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排序方式: 共有342条查询结果,搜索用时 312 毫秒
221.
222.
Poulikakos PI Persaud Y Janakiraman M Kong X Ng C Moriceau G Shi H Atefi M Titz B Gabay MT Salton M Dahlman KB Tadi M Wargo JA Flaherty KT Kelley MC Misteli T Chapman PB Sosman JA Graeber TG Ribas A Lo RS Rosen N Solit DB 《Nature》2011,480(7377):387-390
Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. 相似文献
223.
McLellan JS Pancera M Carrico C Gorman J Julien JP Khayat R Louder R Pejchal R Sastry M Dai K O'Dell S Patel N Shahzad-ul-Hussan S Yang Y Zhang B Zhou T Zhu J Boyington JC Chuang GY Diwanji D Georgiev I Kwon YD Lee D Louder MK Moquin S Schmidt SD Yang ZY Bonsignori M Crump JA Kapiga SH Sam NE Haynes BF Burton DR Koff WC Walker LM Phogat S Wyatt R Orwenyo J Wang LX Arthos J Bewley CA Mascola JR Nabel GJ Schief WR Ward AB Wilson IA Kwong PD 《Nature》2011,480(7377):336-343
Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand. 相似文献
224.
Hinch AG Tandon A Patterson N Song Y Rohland N Palmer CD Chen GK Wang K Buxbaum SG Akylbekova EL Aldrich MC Ambrosone CB Amos C Bandera EV Berndt SI Bernstein L Blot WJ Bock CH Boerwinkle E Cai Q Caporaso N Casey G Cupples LA Deming SL Diver WR Divers J Fornage M Gillanders EM Glessner J Harris CC Hu JJ Ingles SA Isaacs W John EM Kao WH Keating B Kittles RA Kolonel LN Larkin E Le Marchand L McNeill LH Millikan RC Murphy A Musani S Neslund-Dudas C Nyante S Papanicolaou GJ Press MF Psaty BM 《Nature》2011,476(7359):170-175
Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P?value 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution. 相似文献
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226.
Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. 总被引:60,自引:0,他引:60
Dan H Barouch Jennifer Kunstman Marcelo J Kuroda J?rn E Schmitz Sampa Santra Fred W Peyerl Georgia R Krivulka Kristin Beaudry Michelle A Lifton Darci A Gorgone David C Montefiori Mark G Lewis Steven M Wolinsky Norman L Letvin 《Nature》2002,415(6869):335-339
Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by candidate AIDS vaccines have recently been shown to control viral replication and prevent clinical disease progression after pathogenic viral challenges in rhesus monkeys. Here we show that viral escape from CTL recognition can result in the eventual failure of this partial immune protection. Viral mutations that escape from CTL recognition have been previously described in humans infected with human immunodeficiency virus (HIV) and monkeys infected with simian immunodeficiency virus (SIV). In a cohort of rhesus monkeys that were vaccinated and subsequently infected with a pathogenic hybrid simian-human immunodeficiency virus (SHIV), the frequency of viral sequence mutations within CTL epitopes correlated with the level of viral replication. A single nucleotide mutation within an immunodominant Gag CTL epitope in an animal with undetectable plasma viral RNA resulted in viral escape from CTLs, a burst of viral replication, clinical disease progression, and death from AIDS-related complications. These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years. 相似文献
227.
The paper describes a project carried out within a major chemicals corporation to improve the performance of the individual
businesses. This was to be done by clarifying some of the organisational uncertainties in its structure and improving the
way that specialists form coalitions to address market challenges together. The approach used was based on “systems thinking”,
which is an intellectual framework of knowledge that attempts to view organisations as wholes and which studies the processes
of change in any part in the context of the whole organisation. Some of the important concepts of systems thinking are explored
as they might be applied within a business organisation. Specifically the tool used was the Viable System Model of Stafford
Beer, which the authors interpreted and developed into a set of statements (“a Standard”) which describe best practice in
such organisations. Managers have used this to explore possible gaps in their organisations and, with this understanding,
find ways to improve performance. 相似文献
228.
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230.
David A. Eads Jennifer G. Chipault Dean E. Biggins Travis M. Livieri Joshua J. Millspaugh 《西北部美国博物学家》2011,70(2)
We describe observations of black-tailed prairie dogs ( Cynomys ludovicianus ) emerging aboveground at night, apparently in response to wild-born and captive-born black-footed ferrets ( Mustela nigripes ) in South Dakota and New Mexico, respectively. We also discuss other similar observations accumulated on black-tailed prairie dog colonies as well as observations of white-tailed prairie dogs ( Cynomys leucurus ) making nighttime movements, apparently in response to pre-reintroduction ferrets in Wyoming. Our observations suggest that, in addition to documented daytime defenses against ferrets, prairie dogs reduce vulnerability to predation by ferrets by using evasive movements at night. 相似文献