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131.
132.
José Luis Trillo-Contreras Reposo Ramírez-Lorca Laura Hiraldo-González Ismael Sánchez-Gomar Ana Galán-Cobo Nela Suárez-Luna Eva Sánchez de Rojas-de Pedro Juan José Toledo-Aral Javier Villadiego Miriam Echevarría 《生物化学与生物物理学报:疾病的分子基础》2018,1864(10):3515-3526
Aquaporin-4, present in ependymal cells, in glia limiting and abundantly in pericapillary astrocyte foot processes, and aquaporin-1, expressed in choroid plexus epithelial cells, play an important role in cerebrospinal fluid production and may be involved in the pathophysiology of age-dependent hydrocephalus. The finding that brain aquaporins expression is regulated by low oxygen tension led us to investigate how hypoxia and elevated levels of cerebral aquaporins may result in an increase in cerebrospinal fluid production that could be associated with a hydrocephalic condition. Here we have explored, in young and aged mice exposed to hypoxia, whether aquaporin-4 and aquaporin-1 participate in the development of age-related hydrocephalus. Choroid plexus, striatum, cortex and ependymal tissue were analyzed separately both for mRNA and protein levels of aquaporins. Furthermore, parameters such as total ventricular volume, intraventricular pressure, cerebrospinal fluid outflow rate, ventricular compliance and cognitive function were studied in wild type, aquaporin-1 and aquaporin-4 knock-out animals subjected to hypoxia or normoxia. Our data demonstrate that hypoxia is involved in the development of age-related hydrocephalus by a process that depends on aquaporin-4 channels as a main route for cerebrospinal fluid movement. Significant increases in aquaporin-4 expression that occur over the course of animal aging, together with a reduced cerebrospinal fluid outflow rate and ventricular compliance, contribute to produce more severe hydrocephalus related to hypoxic events in aged mice, with a notable impairment in cognitive function. These results indicate that physiological events and/or pathological conditions presenting with cerebral hypoxia/ischemia contribute to the development of chronic adult hydrocephalus. 相似文献
133.
Tomasz Maciej Stepniewski Mariona Torrens-Fontanals Ismael Rodríguez-Espigares Toni Giorgino Karoline G. Primdahl Anders Vik Yngve Stenstrøm Jana Selent Trond Vidar Hansen 《Bioorganic & medicinal chemistry》2018,26(12):3580-3587
The oxoeicosanoid receptor 1 (OXER1) is a member of the G-protein coupled receptors (GPCR) family, and is involved in inflammatory processes and oncogenesis. As such it is an attractive target for pharmacological intervention. The present study aimed to shed light on the molecular fundaments of OXER1 modulation using chemical probes structurally related to the natural agonist 5-oxo-ETE. In a first step, 5-oxo-ETE and its closely related derivatives (5-oxo-EPE and 4-oxo-DHA) were obtained by conducting concise and high-yielding syntheses. The biological activity of obtained compounds was assessed in terms of potency (EC50) and efficacy (Emax) for arrestin recruitment. Finally, molecular modelling and simulation were used to explore binding characteristics of 5-oxo-ETE and derivatives with the aim to rationalize biological activity. Our data suggest that the tested 5-oxo-ETE derivatives (i) insert quickly into the membrane, (ii) access the receptor via transmembrane helices (TMs) 5 and 6 from the membrane side and (iii) drive potency and efficacy by differential interaction with TM5 and 7. Most importantly, we found that the methyl ester of 5-oxo-ETE (1a) showed even a higher maximum response than the natural agonist (1). In contrast, shifting the 5-oxo group into position 4 results in inactive compounds (4-oxo DHA compounds (3) and (3a)). All in all, our study provides relevant structural data that help understanding better OXER1 functionality and its modulation. The structural information presented herein will be useful for designing new lead compounds with desired signalling profiles. 相似文献
134.
Purification and characterization of ryanotoxin, a peptide with actions similar to those of ryanodine.
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We purified and characterized ryanotoxin, an approximately 11.4-kDa peptide from the venom of the scorpion Buthotus judiacus that induces changes in ryanodine receptors of rabbit skeletal muscle sarcoplasmic reticulum analogous to those induced by the alkaloid ryanodine. Ryanotoxin stimulated Ca2+ release from sarcoplasmic reticulum vesicles and induced a state of reduce unit conductance with a mean duration longer than that of unmodified ryanodine receptor channels. With Cs+ as the current carrier, the slope conductance of the state induced by 1 microM ryanotoxin was 163 +/- 12 pS, that of the state induced by 1 microM ryanodine was 173 +/- 26 pS, and that of control channels was 2.3-fold larger (396 +/- 25 pS). The distribution of substate events induced by 1 microM RyTx was biexponential and was fitted with time constants approximately 10 times shorter than those fitted to the distribution of substates induced by 1 microM ryanodine. Bath-applied 5 microM ryanotoxin had no effect on the excitability of mouse myotubes in culture. When 5 microM ryanotoxin was dialyzed into the cell through the patch pipette in the whole-cell configuration, there was a voltage-dependent increase in the amplitude of intracellular Ca2+ transients elicited by depolarizing potentials in the range of -30 to +50 mV. Ryanotoxin increased the binding affinity of [3H]ryanodine in a reversible manner with a 50% effective dose (ED50) of 0.16 microM without altering the maximum number (Bmax) of [3H]ryanodine-binding sites. This result suggested that binding sites for ryanotoxin and ryanodine were different. Ryanotoxin should prove useful in identifying domains coupling the ryanodine receptor to the voltage sensor, or domains affecting the gating and conductance of the ryanodine receptor channel. 相似文献
135.
Raed Yaseen H. Pushpalatha G. Bhanuprakash Reddy Ameer Ismael Ayad Ahmed Alhamza Dheyaa 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1415-1427
Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I–XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III–XI, XIV–XVII, XIX–XXIV, XXVI and XXVIII–XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III–VI, XII, XVI–XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242?μM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs. 相似文献
136.
Effects of hydropriming treatments on the invigoration of aged Dodonaea viscosa seeds and water‐holding polymer on the improvement of seedling growth in a lava field
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Luis V. Pedrero‐López Alejandra Rosete‐Rodríguez Maria E. Sánchez‐Coronado Pedro E. Mendoza‐Hernández Alma Orozco‐Segovia 《Restoration Ecology》2016,24(1):61-70
Restoration requires techniques similar to those used in agriculture to improve germination and seedling vigor. We treated 6‐year‐old (collected in 2003, S‐2003) and 1‐month‐old (S‐2009) seeds of Dodonaea viscosa with hydropriming (HP). Seeds were made permeable with hot water prior to hydration for 24 or 48 hours (HP‐24 and HP‐48, respectively) followed by dehydration. The resulting seedlings exposed to both HP treatments were sown in a lava field in soil mixed with hydrogel (HG) under the shade projected by five vegetation patches. The effects of these treatments on germination, seedling field survival, and growth were assessed. HP‐24 in S‐2009 and HP‐48 in S‐2003 increased the germination percentage from 22.5 and 31.7% in control seeds (permeable seeds) to 63.3 and 98.3%, respectively. The seedlings‐2009 (from S‐2009) with HG maintained high survival in all vegetation patches. Seedlings‐2003, however, had low survival. The lack of HG was negatively related to the photon flux in each patch. Survival of seedlings‐2009 increased with HG of up to 398.41 µmol m?2 s?1; after which survival decreased. During the rainy season, HP enhanced seedling growth, except the basal diameters and number of leaves in the seedlings‐2003 with HP‐24. During the dry season, the effects of HG and HP were similar for all the seedlings. In the following rainy season, the priming effect was lost while HG continued to promote seedling growth. The combined use of HP and HG and the shade projected by the patches resulted in a successful vegetation recovery strategy. 相似文献
137.
Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor 总被引:10,自引:0,他引:10
138.
Sidedness of reconstituted calcium channels from muscle transverse tubules as determined by D600 and D890 blockade. 总被引:5,自引:0,他引:5
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The verapamil-type calcium antagonist, D600, and its charged quaternary derivative, D890, were used to assess the sidedness of blockade in single calcium channels reconstituted from purified transverse tubules of skeletal muscle. Spontaneous single channel openings were induced with the agonist Bay-K8644 and recordings were made in a two-chamber planar bilayer setup so that drugs could be delivered to either side of the channel. Micromolar drug addition resulted in a greater than 10-fold decrease in probability of open channel events (po) without a significant change in single channel currents. Changes in po occurred in parallel with changes in mean open time and both parameters could be titrated with a similar IC50. At pH 7.2, cis or trans D600 blocked with an IC50 of 5 microM but for D890 the IC50 was cis 3 microM and trans greater than 75 microM (cis is the intracellular-equivalent side as defined by the voltage-dependent activation). The asymmetry of D890 blockade indicates that the drug can readily gain access to the blocking site from the aqueous phase adjacent to the inner but not extracellular end of the channel. 相似文献
139.
Phospholipid bilayers were made from phospholipid monolayers at the air/water interface on patch-clamp pipettes. Lipid bilayers were characterized using the K+ carrier nonactin and the channel formers gramicidin and alamethicin. Bilayers were also formed from monolayers spontaneously assembled in a suspension of native vesicles from cardiac sarcolemma and lobster axonal membranes and an excess of lipids. In these types of bilayers we observed several different channels including one contained in the axonal membrane that shows delayed rectifier behavior. This technique permits the study of reconstituted channels on a time scale and noise comparable to cellular patch-clamp standards. 相似文献
140.
Ionic selectivity, saturation, and block in a K+-selective channel from sarcoplasmic reticulum 总被引:18,自引:11,他引:7
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The open-channel conductance properties of a voltage-gated channel from sarcoplasmic reticulum were studied in planar phospholipid membranes. The channel is ideally selective for K+ over Cl- and for K+ over Ca++. In symmetrical 1 M solutions, the single-channel conductance (in pmho) falls in the order: K+ (214) > NH4+ (157) > Rb+ (125) > Na+ (72) > La+ (8.1) > Cs+ (< 3). In neutral bilayers, the channel conductance saturates with ion activity according to a rectangular hyperbolic relation, with half-saturation activities of 54 mM for K+ and 34 mM for Na+. Under symmetrical salt conditions, the K+:Na+ channel conductance ratio increases with salt activity, but the permeability ratio, measured by single-channel bi-ionic potentials, is constant between 20 mM and 2.5 M salt; the permeability ratio is equal to the conductance ratio in the limit of low-salt concentration. The channel conductance varies < 5% in the voltage range -100 to +70 mV. The maximum conductance varies K+ and Na+ is only weakly temperature dependent (delta H++ = 4.6 and 5.3 kcal/mol, respectively), but that of Li+ varies strongly with temperature (delta H++ = 13 kcal/mol). The channel's K+ conductance is blocked asymmetrically by Cs+, and this block is competitive with K+. The results are consistent with an Eyring-type barriers as it permeates the channel. The data conform to Lüger's (1973. Biochem. Biophys. Acta. 311:423-441) predictions for a "pure" single-ion channel. 相似文献