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81.
Manoja K. Brahma Rene C. Adam Nina M. Pollak Doris Jaeger Kathrin A. Zierler Nadja P?cher Renate Schreiber Matthias Romauch Tarek Moustafa Sandra Eder Thomas Ruelicke Karina Preiss-Landl Achim Lass Rudolf Zechner Guenter Haemmerle 《Journal of lipid research》2014,55(11):2229-2241
Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis. 相似文献
82.
Phosphorus (P) flux from wetland soil can be a significant factor affecting overall wetland treatment performance. The purpose of our study was to quantify the effects of water level drawdown on P exchange between surface water and organic soil in a constructed wetland. We used 12 fiberglass mesocosms filled with 30 cm of peat soil to quantify nutrient exchange between surface water and organic soil in a wet-dry-wet cycle. Six mesocosms were planted with emergent macrophytes and six mesocosms were maintained free of emergent vegetation. We evaluated four treatments including continuously and intermittently flooded treatments, both with and without emergent macrophytes. Each treatment was replicated three times and every mesocosm was plumbed to monitor flow volumes and water chemistry. Effluent P concentrations were similar for all four treatments prior to first drawdown period. However, upon re-flooding, all intermittently flooded tanks exhibited a three to fourfold increase in surface water P concentration, which lasted for a period of up to ten weeks. The magnitude of nutrient flux to surface water and the time period over which P release took place were season dependent, with longer duration of high nutrient flux during dry-season drawdowns. Results of repeated measures analysis indicated that hydropattern was the dominant factor affecting P-flux to overlying surface water, while presence or absence of emergent vegetation had no significant influence on effluent concentrations. Organic and particulate phosphorus fluxes were substantially higher in treatments lacking emergent macrophytes, subsequent to the dry-season drawdowns. Intermittently flooded treatments with no emergent vegetation generated the most dissolved and particulate phosphorus. Our results indicate that maintaining saturated soil is sufficient to retain stored P, while plants played no significant role in P retention for a wetland receiving P-loading rate on the order of 0.1 g week−1 during a wet-dry-wet cycle. 相似文献
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Asier González Mitsugu Shimobayashi Tobias Eisenberg David Adrian Merle Tobias Pendl Michael N. Hall Tarek Moustafa 《PloS one》2015,10(3)
The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved sensor of nutrient availability. Genetic and pharmacological studies in the yeast Saccharomyces cerevisiae have provided mechanistic insights on the regulation of TORC1 signaling in response to nutrients. Using a highly specific antibody that recognizes phosphorylation of the bona fide TORC1 target ribosomal protein S6 (Rps6) in yeast, we found that nutrients rapidly induce Rps6 phosphorylation in a TORC1-dependent manner. Moreover, we demonstrate that Ypk3, an AGC kinase which exhibits high homology to human S6 kinase (S6K), is required for the phosphorylation of Rps6 in vivo. Rps6 phosphorylation is completely abolished in cells lacking Ypk3 (ypk3Δ), whereas Sch9, previously reported to be the yeast ortholog of S6K, is dispensable for Rps6 phosphorylation. Phosphorylation-deficient mutations in regulatory motifs of Ypk3 abrogate Rps6 phosphorylation, and complementation of ypk3Δ cells with human S6 kinase restores Rps6 phosphorylation in a rapamycin-sensitive manner. Our findings demonstrate that Ypk3 is a critical component of the TORC1 pathway and that the use of a phospho-S6 specific antibody offers a valuable tool to identify new nutrient-dependent and rapamycin-sensitive targets in vivo. 相似文献
85.
Pragathi Priyadharsini Balasubramani V. Srinivasa Chakravarthy Manal Ali Balaraman Ravindran Ahmed A. Moustafa 《PloS one》2015,10(6)
Impulsivity, i.e. irresistibility in the execution of actions, may be prominent in Parkinson''s disease (PD) patients who are treated with dopamine precursors or dopamine receptor agonists. In this study, we combine clinical investigations with computational modeling to explore whether impulsivity in PD patients on medication may arise as a result of abnormalities in risk, reward and punishment learning. In order to empirically assess learning outcomes involving risk, reward and punishment, four subject groups were examined: healthy controls, ON medication PD patients with impulse control disorder (PD-ON ICD) or without ICD (PD-ON non-ICD), and OFF medication PD patients (PD-OFF). A neural network model of the Basal Ganglia (BG) that has the capacity to predict the dysfunction of both the dopaminergic (DA) and the serotonergic (5HT) neuromodulator systems was developed and used to facilitate the interpretation of experimental results. In the model, the BG action selection dynamics were mimicked using a utility function based decision making framework, with DA controlling reward prediction and 5HT controlling punishment and risk predictions. The striatal model included three pools of Medium Spiny Neurons (MSNs), with D1 receptor (R) alone, D2R alone and co-expressing D1R-D2R. Empirical studies showed that reward optimality was increased in PD-ON ICD patients while punishment optimality was increased in PD-OFF patients. Empirical studies also revealed that PD-ON ICD subjects had lower reaction times (RT) compared to that of the PD-ON non-ICD patients. Computational modeling suggested that PD-OFF patients have higher punishment sensitivity, while healthy controls showed comparatively higher risk sensitivity. A significant decrease in sensitivity to punishment and risk was crucial for explaining behavioral changes observed in PD-ON ICD patients. Our results highlight the power of computational modelling for identifying neuronal circuitry implicated in learning, and its impairment in PD. The results presented here not only show that computational modelling can be used as a valuable tool for understanding and interpreting clinical data, but they also show that computational modeling has the potential to become an invaluable tool to predict the onset of behavioral changes during disease progression. 相似文献
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Moustafa Algamal Julijana Milojevic Naeimeh Jafari William Zhang Giuseppe Melacini 《Biophysical journal》2013
Human serum albumin (HSA) is a potent inhibitor of Aβ self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer’s disease. It is known that HSA interacts with Aβ oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-Aβ interactions beyond domain resolution. Here, we map the HSA-Aβ interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits Aβ self-association. We also show that fatty acids (FAs) compete with Aβ oligomers for binding to domain 3, but the determinant of the HSA/Aβ oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for Aβ oligomer recognition. Specifically, we identified a site of Aβ oligomer recognition that spans the HSA (494–515) region and aligns with the central hydrophobic core of Aβ. The HSA (495–515) segment includes residues affected by FA binding and this segment is prone to self-associate into β-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of Aβ self-association. 相似文献
89.
Alaa M. H. El-Bitar Moustafa Sarhan Mohamed A. Abdel-Rahman Veronica Quintero-Hernandez Chie Aoki-Utsubo Mohsen A. Moustafa Lourival D. Possani Hak Hotta 《International journal of peptide research and therapeutics》2020,26(2):811-821
Growing global viral infections have been a serious public health problem in recent years. This current situation emphasizes the importance of developing m 相似文献
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