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91.
92.
Federico Riu Roberta Ibba Stefano Zoroddu Simona Sestito Michele Lai Sandra Piras Luca Sanna Valentina Bordoni Luigi Bagella Antonio Carta 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):2223
Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents.Results: A novel series of 4′-fluoro-substituted ligands (5–13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability.Discussion: The 4′-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration. 相似文献
93.
Sandra Soo-Jin Lee Stephanie M. Fullerton Caitlin E. McMahon Michael Bentz Aliya Saperstein Melanie Jeske Emily Vasquez Nicole Foti Larissa Saco Janet K. Shim 《The Yale journal of biology and medicine》2022,95(3):317
Scientists have identified a “diversity gap” in genetic samples and health data, which have been drawn predominantly from individuals of European ancestry, as posing an existential threat to the promise of precision medicine. Inadequate inclusion as articulated by scientists, policymakers, and ethicists has prompted large-scale initiatives aimed at recruiting populations historically underrepresented in biomedical research. Despite explicit calls to increase diversity, the meaning of diversity – which dimensions matter for what outcomes and why – remain strikingly imprecise. Drawing on our document review and qualitative data from observations and interviews of funders and research teams involved in five precision medicine research (PMR) projects, we note that calls for increasing diversity often focus on “representation” as the goal of recruitment. The language of representation is used flexibly to refer to two objectives: achieving sufficient genetic variation across populations and including historically disenfranchised groups in research. We argue that these dual understandings of representation are more than rhetorical slippage, but rather allow for the contemporary collection of samples and data from marginalized populations to stand in as correcting historical exclusion of social groups towards addressing health inequity. We trace the unresolved historical debates over how and to what extent researchers should procure diversity in PMR and how they contributed to ongoing uncertainty about what axes of diversity matter and why. We argue that ambiguity in the meaning of representation at the outset of a study contributes to a lack of clear conceptualization of diversity downstream throughout subsequent phases of the study. 相似文献
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Bonacchi A Taddei ML Petrai I Efsen E Defranco R Nosi D Torcia M Rosini P Formigli L Rombouts K Zecchi S Milani S Pinzani M Laffi G Marra F 《Histology and histopathology》2008,23(3):327-340
The liver represents a site of expression of neurotrophins and their receptors. We have characterized the expression and intracellular localization of the nerve growth factor (NGF) receptor, Trk-A, in liver cells in vivo and in vitro. In both normal and fibrotic liver tissue, Trk-A immunostaining was present in different cell types, including parenchymal cells and cells of the inflammatory infiltrate. In hepatocytes and activated stellate cells (HSC), Trk-A showed a predominant nuclear localization, both in the presence and absence of injury. In cultured HSC, Trk-A was found to be functional, because exposure of the cells to recombinant NGF resulted in stimulation of cell migration and activation of intracellular signaling pathways, including Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC, Trk-A staining was found constitutively in the nucleus. In these cells, Trk-A could be stained only by antibodies directed against the intracellular domain but not by those recognizing the extracellular portion of Trk-A suggesting that the intracellular portion of the receptor is the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not show any nuclear localization of the intracellular portion of Trk-A. In pheocromocytoma cells, nuclear staining for Trk-A was not present in conditions of serum deprivation, but could be induced by exposure to NGF or to a mixture of soluble mediators. We conclude that nuclear localization of the intracellular domain of Trk-A is observed constitutively in liver cells such as HSC, while in other cell types it could be induced in response to soluble factors. 相似文献
96.
A unified framework to model the potential and realized distributions of invasive species within the invaded range 下载免费PDF全文
Tarek Hattab Carol X. Garzón‐López Michael Ewald Sandra Skowronek Raf Aerts Hélène Horen Boris Brasseur Emilie Gallet‐Moron Fabien Spicher Guillaume Decocq Hannes Feilhauer Olivier Honnay Pieter Kempeneers Sebastian Schmidtlein Ben Somers Ruben Van De Kerchove Duccio Rocchini Jonathan Lenoir 《Diversity & distributions》2017,23(7):806-819
97.
Solar radiation and functional traits explain the decline of forest primary productivity along a tropical elevation gradient 下载免费PDF全文
Nikolaos M. Fyllas Lisa Patrick Bentley Alexander Shenkin Gregory P. Asner Owen K. Atkin Sandra Díaz Brian J. Enquist William Farfan‐Rios Emanuel Gloor Rossella Guerrieri Walter Huaraca Huasco Yoko Ishida Roberta E. Martin Patrick Meir Oliver Phillips Norma Salinas Miles Silman Lasantha K Weerasinghe Joana Zaragoza‐Castells Yadvinder Malhi 《Ecology letters》2017,20(6):730-740
One of the major challenges in ecology is to understand how ecosystems respond to changes in environmental conditions, and how taxonomic and functional diversity mediate these changes. In this study, we use a trait‐spectra and individual‐based model, to analyse variation in forest primary productivity along a 3.3 km elevation gradient in the Amazon‐Andes. The model accurately predicted the magnitude and trends in forest productivity with elevation, with solar radiation and plant functional traits (leaf dry mass per area, leaf nitrogen and phosphorus concentration, and wood density) collectively accounting for productivity variation. Remarkably, explicit representation of temperature variation with elevation was not required to achieve accurate predictions of forest productivity, as trait variation driven by species turnover appears to capture the effect of temperature. Our semi‐mechanistic model suggests that spatial variation in traits can potentially be used to estimate spatial variation in productivity at the landscape scale. 相似文献
98.
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Van Bergen NJ Crowston JG Kearns LS Staffieri SE Hewitt AW Cohn AC Mackey DA Trounce IA 《PloS one》2011,6(6):e21347
Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies. 相似文献
100.
Predator-induced phenotypic plasticity is widespread among aquatic animals, however the relative contributions of behavioral and morphological shifts to reducing risk of predation remain uncertain. We tested the phenotypic plasticity of a Neotropical tadpole (Rana palmipes) in response to chemical cues from predatory Belostoma water bugs, and how phenotype affects risk of predation. Behavior, morphology, and pigmentation all were plastic, resulting in a predator-induced phenotype with lower activity, deeper tail fin and muscle, and darker pigmentation. Tadpoles in the predator cue treatment also grew more rapidly, possibly as a result of the nutrient subsidy from feeding the caged predator. For comparison to phenotypes induced in the experiment, we quantified the phenotype of tadpoles from a natural pool. Wild-caught tadpoles did not match either experimentally induced phenotype; their morphology was more similar to that produced in the control treatment, but their low swimming activity was similar to that induced by predator cues. Exposure of tadpoles from both experimental treatments and the natural pool to a free-ranging predator confirmed that predator-induced phenotypic plasticity reduces risk of predation. Risk of predation was comparable among wild-caught and predator-induced tadpoles, indicating that behavioral shifts can substantially alleviate risk in tadpoles that lack the typical suite of predator-induced morphological traits. The morphology observed in wild-caught tadpoles is associated with rapid growth and high competition in other tadpole species, suggesting that tadpoles may profitably combine a morphology suited to competition for food with behaviors that minimize risk of predation. 相似文献