全文获取类型
收费全文 | 994篇 |
免费 | 49篇 |
出版年
2023年 | 13篇 |
2022年 | 18篇 |
2021年 | 33篇 |
2020年 | 17篇 |
2019年 | 25篇 |
2018年 | 29篇 |
2017年 | 26篇 |
2016年 | 33篇 |
2015年 | 49篇 |
2014年 | 45篇 |
2013年 | 71篇 |
2012年 | 74篇 |
2011年 | 73篇 |
2010年 | 41篇 |
2009年 | 36篇 |
2008年 | 49篇 |
2007年 | 43篇 |
2006年 | 35篇 |
2005年 | 36篇 |
2004年 | 30篇 |
2003年 | 23篇 |
2002年 | 18篇 |
2001年 | 19篇 |
2000年 | 15篇 |
1999年 | 18篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 5篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 16篇 |
1991年 | 12篇 |
1990年 | 11篇 |
1989年 | 16篇 |
1988年 | 6篇 |
1987年 | 10篇 |
1986年 | 4篇 |
1985年 | 10篇 |
1984年 | 8篇 |
1982年 | 3篇 |
1981年 | 5篇 |
1979年 | 7篇 |
1978年 | 3篇 |
1977年 | 6篇 |
1975年 | 5篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1966年 | 3篇 |
排序方式: 共有1043条查询结果,搜索用时 31 毫秒
101.
Dinesh Addla Balasubramanian Sridhar Anjana Devi Srinivas Kantevari 《Bioorganic & medicinal chemistry letters》2012,22(24):7475-7480
A series of novel 1-benzyl-2-butyl-4-chloroimidazole embodied 4-azafluorenone hybrids, designed via molecular hybridization approach, were synthesized in very good yields using one pot condensation of 1-benzyl-2-butyl-4-chloroimidazole-5-carboxaldehyde, 1,3-indanedione, aryl/heteroaryl methyl ketones and ammonium acetate. All the synthetic derivatives were fully characterized by spectral data and evaluated for antimicrobial activity by disc diffusion method against selected bacteria and fungal strains. Among the 15 new compounds screened, 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(furan-2-yl)-5H-indeno[1,2-b]pyridin-5-one(10k) has pronounced activity with higher zone of inhibition (ZoI) against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Aspergillus flavus and Candida albicans. Also 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(dibenzo[b,d]thiophen-2-yl)-5H-indeno [1,2-b]pyridin-5-one (10n) and 4-(1-benzyl-2-butyl-4-chloro-1H-imidazol-5-yl)-2-(3-tosyl-3H-inden-1-yl)-5H-indeno[1,2-b]pyridin-5-one (10o) showed selective higher inhibitory activity against Aspergillus flavus and Candida albicans. The results demonstrated potential importance of molecular hybridization in the development of 10k as potential antimicrobial agent. 相似文献
102.
Devi Rani Sagar James J. Burston Stephen G. Woodhams Victoria Chapman 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2012,367(1607):3300-3311
The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling. 相似文献
103.
RNA interference mediated inhibition of dengue virus multiplication and entry in HepG2 cells 总被引:1,自引:0,他引:1
Background
Dengue virus-host cell interaction initiates when the virus binds to the attachment receptors followed by endocytic internalization of the virus particle. Successful entry into the cell is necessary for infection initiation. Currently, there is no protective vaccine or antiviral treatment for dengue infection. Targeting the viral entry pathway has become an attractive therapeutic strategy to block infection. This study aimed to investigate the effect of silencing the GRP78 and clathrin-mediated endocytosis on dengue virus entry and multiplication into HepG2 cells.Methodology/Principal Findings
HepG2 cells were transfected using specific siRNAs to silence the cellular surface receptor (GRP78) and clathrin-mediated endocytosis pathway. Gene expression analysis showed a marked down-regulation of the targeted genes (87.2%, 90.3%, and 87.8% for GRP78, CLTC, and DNM2 respectively) in transfected HepG2 cells when measured by RT-qPCR. Intracellular and extracellular viral RNA loads were quantified by RT-qPCR to investigate the effect of silencing the attachment receptor and clathrin-mediated endocytosis on dengue virus entry. Silenced cells showed a significant reduction of intracellular (92.4%) and extracellular viral RNA load (71.4%) compared to non-silenced cells. Flow cytometry analysis showed a marked reduction of infected cells (89.7%) in silenced HepG2 cells compared to non-silenced cells. Furthermore, the ability to generate infectious virions using the plaque assay was reduced 1.07 log in silenced HepG2 cells.Conclusions/Significance
Silencing the attachment receptor and clathrin-mediated endocytosis using siRNA could inhibit dengue virus entry and multiplication into HepG2 cells. This leads to reduction of infected cells as well as the viral load, which might function as a unique and promising therapeutic agent for attenuating dengue infection and prevent the development of dengue fever to the severe life-threatening DHF or DSS. Furthermore, a decrease of viremia in humans can result in the reduction of infected vectors and thus, halt of the transmission cycle. 相似文献104.
105.
106.
Ravi Tandon Maria T. M. Giret Devi SenGupta Vanessa A. York Andrew A. Wiznia Michael G. Rosenberg Esper G. Kallas Lishomwa C. Ndhlovu Douglas F. Nixon 《PloS one》2012,7(9)
As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an “immune exhaustion”, with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28−CD57+CD8+ T cells between the groups. However, the frequency of Tim-3+CD8+ and Tim-3+CD4+ exhausted T cells, but not PD-1+ T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1+CD8+ T cells were directly associated with T cell immune activation in children. The frequency of Tim-3+CD8+ T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion. 相似文献
107.
Büsse S von Grumbkow P Hummel S Shah DN Tachamo Shah RD Li J Zhang X Yoshizawa K Wedmann S Hörnschemeyer T 《PloS one》2012,7(5):e38132
Unusual biogeographic patterns of closely related groups reflect events in the past, and molecular analyses can help to elucidate these events. While ample research on the origin of disjunct distributions of different organism groups in the Western Paleartic has been conducted, such studies are rare for Eastern Palearctic organisms. In this paper we present a phylogeographic analysis of the disjunct distribution pattern of the extant species of the strongly cool-adapted Epiophlebia dragonflies from Asia. We investigated sequences of the usually more conserved 18 S rDNA and 28 S rDNA genes and the more variable sequences of ITS1, ITS2 and CO2 of all three currently recognised Epiophlebia species and of a sample of other odonatan species. In all genes investigated the degrees of similarity between species of Epiophlebia are very high and resemble those otherwise found between different populations of the same species in Odonata. This indicates that substantial gene transfer between these populations occurred in the comparatively recent past. Our analyses imply a wide distribution of the ancestor of extant Epiophlebia in Southeast Asia during the last ice age, when suitable habitats were more common. During the following warming phase, its range contracted, resulting in the current disjunct distribution. Given the strong sensitivity of these species to climatic parameters, the current trend to increasing global temperatures will further reduce acceptable habitats and seriously threaten the existences of these last representatives of an ancient group of Odonata. 相似文献
108.
CE Ormsby D Sengupta R Tandon SG Deeks JN Martin RB Jones MA Ostrowski KE Garrison JA Vázquez-Pérez G Reyes-Terán DF Nixon 《PloS one》2012,7(8):e41021
Human endogenous retroviruses (HERV) are remnants of ancestral retroviral infections integrated into the germ line, and constitute approximately 8% of the genome. Several autoimmune disorders, malignancies, and infectious diseases such as HIV-1 are associated with higher HERV expression. The degree to which HERV expression in vivo results in persistent inflammation is not known. We studied the association of immune activation and HERV-K expression in 20 subjects with chronic, untreated progressive HIV-1 infection and 10 HIV-1 negative controls. The mean HERV-K gag and env RNA expression level in the HIV-1 infected cohort was higher than in the control group (p = 0.0003), and was negatively correlated with the frequency of activated CD38+HLA-DR+CD4+ T cells (Rho = −0.61; p = 0.01) and activated CD38+HLA-DR+CD8+ T cells (Rho = −0.51; p = 0.03). Although HIV-infected persons had higher levels of HERV-K RNA expression (as expected), the level of RNA expression was negatively associated with level of T cell activation. The mechanism for this unexpected association remains to be defined. 相似文献
109.
Ittai Bushlin Achla Gupta Steven D. Stockton Jr Lydia K. Miller Lakshmi A. Devi 《PloS one》2012,7(12)
The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in vitro, the role of these heteromers in normal physiology and disease has been poorly explored. In this study, direct interactions between CB1 cannabinoid and delta opioid receptors in the brain were examined. Additionally, regulation of heteromer levels and signaling in a rodent model of neuropathic pain was explored. First we examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats with a peripheral nerve lesion that resulted in neuropathic pain. We found that, following the peripheral nerve lesion, the expression of both cannabinoid type 1 receptor (CB1R) and the delta opioid receptor (DOR) are increased in select brain regions. Concomitantly, an increase in CB1R activity and decrease in DOR activity was observed. We hypothesize that this decrease in DOR activity could be due to heteromeric interactions between these two receptors. Using a CB1R-DOR heteromer-specific antibody, we found increased levels of CB1R-DOR heteromer protein in the cortex of neuropathic animals. We subsequently examined the functionality of these heteromers by testing whether low, non-signaling doses of CB1R ligands influenced DOR signaling in the cortex. We found that, in cortical membranes from animals that experienced neuropathic pain, non-signaling doses of CB1R ligands significantly enhanced DOR activity. Moreover, this activity is selectively blocked by a heteromer-specific antibody. Together, these results demonstrate an important role for CB1R-DOR heteromers in altered cortical function of DOR during neuropathic pain. Moreover, they suggest the possibility that a novel heteromer-directed therapeutic strategy for enhancing DOR activity, could potentially be employed to reduce anxiety associated with chronic pain. 相似文献
110.
Ritu Tyagi Poonam Rana Mamta Gupta Ahmad Raza Khan M. Memita Devi Deepak Bhatnagar Raja Roy Rajendra P. Tripathi Subash Khushu 《Metabolomics : Official journal of the Metabolomic Society》2012,8(5):940-950
The metabolomic approach has been widely used in toxicology to investigate mechanisms of toxicity. To understand the mammalian system??s response to nickel exposure, we analysed the NiCl2 induced metabolomic changes in urine of rats using 1H nuclear magnetic resonance (1H NMR) spectroscopy together with clinically relevant biochemical parameters. Male Sprague?CDawley rats were administered intraperitoneally with NiCl2 at doses of 4, 10 and 20?mg/kg body weight. Urine samples were collected at 8, 16, 24, 72, 96 and 120?h post treatment. The metabolomic profile of rat urine showed prominent changes in citrate, dimethylamine, creatinine, choline, trimethylamine oxide (TMAO), phenyl alanine and hippurate at all doses. Principal component analysis of urine 1H NMR spectra demonstrated the dose and time dependent development of toxicity. The metabolomic time trajectory, based on pattern recognition analysis of 1H NMR spectra of urine, illustrated clear separation of pre and post treatments (temporal). Only animals treated with a low dose of NiCl2 returned to normal physiology. The 1H NMR spectral data correlated well with the clinically relevant nephrotoxic biomarkers. The urinary metabolomic phenotyping for NiCl2 induced nephrotoxicity was defined according to the predictive ability of the known metabolite biomarkers, creatinine, citrate and TMAO. The current approach demonstrates that metabolomics, one of the most important platform in system biology, may be a promising tool for identifying and characterizing biochemical responses to toxicity. 相似文献