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121.
Vít Nov
ek Gavin McGauran David Matallanas Adrin Vallejo Blanco Piero Conca Emir Muoz Luca Costabello Kamalesh Kanakaraj Zeeshan Nawaz Brian Walsh Sameh K. Mohamed Pierre-Yves Vandenbussche Colm J. Ryan Walter Kolch Dirk Fey 《PLoS computational biology》2020,16(12)
Phosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is time-consuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder). 相似文献
122.
Nasreen Naz Ikramullah Khan Bakhtiar Gul Gohar Ayub Farooq Jan Nawaz Jang Muhammad Shuaib 《农业工程》2019,39(1):30-35
A field trail was carried out at the University of Agriculture Peshawar during spring, 2013 in order to evaluate the effect of different levels of phosphorus fertilizer and various planting times on the growth and development of tomato. The main objective of the research work was to investigate the best sowing time for tomato in combination with suitable dose of P fertilizer in order to get maximum yield of tomato in the climatic conditions of Peshawar. RCB Design with split plot arrangements was used in the trail. The main factor (phosphorous levels of 0, 90, 110, 130) was allotted to main plots while sowing dates in sub plots. A total twelve treatment were replicated thrice. Maximum days to flowering (39.583?days) and fruiting (46.167?days) obtained in the late sowing. Minimum days to flowering (39), minimum days to fruiting (38.778?days) were taken by the early sowing. Maximum number of branches (27.778), maximum fruit length (6.0222), maximum fruit with (6.1667), maximum fruit yield (24.653?tons?ha?1) was produced when the plot fertilize with 130?kg?P?ha?1. Maximum number of fruit?plant?1 (29.778) were produced with application of 130?kg?P?ha?1, minimum number of fruits (23.667?cm), fruit width (3.778?cm), fruit length (4.3667?cm), plant height (56.300?cm) were obtained from the controlled treatment. Among the various treatment studied in experiment, it is concluded that early planting of the tomato in the summer season i.e. in the start of March and the use of higher dose of P (130?kg?P?ha?1) is very beneficial for the excellent growth, development and yield of tomato crop. 相似文献
123.
P P Singh S Singh V C Dhawan W Haq K B Mathur G P Dutta R C Srimal B N Dhawan 《Journal of biological regulators and homeostatic agents》1991,5(4):142-146
Methionine-enkephalin (M-Enk) and its analogue compound 82/205 (10(-5) and 10(-6) M) inhibited elaboration of Plasmodium cynomolgi total antigens soluble in culture medium (P.c.SA)-induced colony-stimulating factors (CSFs) by monkey blood monocyte-derived macrophages, in vitro. Paradoxically, lower concentrations (10(-7)-10(-9) M) of both the peptides greatly augmented CSFs elaboration; 82/205 appeared to be nearly 2.3-fold more potent. Naloxone (10(-5) M) pretreatment of macrophages inhibited only the M-Enk- and 82/205-induced enhanced CSFs elaboration, suggesting an opiate receptors-mediated mechanism of action. None of the peptides or naloxone (10(-5)-10(-9) M) had any direct effect on the CSF elaboration by unstimulated macrophages. 相似文献
124.
125.
Saba Haq Soumyadip Das Dong-Ho Kim Arun Pandian Chandrasekaran Seok-Ho Hong Kye-Seong Kim Suresh Ramakrishna 《生物化学与生物物理学报:疾病的分子基础》2019,1865(3):599-610
RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, migration and ultimately augmenting LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to effective cancer therapeutics. 相似文献
126.
Riaz N Nawaz SA Mukhtar N Malik A Afza N Ali S Ullah S Muhammad P Choudhary MI 《化学与生物多样性》2007,4(1):72-83
Bractin A (=(2S,3S,4R,5E)-2-{[(2R)-2-hydroxydodecanoyl]amino}triacont-5-ene-1,3,4-triol; 1) and bractin B (=(2S,3S,4R,5E,8E)-2-{[(2R)-2-hydroxyhexacosanoyl]amino}pentadeca-5,8-diene-3,4,15-triol 1-O-beta-D-glucopyranoside; 2), new sphingolipids, and bractic acid (=(5Z,10Z,15Z)-2-decyl-4,7,8,12,13,17,18-heptahydroxy-20,23-dioxopentacosa-5,10,15-trienoic acid; 3), a long-chain polyhydroxy acid, were isolated from the whole plant Ajuga bracteosa along with four known diterpenoids 4-7. Their structures were deduced by spectral studies including 1D- and 2D-NMR spectroscopy. Compounds 1-3 displayed inhibitory potential against enzyme lipoxygenase, while compounds 4-7 inhibited cholinesterase enzymes in a concentration-dependent manner with IC(50) values in the range 10.0-33.0, 14.0-35.2, and 10.0-19.0 microM for lipoxygenase, acetylcholinesterase, and butyrylcholinesterase, respectively. Lineweaver-Burk, and Dixon plots, and their secondary replots indicated that all compounds exhibit non-competitive type of inhibition with K(i) values in the range of 9.5-35.2, 15.2-36.0, and 11.6-20.5 microM, for lipoxygenase, acetylcholinesterase, and butyrylcholinesterase, respectively. 相似文献
127.
We investigated the effect ofnanoscale topography on neurite development in pheochromocytoma (PC12 cells) by culturing the cells on substrates having nanoscale pillars and pores with sizes comparable with filipodia. We found that cells on nanopillars and nanopores developed fewer and shorter neurites than cells on smooth substrates, and that cells on nanopores developed more and longer neurites than cells on nanopillars. These results suggest that PC12 cells were spatially aware of the difference in the nanoscale structures of the underlying substrates and responded differently in their neurite extension. This finding points to the possibility of using nanoscale topographic features to control neurite development in neurons. 相似文献
128.
Krumschnabel G Maehr T Nawaz M Schwarzbaum PJ Manzl C 《Apoptosis : an international journal on programmed cell death》2007,12(10):1755-1768
Apoptotic cell death in mammalian models is frequently associated with cell shrinkage. Inhibition of apoptotic volume decrease
(AVD) is cytoprotective, suggesting that cell shrinkage is an important early event in apoptosis. In salmonid hepatoma and
gill cells staurosporine induced apoptosis, as assessed by activation of effector caspases, nuclear condensation, and a decrease
of mitochondrial membrane potential (MMP), and these changes were accompanied by cell shrinkage. The Cl− transport inhibitor DIDS and the K+ channel inhibitor quinidine prevented AVD, but only DIDS inhibited apoptosis. Other Cl− flux inhibitors, as well as a pan-caspase inhibitor, did not prevent cell shrinkage, but still prevented caspase activation.
Furthermore, regulatory volume decrease (RVD) under hypotonic conditions was not facilitated, but diminished in apoptotic
cells. Since all transport inhibitors used blocked RVD, but only DIDS and quinidine inhibited AVD, the ion transporters involved
in both processes are apparently not identical. In addition, our data indicate that inhibition of Cl− fluxes rather than blocking cell shrinkage or K+ fluxes is important for preventing apoptosis. In line with this, inhibition of MAP kinases reduced RVD and not AVD, but still
diminished caspase activation. Finally, we observed that MAP kinases were activated upon staurosporine treatment and that
at least activation of ERK was prevented when AVD was inhibited. 相似文献
129.
McDonald CB Buffa L Bar-Mag T Salah Z Bhat V Mikles DC Deegan BJ Seldeen KL Malhotra A Sudol M Aqeilan RI Nawaz Z Farooq A 《Journal of molecular biology》2012,422(1):58-74
The WW-containing oxidoreductase (WWOX) tumor suppressor participates in a diverse array of cellular activities by virtue of its ability to recognize WW-binding protein 1 (WBP1) and WW-binding protein 2 (WBP2) signaling adaptors among a wide variety of other ligands. Herein, using a multitude of biophysical techniques, we provide evidence that while the WW1 domain of WWOX binds to PPXY motifs within WBP1 and WBP2 in a physiologically relevant manner, the WW2 domain exhibits no affinity toward any of these PPXY motifs. Importantly, our data suggest that while R25/W44 residues located within the binding pocket of a triple-stranded β-fold of WW1 domain are critical for the recognition of PPXY ligands, they are replaced by the chemically distinct E66/Y85 duo at structurally equivalent positions within the WW2 domain, thereby accounting for its failure to bind PPXY ligands. Predictably, not only does the introduction of E66R/Y85W double substitution within the WW2 domain result in gain of function but the resulting engineered domain, hereinafter referred to as WW2_RW, also appears to be a much stronger binding partner of WBP1 and WBP2 than the wild-type WW1 domain. We also show that while the WW1 domain is structurally disordered and folds upon ligand binding, the WW2 domain not only adopts a fully structured conformation but also aids stabilization and ligand binding to WW1 domain. This salient observation implies that the WW2 domain likely serves as a chaperone to augment the physiological function of WW1 domain within WWOX. Collectively, our study lays the groundwork for understanding the molecular basis of a key protein-protein interaction pertinent to human health and disease. 相似文献
130.
Abraldes JG Iwakiri Y Loureiro-Silva M Haq O Sessa WC Groszmann RJ 《American journal of physiology. Gastrointestinal and liver physiology》2006,290(5):G980-G987
Increased nitric oxide (NO) is the main factor leading to the hyperdynamic circulation associated with advanced portal hypertension (PHT), but the initial mechanisms and the magnitude of increase in portal pressure required to trigger NO production are not known. We addressed these issues by studying systemic and splanchnic hemodynamics and endothelial NO synthase (eNOS) and VEGF expression in rats with different degrees of portal hypertension. Portal vein ligation (PVL) performed over needles of three different calibers (16-, 18-, and 20-gauge) yielded different degrees of PHT and portosystemic shunting. Compared with sham rats, all three groups of PVL rats exhibited features of hyperdynamic circulation. Rats with minimal portal hypertension (PVL with a 16-gauge needle) showed an early increase in VEGF and eNOS expression selectively at the jejunum. Immunofluorescence showed that VEGF expression was located in highly vascularized areas of the mucosa. Inhibition of VEGF signaling markedly attenuated the increase in eNOS expression. In conclusion, mild increases in portal pressure are enough to upregulate eNOS at the intestinal microcirculation, and this occurs, at least in part, through VEGF upregulation. 相似文献