全文获取类型
收费全文 | 1042篇 |
免费 | 98篇 |
出版年
2021年 | 15篇 |
2020年 | 8篇 |
2019年 | 16篇 |
2018年 | 22篇 |
2017年 | 17篇 |
2016年 | 25篇 |
2015年 | 45篇 |
2014年 | 38篇 |
2013年 | 49篇 |
2012年 | 67篇 |
2011年 | 86篇 |
2010年 | 55篇 |
2009年 | 45篇 |
2008年 | 51篇 |
2007年 | 73篇 |
2006年 | 52篇 |
2005年 | 64篇 |
2004年 | 54篇 |
2003年 | 48篇 |
2002年 | 47篇 |
2001年 | 10篇 |
2000年 | 6篇 |
1999年 | 10篇 |
1998年 | 15篇 |
1997年 | 20篇 |
1996年 | 9篇 |
1995年 | 9篇 |
1993年 | 10篇 |
1992年 | 10篇 |
1991年 | 6篇 |
1990年 | 9篇 |
1989年 | 4篇 |
1987年 | 8篇 |
1985年 | 10篇 |
1984年 | 9篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1977年 | 8篇 |
1974年 | 5篇 |
1973年 | 4篇 |
1972年 | 5篇 |
1971年 | 7篇 |
1969年 | 6篇 |
1968年 | 5篇 |
1965年 | 4篇 |
1963年 | 3篇 |
1960年 | 4篇 |
排序方式: 共有1140条查询结果,搜索用时 15 毫秒
91.
Mala Isrie Martin Breuss Guoling Tian Andi?Harley Hansen Francesca Cristofoli Jasmin Morandell Zachari?A. Kupchinsky Alejandro Sifrim Celia?Maria Rodriguez-Rodriguez Elena?Porta Dapena Kurston Doonanco Norma Leonard Faten Tinsa Stéphanie Moortgat Hakan Ulucan Erkan Koparir Ender Karaca Nicholas Katsanis Valeria Marton Joris?Robert Vermeesch Erica?E. Davis Nicholas?J. Cowan David?Anthony Keays Hilde Van?Esch 《American journal of human genetics》2015,97(6):790-800
Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect. 相似文献
92.
Heather Miller Thiago Castro-Gomes Matthias Corrotte Christina Tam Timothy K. Maugel Norma W. Andrews Wenxia Song 《The Journal of cell biology》2015,211(6):1193-1205
Cells rapidly repair plasma membrane (PM) damage by a process requiring Ca2+-dependent lysosome exocytosis. Acid sphingomyelinase (ASM) released from lysosomes induces endocytosis of injured membrane through caveolae, membrane invaginations from lipid rafts. How B lymphocytes, lacking any known form of caveolin, repair membrane injury is unknown. Here we show that B lymphocytes repair PM wounds in a Ca2+-dependent manner. Wounding induces lysosome exocytosis and endocytosis of dextran and the raft-binding cholera toxin subunit B (CTB). Resealing is reduced by ASM inhibitors and ASM deficiency and enhanced or restored by extracellular exposure to sphingomyelinase. B cell activation via B cell receptors (BCRs), a process requiring lipid rafts, interferes with PM repair. Conversely, wounding inhibits BCR signaling and internalization by disrupting BCR–lipid raft coclustering and by inducing the endocytosis of raft-bound CTB separately from BCR into tubular invaginations. Thus, PM repair and B cell activation interfere with one another because of competition for lipid rafts, revealing how frequent membrane injury and repair can impair B lymphocyte–mediated immune responses. 相似文献
93.
María B Mazzucco Laura B Talarico Sezen Vatansever Ana C Carro Mirta L Fascio Norma B D’Accorso Cybele C García Elsa B Damonte 《Journal of biomedical science》2015,22(1)
Background
Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized.Results
The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 μM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 μM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2.Conclusions
The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis. 相似文献94.
Norma Espinoza-Herrera Ruth Pedroza-Islas Eduardo San Mart��n-Martinez Alfredo Cruz-Orea Sergio Armando Tom��s 《Food biophysics》2011,6(1):106-114
The proposal in this study was to evaluate the physical properties of different biopolymers films. The materials used were:
pectin, carboxyl methylcellulose, methylcellulose, hydroxyl propylcellulose, hydroxypropyl-methylcellulose, and corn waxy
starch; from these polysaccharides aqueous dispersions were prepared to 3% (w/v) for obtained films. In these biopolymer films, the thermal diffusivities (α) was evaluated by the Open Photoacoustic Cell
method; also, their mechanical properties as tensile strength, elongation, and Young’s modulus were measured, their crystallinity
percentage was evaluated by X-ray diffraction and microstructure through atomic force microscopy in contact mode. From the
polysaccharide films, it was observed that most of them were flexible and transparent. In the case of the films, mechanical
properties were found that the highest value of tensile strength and Young’s modulus corresponded to carboxyl methylcellulose
with 69.17 and 1,912.20 MPa values, respectively. Also, Open Photoacoustic Cell method and X-ray diffraction measurements
showed that there exist a correlation between the thermal diffusivity values and the crystallinity measured in the biopolymer
films. It was also observed that α values of cellulose derived was affected by the substitution group in the molecule, reaching
the highest α value, the films of carboxyl methylcellulose. Regarding the microstructural of the films, starch showed the
highest roughness value (88.6 nm) whereas hydroxypropyl-methylcellulose resulted with the lowest roughness value (7.67 nm). 相似文献
95.
Uribe-Carvajal S Luévano-Martínez LA Guerrero-Castillo S Cabrera-Orefice A Corona-de-la-Peña NA Gutiérrez-Aguilar M 《Mitochondrion》2011,11(3):382-390
Mitochondria from diverse species can undergo a massive permeability increase known as the permeability transition, a process first thought to be an artifact. It is currently accepted that in the inner mitochondrial membrane there is a Mitochondrial Unselective Channel (MUC), also known as the permeability transition pore. Regardless of the species, MUC opening leads to uncoupling of oxidative phosphorylation. In each species, MUC regulation appears to be different, probably as a result of the adaptation of each organism to its specific environment. To date, the components and the putative physiological role of MUCs are still a matter of debate. Current hypothesis suggests that proteins normally participating in diverse metabolic functions constitute MUCs. Among these proteins, the Adenine Nucleotide Translocase and the phosphate carrier have been proposed as putative MUC components in mammalian and yeast mitochondria. In this review, the characteristics of MUCs from different species and strains are discussed. The data from the literature reinforce the current notion that these channels are preserved through evolution albeit with different control factors. We emphasize the knowledge available of Mitochondrial Unselective Channels from different yeast species. 相似文献
96.
Gutiérrez-Pérez RM Flores-Holguín N Glossmann-Mitnik D Rodriguez-Valdez LM 《Journal of molecular modeling》2011,17(8):1963-1972
The electronic and structural properties of pyrrolic ring derivatives were studied using density functional theory (DFT) in
terms of their application as organic semiconductor materials in photovoltaic devices. The B3LYP hybrid functional in combination
with Pople type 6-31G(d) basis set with a polarization function was used in order to determine the optimized geometries and
the electronic properties of the ground state, while transition energies and excited state properties were obtained from time-dependent
(TD)-DFT with B3LYP/6-31G(d) calculation. The investigation of pyrrolic derivatives formed by the arrangement of several monomeric
units revealed that three-dimensional (3D) conjugated architectures in which the combination of a triphenylamine (TPA) core
with π-conjugated rings attached to the core, present the best geometric and electronic characteristics for use as an organic
semiconductor material. The highest occupied molecular orbital (HOMO) − lowest unoccupied molecular orbital (LUMO) energy
gap was decreased in 3D-structures that extend the absorption spectrum toward longer wavelengths, revealing a feasible intramolecular
charge transfer process in these systems. All calculations in this work were performed using the Gaussian 03 W software package. 相似文献
97.
98.
Hong E Larios F Gómez-Viquez NL Huang F Bravo G 《Journal of physiology and biochemistry》2011,67(3):427-435
The contribution of α-adrenoceptors and nitric oxide (NO) on the alterations of sympathetically mediated cardiovascular responses
after acute (AcH) and chronic (ChH) hypertension was evaluated in pithed aortic coarcted hypertensive rats. Pressor and tachycardia
response produced by electrical stimulation of preganglionic sympathetic fibers or exogenous noradrenaline (NA) were recorded
in the absence and presence of prazosin (α1-antagonist), rauwolscine (α2-antagonist), or N
G-nitro-l-arginine methyl ester (l-NAME; an inhibitor of NO synthase). Compared with age-matched sham-operated rats (Nt), the pressor response produced by electrical
stimulation or NA was smaller in AcH rats and larger in ChH rats. Prazosin caused a decrease of pressor response elicited
by electrical stimulation or NA in all groups. However, this effect was higher in ChH. Rauwolscine produced a similar increase
of sympathetically mediated pressor response in Nt and AcH rats. Nevertheless, this antagonist did not affect the sympathetically
mediated pressor response in ChH rats. In addition, rauwolscine did not affect the NA-induced pressor response in all groups.
The pressor response elicited by l-NAME was larger in all groups compared without l-NAME and in presence of l-arginine. Moreover, l-NAME in the presence of NA increased sympathetically mediated pressor response is in all groups, compared without it or in
the presence of l-arginine. Compared with Nt, basally produced NO in aortic rings was increased in AcH but decreased in ChH. Collectively,
our data suggest that decreased cardiovascular reactivity in AcH is due to an increase in basally produced NO. In ChH, enhanced
cardiovascular response appears to be associated with a decrease in produced NO and an increase in released NA from sympathetic
nerves. 相似文献
99.
Corina M. Fusari Verónica V. Lia Verónica Nishinakamasu Jeremías E. Zubrzycki Andrea F. Puebla Alberto E. Maligne H. Esteban Hopp Ruth A. Heinz Norma B. Paniego 《Molecular breeding : new strategies in plant improvement》2011,28(1):73-89
Single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) are increasingly used for cultivar identification,
construction of genetic maps, genetic diversity assessment, association mapping and marker-assisted breeding. Although there
are several highly sensitive methods for the detection of polymorphisms, most of them are often beyond the budget of medium-throughput
academic laboratories or seed companies. Heteroduplex analysis by enzymatic cleavage (CEL1CH) or denaturing high-performance
liquid chromatography (dHPLC) has been successfully used to examine genetic variation in several plant and animal species.
In this work, we assess and compare the performance of both methods in sunflower by genotyping SNPs from a set of 24 selected
polymorphic candidate genes. The CEL1CH method allowed us to accurately detect allele differences in 10 out of 24 regions
using an in-house prepared CEL1 enzyme (celery single strand endonuclease 1, Apium graveolens L.). Similarly, a total of 11 regions were successfully optimized for dHPLC analysis. As a scaling-up approach, both strategies
were tested to genotype either 42 SNPs/indels in 22 sunflower accessions from the local germplasm bank or 33 SNPs/indels in
90 recombinant inbred lines (RILs) for genetic mapping purposes. Summarizing, a total of 601 genotypes were efficiently analyzed
either with CEL1CH (110) or dHPCL (491). In conclusion, CEL1CH and dHPLC proved to be robust, complementary methods, allowing
medium-scale laboratories to scale up the number of both SNPs and individuals to be included in genetic studies and targeted
germplasm diversity characterization (EcoTILLING). 相似文献
100.
Comparative proteomics of seed maturation in oilseeds reveals differences in intermediary metabolism 总被引:1,自引:0,他引:1
Proteomics is increasingly being used to understand enzyme expression and regulatory mechanisms involved in the accumulation of storage reserves in crops with sequenced genomes. During the past six years, considerable progress has been made to characterize proteomes of both mature and developing seeds, particularly oilseeds - plants which accumulate principally oil and protein as storage reserves. This review summarizes the emerging proteomics data, with emphasis on seed filling in soy, rapeseed, castor and Arabidopsis as each of these oilseeds were analyzed using very similar proteomic strategies. These parallel studies provide a comprehensive view of source-sink relationships, specifically sucrose assimilation into organic acid intermediates for de novo amino acid and fatty acid synthesis. We map these biochemical processes for seed maturation and illustrate the differences and similarities among the four oilseeds. For example, while the four oilseeds appear capable of producing cytosolic phosphoenolpyruvate as the principal carbon intermediate, soybean and castor also express malic enzymes and malate dehydrogenase, together capable of producing malate that has been previously proposed to be the major intermediate for fatty acid synthesis in castor. We discuss these and other differences in the context of intermediary metabolism for developing oilseeds. 相似文献