全文获取类型
收费全文 | 842篇 |
免费 | 106篇 |
出版年
2022年 | 6篇 |
2021年 | 19篇 |
2020年 | 7篇 |
2019年 | 11篇 |
2018年 | 20篇 |
2017年 | 17篇 |
2016年 | 27篇 |
2015年 | 40篇 |
2014年 | 47篇 |
2013年 | 51篇 |
2012年 | 60篇 |
2011年 | 52篇 |
2010年 | 24篇 |
2009年 | 34篇 |
2008年 | 54篇 |
2007年 | 47篇 |
2006年 | 32篇 |
2005年 | 43篇 |
2004年 | 33篇 |
2003年 | 35篇 |
2002年 | 30篇 |
2001年 | 15篇 |
2000年 | 16篇 |
1999年 | 12篇 |
1997年 | 10篇 |
1996年 | 5篇 |
1995年 | 9篇 |
1994年 | 7篇 |
1992年 | 8篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1987年 | 11篇 |
1986年 | 11篇 |
1985年 | 9篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1981年 | 10篇 |
1980年 | 7篇 |
1979年 | 11篇 |
1978年 | 8篇 |
1976年 | 10篇 |
1975年 | 5篇 |
1974年 | 11篇 |
1973年 | 7篇 |
1972年 | 3篇 |
1970年 | 4篇 |
1968年 | 4篇 |
排序方式: 共有948条查询结果,搜索用时 109 毫秒
31.
32.
Synfire waves are propagating spike packets in synfire chains, which are feedforward chains embedded in random networks. Although synfire waves have proved to be effective quantification for network activity with clear relations to network structure, their utilities are largely limited to feedforward networks with low background activity. To overcome these shortcomings, we describe a novel generalisation of synfire waves, and define ‘synconset wave’ as a cascade of first spikes within a synchronisation event. Synconset waves would occur in ‘synconset chains’, which are feedforward chains embedded in possibly heavily recurrent networks with heavy background activity. We probed the utility of synconset waves using simulation of single compartment neuron network models with biophysically realistic conductances, and demonstrated that the spread of synconset waves directly follows from the network connectivity matrix and is modulated by top-down inputs and the resultant oscillations. Such synconset profiles lend intuitive insights into network organisation in terms of connection probabilities between various network regions rather than an adjacency matrix. To test this intuition, we develop a Bayesian likelihood function that quantifies the probability that an observed synfire wave was caused by a given network. Further, we demonstrate it''s utility in the inverse problem of identifying the network that caused a given synfire wave. This method was effective even in highly subsampled networks where only a small subset of neurons were accessible, thus showing it''s utility in experimental estimation of connectomes in real neuronal-networks. Together, we propose synconset chains/waves as an effective framework for understanding the impact of network structure on function, and as a step towards developing physiology-driven network identification methods. Finally, as synconset chains extend the utilities of synfire chains to arbitrary networks, we suggest utilities of our framework to several aspects of network physiology including cell assemblies, population codes, and oscillatory synchrony. 相似文献
33.
Chandrasekaran Meganathan Sugunadevi Sakkiah Yuno Lee Jayavelu Venkat Narayanan Keun Woo Lee 《Journal of molecular modeling》2013,19(2):715-726
In our study, a structure-based virtual screening study was conducted to identify potent ITK inhibitors, as ITK is considered to play an important role in the treatment of inflammatory diseases. We developed a structure-based pharmacophore model using the crystal structure (PDB ID: 3MJ2) of ITK complexed with BMS-50944. The most predictive model, SB-Hypo1, consisted of six features: three hydrogen-bond acceptors (HBA), one hydrogen-bond donor (HBD), one ring aromatic (RA), and one hydrophobic (HY). The statistical significance of SB-Hypo1 was validated using wide range of test set molecules and a decoy set. The resulting well-validated model could then be confidently used as a 3D query to screen for drug-like molecules in a database, in order to retrieve new chemical scaffolds that may be potent ITK inhibitors. The hits retrieved from this search were filtered based on the maximum fit value, drug-likeness, and ADMET properties, and the hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the protein. These hits were then fed into a molecular dynamics simulation to study the flexibility of the activation loop of ITK upon ligand binding. This combination of methodologies is a valuable tool for identifying structurally diverse molecules with desired biological activities, and for designing new classes of selective ITK inhibitors. Figure
A structure-based pharmacophore model was developed, using a fully resolved crystal structure, in order to identify novel virtual lead compounds for use in ITK inhibitor design 相似文献
34.
Shalaka Mulherkar Feng Liu Qin Chen Anjana Narayanan Anthony D. Couvillon H. David Shine Kimberley F. Tolias 《PloS one》2013,8(6)
The assembly of neuronal circuits during development requires the precise navigation of axons, which is controlled by attractive and repulsive guidance cues. In the developing spinal cord, ephrinB3 functions as a short-range repulsive cue that prevents EphA4 receptor-expressing corticospinal tract and spinal interneuron axons from crossing the midline, ensuring proper formation of locomotor circuits. Here we report that the small GTPase RhoA, a key regulator of cytoskeletal dynamics, is also required for ephrinB3/EphA4-dependent locomotor circuit formation. Deletion of RhoA from neural progenitor cells results in mice that exhibit a rabbit-like hopping gait, which phenocopies mice lacking ephrinB3 or EphA4. Consistent with this locomotor defect, we found that corticospinal tract axons and spinal interneuron projections from RhoA-deficient mice aberrantly cross the spinal cord midline. Furthermore, we determined that loss of RhoA blocks ephrinB3-induced growth cone collapse of cortical axons and disrupts ephrinB3 expression at the spinal cord midline. Collectively, our results demonstrate that RhoA is essential for the ephrinB3/EphA4-dependent assembly of cortical and spinal motor circuits that control normal locomotor behavior. 相似文献
35.
J?rg Lesting Thiemo Daldrup Venu Narayanan Christian Himpe Thomas Seidenbecher Hans-Christian Pape 《PloS one》2013,8(10)
Theta oscillations are considered crucial mechanisms in neuronal communication across brain areas, required for consolidation and retrieval of fear memories. One form of inhibitory learning allowing adaptive control of fear memory is extinction, a deficit of which leads to maladaptive fear expression potentially leading to anxiety disorders. Behavioral responses after extinction training are thought to reflect a balance of recall from extinction memory and initial fear memory traces. Therefore, we hypothesized that the initial fear memory circuits impact behavioral fear after extinction, and more specifically, that the dynamics of theta synchrony in these pathways signal the individual fear response. Simultaneous multi-channel local field and unit recordings were obtained from the infralimbic prefrontal cortex, the hippocampal CA1 and the lateral amygdala in mice. Data revealed that the pattern of theta coherence and directionality within and across regions correlated with individual behavioral responses. Upon conditioned freezing, units were phase-locked to synchronized theta oscillations in these pathways, characterizing states of fear memory retrieval. When the conditioned stimulus evoked no fear during extinction recall, theta interactions were directional with prefrontal cortical spike firing leading hippocampal and amygdalar theta oscillations. These results indicate that the directional dynamics of theta-entrained activity across these areas guide changes in appraisal of threatening stimuli during fear memory and extinction retrieval. Given that exposure therapy involves procedures and pathways similar to those during extinction of conditioned fear, one therapeutical extension might be useful that imposes artificial theta activity to prefrontal cortical-amygdalo-hippocampal pathways that mimics the directionality signaling successful extinction recall. 相似文献
36.
Naiomy D. Rios-Arce Andrew Dagenais Derrick Feenstra Brandon Coughlin Ho Jun Kang Susanne Mohr Laura R. McCabe Narayanan Parameswaran 《Journal of cellular physiology》2020,235(3):2350-2365
Type-1 diabetes (T1D) increases systemic inflammation, bone loss, and risk for bone fractures. Levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are decreased in T1D, however their role in T1D-induced osteoporosis is unknown. To address this, diabetes was induced in male IL-10 knockout (KO) and wild-type (WT) mice. Analyses of femur and vertebral trabecular bone volume fraction identified bone loss in T1D-WT mice at 4 and 12 weeks, which in T1D-IL-10-KO mice was further reduced at 4 weeks but not 12 weeks. IL-10 deficiency also increased the negative effects of T1D on cortical bone. Osteoblast marker osterix was decreased, while osteoclast markers were unchanged, suggesting that IL-10 promotes anabolic processes. MC3T3-E1 osteoblasts cultured under high glucose conditions displayed a decrease in osterix which was prevented by addition of IL-10. Taken together, our results suggest that IL-10 is important for promoting osteoblast maturation and reducing bone loss during early stages of T1D. 相似文献
37.
Probiotics are a cultured product or live microbial feed supplement, which beneficially affects the host by improving its intestinal balance and health of the host. In the present study an attempt was made to study the effect of Pseudomonas aeruginosa (MICC 741) as a colour enhancing probiont in addition to growth and disease resistance in the ornamental cichlid, Pseudotropheus lombardoi. The experimental fishes were fed with different concentrations of P. aeruginosa. Incorporation of P. aeruginosa to the maximum of 30 mL (103 CFU/mL) resulted in the gain of carotenoid pigment to the tune of 400 % over the control (p < 0.05) which again showed a significant increase in the growth rate of P. lombardoi. Disease resistance against the pathogens Vibrio parahaemolyticus and Bacillus cereus which were isolated from a diseased P. lombardoi were measured by zone of inhibition. Pseudomonas aeruginosa was found to be significantly effective in controlling both the pathogens. The investigation on P. aeruginosa proved that it not only improves the pigmentation, but also promotes growth and immunity to P. lombardoi. 相似文献
38.
Myung-Chul Chung Aarthi Narayanan Taissia G. Popova Fatah Kashanchi Charles L. Bailey Serguei G. Popov 《Biochemical and biophysical research communications》2013,430(1):125-130
Bacillus anthracis, a causative agent of anthrax, is able to germinate and survive within macrophages. A recent study suggested that B. anthracis-derived nitric oxide (bNO) is a key aspect of bacterial defense that protects bacterial DNA from oxidative burst in the macrophages. However, the virulent effect of bNO in host cells has not been investigated. Here, we report that bNO contributes macrophage killing by S-nitrosylation of bioenergetic-relating proteins within mitochondria. Toxigenic Sterne induces expression of the bnos gene and produces bNO during early stage of infection. Nitroso-proteomic analysis coupled with a biotin-switch technique demonstrated that toxigenic infection induces protein S-nitrosylation in B. anthracis-susceptible RAW264.7. For each target enzyme tested (complex I, complex III and complex IV), infection by B. anthracis Sterne caused enzyme inhibition. Nω-nitro-l-arginine methyl ester, a NO synthase inhibitor, reduced S-nitrosylation and partially restored cell viability evaluated by intracellular ATP levels in macrophages. Our data suggest that bNO leads to energy depletion driven by impaired mitochondrial bioenergetic machinery that ultimately contributes to macrophage death. This novel mechanism of anthrax pathogenesis may offer specific approach to the development of therapeutics. 相似文献
39.
40.
Jaymin C. Patel Jenna Oberstaller Maniphet Xayavong Jothikumar Narayanan Jeremy D. DeBarry Ganesh Srinivasamoorthy Leopoldo Villegas Ananias A. Escalante Alexandre DaSilva David S. Peterson John W. Barnwell Jessica C. Kissinger Venkatachalam Udhayakumar Naomi W. Lucchi 《PloS one》2013,8(1)
Plasmodium vivax infections remain a major source of malaria-related morbidity and mortality. Early and accurate diagnosis is an integral component of effective malaria control programs. Conventional molecular diagnostic methods provide accurate results but are often resource-intensive, expensive, have a long turnaround time and are beyond the capacity of most malaria-endemic countries. Our laboratory has recently developed a new platform called RealAmp, which combines loop-mediated isothermal amplification (LAMP) with a portable tube scanner real-time isothermal instrument for the rapid detection of malaria parasites. Here we describe new primers for the detection of P. vivax using the RealAmp method. Three pairs of amplification primers required for this method were derived from a conserved DNA sequence unique to the P. vivax genome. The amplification was carried out at 64°C using SYBR Green or SYTO-9 intercalating dyes for 90 minutes with the tube scanner set to collect fluorescence signals at 1-minute intervals. Clinical samples of P. vivax and other human-infecting malaria parasite species were used to determine the sensitivity and specificity of the primers by comparing with an 18S ribosomal RNA-based nested PCR as the gold standard. The new set of primers consistently detected laboratory-maintained isolates of P. vivax from different parts of the world. The primers detected P. vivax in the clinical samples with 94.59% sensitivity (95% CI: 87.48–98.26%) and 100% specificity (95% CI: 90.40–100%) compared to the gold standard nested-PCR method. The new primers also proved to be more sensitive than the published species-specific primers specifically developed for the LAMP method in detecting P. vivax. 相似文献