全文获取类型
收费全文 | 434篇 |
免费 | 0篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 8篇 |
理论与方法论 | 1篇 |
现状及发展 | 85篇 |
研究方法 | 36篇 |
综合类 | 285篇 |
自然研究 | 20篇 |
出版年
2017年 | 3篇 |
2014年 | 3篇 |
2013年 | 3篇 |
2012年 | 17篇 |
2011年 | 38篇 |
2010年 | 8篇 |
2009年 | 2篇 |
2008年 | 20篇 |
2007年 | 15篇 |
2006年 | 15篇 |
2005年 | 13篇 |
2004年 | 10篇 |
2003年 | 15篇 |
2002年 | 12篇 |
2001年 | 25篇 |
2000年 | 21篇 |
1999年 | 9篇 |
1995年 | 3篇 |
1993年 | 1篇 |
1992年 | 15篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1980年 | 7篇 |
1979年 | 1篇 |
1978年 | 11篇 |
1977年 | 5篇 |
1976年 | 8篇 |
1975年 | 5篇 |
1974年 | 5篇 |
1973年 | 6篇 |
1972年 | 4篇 |
1971年 | 13篇 |
1970年 | 20篇 |
1969年 | 5篇 |
1968年 | 10篇 |
1967年 | 10篇 |
1966年 | 6篇 |
1965年 | 4篇 |
1964年 | 3篇 |
1963年 | 2篇 |
1960年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有435条查询结果,搜索用时 31 毫秒
11.
12.
Haematopoietic stem cells (HSCs) are a self-renewing population of cells that continuously replenish all blood and immune cells during the lifetime of an individual. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune-compatible donors remain serious problems. These difficulties have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in the specification of HSCs during embryonic development. Here we demonstrate in zebrafish that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signalling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are, in turn, required for the establishment of definitive haematopoiesis. Notch signalling downstream of Dlc and Dld is earlier than, and distinct from, known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium. 相似文献
13.
14.
This article by Curtis Wilson is an account of the origin of Hansen’s powerful systematic method for finding contributions of higher order perturbations in celestial mechanics. Hansen’s method was developed in the course of improving on Laplace’s treatment of the mutual perturbations of Jupiter and Saturn. This method, an entirely new way of doing celestial mechanics when it first appeared, later made possible the successful treatment of the complicated motions of our moon (see Wilson 2010). In this paper Wilson gives a brief historical introduction followed by an account of relevant technical details of the Laplacian background, an account illustrating technical details in Hansen’s initial development in his Disquisitions of 1829, and a treatment illustrating details contributing to the achievement of Hansen’s more refined development in his Untersuchung of 1831. These details include conditional equations Hansen provides for checking the accuracy of calculations. Wilson also includes a detailed assessment showing the extraordinary improvement in empirical accuracy of Hansen’s treatment over the best earlier treatment of the Jupiter-Saturn interactions. 相似文献
15.
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas 总被引:1,自引:0,他引:1
Wu G Broniscer A McEachron TA Lu C Paugh BS Becksfort J Qu C Ding L Huether R Parker M Zhang J Gajjar A Dyer MA Mullighan CG Gilbertson RJ Mardis ER Wilson RK Downing JR Ellison DW Zhang J Baker SJ;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project 《Nature genetics》2012,44(3):251-253
To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration. 相似文献
16.
Harakalova M van Harssel JJ Terhal PA van Lieshout S Duran K Renkens I Amor DJ Wilson LC Kirk EP Turner CL Shears D Garcia-Minaur S Lees MM Ross A Venselaar H Vriend G Takanari H Rook MB van der Heyden MA Asselbergs FW Breur HM Swinkels ME Scurr IJ Smithson SF Knoers NV van der Smagt JJ Nijman IJ Kloosterman WP van Haelst MM van Haaften G Cuppen E 《Nature genetics》2012,44(7):793-796
Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome. 相似文献
17.
Vitart V Rudan I Hayward C Gray NK Floyd J Palmer CN Knott SA Kolcic I Polasek O Graessler J Wilson JF Marinaki A Riches PL Shu X Janicijevic B Smolej-Narancic N Gorgoni B Morgan J Campbell S Biloglav Z Barac-Lauc L Pericic M Klaric IM Zgaga L Skaric-Juric T Wild SH Richardson WA Hohenstein P Kimber CH Tenesa A Donnelly LA Fairbanks LD Aringer M McKeigue PM Ralston SH Morris AD Rudan P Hastie ND Campbell H Wright AF 《Nature genetics》2008,40(4):437-442
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes. 相似文献
18.
The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism
Dieterich C Clifton SW Schuster LN Chinwalla A Delehaunty K Dinkelacker I Fulton L Fulton R Godfrey J Minx P Mitreva M Roeseler W Tian H Witte H Yang SP Wilson RK Sommer RJ 《Nature genetics》2008,40(10):1193-1198
Here we present a draft genome sequence of the nematode Pristionchus pacificus, a species that is associated with beetles and is used as a model system in evolutionary biology. With 169 Mb and 23,500 predicted protein-coding genes, the P. pacificus genome is larger than those of Caenorhabditis elegans and the human parasite Brugia malayi. Compared to C. elegans, the P. pacificus genome has more genes encoding cytochrome P450 enzymes, glucosyltransferases, sulfotransferases and ABC transporters, many of which were experimentally validated. The P. pacificus genome contains genes encoding cellulase and diapausin, and cellulase activity is found in P. pacificus secretions, indicating that cellulases can be found in nematodes beyond plant parasites. The relatively higher number of detoxification and degradation enzymes in P. pacificus is consistent with its necromenic lifestyle and might represent a preadaptation for parasitism. Thus, comparative genomics analysis of three ecologically distinct nematodes offers a unique opportunity to investigate the association between genome structure and lifestyle. 相似文献
19.
The chromosomes of eukaryotic cells are separated from the cytoplasm by the nuclear envelope. The nuclear envelope includes two riveted membranes, plus embedded pore complexes that mediate nuclear import and export. In this sense, the nuclear envelope is truly a border zone. However, the envelope also links directly to chromosomes, and anchors two major infrastructures--the nuclear lamina and Tpr filaments--to the nuclear perimeter. Proteins of the nuclear envelope mediate a variety of fundamental activities, including DNA replication, gene expression and silencing, chromatin organization, cell division, apoptosis, sperm nuclear remodeling, the behavior of pronuclei, cell fate determination, nuclear migration and cell polarity. Furthermore, mutations in nuclear lamins and lamin-binding proteins cause tissue-specific inherited diseases. This special issue of Cell and Molecular Life Sciences is devoted to recent major advances in the characterization of nuclear envelope proteins and their roles. We offer here an overview of the topics covered in this issue of CMLS, and also discuss the emerging recognition that the nuclear envelope is an organelle critical for a wide range of genetic and developmental activity in multicellular organisms. 相似文献
20.
Horses damp the spring in their step. 总被引:6,自引:0,他引:6
The muscular work of galloping in horses is halved by storing and returning elastic strain energy in spring-like muscle-tendon units.These make the legs act like a child's pogo stick that is tuned to stretch and recoil at 2.5 strides per second. This mechanism is optimized by unique musculoskeletal adaptations: the digital flexor muscles have extremely short fibres and significant passive properties, whereas the tendons are very long and span several joints. Length change occurs by a stretching of the spring-like digital flexor tendons rather than through energetically expensive length changes in the muscle. Despite being apparently redundant for such a mechanism, the muscle fibres in the digital flexors are well developed. Here we show that the mechanical arrangement of the elastic leg permits it to vibrate at a higher frequency of 30-40 Hz that could cause fatigue damage to tendon and bone. Furthermore, we show that the digital flexor muscles have minimal ability to contribute to or regulate significantly the 2.5-Hz cycle of movement, but are ideally arranged to damp these high-frequency oscillations in the limb. 相似文献