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Linda O'Reilly Peter Bross Thomas J Corydon Simon E Olpin Jakob Hansen John M Kenney Shawn E McCandless Dianne M Frazier Vibeke Winter Niels Gregersen Paul C Engel Brage Storstein Andresen 《European journal of biochemistry》2004,271(20):4053-4063
Medium-chain acyl-CoA dehydrogenase (MCAD) is a homotetrameric flavoprotein which catalyses the initial step of the beta-oxidation of medium-chain fatty acids. Mutations in MCAD may cause disease in humans. A Y42H mutation is frequently found in babies identified by newborn screening with MS/MS, yet there are no reports of patients presenting clinically with this mutation. As a basis for judging its potential consequences we have examined the protein phenotype of the Y42H mutation and the common disease-associated K304E mutation. Our studies of the intracellular biogenesis of the variant proteins at different temperatures in isolated mitochondria after in vitro translation, together with studies of cultured patient cells, indicated that steady-state levels of the Y42H variant in comparison to wild-type were decreased at higher temperature though to a lesser extent than for the K304E variant. To distinguish between effects of temperature on folding/assembly and the stability of the native enzyme, the thermal stability of the variant proteins was studied after expression and purification by dye affinity chromatography. This showed that, compared with the wild-type enzyme, the thermostability of the Y42H variant was decreased, but not to the same degree as that of the K304E variant. Substrate binding, interaction with the natural electron acceptor, and the binding of the prosthetic group, FAD, were only slightly affected by the Y42H mutation. Our study suggests that Y42H is a temperature sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures. 相似文献
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A unique family of endothelial cell polypeptide mitogens: the antigenic and receptor cross-reactivity of bovine endothelial cell growth factor, brain-derived acidic fibroblast growth factor, and eye-derived growth factor-II 总被引:9,自引:0,他引:9 下载免费PDF全文
A B Schreiber J Kenney J Kowalski K A Thomas G Gimenez-Gallego M Rios-Candelore J Di Salvo D Barritault J Courty Y Courtois 《The Journal of cell biology》1985,101(4):1623-1626
Bovine brain, hypothalamus, pituitary, and retina contain potent anionic polypeptide mitogens for endothelial cells. Immunological assays using murine monoclonal antibodies against bovine endothelial cell growth factor (ECGF) and radioreceptor assays using [125I]ECGF were performed to determine the cross-reactivity of ECGF with bovine acidic pI brain-derived fibroblast growth factor (acidic FGF) and bovine eye-derived growth factor-II [EDGF-II). We observed that acidic FGF and EDGF-II are recognized by anti-ECGF monoclonal antibodies and compete with [125I] ECGF for receptor occupancy. Furthermore, the biological activity of ECGF, acidic FGF, and EDGF-II is potentiated by the glycosaminoglycan, heparin. These results argue that ECGF, acidic FGF, and EDGF-II belong to a common family of polypeptide growth factors. 相似文献
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Kenney MJ Weiss ML Mendes T Wang Y Fels RJ 《American journal of physiology. Heart and circulatory physiology》2003,284(5):H1710-H1720
Autospectral and coherence analyses were used to determine the role of and interactions between paraventricular nucleus (PVN) nitric oxide, gamma-aminobutyric acid (GABA), and the N-methyl-D-aspartic acid (NMDA)-glutamate receptor in regulation of sympathetic nerve discharge (SND) frequency components in anesthetized rats. Four observations were made. First, PVN microinjection of bicuculline (BIC) (GABA(A) receptor antagonist), but not single PVN injections of NMDA (excitatory amino acid) or N(G)-monomethyl-L-arginine (L-NMMA; a nitric oxide synthase inhibitor), altered SND frequency components. Second, combined PVN microinjections of L-NMMA and NMDA changed the SND bursting pattern; however, the observed pattern change was different from that produced by PVN BIC and not observed after sinoaortic denervation. Third, PVN microinjection of kynurenic acid prevented and reversed BIC-induced changes in the SND bursting pattern. Finally, vascular resistance (renal and splenic) was significantly increased after PVN BIC microinjection despite the lack of change in the level of renal and splenic SND. These data demonstrate that the PVN contains the neural substrate for altering SND frequency components and suggest complex interactions between specific PVN neurotransmitters and between PVN neurotransmitters and the arterial baroreceptor reflex in SND regulation. 相似文献
65.
Degroot DW Kenney WL 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,292(1):R103-R108
Aged humans often exhibit an impaired defense of core temperature during cold stress. However, research documenting this response has typically used small subject samples and strong cold stimuli. The purpose of this study was to determine the responses of young and older subjects, matched for anthropometric characteristics, during mild cold stress. Thirty-six young (YS; 23 +/- 1 years, range 18-30) and 46 older (OS; 71 +/- 1 years, range 65-89) subjects underwent a slow transient cold air exposure from a thermoneutral baseline, during which esophageal (T(es)) and mean skin temperatures (T(sk)), O(2) consumption, and skin blood flow (SkBF; laser-Doppler flowmetry) were measured. Cold exposure was terminated at the onset of visible sustained shivering. Net metabolic heat production (M(net)), heat debt, predicted change in midregion temperature (DeltaT(mid)), and tissue insulation (I(t)) were calculated. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial pressure and expressed as percent change from baseline (DeltaCVC(%base)). There were no baseline group differences for T(es), but OS M(net) was lower (OS: 38.0 +/- 1.1; YS: 41.9 +/- 1.1 W . m(-2), P < 0.05). T(es) was well maintained in YS but fell progressively in OS (P < 0.01 for all timepoints after 35 min). The skin vasoconstrictor response to mild cold stress was attenuated in OS (42 +/- 3 vs. 53 +/- 4 DeltaCVC(%base), P < 0.01). There were no group differences for T(sk) or I(t), while M(net) remained lower in OS (P < 0.05). The DeltaT(mid) did not account for the drop in T(es) in OS. Healthy aged humans failed to maintain T(es); however, the mechanisms underlying this response are not clear. 相似文献
66.
Fesselin is a heat stable proline-rich actin binding protein. The stability, amino acid composition, and ability to bind to several proteins suggested that fesselin may be unfolded under native conditions. While the complete sequence of fesselin is unknown an analysis of a closely related protein, synaptopodin 2 from Gallus gallus, indicates that fesselin consists of a series of unstructured regions interspersed between short folded regions. To determine if fesselin is natively unfolded, we compared fesselin to a known globular protein (myosin S1) and a known unfolded protein Cad22 (the COOH terminal 22 kDa fragment of caldesmon). Fesselin, and Cad22, had larger Stokes radii than globular proteins of equivalent mass. The environments of tryptophan residues of fesselin and Cad22 were the same in the presence and absence of 6 M guanidine hydrochloride. Fesselin had a circular dichroism spectrum that was primarily random coil. Changes in pH over the range of 1.5-11.5 did not alter that spectrum. Increasing the temperature to 85 degrees C caused an increase in the degree of secondary structure. Calmodulin binding to fesselin altered the environment of the tryptophan residues so that they became less sensitive to the quencher acrylamide. These results show that fesselin is a natively unfolded protein. 相似文献
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Lang JA Holowatz LA Kenney WL 《American journal of physiology. Regulatory, integrative and comparative physiology》2010,299(6):R1651-R1655
We have recently demonstrated that tetrahydrobiopterin (BH(4)) augments reflex vasoconstriction (VC) in aged skin. Although this appears to occur through its role in norepinephrine (NE) biosynthesis, the extent with which vascular mechanisms are affected are unknown. We hypothesized that localized BH(4) supplementation would not affect the VC response to exogenous NE when sympathetic nerves were blocked. Two microdialysis fibers were placed in bretylium tosylate pretreated (presynaptically blocks neurotransmitter release from sympathetic adrenergic nerve terminals; iontophoresis, 200 μA for 20 min) 3-cm(2) forearm skin of 10 young (Y) and 10 older (O) subjects for perfusion of 1) Ringer (control) and 2) 5 mM BH(4). While local skin temperature was clamped at 34°C, six concentrations of NE (10(-12), 10(-10), 10(-8), 10(-6), 10(-4), 10(-2) M) were infused at each drug-treated site. Cutaneous vascular conductance (CVC) was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to baseline (%ΔCVC(base)). Despite prejunctional adrenergic blockade, NE-mediated VC was blunted in aged skin at each NE dose (10(-12): -12 ± 2 vs. -21 ± 2; 10(-10): -15 ± 2 vs. -27 ± 1; 10(-8): -22 ± 2 vs. -32 ± 2; 10(-6): -27 ± 2 vs. -38 ± 1; 10(-4): -52 ± 3 vs. -66 ± 5; 10(-2): -62 ± 3 vs. -75 ± 4%ΔCVC(base); P < 0.01), and this response was not affected by pretreatment with BH(4) (P > 0.05). Localized BH(4) did not affect end-organ responsiveness to exogenous NE, suggesting that the effects of BH(4) on cutaneous VC are primarily isolated to the NE biosynthetic pathway. 相似文献
70.
Holowatz LA Thompson CS Kenney WL 《American journal of physiology. Heart and circulatory physiology》2006,291(6):H2965-H2970
Full expression of reflex cutaneous vasodilation (VD) is dependent on nitric oxide (NO) and is attenuated in older humans. NO may be decreased by an age-related increase in reactive oxygen species or a decrease in L-arginine availability via upregulated arginase. The purpose of this study was to determine the effect of acute antioxidant supplementation alone and combined with arginase inhibition on reflex VD in aged skin. Eleven young (Y; 22 +/- 1 yr) and 10 older (O; 68 +/- 1 yr) human subjects were instrumented with four intradermal microdialysis (MD) fibers. MD sites were control (Co), NO synthase inhibited (NOS-I), L-ascorbate supplemented (Asc), and Asc + arginase-inhibited (Asc + A-I). After baseline measurements, subjects underwent whole body heating to increase oral temperature (T(or)) by 0.8 degrees C. Red blood cell flux was measured by using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure) and normalized to maximal (CVC(max)). VD during heating was attenuated in O (Y: 37 +/- 3 vs. O: 28 +/- 3% CVC(max); P < 0.05). NOS-I decreased VD in both groups compared with Co (Y: 20 +/- 4; O: 15 +/- 2% CVC(max); P < 0.05 vs. Co within group). Asc and Asc + A-I increased VD beyond Co in O (Asc: 35 +/- 4% CVC(max); Asc + A-I: 41 +/- 3% CVC(max); P < 0.001) but not in Y (Asc: 36 +/- 3% CVC(max); Asc + A-I: 40 +/- 5% CVC(max); P > 0.05). Combined Asc + A-I resulted in a greater increase in VD than Asc alone in O (P = 0.001). Acute Asc supplementation increased reflex VD in aged skin. Asc combined with arginase inhibition resulted in a further increase in VD above Asc alone, effectively restoring CVC to the level of young subjects. 相似文献