全文获取类型
收费全文 | 773篇 |
免费 | 148篇 |
国内免费 | 3篇 |
出版年
2022年 | 6篇 |
2020年 | 6篇 |
2018年 | 9篇 |
2017年 | 10篇 |
2016年 | 9篇 |
2015年 | 30篇 |
2014年 | 23篇 |
2013年 | 39篇 |
2012年 | 55篇 |
2011年 | 55篇 |
2010年 | 33篇 |
2009年 | 27篇 |
2008年 | 33篇 |
2007年 | 27篇 |
2006年 | 25篇 |
2005年 | 24篇 |
2004年 | 26篇 |
2003年 | 25篇 |
2002年 | 22篇 |
2001年 | 24篇 |
2000年 | 26篇 |
1999年 | 22篇 |
1998年 | 10篇 |
1997年 | 6篇 |
1996年 | 7篇 |
1995年 | 14篇 |
1994年 | 13篇 |
1993年 | 11篇 |
1992年 | 29篇 |
1991年 | 19篇 |
1990年 | 21篇 |
1989年 | 18篇 |
1988年 | 16篇 |
1987年 | 13篇 |
1986年 | 13篇 |
1985年 | 18篇 |
1984年 | 12篇 |
1983年 | 8篇 |
1982年 | 8篇 |
1981年 | 15篇 |
1980年 | 7篇 |
1979年 | 9篇 |
1978年 | 14篇 |
1977年 | 10篇 |
1976年 | 15篇 |
1975年 | 8篇 |
1974年 | 9篇 |
1973年 | 5篇 |
1972年 | 6篇 |
1971年 | 7篇 |
排序方式: 共有924条查询结果,搜索用时 31 毫秒
31.
Transient-receptor-potential channels (TRPs) underlie the sensing of chemicals, heat, and mechanical force. We expressed the rat TRPV1 and TRPV4 subtypes in yeast and monitored their activities in vivo as Ca2+ rise using transgenic aequorin. Heat and capsaicin activate TRPV1 but not TRPV4 in yeast. Hypotonic shocks activate TRPV4 but not TRPV1. Osmotic swelling is modeled to activate enzyme(s), producing polyunsaturated fatty acids (PUFAs) to open TRPV4 in mammalian cells. This model relegates mechanosensitivity to the enzyme and not the channel. Yeast has only a single Δ9 fatty-acid monodesaturase and cannot make PUFAs suggesting an alternative mechanism for TRPV4 activation. We discuss possible explanations of this difference. 相似文献
32.
The “paranoiac” mutants of Paramecium aurelia show prolonged backward swimming in solutions containing Na+, unlike wild-type paramecia, which jerk back and forth in Na+ solutions. The paranoiac mutants in Na+ solutions also show large losses of cellular K+ and large influxes of Na+. Three different paranoiac mutants all show similar defects in ion regulation but to different degrees. Wild-type Paramecium, in contrast, shows no Na+-dependent loss of cellular K+ and a much smaller Na+ influx. In K+-containing solutions, there is no difference between wild-type and paranoiac paramecia with respect to their cellular K+ content.The Na+ influx, the K+ loss, and the duration of backward swimming are all proportional to the extracellular Na+ concentration. Electrophysiologically, the backward swimming of the paranoiac mutants corresponds to a prolonged depolarization of the membrane potential, while the backward jerks of wild-type Paramecium correspond to a series of transient depolarizations. We propose that the large Na+ influxes and the large K+ effluxes in paranoiacs occur during the periods of backward swimming, while the membrane is depolarized. 相似文献
33.
34.
Thirty-five mutants of Pseudomonas aeruginosa sensitive to methyl methanesulfonate (MMS) have been genetically characterized. They constitute ten separable groups as defined by transduction and conjugation. Three of the groups have been shown to be cotransducible with auxotrophic markers. 相似文献
35.
36.
Yongxiong Chen Shiuh-Lin Hwang Vera S. F. Chan Nancy P. Y. Chung Shu-Rong Wang Zhongye Li Jing Ma Chia-Wei Lin Ya-Ju Hsieh Kao-Ping Chang Sui-Sum Kung Yi-Chia Wu Cheng-Wei Chu Hsiao-Ting Tai George F. Gao Bojian Zheng Kazunari K. Yokoyama Jonathan M. Austyn Chen-Lung S. Lin 《PLoS pathogens》2013,9(1)
During disease progression to AIDS, HIV-1 infected individuals become increasingly immunosuppressed and susceptible to opportunistic infections. It has also been demonstrated that multiple subsets of dendritic cells (DC), including DC-SIGN(+) cells, become significantly depleted in the blood and lymphoid tissues of AIDS patients, which may contribute to the failure in initiating effective host immune responses. The mechanism for DC depletion, however, is unclear. It is also known that vast quantities of viral envelope protein gp120 are shed from maturing HIV-1 virions and form circulating immune complexes in the serum of HIV-1-infected individuals, but the pathological role of gp120 in HIV-1 pathogenesis remains elusive. Here we describe a previously unrecognized mechanism of DC death in chronic HIV-1 infection, in which ligation of DC-SIGN by gp120 sensitizes DC to undergo accelerated apoptosis in response to a variety of activation stimuli. The cultured monocyte-derived DC and also freshly-isolated DC-SIGN(+) blood DC that were exposed to either cross-linked recombinant gp120 or immune-complex gp120 in HIV(+) serum underwent considerable apoptosis after CD40 ligation or exposure to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines such as TNFα and IL-1β. Furthermore, circulating DC-SIGN(+) DC that were isolated directly from HIV-1(+) individuals had actually been pre-sensitized by serum gp120 for activation-induced exorbitant apoptosis. In all cases the DC apoptosis was substantially inhibited by DC-SIGN blockade. Finally, we showed that accelerated DC apoptosis was a direct consequence of excessive activation of the pro-apoptotic molecule ASK-1 and transfection of siRNA against ASK-1 significantly prevented the activation-induced excessive DC death. Our study discloses a previously unknown mechanism of immune modulation by envelope protein gp120, provides new insights into HIV immunopathogenesis, and suggests potential therapeutic approaches to prevent DC depletion in chronic HIV infection. 相似文献
37.
38.
Kuo-Lun Huang Kun-Ju Lin Ing-Tsung Hsiao Hung-Chou Kuo Wen-Chuin Hsu Wen-Li Chuang Mei-Ping Kung Shiaw-Pyng Wey Chia-Ju Hsieh Yau-Yau Wai Tzu-Chen Yen Chin-Chang Huang 《PloS one》2013,8(3)
Background
To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer''s disease (AD) subjects with [18F]AV-45 positron emission tomography (PET).Materials and Methods
[18F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [18F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed.Results
The global cortical [18F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment.Conclusions
Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [18F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [18F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects. 相似文献39.
Han-En Tsai Jian-Ching Wu Mei-Lang Kung Li-Feng Liu Lai-Hsin Kuo Hsiao-Mei Kuo San-Cher Chen Elsa C. Chan Chieh-Shan Wu Ming-Hong Tai Guei-Sheung Liu 《PloS one》2013,8(3)
Cutaneous malignant melanoma is the fastest increasing malignancy in humans. Hepatoma-derived growth factor (HDGF) is a novel growth factor identified from human hepatoma cell line. HDGF overexpression is correlated with poor prognosis in various types of cancer including melanoma. However, the underlying mechanism of HDGF overexpression in developing melanoma remains unclear. In this study, human melanoma cell lines (A375, A2058, MEL-RM and MM200) showed higher levels of HDGF gene expression, whereas human epidermal melanocytes (HEMn) expressed less. Exogenous application of HDGF stimulated colony formation and invasion of human melanoma cells. Moreover, HDGF overexpression stimulated the degree of invasion and colony formation of B16–F10 melanoma cells whereas HDGF knockdown exerted opposite effects in vitro. To evaluate the effects of HDGF on tumour growth and metastasis in vivo, syngeneic mouse melanoma and metastatic melanoma models were performed by manipulating the gene expression of HDGF in melanoma cells. It was found that mice injected with HDGF-overexpressing melanoma cells had greater tumour growth and higher metastatic capability. In contrast, mice implanted with HDGF-depleted melanoma cells exhibited reduced tumor burden and lung metastasis. Histological analysis of excised tumors revealed higher degree of cell proliferation and neovascularization in HDGF-overexpressing melanoma. The present study provides evidence that HDGF promotes tumor progression of melanoma and targeting HDGF may constitute a novel strategy for the treatment of melanoma. 相似文献
40.
Juhyun Lee Mahdi Esmaily Moghadam Ethan Kung Hung Cao Tyler Beebe Yury Miller Beth L. Roman Ching-Ling Lien Neil C. Chi Alison L. Marsden Tzung K. Hsiai 《PloS one》2013,8(8)
Peristaltic contraction of the embryonic heart tube produces time- and spatial-varying wall shear stress (WSS) and pressure gradients (∇P) across the atrioventricular (AV) canal. Zebrafish (Danio rerio) are a genetically tractable system to investigate cardiac morphogenesis. The use of Tg(fli1a:EGFP)y1 transgenic embryos allowed for delineation and two-dimensional reconstruction of the endocardium. This time-varying wall motion was then prescribed in a two-dimensional moving domain computational fluid dynamics (CFD) model, providing new insights into spatial and temporal variations in WSS and ∇P during cardiac development. The CFD simulations were validated with particle image velocimetry (PIV) across the atrioventricular (AV) canal, revealing an increase in both velocities and heart rates, but a decrease in the duration of atrial systole from early to later stages. At 20-30 hours post fertilization (hpf), simulation results revealed bidirectional WSS across the AV canal in the heart tube in response to peristaltic motion of the wall. At 40-50 hpf, the tube structure undergoes cardiac looping, accompanied by a nearly 3-fold increase in WSS magnitude. At 110-120 hpf, distinct AV valve, atrium, ventricle, and bulbus arteriosus form, accompanied by incremental increases in both WSS magnitude and ∇P, but a decrease in bi-directional flow. Laminar flow develops across the AV canal at 20-30 hpf, and persists at 110-120 hpf. Reynolds numbers at the AV canal increase from 0.07±0.03 at 20-30 hpf to 0.23±0.07 at 110-120 hpf (p< 0.05, n=6), whereas Womersley numbers remain relatively unchanged from 0.11 to 0.13. Our moving domain simulations highlights hemodynamic changes in relation to cardiac morphogenesis; thereby, providing a 2-D quantitative approach to complement imaging analysis. 相似文献