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41.
42.
Kristina Warton Vita Lin Tina Navin Nicola J Armstrong Warren Kaplan Kevin Ying Brian Gloss Helena Mangs Shalima S Nair Neville F Hacker Robert L Sutherland Susan J Clark Goli Samimi 《BMC genomics》2014,15(1)
Background
Free circulating DNA (fcDNA) has many potential clinical applications, due to the non-invasive way in which it is collected. However, because of the low concentration of fcDNA in blood, genome-wide analysis carries many technical challenges that must be overcome before fcDNA studies can reach their full potential. There are currently no definitive standards for fcDNA collection, processing and whole-genome sequencing. We report novel detailed methodology for the capture of high-quality methylated fcDNA, library preparation and downstream genome-wide Next-Generation Sequencing. We also describe the effects of sample storage, processing and scaling on fcDNA recovery and quality.Results
Use of serum versus plasma, and storage of blood prior to separation resulted in genomic DNA contamination, likely due to leukocyte lysis. Methylated fcDNA fragments were isolated from 5 donors using a methyl-binding protein-based protocol and appear as a discrete band of ~180 bases. This discrete band allows minimal sample loss at the size restriction step in library preparation for Next-Generation Sequencing, allowing for high-quality sequencing from minimal amounts of fcDNA. Following sequencing, we obtained 37×106-86×106 unique mappable reads, representing more than 50% of total mappable reads. The methylation status of 9 genomic regions as determined by DNA capture and sequencing was independently validated by clonal bisulphite sequencing.Conclusions
Our optimized methods provide high-quality methylated fcDNA suitable for whole-genome sequencing, and allow good library complexity and accurate sequencing, despite using less than half of the recommended minimum input DNA.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-476) contains supplementary material, which is available to authorized users. 相似文献43.
Fereshteh Pourabdolhossein Sabah Mozafari Ghislaine Morvan-Dubois Javad Mirnajafi-Zadeh Alejandra Lopez-Juarez Jacqueline Pierre-Simons Barbara A. Demeneix Mohammad Javan 《PloS one》2014,9(9)
Background
Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.Methodology/Principal Findings
A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time.Conclusions/Significance
Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis. 相似文献44.
Mahboobeh Omidvar Hamzeh Mehrabi Fereshteh Sajjadi Hassan Bahramizadeh-Sajjadi Hossain Rahimpour-Bonab Alireza Ashrafzadeh 《Revue de Micropaléontologie》2014
Cretaceous carbonate successions of the Bangestan Group, such as the Sarvak and Ilam formations, are among the most prolific hydrocarbon reserves of the Middle East. However, relatively little is known about their detailed palaeontology and biostratigraphy. Moreover, due to lithological similarity of these carbonate formations recognition of their boundaries in subsurface studies is problematic. To investigate these units, biostratigraphic analyses were carried out on nearly 1100 m of cores, including core plug samples and thin sections prepared from five giant and supergiant oilfields in the northern and southern Dezful Embayment, SW Iran. Accordingly, 59 species of foraminifera (assigned to 43 genera) as well as 11 species of non-foraminifera (10 genera) were recognized. As a result, three biozones were identified, which in stratigraphic order are: Nezzazata-Alveolinids Assemblage Zone; Moncharmontia apenninica-Nezzazatinella-Dicyclina Assemblage Zone; and Rotalia skourensis-algae Assemblage Zone. These are compared with the Wynd's (1965) biozonation scheme, previously introduced in the Zagros area, and a revised scheme is presented. Accordingly, a Cenomanian–Turonian age and a Coniacian–Campanian age are envisaged for the Upper Sarvak and Ilam formations, respectively. In our new biostratigraphic scheme, the Sarvak–Ilam formations boundary is considered to be located above the Moncharmontia apenninica-Nezzazatinella-Dicyclina Assemblage Zone (equivalent of Valvulammina-Dicyclina Assemblage Zone of Wynd, 1965), that is Turonian in age. This zone is bounded by two palaeoexposure surfaces, which correspond approximately to the C–T boundary transitional interval and a post-Turonian, which can be possibly assigned to the Coniacian. Significant sedimentological features of these disconformities include bauxitic–lateritic horizons, karstified profiles and solution-collapsed breccias. Geochemical signatures of these meteorically altered surfaces are also considered to calibrate biofacies and biozones. Finally, we compared our new biozonation scheme with other studies in neighboring areas of SW Iran and the Middle East. 相似文献
45.
Otilija Keta Tanja Bulat Igor Golić Sebastien Incerti Aleksandra Korać Ivan Petrović Aleksandra Ristić-Fira 《Cell biology and toxicology》2016,32(2):83-101
In most patients with lung cancer radiation treatment is used either as single agent or in combination with radiosensitizing drugs. However, the mechanisms underlying combined therapy and its impact on different modes of cell death have not yet been fully elucidated. We aimed to examine effects of single and combined treatments with γ-rays and erlotinib on radioresistant CRL-5876 human lung adenocarcinoma cells with particular emphasis on cell death. CRL-5876 cells were treated with γ-rays and/or erlotinib and changes in cell cycle, DNA repair dynamics, ultrastructure, nuclear morphology and protein expression were monitored at different time points. To reveal the relationship between types of cell death that arise after these treatments, autophagy was blocked with chloroquine. We found that higher dose of γ-rays causes G2/M arrest while adding of erlotinib to this treatment decreases the number of cells in S phase. Impact of erlotinib on kinetics of disappearance of irradiation-induced DNA double strand breaks is reflected in the increase of residual γ-H2AX foci after 24 h. γ-rays provoke cytoprotective autophagy which precedes development of senescence. Erlotinib predominantly induces apoptosis and enlarges the number of apoptotic cells in the irradiated CRL-5876 cells. Chloroquine improved cytotoxicity induced by radiation and erlotinib, increased apoptosis and decreased senescence in the CRL-5876 cells. The results obtained on CRL-5876 cells indicate significant radiosensitizing effect of erlotinib and suggest that chloroquine in the combination with the above treatments may have an additional antitumor effect in lung adenocarcinoma. 相似文献
46.
Three wheat samples collected in 1987 in Central Poland and naturally infected withFusarium spp were analyzed for the presence ofFusarium spp andFusarium toxins. Heads were separated into three fractions: kernels with visibleFusarium damage, healthy looking kernels, and chaff + rachis. The samples contained deoxynivalenol (2.0 – 40.0μg/g), nivalenol (O.O1μg/g), 4,7-dideoxynivalenol (0.10 – 0.15μg/g). 15-acetyldeoxynivalenol (0.10–2.00 μg/g), 3-acetyldeoxynivalenol (O/1Oμg/g), and zearalenone (0.01–2.00μg/g). This is the first report about 15 - acetyldeoxynivalenol in European wheat and the co-occurrence of 3 - acetyldeoxynivalenol and 15-acetyldeoxynivalenol in the same sample of contaminated cereals. 相似文献
47.
3-Phosphonopropionic acids inhibit carboxypeptidase A as multisubstrate analogues or transition-state analogues.
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A series of phosphonic acid analogues of 2-benzylsuccinate were tested as inhibitors of carboxypeptidase A. The most potent of these, (2RS)-2-benzyl-3-phosphonopropionic acid, had a Ki of 0.22 +/- 0.05 microM, equipotent to (2RS)-2-benzylsuccinate and thus one of the most potent reversible inhibitors known for this enzyme. Lengthening by one methylene group to (2RS)-2-benzyl-4-phosphonobutyric acid increased the Ki to 370 +/- 60 microM. The monoethyl ester (2RS)-2-benzyl-3-(O-ethylphosphono)propionic acid was nearly as potent as (2RS)-2-benzyl-3-phosphonopropionic acid, with a Ki of 0.72 +/- 0.3 microM. The sulphur analogue of the monoethyl ester, 2-ambo-P-ambo-2-benzyl-3-(O-ethylthiophosphono)propionic acid, had a Ki of 2.1 +/- 0.6 microM, nearly as active as (2RS)-2-benzyl-3-(O-ethylphosphono)propionic acid. These phosphonic acids and esters could be considered to be multisubstrate inhibitors of carboxypeptidase A by virtue of their structural analogy with 2-benzylsuccinate. Alternatively, the tetrahedral hybridization at the phosphorus atom suggests that they could be mimicking a tetrahedral transition state for the enzyme-catalysed hydrolysis of substrate. 相似文献
48.
Fereshteh Haghighi Julia Dahlmann Saeideh Nakhaei-Rad Alexander Lang Ingo Kutschka Martin Zenker George Kensah Roland P. Piekorz Mohammad Reza Ahmadian 《Cell communication and signaling : CCS》2018,16(1):96
Background
Human pluripotent stem cells (PSCs) open new windows for basic research and regenerative medicine due to their remarkable properties, i.e. their ability to self-renew indefinitely and being pluripotent. There are different, conflicting data related to the role of basic fibroblast growth factor (bFGF) in intracellular signal transduction and the regulation of pluripotency of PSCs. Here, we investigated the effect of bFGF and its downstream pathways in pluripotent vs. differentiated human induced (hi) PSCs.Methods
bFGF downstream signaling pathways were investigated in long-term culture of hiPSCs from pluripotent to differentiated state (withdrawing bFGF) using immunoblotting, immunocytochemistry and qPCR. Subcellular distribution of signaling components were investigated by simple fractionation and immunoblotting upon bFGF stimulation. Finally, RAS activity and RAS isoforms were studied using RAS assays both after short- and long-term culture in response to bFGF stimulation.Results
Our results revealed that hiPSCs were differentiated into the ectoderm lineage upon withdrawing bFGF as an essential pluripotency mediator. Pluripotency markers OCT4, SOX2 and NANOG were downregulated, following a drastic decrease in MAPK pathway activity levels. Notably, a remarkable increase in phosphorylation levels of p38 and JAK/STAT3 was observed in differentiated hiPSCs, while the PI3K/AKT and JNK pathways remained active during differentiation. Our data further indicate that among the RAS paralogs, NRAS predominantly activates the MAPK pathway in hiPSCs.Conclusion
Collectively, the MAPK pathway appears to be the prime signaling pathway downstream of bFGF for maintaining pluripotency in hiPSCs and among the MAPK pathways, the activity of NRAS-RAF-MEK-ERK is decreased during differentiation, whereas p38 is activated and JNK remains constant.49.
50.
1. The effect of melatonin on forskolin-stimulated adenylate cyclase activity was measured in homogenates of Syrian hamster hypothalamus. In addition, the saturation binding characteristics of the melatonin receptor ligand, [125I]iodomelatonin, was examined using an incubation temperature (30 degrees C) similar to that used in enzyme assays. 2. At concentrations ranging from 10 pM to 1 nM, melatonin caused a significant decrease in stimulated adenylate cyclase activity with a maximum inhibition of approximately 22%. 3. Binding experiments utilizing [125I]iodomelatonin in a range of approximately 5-80 pM indicated a single class of high-affinity sites: Kd = 55 +/- 9 pM, Bmax = 1.1 +/- 0.3 fmol/mg protein. 4. The ability of picomolar concentrations of melatonin to inhibit forskolin-stimulated adenylate cyclase activity suggests that this affect is mediated by picomolar-affinity receptor binding sites for this hormone in the hypothalamus. 相似文献