全文获取类型
收费全文 | 524篇 |
免费 | 39篇 |
专业分类
563篇 |
出版年
2023年 | 1篇 |
2022年 | 8篇 |
2021年 | 10篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 13篇 |
2017年 | 7篇 |
2016年 | 9篇 |
2015年 | 23篇 |
2014年 | 36篇 |
2013年 | 55篇 |
2012年 | 37篇 |
2011年 | 52篇 |
2010年 | 19篇 |
2009年 | 23篇 |
2008年 | 37篇 |
2007年 | 22篇 |
2006年 | 34篇 |
2005年 | 24篇 |
2004年 | 34篇 |
2003年 | 23篇 |
2002年 | 23篇 |
2001年 | 6篇 |
1999年 | 1篇 |
1998年 | 8篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 5篇 |
1993年 | 6篇 |
1992年 | 2篇 |
1991年 | 3篇 |
1990年 | 1篇 |
1989年 | 7篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有563条查询结果,搜索用时 0 毫秒
91.
Patel SD Habeski WM Min H Zhang J Roof R Snyder B Bora G Campbell B Li C Hidayetoglu D Johnson DS Chaudhry A Charlton ME Kablaoui NM 《Bioorganic & medicinal chemistry letters》2008,18(20):5689-5693
The discovery of the CNS-penetrant and selective alpha(2C) adrenergic receptor antagonist N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-[1,4]diazepan-1-yl]-ethyl}-2-phenoxy-nicotinamide, 13 is described. Structure-activity studies demonstrate the structural requirements for binding affinity, functional activity, and selectivity over other alpha(2)-AR subtypes. 相似文献
92.
Antwi K Mahar M Srikanth R Olbris MR Tyson JF Vachet RW 《Protein science : a publication of the Protein Society》2008,17(4):748-759
beta-2-Microglobulin (beta2m) is deposited as amyloid fibrils in the bones and joints of patients undergoing long-term dialysis treatment as a result of kidney failure. Previous work has shown that biologically relevant amounts of Cu(II) can cause beta2m to be converted to amyloid fibrils under physiological conditions in vitro. In this work, dynamic light scattering, mass spectrometry, and size-exclusion chromatography are used to characterize the role that Cu plays in the formation of oligomeric intermediates that precede fibril formation. Cu(II) is found to be necessary for the stability of the dimer and an initial form of the tetramer. The initially formed tetramer then undergoes a structural change to a state that no longer binds Cu(II) before progressing to a hexameric state. Based on these results, we propose that the lag phase associated with beta2m fibril formation is partially accounted for by the structural transition of the tetramer that results in Cu(II) loss. Consistent with this observation is the determination that the mature beta2m amyloid fibrils do not contain Cu. Thus, Cu(II) appears to play a catalytic role by enabling the organization of the necessary oligomeric intermediates that precede beta2m amyloid formation. 相似文献
93.
To date, the existence of the plant inner membrane anion channel (PIMAC) has been shown only in potato mitochondria, but its physiological role remains unclear. In this study, by means of swelling experiments in K(+) and ammonium salts, we characterize a PIMAC-like anion-conducting pathway in mitochondria from durum wheat (DWM), a monocotyledonous species phylogenetically far from potato. DWM were investigated since they possess a very active potassium channel (PmitoK(ATP)), so implying a very active matching anion uniport pathway and, possibly, a coordinated function. As in potato mitochondria, the electrophoretic uptake of chloride and succinate was inhibited by matrix [H(+)], propranolol, and tributyltin, and was insensitive to Mg(2+), N,N'-dicyclohexylcarbodiimide (DCCD) and mercurials, thus showing PIMAC's existence in DWM. PIMAC actively transports dicarboxylates, oxodicarboxylates, tricarboxylates and Pi. Interestingly, a novel mechanism of swelling in ammonium salts of isolated plant mitochondria is reported, based on electrophoretic anion uptake via PIMAC and ammonium uniport via PmitoK(ATP). PIMAC is inhibited by physiological compounds, such as ATP and free fatty acids, by high electrical membrane potential (Delta Psi), but not by acyl-CoAs or reactive oxygen species. PIMAC was found to cooperate with dicarboxylate carrier by allowing succinate uptake that triggers succinate/malate exchange in isolated DWM. Similar results were obtained using mitochondria from the dicotyledonous species topinambur, so suggesting generalization of results. We propose that PIMAC is normally inactive in vivo due to ATP and Delta Psi inhibition, but activation may occur in mitochondria de-energized by PmitoK(ATP) (or other dissipative systems) to replace or integrate the operation of classical anion carriers. 相似文献
94.
Mathis Hodge Qiao-Hong Chen Susan Bane Shubhada Sharma Maura Loew Abhijit Banerjee Ana A. Alcaraz James P. Snyder David G.I. Kingston 《Bioorganic & medicinal chemistry letters》2009,19(10):2884-2887
A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol?) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation. 相似文献
95.
An Integrated Approach for Experimental Target Identification of Hypoxia-induced miR-210 总被引:1,自引:0,他引:1
96.
Andrea Salis Mani Shankar Bhattacharyya Maura Monduzzi Vincenzo Solinas 《Journal of Molecular Catalysis .B, Enzymatic》2009,57(1-4):262-269
The present work investigates the influence of the support surface on the loading and the enzymatic activity of the immobilized Pseudomonas fluorescens lipase. Different porous materials, polypropylene (Accurel), polymethacrylate (Sepabeads EC-EP), silica (SBA-15 and surface modified SBA-15), and an organosilicate (MSE), were used as supports. The immobilized biocatalysts were compared towards sunflower oil ethanolysis for the sustainable production of biodiesel. Since the supports have very different structural (ordered hexagonal and disordered) and textural features (surface area, pore size, and total pore volume), in order to consider only the effect of the support surface, experiments were performed at low surface coverage. The different functional groups occurring on the support surface allowed either physical (Accurel, MSE, and SBA-15) or chemical adsorption (Sepabeads EC-EP and SBA-15–R-CHO). The surface-modified SBA-15 (SBA-15–R-CHO) allowed the highest loading. The lipase immobilized on the MSE was the most active biocatalyst. However, in terms of catalytic efficiency (activity/loading) the lipase immobilized on the SBA-15, the support that allowed the lowest loading, was the most efficient. 相似文献
97.
14-3-3 proteins are a family of signaling molecules involved in diverse cellular functions, which can mediate anti-apoptotic effects. Seizure-induced neuronal death may involve programmed (apoptotic) cell death pathways and is associated with a decline in brain 14-3-3 levels. Presently, we investigated the subcellular localization and effects of seizures on isoforms of 14-3-3 in rat hippocampus, and contrasted these to findings in human temporal lobe epilepsy (TLE). All brain isoforms of 14-3-3 were detected in the cytoplasmic compartment of rat hippocampus, while 14-3-3gamma and -zeta were also present in mitochondrial and microsome-enriched fractions. Focally evoked seizures in rats significantly reduced 14-3-3gamma levels within the microsome-enriched compartment at 4 h, with similar responses for 14-3-3zeta, while cytoplasm-localized 14-3-3beta, -epsilon and -eta remained unchanged. Analysis of human autopsy control hippocampus revealed similar 14-3-3 isoform expression profiles. In TLE samples, the microsome-enriched fraction also showed differences, but here 14-3-3epsilon and -zeta levels were higher than controls. TLE sample 14-3-3 isoform abundance within the cytoplasmic fraction was not different to controls. This study defines the subcellular localization of 14-3-3 isoforms in rat and human hippocampus and identifies the microsome-enriched fraction as the main site of altered 14-3-3 levels in response to acute prolonged and chronic recurrent seizures. 相似文献
98.
Transglutaminases (TGs) are a large family of related and ubiquitous enzymes that catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In the absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. The TG enzymes are also capable of catalyzing other reactions important for cell viability. The distribution and the physiological roles of TG enzymes have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified. "Tissue" TG (TG2), a member of the TG family of enzymes, has definitely been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology: i.e. celiac disease (CD). TG activity has also been hypothesized to be directly involved in the pathogenetic mechanisms responsible for several other human diseases, including neurodegenerative diseases, which are often associated with CD. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, supranuclear palsy, Huntington's disease and other recently identified polyglutamine diseases, are characterized, in part, by aberrant cerebral TG activity and by increased cross-linked proteins in affected brains. In this review, we discuss the physio-pathological role of TG-catalyzed reactions, with particular interest in the molecular mechanisms that could involve these enzymes in the physio-pathological processes responsible for human neurodegenerative diseases. 相似文献
99.
Laura Azeredo Miranda Mota Jo?o Roberto Neto Ver?nica Gomes Monteiro Caroliny Samary Silva Lobato Marco Antonio de Oliveira Maura da Cunha Heloisa D’ávila Sérgio Henrique Seabra Patrícia Torres Bozza Renato Augusto DaMatta 《Memórias do Instituto Oswaldo Cruz》2014,109(6):767-774
Lipid bodies [lipid droplets (LBs)] are lipid-rich organelles involved in lipid
metabolism, signalling and inflammation. Recent findings suggest a role for LBs in
host response to infection; however, the potential functions of this organelle
in Toxoplasma gondii infection and how it alters macrophage
microbicidal capacity during infection are not well understood. Here, we investigated
the role of host LBs in T. gondii infection in mouse peritoneal
macrophages in vitro. Macrophages cultured with mouse serum (MS) had higher numbers
of LBs than those cultured in foetal bovine serum and can function as a model to
study the role of LBs during intracellular pathogen infection. LBs were found in
association with the parasitophorous vacuole, suggesting that T. gondii
may benefit from this lipid source. Moreover, increased numbers of
macrophage LBs correlated with high prostaglandin E2 (PGE2) production and decreased
nitric oxide (NO) synthesis. Accordingly, LB-enriched macrophages cultured with MS
were less efficient at controlling T. gondii growth. Treatment of
macrophages cultured with MS with indomethacin, an inhibitor of PGE2 production,
increased the microbicidal capacity against T. gondii. Collectively,
these results suggest that culture with MS caused a decrease in microbicidal activity
of macrophages against T. gondii by increasing PGE2 while lowering
NO production. 相似文献
100.
Porta M Zima AV Nani A Diaz-Sylvester PL Copello JA Ramos-Franco J Blatter LA Fill M 《Biophysical journal》2011,100(4):931-938
Caffeine (1, 3, 7-trimethylxanthine) is a widely used pharmacological agonist of the cardiac ryanodine receptor (RyR2) Ca(2+) release channel. It is also a well-known stimulant that can produce adverse side effects, including arrhythmias. Here, the action of caffeine on single RyR2 channels in bilayers and Ca(2+) sparks in permeabilized ventricular cardiomyocytes is defined. Single RyR2 caffeine activation depended on the free Ca(2+) level on both sides of the channel. Cytosolic Ca(2+) enhanced RyR2 caffeine affinity, whereas luminal Ca(2+) essentially scaled maximal caffeine activation. Caffeine activated single RyR2 channels in diastolic quasi-cell-like solutions (cytosolic MgATP, pCa 7) with an EC(50) of 9.0 ± 0.4 mM. Low-dose caffeine (0.15 mM) increased Ca(2+) spark frequency ~75% and single RyR2 opening frequency ~150%. This implies that not all spontaneous RyR2 openings during diastole are associated with Ca(2+) sparks. Assuming that only the longest openings evoke sparks, our data suggest that a spark may result only when a spontaneous single RyR2 opening lasts >6 ms. 相似文献