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排序方式: 共有324条查询结果,搜索用时 646 毫秒
311.
Hanks S Coleman K Reid S Plaja A Firth H Fitzpatrick D Kidd A Méhes K Nash R Robin N Shannon N Tolmie J Swansbury J Irrthum A Douglas J Rahman N 《Nature genetics》2004,36(11):1159-1161
Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development. 相似文献
312.
5-hydroxytryptamine type 3 (5-HT3) receptors are members of the Cys-loop receptor superfamily. Neurotransmitter binding in these proteins triggers the opening (gating) of an ion channel by means of an as-yet-uncharacterized conformational change. Here we show that a specific proline (Pro 8*), located at the apex of the loop between the second and third transmembrane helices (M2-M3), can link binding to gating through a cis-trans isomerization of the protein backbone. Using unnatural amino acid mutagenesis, a series of proline analogues with varying preference for the cis conformer was incorporated at the 8* position. Proline analogues that strongly favour the trans conformer produced non-functional channels. Among the functional mutants there was a strong correlation between the intrinsic cis-trans energy gap of the proline analogue and the activation of the channel, suggesting that cis-trans isomerization of this single proline provides the switch that interconverts the open and closed states of the channel. Consistent with this proposal, nuclear magnetic resonance studies on an M2-M3 loop peptide reveal two distinct, structured forms. Our results thus confirm the structure of the M2-M3 loop and the critical role of Pro 8* in the 5-HT3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore. 相似文献
313.
Sheep retrovirus structural protein induces lung tumours 总被引:1,自引:0,他引:1
Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase 2 (Hyal2), which is not functional as a receptor in mice but is functional in humans. Sheep are immunotolerant of JSRV because of the expression of closely related endogenous retroviruses, which are not present in humans and most other species, and this may facilitate oncogenesis. Here we show that expression of the JSRV envelope (Env) protein alone in lungs of mice, by using a replication-incompetent adeno-associated virus vector, results in tumours with a bronchiolo-alveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumour development was almost entirely blocked in immunocompetent mice. Our results provide a rare example of an oncogenic viral structural protein, show that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicate that immune recognition of Env can protect against JSRV tumorigenesis. 相似文献
314.
Smith-Magenis syndrome (SMS) is a mental retardation syndrome associated with deletions involving chromosome 17p11.2. Persons with SMS have characteristic behavioral abnormalities, including self-injurious behaviors and sleep disturbance, and distinct craniofacial and skeletal anomalies. We identified dominant frameshift mutations leading to protein truncation in RAI1 in three individuals who have phenotypic features consistent with SMS but do not have 17p11.2 deletions detectable by standard fluorescence in situ hybridization techniques. 相似文献
315.
Ueda H Howson JM Esposito L Heward J Snook H Chamberlain G Rainbow DB Hunter KM Smith AN Di Genova G Herr MH Dahlman I Payne F Smyth D Lowe C Twells RC Howlett S Healy B Nutland S Rance HE Everett V Smink LJ Lam AC Cordell HJ Walker NM Bordin C Hulme J Motzo C Cucca F Hess JF Metzker ML Rogers J Gregory S Allahabadia A Nithiyananthan R Tuomilehto-Wolf E Tuomilehto J Bingley P Gillespie KM Undlien DE Rønningen KS Guja C Ionescu-Tîrgovişte C Savage DA Maxwell AP Carson DJ Patterson CC Franklyn JA 《Nature》2003,423(6939):506-511
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction. 相似文献
316.
317.
Flagel SB Clark JJ Robinson TE Mayo L Czuj A Willuhn I Akers CA Clinton SM Phillips PE Akil H 《Nature》2011,469(7328):53-57
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control. 相似文献
318.
Chen DY Stern SA Garcia-Osta A Saunier-Rebori B Pollonini G Bambah-Mukku D Blitzer RD Alberini CM 《Nature》2011,469(7331):491-497
319.
Synthetic chromosome arms function in yeast and generate phenotypic diversity by design 总被引:1,自引:0,他引:1
Dymond JS Richardson SM Coombes CE Babatz T Muller H Annaluru N Blake WJ Schwerzmann JW Dai J Lindstrom DL Boeke AC Gottschling DE Chandrasegaran S Bader JS Boeke JD 《Nature》2011,477(7365):471-476
Recent advances in DNA synthesis technology have enabled the construction of novel genetic pathways and genomic elements, furthering our understanding of system-level phenomena. The ability to synthesize large segments of DNA allows the engineering of pathways and genomes according to arbitrary sets of design principles. Here we describe a synthetic yeast genome project, Sc2.0, and the first partially synthetic eukaryotic chromosomes, Saccharomyces cerevisiae chromosome synIXR, and semi-synVIL. We defined three design principles for a synthetic genome as follows: first, it should result in a (near) wild-type phenotype and fitness; second, it should lack destabilizing elements such as tRNA genes or transposons; and third, it should have genetic flexibility to facilitate future studies. The synthetic genome features several systemic modifications complying with the design principles, including an inducible evolution system, SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution). We show the utility of SCRaMbLE as a novel method of combinatorial mutagenesis, capable of generating complex genotypes and a broad variety of phenotypes. When complete, the fully synthetic genome will allow massive restructuring of the yeast genome, and may open the door to a new type of combinatorial genetics based entirely on variations in gene content and copy number. 相似文献
320.
Cadwell K Liu JY Brown SL Miyoshi H Loh J Lennerz JK Kishi C Kc W Carrero JA Hunt S Stone CD Brunt EM Xavier RJ Sleckman BP Li E Mizushima N Stappenbeck TS Virgin HW 《Nature》2008,456(7219):259-263