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131.
Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome 总被引:6,自引:0,他引:6
Windpassinger C Auer-Grumbach M Irobi J Patel H Petek E Hörl G Malli R Reed JA Dierick I Verpoorten N Warner TT Proukakis C Van den Bergh P Verellen C Van Maldergem L Merlini L De Jonghe P Timmerman V Crosby AH Wagner K 《Nature genetics》2004,36(3):271-276
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration. 相似文献
132.
Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis 总被引:11,自引:0,他引:11
Hellemans J Preobrazhenska O Willaert A Debeer P Verdonk PC Costa T Janssens K Menten B Van Roy N Vermeulen SJ Savarirayan R Van Hul W Vanhoenacker F Huylebroeck D De Paepe A Naeyaert JM Vandesompele J Speleman F Verschueren K Coucke PJ Mortier GR 《Nature genetics》2004,36(11):1213-1218
Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells. 相似文献
133.
Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using standard transposon insertion-deletion approaches. We also targeted an engineered green fluorescent protein insertion-replacement cassette to one of these genes, thereby confirming that custom alleles of different types can be created in vitro to make the corresponding mutations in vivo. This approach should also be applicable to heterologous transposons in C. elegans and other organisms, including vertebrates. 相似文献
134.
135.
Signal sequences target proteins for secretion from cells or for integration into cell membranes. As nascent proteins emerge from the ribosome, signal sequences are recognized by the signal recognition particle (SRP), which subsequently associates with its receptor (SR). In this complex, the SRP and SR stimulate each other's GTPase activity, and GTP hydrolysis ensures unidirectional targeting of cargo through a translocation pore in the membrane. To define the mechanism of reciprocal activation, we determined the 1.9 A structure of the complex formed between these two GTPases. The two partners form a quasi-two-fold symmetrical heterodimer. Biochemical analysis supports the importance of the extensive interaction surface. Complex formation aligns the two GTP molecules in a symmetrical, composite active site, and the 3'OH groups are essential for association, reciprocal activation and catalysis. This unique circle of twinned interactions is severed twice on hydrolysis, leading to complex dissociation after cargo delivery. 相似文献
136.
137.
Kiepiela P Leslie AJ Honeyborne I Ramduth D Thobakgale C Chetty S Rathnavalu P Moore C Pfafferott KJ Hilton L Zimbwa P Moore S Allen T Brander C Addo MM Altfeld M James I Mallal S Bunce M Barber LD Szinger J Day C Klenerman P Mullins J Korber B Coovadia HM Walker BD Goulder PJ 《Nature》2004,432(7018):769-775
The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design. 相似文献
138.
Wet periods in northeastern Brazil over the past 210 kyr linked to distant climate anomalies 总被引:1,自引:0,他引:1
Wang X Auler AS Edwards RL Cheng H Cristalli PS Smart PL Richards DA Shen CC 《Nature》2004,432(7018):740-743
The tropics are the main source of the atmosphere's sensible and latent heat, and water vapour, and are therefore important for reconstructions of past climate. But long, accurately dated records of southern tropical palaeoclimate, which would allow the establishment of climatic connections to distant regions, have not been available. Here we present a 210,000-year (210-kyr) record of wet periods in tropical northeastern Brazil--a region that is currently semi-arid. The record is obtained from speleothems and travertine deposits that are accurately dated using the U/Th method. We find wet periods that are synchronous with periods of weak East Asian summer monsoons, cold periods in Greenland, Heinrich events in the North Atlantic and periods of decreased river runoff to the Cariaco basin. We infer that the wet periods may be explained with a southward displacement of the Intertropical Convergence Zone. This widespread synchroneity of climate anomalies suggests a relatively rapid global reorganization of the ocean-atmosphere system. We conclude that the wet periods probably affected rainforest distribution, as plant fossils show that forest expansion occurred during these intermittent wet intervals, and opened a forest corridor between the Amazonian and Atlantic rainforests. 相似文献
139.
The interface between silicon and a high-k oxide 总被引:1,自引:0,他引:1
The ability of the semiconductor industry to continue scaling microelectronic devices to ever smaller dimensions (a trend known as Moore's Law) is limited by quantum mechanical effects: as the thickness of conventional silicon dioxide (SiO(2)) gate insulators is reduced to just a few atomic layers, electrons can tunnel directly through the films. Continued device scaling will therefore probably require the replacement of the insulator with high-dielectric-constant (high-k) oxides, to increase its thickness, thus preventing tunnelling currents while retaining the electronic properties of an ultrathin SiO(2) film. Ultimately, such insulators will require an atomically defined interface with silicon without an interfacial SiO(2) layer for optimal performance. Following the first reports of epitaxial growth of AO and ABO(3) compounds on silicon, the formation of an atomically abrupt crystalline interface between strontium titanate and silicon was demonstrated. However, the atomic structure proposed for this interface is questionable because it requires silicon atoms that have coordinations rarely found elsewhere in nature. Here we describe first-principles calculations of the formation of the interface between silicon and strontium titanate and its atomic structure. Our study shows that atomic control of the interfacial structure by altering the chemical environment can dramatically improve the electronic properties of the interface to meet technological requirements. The interface structure and its chemistry may provide guidance for the selection process of other high-k gate oxides and for controlling their growth. 相似文献
140.