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171.
GABA is the major inhibitory neurotransmitter in the nervous system and acts at a variety of receptors including GABAC receptors, which are a subclass of GABAA receptors. Here we have used molecular dynamics simulations of GABA docked into the extracellular domain of the GABAC receptor to explain the molecular interactions of the neurotransmitter with the residues that contribute to the binding site; in particular, we have explored the interaction of GABA with Arg104. The simulations suggest that the amine group of GABA forms cation-π interactions with Tyr102 and Tyr198, and hydrogen-bonds with Gln83, Glu220, Ser243, and Ser168, and, most prominently, with Arg104. Substituting Arg104 with Ala, Glu, or Lys, which experimentally disrupt GABAC receptor function, and repeating the simulation revealed fewer and different bonding patterns with GABA, or the rapid exit of GABA from the binding pocket. The simulations therefore unveil interactions of GABA within the binding pocket, and explain experimental data, which indicate that Arg104 is critical for the efficient functioning of the receptor. 相似文献
172.
Kanadia RN Clark VE Punzo C Trimarchi JM Cepko CL 《Development (Cambridge, England)》2008,135(23):3923-3933
Alternative splicing is the primary mechanism by which a limited number of protein-coding genes can generate proteome diversity. We have investigated the role of the alternative-splicing factor Sfrs1, an arginine/serine-rich (SR) protein family member, during mouse retinal development. Loss of Sfrs1 function during embryonic retinal development had a profound effect, leading to a small retina at birth. In addition, the retina underwent further degeneration in the postnatal period. Loss of Sfrs1 function resulted in the death of retinal neurons that were born during early to mid-embryonic development. Ganglion cells, cone photoreceptors, horizontal cells and amacrine cells were produced and initiated differentiation. However, these neurons subsequently underwent cell death through apoptosis. By contrast, Sfrs1 was not required for the survival of the neurons generated later, including later-born amacrine cells, rod photoreceptors, bipolar cells and Müller glia. Our results highlight the requirement of Sfrs1-mediated alternative splicing for the survival of retinal neurons, with sensitivity defined by the window of time in which the neuron was generated. 相似文献
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Moretto N Bolchi A Rivetti C Imbimbo BP Villetti G Pietrini V Polonelli L Del Signore S Smith KM Ferrante RJ Ottonello S 《The Journal of biological chemistry》2007,282(15):11436-11445
Immunotherapy against the amyloid-beta (Abeta) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of Abeta, and yet be capable of eliciting antibodies that recognize Abeta fibrils and neurotoxic Abeta oligomers but not the physiological monomeric species of Abeta. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide Abeta1-15 (Abeta15) within the active site loop of bacterial thioredoxin (Trx). Chimeric Trx(Abeta15)n polypeptides bearing one, four, or eight copies of Abeta15 were constructed and injected into mice in combination with alum, an adjuvant approved for human use. All three polypeptides were found to be immunogenic, yet eliciting antibodies with distinct recognition specificities. The anti-Trx(Abeta15)4 antibody, in particular, recognized Abeta42 fibrils and oligomers but not monomers and exhibited the same kind of conformational selectivity against transthyretin, an amyloidogenic protein unrelated in sequence to Abeta. We have also demonstrated that anti-Trx(Abeta15)4, which binds to human AD plaques, markedly reduces Abeta pathology in transgenic AD mice. The data indicate that a conformational epitope shared by oligomers and fibrils can be mimicked by a thioredoxin-constrained Abeta fragment repeat and identify Trx(Abeta15)4 as a promising new tool for AD immunotherapy. 相似文献
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Aquaporins and plant water balance 总被引:4,自引:0,他引:4
Kaldenhoff R Ribas-Carbo M Sans JF Lovisolo C Heckwolf M Uehlein N 《Plant, cell & environment》2008,31(5):658-666
The impact of aquaporin function on plant water balance is discussed. The significance of these proteins for root water uptake, water conductance in the xylem, including embolism refilling and the role of plant aquaporins in leaf physiology, is described. Emphasis is placed on certain aspects of water stress reactions and the correlation of aquaporins to abscisic acid as well as on the relation of water and CO2 permeability in leaves. 相似文献
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Giovanni?Luca?Gravina William?Senapedis Dilara?McCauley Erkan?Baloglu Sharon?Shacham Claudio?FestucciaEmail author 《Journal of hematology & oncology》2014,7(1):85
Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer. 相似文献
179.
Culturally supported accumulation (or ratcheting) of technological complexity is widely seen as characterizing hominin technology relative to that of the extant great apes, and thus as representing a threshold in cultural evolution. To explain this divide, we modeled the process of cultural accumulation of technology, which we defined as adding new actions to existing ones to create new functional combinations, based on a model for great ape tool use. The model shows that intraspecific and interspecific variation in the presence of simple and cumulative technology among extant orangutans and chimpanzees is largely due to variation in sociability, and hence opportunities for social learning. The model also suggests that the adoption of extensive allomaternal care (cooperative breeding) in early Pleistocene Homo, which led to an increase in sociability and to teaching, and hence increased efficiency of social learning, was enough to facilitate technological ratcheting. Hence, socioecological changes, rather than advances in cognitive abilities, can account for the cumulative cultural changes seen until the origin of the Acheulean. The consequent increase in the reliance on technology could have served as the pacemaker for increased cognitive abilities. Our results also suggest that a more important watershed in cultural evolution was the rise of donated culture (technology or concepts), in which technology or concepts was transferred to naïve individuals, allowing them to skip many learning steps, and specialization arose, which allowed individuals to learn only a subset of the population's skills. 相似文献
180.