs, especially in mouse cells. Both the full-length and cleaved fragments of TLR3 can bind poly(I:C) and are present in endosomes. However, although the full-length TLR3 has a half-life in HEK293T cells of 3 h, the cleaved fragments have half-lives in excess of 7 h. Inhibition of TLR3 cleavage by either treatment with cathepsin inhibitor or by a mutation in Loop1 decreased the abundance of TLR3 in endosomes targeted for lysosomal degradation. 相似文献
986.
987.
Yu‐Ching Cheng Wen‐Hong L. Kao Braxton D. Mitchell A. Richey Sharrett Kathleen A. Ryan Robert A. Vogel Alan R. Shuldiner Toni I. Pollin 《Obesity (Silver Spring, Md.)》2010,18(7):1417-1422
Circulating levels of inflammatory markers predict the risk of cardiovascular disease (CVD), mediated perhaps in part by dietary fat intake, through mechanisms only partially understood. To evaluate post‐fat load changes in inflammatory markers and genetic influences on these changes, we administered a standardized high‐fat meal to 838 related Amish subjects as part of the Heredity and Phenotype Intervention (HAPI) Heart Study and measured a panel of inflammatory markers, including C‐reactive protein (CRP), interleukin‐1β (IL‐1β), matrix metalloproteinase‐1 and ‐9 (MMP‐1 and MMP‐9), and white blood cell (WBC) count, before and 4 h after fat challenge (CRP prechallenge only). Heritabilities (h2 ± s.d.) of basal inflammatory levels ranged from 16 ± 8% for MMP‐9 (P = 0.02) to 90 ± 7% for MMP‐1 (P < 0.0001). Post‐fat load, circulating levels of WBC, MMP‐1, and MMP‐9 increased by 16, 32, and 43% (all P < 0.0001), with no significant changes in IL‐1β. Postprandial changes over the 4‐h period were modestly heritable for WBC (age‐ and sex‐adjusted h2 = 14 ± 9%, P = 0.04), but the larger MMP‐1 and MMP‐9 changes appeared to be independent of additive genetic effects. These results reveal that a high‐fat meal induces a considerable inflammatory response. Genetic factors appear to play a significant role influencing basal inflammatory levels but to have minimal influence on post‐fat intake inflammatory changes. 相似文献
988.
During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression. 相似文献
989.
Leslie A Khawli Sirj Goswami Ryan Hutchinson Zephania W Kwong Jihong Yang Xiangdan Wang Zhenling Yao Alavattam Sreedhara Tony Cano Devin Tesar Ihsan Nijem David E Allison Pin Yee Wong Yung-Hsiang Kao Cynthia Quan Amita Joshi Reed J Harris Paul Motchnik 《MABS-AUSTIN》2010,2(6):613-624
Antibody charge variants have gained considerable attention in the biotechnology industry due to their potential influence on stability and biological activity. Subtle differences in the relative proportions of charge variants are often observed during routine biomanufacture or process changes and pose a challenge to demonstrating product comparability. To gain further insights into the impact on biological activity and pharmacokinetics (PK) of monoclonal antibody (mAb) charge heterogeneity, we isolated the major charge forms of a recombinant humanized IgG1 and compared their in vitro properties and in vivo PK. The mAb starting material had a pI range of 8.7–9.1 and was composed of about 20% acidic variants, 12% basic variants and 68% main peak. Cation exchange displacement chromatography was used to isolate the acidic, basic and main peak fractions for animal studies. Detailed analyses were performed on the isolated fractions to identify specific chemical modification contributing to the charge differences and were also characterized for purity and in vitro potency prior to being administered either subcutaneously (SC) or intravenously (IV) in rats. All isolated materials had similar potency and rat FcRn binding relative to the starting material. Following IV or SC administration (10 mg/kg) in rats, no difference in serum PK was observed, indicating that physiochemical modifications and pI differences among charge variants were not sufficient to result in PK changes. Thus, these results provided meaningful information for the comparative evaluation of charge-related heterogeneity of mAbs and suggested that charge variants of IgGs do not affect the in vitro potency, FcRn binding affinity or the PK properties in rats.Key words: mAb IgG1, charge heterogeneity, isoelectric point, neonatal Fc receptor (FcRn), pharmacokinetics, potency 相似文献
990.
Ku‐Chung Chen Wen‐Hsin Liu Pei‐Hsiu Kao Long‐Sen Chang 《Journal of cellular physiology》2010,222(1):177-186
Notechis scutatus scutatus notexin induced apoptotic death of SK‐N‐SH cells accompanied with downregulation of Bcl‐xL, upregulation of Bak, mitochondrial depolarization, and ROS generation. Upon exposure to notexin, Ca2+‐mediated JNK and p38 MAPK activation were observed in SK‐N‐SH cells. Production of ROS was a downstream event followed by Ca2+‐mediated mitochondrial alteration. Notexin‐induced cell death, mitochondrial depolarization, and ROS generation were suppressed by SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). Moreover, phospho‐p38 MAPK and phospho‐JNK were proved to be involved in Bcl‐xL degradation, and overexpression of Bcl‐xL attenuated the cytotoxic effect of notexin. Bak upregulation was elicited by p38 MAPK‐mediated ATF‐2 activation and JNK‐mediated c‐Jun activation. Suppression of Bak upregulation by ATF‐2 siRNA or c‐Jun siRNA attenuated notexin‐evoked mitochondrial depolarization and rescued viability of notexin‐treated cells. Taken together, our data indicate that notexin‐induced apoptotic death of SK‐N‐SH cells is mediated through mitochondrial alteration triggering by Ca2+‐evoked p38 MAPK/ATF‐2 and JNK/c‐Jun signaling pathways. J. Cell. Physiol. 222:177–186, 2010. © 2009 Wiley‐Liss, Inc. 相似文献