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711.
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche 总被引:4,自引:0,他引:4
Kaplan RN Riba RD Zacharoulis S Bramley AH Vincent L Costa C MacDonald DD Jin DK Shido K Kerns SA Zhu Z Hicklin D Wu Y Port JL Altorki N Port ER Ruggero D Shmelkov SV Jensen KK Rafii S Lyden D 《Nature》2005,438(7069):820-827
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread. 相似文献
712.
Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma 总被引:2,自引:0,他引:2
Garraway LA Widlund HR Rubin MA Getz G Berger AJ Ramaswamy S Beroukhim R Milner DA Granter SR Du J Lee C Wagner SN Li C Golub TR Rimm DL Meyerson ML Fisher DE Sellers WR 《Nature》2005,436(7047):117-122
713.
A lentivirus-based system to functionally silence genes in primary mammalian cells,stem cells and transgenic mice by RNA interference 总被引:87,自引:0,他引:87
714.
Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots 总被引:19,自引:0,他引:19
Phillips MS Lawrence R Sachidanandam R Morris AP Balding DJ Donaldson MA Studebaker JF Ankener WM Alfisi SV Kuo FS Camisa AL Pazorov V Scott KE Carey BJ Faith J Katari G Bhatti HA Cyr JM Derohannessian V Elosua C Forman AM Grecco NM Hock CR Kuebler JM Lathrop JA Mockler MA Nachtman EP Restine SL Varde SA Hozza MJ Gelfand CA Broxholme J Abecasis GR Boyce-Jacino MT Cardon LR 《Nature genetics》2003,33(3):382-387
Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins. 相似文献
715.
Yamada K Andrews C Chan WM McKeown CA Magli A de Berardinis T Loewenstein A Lazar M O'Keefe M Letson R London A Ruttum M Matsumoto N Saito N Morris L Del Monte M Johnson RH Uyama E Houtman WA de Vries B Carlow TJ Hart BL Krawiecki N Shoffner J Vogel MC Katowitz J Goldstein SM Levin AV Sener EC Ozturk BT Akarsu AN Brodsky MC Hanisch F Cruse RP Zubcov AA Robb RM Roggenkäemper P Gottlob I Kowal L Battu R Traboulsi EI Franceschini P Newlin A Demer JL Engle EC 《Nature genetics》2003,35(4):318-321
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis. 相似文献
716.
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia 总被引:22,自引:0,他引:22
Abifadel M Varret M Rabès JP Allard D Ouguerram K Devillers M Cruaud C Benjannet S Wickham L Erlich D Derré A Villéger L Farnier M Beucler I Bruckert E Chambaz J Chanu B Lecerf JM Luc G Moulin P Weissenbach J Prat A Krempf M Junien C Seidah NG Boileau C 《Nature genetics》2003,34(2):154-156
Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis. 相似文献
717.
The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes 总被引:2,自引:0,他引:2
Skaletsky H Kuroda-Kawaguchi T Minx PJ Cordum HS Hillier L Brown LG Repping S Pyntikova T Ali J Bieri T Chinwalla A Delehaunty A Delehaunty K Du H Fewell G Fulton L Fulton R Graves T Hou SF Latrielle P Leonard S Mardis E Maupin R McPherson J Miner T Nash W Nguyen C Ozersky P Pepin K Rock S Rohlfing T Scott K Schultz B Strong C Tin-Wollam A Yang SP Waterston RH Wilson RK Rozen S Page DC 《Nature》2003,423(6942):825-837
718.
Irregular satellites have eccentric orbits that can be highly inclined or even retrograde relative to the equatorial planes of their planets. These objects cannot have formed by circumplanetary accretion, unlike the regular satellites that follow uninclined, nearly circular and prograde orbits. Rather, they are probably products of early capture from heliocentric orbits. Although the capture mechanism remains uncertain, the study of irregular satellites provides a window on processes operating in the young Solar System. Families of irregular satellites recently have been discovered around Saturn (thirteen members, refs 6, 7), Uranus (six, ref. 8) and Neptune (three, ref. 9). Because Jupiter is closer than the other giant planets, searches for smaller and fainter irregular satellites can be made. Here we report the discovery of 23 new irregular satellites of Jupiter, so increasing the total known population to 32. There are five distinct satellite groups, each dominated by one relatively large body. The groups were most probably produced by collisional shattering of precursor objects after capture by Jupiter. 相似文献
719.
QUAD system offers fair shares to all authors 总被引:1,自引:0,他引:1
720.
Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor 总被引:1,自引:0,他引:1
Small GTP-binding (G) proteins are activated by GDP/GTP nucleotide exchange stimulated by guanine nucleotide exchange factors (GEFs). Nucleotide dissociation from small G protein-GEF complexes involves transient GDP-bound intermediates whose structures have never been described. In the case of Arf proteins, small G proteins that regulate membrane traffic in eukaryotic cells, such intermediates can be trapped either by the natural inhibitor brefeldin A or by charge reversal at the catalytic glutamate of the Sec7 domain of their GEFs. Here we report the crystal structures of these intermediates that show that membrane recruitment of Arf and nucleotide dissociation are separate reactions stimulated by Sec7. The reactions proceed through sequential rotations of the Arf.GDP core towards the Sec7 catalytic site, and are blocked by interfacial binding of brefeldin A and unproductive stabilization of GDP by charge reversal. The structural characteristics of the reaction and its modes of inhibition reveal unexplored ways in which to inhibit the activation of small G proteins. 相似文献