全文获取类型
收费全文 | 28863篇 |
免费 | 82篇 |
国内免费 | 158篇 |
专业分类
系统科学 | 139篇 |
丛书文集 | 499篇 |
教育与普及 | 42篇 |
理论与方法论 | 100篇 |
现状及发展 | 13451篇 |
研究方法 | 1278篇 |
综合类 | 13198篇 |
自然研究 | 396篇 |
出版年
2013年 | 269篇 |
2012年 | 411篇 |
2011年 | 809篇 |
2010年 | 168篇 |
2008年 | 523篇 |
2007年 | 576篇 |
2006年 | 576篇 |
2005年 | 535篇 |
2004年 | 538篇 |
2003年 | 498篇 |
2002年 | 499篇 |
2001年 | 936篇 |
2000年 | 865篇 |
1999年 | 615篇 |
1992年 | 595篇 |
1991年 | 414篇 |
1990年 | 486篇 |
1989年 | 494篇 |
1988年 | 460篇 |
1987年 | 546篇 |
1986年 | 474篇 |
1985年 | 596篇 |
1984年 | 484篇 |
1983年 | 364篇 |
1982年 | 340篇 |
1981年 | 367篇 |
1980年 | 462篇 |
1979年 | 889篇 |
1978年 | 757篇 |
1977年 | 740篇 |
1976年 | 611篇 |
1975年 | 632篇 |
1974年 | 845篇 |
1973年 | 756篇 |
1972年 | 779篇 |
1971年 | 840篇 |
1970年 | 1073篇 |
1969年 | 813篇 |
1968年 | 820篇 |
1967年 | 795篇 |
1966年 | 681篇 |
1965年 | 472篇 |
1964年 | 156篇 |
1959年 | 249篇 |
1958年 | 440篇 |
1957年 | 292篇 |
1956年 | 259篇 |
1955年 | 246篇 |
1954年 | 239篇 |
1948年 | 162篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
871.
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis 总被引:21,自引:0,他引:21
Palmer CN Irvine AD Terron-Kwiatkowski A Zhao Y Liao H Lee SP Goudie DR Sandilands A Campbell LE Smith FJ O'Regan GM Watson RM Cecil JE Bale SJ Compton JG DiGiovanna JJ Fleckman P Lewis-Jones S Arseculeratne G Sergeant A Munro CS El Houate B McElreavey K Halkjaer LB Bisgaard H Mukhopadhyay S McLean WH 《Nature genetics》2006,38(4):441-446
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease. 相似文献
872.
Greenway MJ Andersen PM Russ C Ennis S Cashman S Donaghy C Patterson V Swingler R Kieran D Prehn J Morrison KE Green A Acharya KR Brown RH Hardiman O 《Nature genetics》2006,38(4):411-413
We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration. 相似文献
873.
Foser S Redwanz I Ebeling M Heizmann CW Certa U 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2387-2396
A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-alpha and TGF-beta, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes. 相似文献
874.
Wang X Rochon M Lamprokostopoulou A Lünsdorf H Nimtz M Römling U 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2352-2363
Commensal Escherichia coli form biofilms at body temperature by expressing the extracellular matrix components curli fimbriae and cellulose. The role of curli fimbriae and cellulose in the interaction of commensal E. coli with the intestinal epithelial cell line HT-29 was investigated. Expression of curli fimbriae by the typical commensal isolate E. coli TOB1 caused adherence and internalization of the bacteria and triggered IL-8 production in HT-29 cells. In particular, induction of IL-8 production was complex and involved curli-bound flagellin. While cellulose alone had no effect on the interaction of TOB1 with HT-29 cells, co-expression of cellulose with curli fimbriae decreased adherence to, internalization and IL-8 induction of HT-29 cells. Investigation of a panel of commensal isolates showed a partial correlation between expression of curli fimbriae and enhanced internalization and IL-8 production. In addition, a high immunostimulatory flagellin was identified. Thus, the consequences of expression of extracellular matrix components on commensal bacterial-host interactions are complex. 相似文献
875.
Epigenetic asymmetry of imprinted genes in plant gametes 总被引:12,自引:0,他引:12
Gutiérrez-Marcos JF Costa LM Dal Prà M Scholten S Kranz E Perez P Dickinson HG 《Nature genetics》2006,38(8):876-878
Plant imprinted genes show parent-of-origin expression in seed endosperm, but little is known about the nature of parental imprints in gametes before fertilization. We show here that single differentially methylated regions (DMRs) correlate with allele-specific expression of two maternally expressed genes in the seed and that one DMR is differentially methylated between gametes. Thus, plants seem to have developed similar strategies as mammals to epigenetically mark imprinted genes. 相似文献
876.
The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders. 相似文献
877.
Huet J Wyckmans J Wintjens R Boussard P Raussens V Vandenbussche G Ruysschaert JM Azarkan M Looze Y 《Cellular and molecular life sciences : CMLS》2006,63(24):3042-3054
Two chitinases, able to use tetra-N-acetylglucosamine, chitin and chitosan as substrates, were characterized after purification from Carica papaya latex. The complete amino acid sequence of the major form and about 40% of the minor one were determined through proteolytic
digestions and mass spectroscopy analysis. Sequencing demonstrated that both papaya chitinases are members of the family 19
of glycosyl hydrolases (GH19). Based on the known 3-D structures of other members of family GH19, it was expected that papaya
chitinases would adopt all-alpha structures. However, circular dichroism and infrared spectroscopy indicated, for the papaya
chitinases, a content of 15–20% of extended structures besides the expected 40% of alpha helices. Since the fully sequenced
papaya chitinase contains a large number of proline residues the possibility that papaya chitinase contains polyproline II
stretches was examined in the context of their resistance against proteolytic degradation.
Received 11 July 2006; received after revision 13 October 2006; accepted 25 October 2006 相似文献
878.
The use of anti-5-methylcytosine antibodies in affinity columns allowed the identification of methylated sequences in the
genome of Drosophila melanogaster adults. In view of the presence of transposable elements amongst the identified sequences, it has been suggested that DNA
methylation is involved in transposon control in the fly genome. On the contrary, a reanalysis of these data furnishes several
intriguing elements that could raise new questions about the role that DNA methylation plays in the fly genome. The aim of
the present paper is to discuss some features that emerge from the analysis of the identified methylated sequences.
Received 26 January 2006; received after revision 8 May 2006; accepted 2 June 2006 相似文献
879.
Myelin basic protein: a multifunctional protein 总被引:1,自引:1,他引:0
Boggs JM 《Cellular and molecular life sciences : CMLS》2006,63(17):1945-1961
Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion
of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable
protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including
actin, tubulin, Ca2+-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane
actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in
oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may
also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation
of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it
is utilized by the oligodendrocyte and myelin for different purposes.
Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006 相似文献
880.
Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic
acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place
by α-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a
general peroxisomal dysfunction or from a defect in one of the enzymes involved in α-oxidation. Research on Refsum disease,
belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of α-oxidation, has extended
our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will
centre on this research on phytanic acid: its origin, the mechanism by which its α-oxidation takes place, its role in human
disease and the way it is produced from phytol.
Received 4 October 2005; received after revision 24 February 2006; accepted 26 April 2006 相似文献