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81.
A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy 总被引:4,自引:0,他引:4
Langton KP McKie N Curtis A Goodship JA Bond PM Barker MD Clarke M 《The Journal of biological chemistry》2000,275(35):27027-27031
Sorsby's fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies. 相似文献
82.
Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes 总被引:1,自引:0,他引:1
Lewis RJ Nielsen KJ Craik DJ Loughnan ML Adams DA Sharpe IA Luchian T Adams DJ Bond T Thomas L Jones A Matheson JL Drinkwater R Andrews PR Alewood PF 《The Journal of biological chemistry》2000,275(45):35335-35344
omega-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta(3) in Xenopus oocytes. However, the potency of CVID and MVIIA increased when alpha(1B-d) and alpha(1B-b) were expressed in the absence of rat beta(3), an effect most pronounced for CVID at alpha(1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined. 相似文献
83.
Koltunow Anna M. Brennan Peter Bond James E. Barker Susan J. 《Molecular breeding : new strategies in plant improvement》1998,4(3):235-251
Seedlessness is a highly desirable characteristic in fresh fruit. Marketability of a fruit as seedless does not require complete absence of seeds as long as the seed structures are imperceptible during consumption. Chimaeric genes comprised of soybean -conglycinin seed storage protein gene promoters linked to the bacterial RNase gene, Barnase, were tested for their efficacy to cause seed death and decrease seed size in tobacco and Arabidopsis. These species were used because they undergo two distinct seed developmental pathways and produce albuminous and exalbuminous seeds, respectively. In both species, the death of embryo and endosperm tissues occurred, resulting in a dominant seed lethal phenotype with segregation distortion. Reduction in seed size was only observed in Arabidopsis seeds and the phenotype resembled that of stenospermocarpic seeds in grape. Some transformants of both species were male-sterile and this correlated with the expression of the gene in anthers indicating that expression of the gene is not strictly seed-specific. The promoters also direct expression of a linked GUS gene to Citrus embryos of various developmental stages, and Citrus forms exalbuminous seeds, therefore, the Barnase constructions may be useful in eliciting a reduction in seed size of around 75% of the seeds found in the fruit. This may be sufficient to warrant marketing as less seedy if trials in the cultivar of interest indicate that the smaller seeds are less detectable to the consumer. Abbreviations: GUS, -glucuronidase; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; DTA, diphtheria toxin-A chain; CFDA, 5(6)-carboxy-fluorescein di-acetate; CG, -conglycinin; DAP, days after pollination; FAA, formaldehyde-acetic acid alcohol fixative. 相似文献
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L R Bond S R Hatty M E Horn M Dick H B Meire A J Bellingham 《BMJ (Clinical research ed.)》1987,295(6592):234-236
The prevalence of gall stones was studied prospectively by abdominal ultrasound examination in 131 patients with sickle cell disease aged 10-65 years. Of 95 patients with homozygous sickle cell disease, 55 (58%) had gall stones or had had a cholecystectomy. Gall stones were present in four out of 24 (17%) patients with haemoglobin S + C disease and two out of 12 (17%) with haemoglobin S beta thalassaemia. The presence of gall stones was not related to sex, geographical origin, or haematological variables and was not associated with abnormal results of liver function tests. Symptoms typical of biliary colic were reported by 32 out of 47 adult patients with gall stones, and cholecystitis or cholestasis was diagnosed in 18. Cholecystectomy was performed in 29 patients with good relief of symptoms in most cases. Postoperative complications were common, occurring in 10 of the 28 patients who could be evaluated, but not generally serious; they were considerably lessened by a preoperative exchange transfusion that reduced the haemoglobin S concentration to below 40%. It is suggested that all patients with sickle cell disease should be screened for gall stones and that elective cholecystectomy should be performed in those with symptoms or complications. 相似文献
89.
The Cape Fynbos region of South Africa, a global biodiversity hotspot, hosted a diverse large mammal fauna till shortly after
permanent European settlement (1652). How these animals survived in this exceptionally nutrient-poor environment is puzzling
and it is generally believed that they restricted their movements to the more fertile shale areas. We tested the hypothesis
that large herbivores avoid nutrient-poor limestone and sandstone fynbos shrublands in favour of shale-derived renosterveld
vegetation using strontium (Sr) isotope analysis. If this technique could reconstruct the preferred feeding habitats of the
contemporary fauna, it might also be useful for reconstructing the preferred feeding grounds of an extinct fauna. Using the
assumption that small rodents have spatially restricted foraging activities, we determined the 87Sr/86Sr isotope ratios of rodent teeth to establish the isotopic signal characteristic of the different geological substrates in
the area. We then analysed 87Sr/86Sr isotope ratios in the bones of a number of different large herbivores found in De Hoop Nature Reserve using laser ablation
multi-collector inductively coupled plasma mass spectrometry. These values were compared to the bioavailable (rodent) values
on the respective geological substrates. The technique identified differences in feeding substrate selection between different
species and groups of the same species. The results also showed that shale renosterveld shrubland is not the exclusive source
of nutrition for the large herbivores. Strikingly different isotope ratios among individuals in some populations pointed to
significant dispersal events from distant sources. However, we were unable to pinpoint the exact feeding areas using Sr isotope
analysis probably because some animals use a combination of substrates for feeding and because the geology of the study area
is complex with graded isotope signals. We suggest that this technique is a valuable additional tool for exploring large mammal
foraging behaviour on habitats associated with contrasting and less complex geology. 相似文献
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