全文获取类型
收费全文 | 49503篇 |
免费 | 130篇 |
国内免费 | 172篇 |
专业分类
系统科学 | 250篇 |
丛书文集 | 1052篇 |
教育与普及 | 108篇 |
理论与方法论 | 271篇 |
现状及发展 | 22218篇 |
研究方法 | 1875篇 |
综合类 | 23273篇 |
自然研究 | 758篇 |
出版年
2013年 | 360篇 |
2012年 | 666篇 |
2011年 | 1423篇 |
2010年 | 302篇 |
2008年 | 843篇 |
2007年 | 934篇 |
2006年 | 917篇 |
2005年 | 941篇 |
2004年 | 969篇 |
2003年 | 871篇 |
2002年 | 904篇 |
2001年 | 1408篇 |
2000年 | 1311篇 |
1999年 | 917篇 |
1992年 | 878篇 |
1991年 | 691篇 |
1990年 | 721篇 |
1989年 | 733篇 |
1988年 | 712篇 |
1987年 | 730篇 |
1986年 | 760篇 |
1985年 | 945篇 |
1984年 | 742篇 |
1983年 | 605篇 |
1982年 | 531篇 |
1981年 | 563篇 |
1980年 | 689篇 |
1979年 | 1546篇 |
1978年 | 1303篇 |
1977年 | 1270篇 |
1976年 | 952篇 |
1975年 | 995篇 |
1974年 | 1469篇 |
1973年 | 1240篇 |
1972年 | 1283篇 |
1971年 | 1510篇 |
1970年 | 2033篇 |
1969年 | 1602篇 |
1968年 | 1437篇 |
1967年 | 1508篇 |
1966年 | 1338篇 |
1965年 | 995篇 |
1964年 | 291篇 |
1959年 | 559篇 |
1958年 | 938篇 |
1957年 | 715篇 |
1956年 | 571篇 |
1955年 | 519篇 |
1954年 | 591篇 |
1948年 | 346篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
831.
832.
833.
Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health. 相似文献
834.
Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band 总被引:8,自引:0,他引:8
We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer. 相似文献
835.
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
836.
Richardson RJ Dixon J Malhotra S Hardman MJ Knowles L Boot-Handford RP Shore P Whitmarsh A Dixon MJ 《Nature genetics》2006,38(11):1329-1334
The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process. 相似文献
837.
The coagulum proteins of human semen, semenogelins I and II, are secreted in abundance by the seminal vesicles. Their function
in reproduction is poorly understood as they are rapidly degraded in ejaculated semen. However, more recent results indicate
that it is time to put the semenogelins in a broader physiological perspective that goes beyond reproduction and fertility.
Received 21 June 2006; received after revision 16 August 2006; accepted 28 September 2006 相似文献
838.
Lehmann F Tiralongo E Tiralongo J 《Cellular and molecular life sciences : CMLS》2006,63(12):1331-1354
Sialic acids consist of a family of acidic ninecarbon sugars that are typically located at the terminal positions of a variety
of glycoconjugates. Naturally occurring sialic acids show an immense diversity of structure, and this reflects their involvement
in a variety of biologically important processes. One such process involves the direct participation of sialic acids in recognition
events through specific interactions with lectins, a family of proteins that recognise and bind sugars. This review will present
a detailed overview of our current knowledge regarding the occurrence, specificity and function of sialic acid-specific lectins,
particularly those that occur in viruses, bacteria and non-vertebrate eukaryotes.
Received 13 December 2005; received after revision 9 February 2006; accepted 15 February 2006 相似文献
839.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
840.
Amundadottir LT Sulem P Gudmundsson J Helgason A Baker A Agnarsson BA Sigurdsson A Benediktsdottir KR Cazier JB Sainz J Jakobsdottir M Kostic J Magnusdottir DN Ghosh S Agnarsson K Birgisdottir B Le Roux L Olafsdottir A Blondal T Andresdottir M Gretarsdottir OS Bergthorsson JT Gudbjartsson D Gylfason A Thorleifsson G Manolescu A Kristjansson K Geirsson G Isaksson H Douglas J Johansson JE Bälter K Wiklund F Montie JE Yu X Suarez BK Ober C Cooney KA Gronberg H Catalona WJ Einarsson GV 《Nature genetics》2006,38(6):652-658
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry. 相似文献