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81.
Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to cell membrane leading to glucose uptake is the rate-limiting
step in diabetes. It is also a defined target of antidiabetic drug research. Existing GLUT4 translocation assays are based
on time-consuming immunoassays and are hampered by assay variability and low sensitivity. We describe a real-time, visual,
cell-based qualitative GLUT4 translocation assay using CHO-HIRc-myc-GLUT4eGFP cells that stably express myc- and eGFP-tagged
GLUT4 in addition to human insulin receptor (HIRc). GLUT4 translocation is visualized by live cell imaging based on GFP fluorescence
by employing a cooled charge-coupled device camera attached to a fluorescent microscope. This video imaging method and further
quantitative analysis of GLUT4 on the cell membrane provide rapid and foolproof visual evidence that this method is suitable
for screening GLUT4 translocation modulators. 相似文献
82.
Ranbir Chander Sobti Nega Berhane Salih Abedule Mehedi Rupinder Kler Seyed Ali Hosseini Vijish Kuttiat Ajay Wanchu 《Molecular biology reports》2010,37(1):317-324
Various efforts made to stop the deadly epidemic of HIV since its discovery in 1983 remain unsuccessful and this virus still
continues to claim the lives of millions of individuals every year. The viral effect in the cell is complicated and the overall
disease outcome is the result of interaction between a few viral proteins and complex host immune response. Because it has
been reported that XPG (Xeroderma pigementesum group G) gene does play a role in reducing UV induced apoptosis and participate in Nucleotide Excision
Repair (NER) process of DNA damage, it was hypothesized that polymorphism in this gene may have a role in HIV 1 disease progression
to AIDS. The aim of the present study, therefore, was to find out the association between XPG gene polymorphism and its effect on the rate of HIV 1 disease progression to AIDS. 300 HIV seropositive cases and an equal
number of age and sex matched controls were recruited for the study from north Indian population. The PCR-RFLP method was
utilized to genotype 600 study subject for the XPG Asp
1104
His gene polymorphism. There was significant difference in the frequency of the His/His variant genotype (OR 1.95, 95% CI = 1.93–3.63, P = 0.04) between cases and controls indicating a probable role of this gene in host viral interactions. 相似文献
83.
Archana Mathur Ajay Kumar Mathur Anita Gangwar Sharawan Yadav Priyanka Verma Rajender Singh Sangwan 《In vitro cellular & developmental biology. Plant》2010,46(1):13-21
A root-derived callus line of Panax sikkimensis that stably accumulates anthocyanins was established by small cell aggregate selection method. The selected line showed a
growth index of 221.36 and an anthocyanin content of 2.76 mg/g fw (7.076% dw) in 50–60 d of growth on a modified MS medium
containing 4.5 μM 2,4-dichlorophenoxy acetic acid and 1.2 μM kinetin under 16-h light and 8-h dark photoperiodic conditions.
Incubation under continuous light increased the growth index to 435.57 but led to a marginal dilution of anthocyanin content
to 2.192 mg/g fw (6.928% dw). The purple-red pigment had absorption maximum at 528 nm. The selected callus line has shown
sustained growth and productivity for more than 6 yr now. Interestingly, pigment accumulation in the selected line did not
hinder the ginsenoside production in the callus tissue (0.9–1.2% fw). 相似文献
84.
Wu E Thivierge C Flamand M Mathonnet G Vashisht AA Wohlschlegel J Fabian MR Sonenberg N Duchaine TF 《Molecular cell》2010,40(4):558-570
To understand how miRNA-mediated silencing impacts on embryonic mRNAs, we conducted a functional survey of abundant maternal and zygotic miRNA families in the C. elegans embryo. We show that the miR-35-42 and the miR-51-56 miRNA families define maternal and zygotic miRNA-induced silencing complexes (miRISCs), respectively, that share a large number of components. Using a cell-free C. elegans embryonic extract, we demonstrate that the miRISC directs the rapid deadenylation of reporter mRNAs with natural 3'UTRs. The deadenylated targets are translationally suppressed and remarkably stable. Sampling of the predicted miR-35-42 targets reveals that roughly half are deadenylated in a miRNA-dependent manner, but with each target displaying a distinct efficiency and pattern of deadenylation. Finally, we demonstrate that functional cooperation between distinct miRISCs within 3'UTRs is required to potentiate deadenylation. With this report, we reveal the extensive and direct impact of miRNA-mediated deadenylation on embryonic mRNAs. 相似文献
85.
Wilna J. Moree Florence Jovic Timothy Coon Jinghua Yu Bin-Feng Li Fabio C. Tucci Dragan Marinkovic Raymond S. Gross Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Zhihong O’Brien Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(7):2316-2320
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. 相似文献
86.
Wilna J. Moree Bin-Feng Li Said Zamani-Kord Jinghua Yu Timothy Coon Charles Huang Dragan Marinkovic Fabio C. Tucci Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Kayvon Jalali Chun Yang Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(19):5874-5878
Analogs of the known H1-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study. 相似文献
87.
Lee A Mathuru AS Teh C Kibat C Korzh V Penney TB Jesuthasan S 《Current biology : CB》2010,20(24):2211-2216
Animals quickly learn to avoid predictable danger. However, if pre-exposed to a strong stressor, they do not display avoidance even if this causes continued contact with painful stimuli [1, 2]. In rodents, lesioning the habenula, an epithalamic structure that regulates the monoaminergic system, has been reported to reduce avoidance deficits caused by inescapable shock [3]. This is consistent with findings that inability to overcome a stressor is accompanied by an increase in serotonin levels [4]. However, other studies conclude that habenula lesions cause avoidance deficits [5, 6]. These contradictory results may be caused by lesions affecting unintended regions [6]. To clarify the role of the habenula, we used larval zebrafish, whose transparency and amenability to genetic manipulation enables more precise disruption of cells. We show that larval zebrafish learn to avoid a light that has been paired with a mild shock but fail to do so when pre-exposed to inescapable shock. Photobleaching of habenula afferents expressing the photosensitizer KillerRed causes a similar failure in avoidance. Expression of tetanus toxin in dorsal habenula neurons is sufficient to prevent avoidance. We suggest that this region may signal the ability to control a stressor, and that its disruption could contribute to anxiety disorders. 相似文献
88.
Archana Mathur Anita Gangwar Ajay K. Mathur Priyanka Verma Girish C. Uniyal Raj K. Lal 《Biotechnology letters》2010,32(3):457-461
A thin, profusely branched, fast growing hairy root line of Panax quinquefolium (American ginseng) was established by co-culturing epicotyl explants with a wild type strain of Agrobacterium rhizogenes. The transformed roots grew by over 10-fold from the initial inoculum within 8 weeks. The crude ginsenosides content in the roots was about 0.2 g/g dry wt level up to the 10th week of culture. Ginsenosides Rb2, Rd, Re, Rf and Rg1 constituted 47–49% of the crude saponin fraction between 6 and 8 weeks of growth whereas, Rc ginsenoside was accumulated only after 9th weeks when the biomass started receding. PCR amplification analysis of the hairy roots confirmed their transgenic nature by showing the presence of Ri-TL DNA with rolA, rolB and rolC genes in their genome. 相似文献
89.
Christoph Kleinschnitz Henrike Grund Kirstin Wingler Melanie E. Armitage Emma Jones Manish Mittal David Barit Tobias Schwarz Christian Geis Peter Kraft Konstanze Barthel Michael K. Schuhmann Alexander M. Herrmann Sven G. Meuth Guido Stoll Sabine Meurer Anja Schrewe Lore Becker Valérie Gailus-Durner Helmut Fuchs Thomas Klopstock Martin Hrabé de Angelis Karin Jandeleit-Dahm Ajay M. Shah Norbert Weissmann Harald H. H. W. Schmidt 《PLoS biology》2010,8(9)
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4
−/−) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4
−/− mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. 相似文献
90.
An understanding of flow and dispersion in the human respiratory airways is necessary to assess the toxicological impact of inhaled particulate matter as well as to optimize the design of inhalable pharmaceutical aerosols and their delivery systems. Secondary flows affect dispersion in the lung by mixing solute in the lumen cross section. The goal of this study is to measure and interpret these secondary velocity fields using in vitro lung models. Particle image velocimetry experiments were conducted in a three-generational, anatomically accurate model of the conducting region of the lung. Inspiration and expiration flows were examined under steady and oscillatory flow conditions. Results illustrate secondary flow fields as a function of flow direction, Reynolds number, axial location with respect to the bifurcation junction, generation, branch, phase in the oscillatory cycle, and Womersley number. Critical Dean number for the formation of secondary vortices in the airways, as well as the strength and development length of secondary flow, is characterized. The normalized secondary velocity magnitude was similar on inspiration and expiration and did not vary appreciably with generation or branch. Oscillatory flow fields were not significantly different from corresponding steady flow fields up to a Womersley number of 1 and no instabilities related to shear were detected on flow reversal. These observations were qualitatively interpreted with respect to the simple streaming, augmented dispersion, and steady streaming convective dispersion mechanisms. 相似文献