全文获取类型
收费全文 | 249篇 |
免费 | 22篇 |
专业分类
271篇 |
出版年
2021年 | 7篇 |
2020年 | 9篇 |
2019年 | 14篇 |
2018年 | 6篇 |
2017年 | 12篇 |
2016年 | 12篇 |
2015年 | 11篇 |
2014年 | 9篇 |
2013年 | 9篇 |
2012年 | 13篇 |
2011年 | 12篇 |
2010年 | 9篇 |
2009年 | 8篇 |
2008年 | 6篇 |
2007年 | 9篇 |
2006年 | 13篇 |
2005年 | 6篇 |
2004年 | 8篇 |
2002年 | 7篇 |
2001年 | 2篇 |
2000年 | 8篇 |
1999年 | 5篇 |
1998年 | 10篇 |
1996年 | 2篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 4篇 |
1989年 | 6篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1969年 | 2篇 |
1968年 | 3篇 |
1967年 | 5篇 |
1966年 | 3篇 |
1965年 | 3篇 |
1964年 | 1篇 |
排序方式: 共有271条查询结果,搜索用时 0 毫秒
21.
The purpose of this research was to improve the solubility and therefore dissolution and bioavailability of triamterene, a
poorly water soluble diuretic, by complexation with β-cyclodextrin. Triamterene has been reported to show low bioavailability
after oral administration, with wide intersubject variation. This study presents the formulation of solid dispersions of triamterene
with β-cyclodextrin—by cogrinding, kneading, and coevaporation, using low pH conditions—and their characterizations, evaluation
of improvement in dissolution profiles, and in vivo advantage. Phase solubility studies indicated complex with possible stoichiometry
of 1∶1 and a stability constant of 167.67M−1. The solid dispersions were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, x-ray diffraction,
and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the phenyl ring of triamterene
within the nonpolar cavity of β-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles
in 0.1 N HCl and pH 6.8 phosphate buffer was observed with all dispersions, especially the coevaporate. The coevaporate, when
administered orally in rats, also exhibited improved in vivo activity, as measured by net sodium ion excretion, as compared
with triamterene powder. Thus, coevaporation of the drug and β-cyclodextrin from acidified alcohol provide the optimum condition
for inclusion complexation to give a binary system with remarkable improvement in in vitro drug release profile and in vivo
performance. 相似文献
22.
Vestibular mechanisms involved in idiopathic scoliosis 总被引:2,自引:0,他引:2
Patients affected by idiopathic scoliosis (IS) show not only a spinal deformity, but also postural and oculomotor deficits suggesting that such syndrome can be related to a vestibular disfunction. It appears, however, that, in children, a slight unbalance in the activity of vestibular complex of both sides escapes the neuronal mechanisms responsible for vestibular compensation and leads to the spinal curvature which characterises IS. Such process could be reinforced by a disrupted integration of vestibular and visual signals at cortical level, leading to an altered perception of the vertical and to abnormal motor commands. In addition to the classical ascending and descending pathways arising from the vestibular nuclei, which utilize glutamate or GABA as neurotransmitters, labyrinthine afferents may also affect spinal, cerebellar and cerebrocortical structures, through the noradrenergic and serotoninergic systems, which originate from the locus coeruleus and the raphe nuclei, respectively. Due to the role of these neuromodulators in brain plasticity, a disruption in the activity of monoaminergic neurons could favour the development of postural and oculomotor deficits. An impaired release of monoamine at cerebrocortical level could also explain the cognitive deficits which may occur in IS patients. 相似文献
23.
Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs 总被引:6,自引:0,他引:6
Hypercholesterolemia is considered an important risk factor in coronary artery disease. Thus the possibility of controlling de novo synthesis of endogenous cholesterol, which is nearly two-thirds of total body cholesterol, represents an effective way of lowering plasma cholesterol levels. Statins, fungal secondary metabolites, selectively inhibit hydroxymethyl glutaryl-coenzyme A (HMG-CoA) reductase, the first enzyme in cholesterol biosynthesis. The mechanism involved in controlling plasma cholesterol levels is the reversible inhibition of HMG-CoA reductase by statins, related to the structural similarity of the acid form of the statins to HMG-CoA, the natural substrate of the enzymatic reaction. Currently there are five statins in clinical use. Lovastatin and pravastatin (mevastatin derived) are natural statins of fungal origin, while symvastatin is a semi-synthetic lovastatin derivative. Atorvastatin and fluvastatin are fully synthetic statins, derived from mevalonate and pyridine, respectively. In addition to the principal natural statins, several related compounds, monacolins and dihydromonacolins, isolated fungal intermediate metabolites, have also been characterized. All natural statins possess a common polyketide portion, a hydroxy-hexahydro naphthalene ring system, to which different side chains are linked. The biosynthetic pathway involved in statin production, starting from acetate units linked to each other in head-to-tail fashion to form polyketide chains, has been elucidated by both early biogenetic investigations and recent advances in gene studies. Natural statins can be obtained from different genera and species of filamentous fungi. Lovastatin is mainly produced by Aspergillus terreus strains, and mevastatin by Penicillium citrinum. Pravastatin can be obtained by the biotransformation of mevastatin by Streptomyces carbophilus and simvastatin by a semi-synthetic process, involving the chemical modification of the lovastatin side chain. The hypocholesterolemic effect of statins lies in the reduction of the very low-density lipoproteins (VLDL) and LDL involved in the translocation of cholesterol, and in the increase in the high-density lipoproteins (HDL), with a subsequent reduction of the LDL- to HDL-cholesterol ratio, the best predictor of atherogenic risk. The use of statins can lead to a reduction in coronary events related to hypercholesterolemia, but the relationship between benefit and risk, and any possible interaction with other drugs, must be taken into account. 相似文献
24.
P. Risé S. Ghezzi C. Manzoni C. Colombo C. Galli 《Prostaglandins, leukotrienes, and essential fatty acids》2009,80(1):71-75
BackgroundStatins enhance the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) from their precursors both in vitro and in vivo. In particular, an increased conversion of linoleic acid (LA) and of alpha-linolenic acid to their derivatives is observed in cultured cells. On the contrary, cigarette smoke (CS) negatively and dose-dependently affects the LC-PUFA production.AimTo evaluate the effects of CS alone or with simvastatin, on [1-14C] LA metabolism in THP-1 cells.ResultsCS inhibits LA conversion; after co-incubation, simvastatin nullifies the effects of CS, maintaining LA conversion comparable to controls. However, at the highest CS concentration, simvastatin is unable to counteract the effects of CS. Changes of LA conversion reflect the modulation of desaturase activities by simvastatin and CS.ConclusionCS decreases PUFA conversion and its effects are modulated by the opposite effect of statins. It can be speculated that statin treatments in smoking patients may provide some beneficial effects on PUFA metabolism in addition to lowering cholesterol levels. 相似文献
25.
26.
Giulio Cerullo Cristian Manzoni Larry Lüer Dario Polli 《Photochemical & photobiological sciences》2007,6(2):135-144
In this paper we discuss how to push the temporal resolution limits of transient absorption spectroscopy in order to detect very fast processes (energy relaxation, energy or charge transfer, vibrational coherence) taking place in molecules of biological relevance. After reviewing the main principles of femtosecond pump-probe spectroscopy, we describe an experimental setup based on two synchronized non-collinear optical parametric amplifiers (NOPAs). Each NOPA can be independently configured to generate ultra-broadband sub-10 fs visible pulses, tunable 10-15 fs visible pulses, tunable 15-40 fs near-infrared pulses (900-1500 nm). This system enables to perform pump-probe experiments over nearly two octaves of spectrum with sub-20 fs temporal resolution. We then present an application example highlighting the capability of this instrument to track excited state dynamics in biomolecules on the sub-100 fs timescale: the study of carotenoid-bacteriochlorophyll energy transfer processes in peripheral light-harvesting complexes (LH2) from purple bacteria. We show that, by comparing excited-state dynamics of the carotenoids in organic solvents and inside the LH2 complexes, it is possible to visualize in the time domain the primary events in photosynthesis. 相似文献
27.
EC Costa A Moreira B Cavalcanti K Krinski MS Aoki 《Biology of sport / Institute of Sport》2015,32(1):35-40
The present study investigated the effect of unilateral and bilateral resistance exercise (RE) on maximal voluntary strength, total volume of load lifted (TVLL), rating of perceived exertion (RPE) and blood lactate concentration of resistance-trained males. Twelve healthy men were assessed for the leg extension one-repetition maximum (1RM) strength using bilateral and unilateral contractions. Following this assessment, an RE session (3 sets of repetitions to failure) was conducted with bilateral and unilateral (both limbs) contractions using a load of 50% 1RM. The TVLL was calculated by the product of the number of repetitions and the load lifted per repetition. RPE and blood lactate were measured before, during and after each set. Session RPE was measured 30 minutes after RE sessions. There was a significant difference in the bilateral (120.0±11.9) and unilateral (135.0±20.2 kg) 1RM strength (p < 0.05). The TVLL was similar between both RE sessions. Although the repetitions decreased with each successive set, the total number of repetitions completed in the bilateral protocol (48) was superior to the unilateral (40) protocol (p < 0.05). In both bouts, RPE increased with each subsequent set whilst blood lactate increased after set 1 and thereafter remained stable (p < 0.05). The RPE and lactate responses were not significantly different between both sessions. In conclusion, a bilateral deficit in leg extension strength was confirmed, but the TVLL was similar between both RE sessions when exercising to voluntary fatigue. This outcome could be attributed to the number of repetitions completed in the unilateral RE bout. The equal TVLL would also explain the similar perceptual and metabolic responses across each RE session. 相似文献
28.
Manzoni C Colombo L Bigini P Diana V Cagnotto A Messa M Lupi M Bonetto V Pignataro M Airoldi C Sironi E Williams A Salmona M 《PloS one》2011,6(9):e24909
Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1-40 and Aβ 1-42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity. 相似文献
29.
Bassi MT Manzoni M Bresciani R Pizzo MT Della Monica A Barlati S Monti E Borsani G 《Gene》2005,350(2):173-182
Phospholipase D (PLD) is a ubiquitous enzyme in eukaryotes that participates in various cellular processes. Its catalytic domain is characterized by two HKD motifs in the C-terminal part. Until now, two subfamilies were recognized based on their N-terminal domain structure. The first has a PX domain in combination with a PH domain and is designated as PXPH-PLD. Members of the second subfamily, named C2-PLD, have a C2 domain and have, so far, only been found in plants. Here we describe a novel PLD subfamily that we identified in Phytophthora, a genus belonging to the class oomycetes and comprising many important plant pathogens. We cloned Pipld1 from Phytophthora infestans and retrieved full-length sequences of its homologues from Phytophthora sojae and Phytophthora ramorum genome databases. Their promoters contain two putative regulatory elements, one of which is highly conserved in all three genes. The three Phytophthora pld1 genes encode nearly identical proteins of around 1807 amino acids, with the two characteristic HKD motifs in the C-terminal part. Homology of the predicted proteins with known PLDs however is restricted to the two catalytic HKD motifs and adjacent domains. In the N-terminal part Phytophthora PLD1 has a PX-like domain, but it lacks a PH domain. Instead the N-terminal region contains five putative membrane spanning domains suggesting that Phytophthora PLD1 is a transmembrane protein. Since Phytophthora PLD1 cannot be categorized in one of the two existing subfamilies we propose to create a novel subfamily named PXTM-PLD. 相似文献
30.
Manzoni M Monti E Bresciani R Bozzato A Barlati S Bassi MT Borsani G 《FEBS letters》2004,567(2-3):219-224
Mucolipin-1 is a 65-kDa membrane protein encoded by the MCOLN1 gene, which is mutated in patients with mucolipidosis type IV (MLIV), a rare neurodegenerative lysosomal storage disorder. We studied the subcellular localization of wild-type and three different mutant forms (T232P, F408del and F465L) of mucolipin by expressing Myc-tagged proteins in HeLa cells. The overexpressed wild-type mucolipin colocalizes to late endocytic structures and induces an aberrant distribution of these compartments. F408del and F465L MLIV mutant proteins show a distribution similar to the wild-type protein, whereas T232P is retained in the endoplasmic reticulum. Among the mutants, only F408del induces a redistribution of the late endocytic compartment. These findings suggest that the overexpression of the mucolipin cation channel influences the dynamic equilibrium of late endocytic compartments. 相似文献