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Anthony B. Pinkerton Eduard Sergienko Yalda Bravo Russell Dahl Chen-Ting Ma Qing Sun Michael R. Jackson Nicholas D.P. Cosford José Luis Millán 《Bioorganic & medicinal chemistry letters》2018,28(1):31-34
Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo. 相似文献
104.
C Hallbrucker S vom Dahl F Lang W Gerok D H?ussinger 《European journal of biochemistry》1991,199(2):467-474
1. Proteolysis was measured as [3H]leucine release from isolated perfused livers from rats, which had been labeled in vivo by an intraperitoneal injection of [3H]leucine about 16 h prior to the perfusion experiment. In livers from fed rats, insulin (35 nM) inhibited [3H]leucine release by 24.5 +/- 1.3% (n = 15) and led to an amiloride-sensitive, bumetanide-sensitive and furosemide-sensitive net K+ uptake of 5.53 +/- 0.31 mumol.g-1 (n = 15). Both the insulin effects on net K+ uptake and on [3H]leucine release were diminished by about 65% or 55% in presence of furosemide (0.1 mM) or bumetanide (5 microM), respectively. The insulin-induced net K+ uptake was virtually abolished in the presence of amiloride (1 mM) plus furosemide (0.1 mM). 2. In perfused livers from 24-h-starved rats, both the insulin-stimulated net K+ uptake and the insulin-induced inhibition of [3H]leucine release were about 80% lower than observed in experiments with livers from fed rats. The insulin effects on K+ balance and [3H]leucine release were not significantly influenced in the presence of glycine (2 mM), although glycine itself inhibited [3H]leucine release by 30.3 +/- 0.3% (n = 4) and 13.8 +/- 1.2% (n = 5) in livers from starved and fed rats, respectively. When livers from fed rats were preswollen by hypoosmotic perfusion (225 mOsmol.l-1), both the insulin-induced net K+ uptake and the inhibition of [3H]leucine release were diminished by 50-60%. 3. During inhibition of [3H]leucine release by insulin, further addition of glucagon (100 nM) led to a marked net K+ release from the liver (3.82 +/- 0.24 mumol.g-1), which was accompanied by stimulation of [3H]leucine release by 16.4 +/- 4.6% (n = 4). 4. Ba2+ (1 mM) infusion led to a net K+ uptake by the liver of 3.2 +/- 0.2 mumol.g-1 (n = 4) and simultaneously inhibited [3H]leucine release by 12.4 +/- 1.7% (n = 4). 5. There was a close relationship between the Ba2+ or insulin-induced net K+ uptake and the degree of inhibition of [3H]leucine release, even when the K+ response to insulin was modulated by bumetanide, furosemide, glucagon, hypotonic or glycine-induced cell swelling or the nutritional state. 6. The data suggest that the insulin-induced net K+ uptake involves activation of both NaCl/KCl cotransport and Na+/H+ exchange.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
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Megan M. Herting Prapti Gautam Jeffrey M. Spielberg Ronald E. Dahl Elizabeth R. Sowell 《PloS one》2015,10(3)
Sex hormones have been shown to contribute to the organization and function of the brain during puberty and adolescence. Moreover, it has been suggested that distinct hormone changes in girls versus boys may contribute to the emergence of sex differences in internalizing and externalizing behavior during adolescence. In the current longitudinal study, the influence of within-subject changes in puberty (physical and hormonal) on cortical thickness and surface area was examined across a 2-year span, while controlling for age. Greater increases in Tanner Stage predicted less superior frontal thinning and decreases in precuneus surface area in both sexes. Significant Tanner Stage and sex interactions were also seen, with less right superior temporal thinning in girls but not boys, as well as greater decreases in the right bank of the superior temporal sulcus surface area in boys compared to girls. In addition, within-subject changes in testosterone over the 2-year follow-up period were found to relate to decreases in middle superior frontal surface area in boys, but increases in surface area in girls. Lastly, larger increases in estradiol in girls predicted greater middle temporal lobe thinning. These results show that within-subject physical and hormonal markers of puberty relate to region and sex-specific changes in cortical development across adolescence. 相似文献
107.
Emmanuel Bikorimana Danica Lapid Hyewon Choi Richard Dahl 《Journal of visualized experiments : JoVE》2014,(92)
Embryonic stem cells (ESCs) are an outstanding model for elucidating the molecular mechanisms of cellular differentiation. They are especially useful for investigating the development of early hematopoietic progenitor cells (HPCs). Gene expression in ESCs can be manipulated by several techniques that allow the role for individual molecules in development to be determined. One difficulty is that expression of specific genes often has different phenotypic effects dependent on their temporal expression. This problem can be circumvented by the generation of ESCs that inducibly express a gene of interest using technology such as the doxycycline-inducible transgene system. However, generation of these inducible cell lines is costly and time consuming. Described here is a method for disaggregating ESC-derived embryoid bodies (EBs) into single cell suspensions, retrovirally infecting the cell suspensions, and then reforming the EBs by hanging drop. Downstream differentiation is then evaluated by flow cytometry. Using this protocol, it was demonstrated that exogenous expression of a microRNA gene at the beginning of ESC differentiation blocks HPC generation. However, when expressed in EB derived cells after nascent mesoderm is produced, the microRNA gene enhances hematopoietic differentiation. This method is useful for investigating the role of genes after specific germ layer tissue is derived. 相似文献
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Seasonal time constraints can pose strong selection on life histories. Time-constrained animals should prioritise fast development over predation risk to avoid unfavourable growing conditions. However, changes in phenology could alter the balance between anti-predator and developmental needs. We studied variation of anti-predator strategies in common frog (Rana temporaria) tadpoles in four populations from the two extremes of a latitudinal gradient across Sweden. We examined, under common conditions in the laboratory, the anti-predator responses and life histories of tadpoles raised with predatory Aeshna dragonfly larvae in two consecutive years with a difference of 20 days in breeding time in the north, but no difference in breeding time in the nouth. In a year with late breeding, northern tadpoles did not modify their behaviour and morphology in the presence of predators, and metamorphosed faster and smaller than tadpoles born in a year with early breeding. In the year with early breeding, northern tadpoles showed a completely different anti-predator strategy by reducing activity and developing morphological defences in the presence of predators. We discuss the possible mechanisms that could activate these responses (likely a form of environmentally-mediated parental effect). To our knowledge, this is the first study to show that a vertebrate modifies the anti-predator strategy of its offspring in response to natural variation in reproductive phenology, which highlights the need to consider phenology in studies of life-history evolution. 相似文献
110.
The distribution of glial fibrillary acidic (GFA) protein and desmin was compared in cryostat sections of rat brain, spinal cord, and eye by immunofluorescence and peroxidase-antiperoxidase (PAP) staining. Desmin antisera were raised to antigen purified from chicken gizzard. In rat brain and spinal cord, GFA protein and desmin were selectively localized in astrocytes. Neurons and axons were not stained. The only difference between GFA and desmin antisera was the staining of smooth muscle in small arteries with anti-desmin. It was only in retinal glia that a difference in the localization of the two proteins was apparent. As previously reported, only the glia limitans on the inner surface of the retina was demonstrated with GFA antisera in the normal eye. With anti-desmin Müller fibers spanning the whole thickness of the retina were stained. It is concluded that GFA and desmin form two distinct systems of 100 A filaments in astroglia, as previously reported for GFA and vimentin. 相似文献