全文获取类型
收费全文 | 1076篇 |
免费 | 69篇 |
出版年
2023年 | 6篇 |
2022年 | 13篇 |
2021年 | 16篇 |
2020年 | 6篇 |
2019年 | 14篇 |
2018年 | 11篇 |
2017年 | 12篇 |
2016年 | 19篇 |
2015年 | 47篇 |
2014年 | 54篇 |
2013年 | 51篇 |
2012年 | 85篇 |
2011年 | 89篇 |
2010年 | 47篇 |
2009年 | 33篇 |
2008年 | 63篇 |
2007年 | 84篇 |
2006年 | 63篇 |
2005年 | 56篇 |
2004年 | 43篇 |
2003年 | 50篇 |
2002年 | 59篇 |
2001年 | 17篇 |
2000年 | 12篇 |
1999年 | 14篇 |
1998年 | 24篇 |
1997年 | 14篇 |
1996年 | 14篇 |
1995年 | 22篇 |
1994年 | 11篇 |
1993年 | 15篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 12篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 6篇 |
1985年 | 1篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 3篇 |
1977年 | 7篇 |
1976年 | 1篇 |
排序方式: 共有1145条查询结果,搜索用时 15 毫秒
91.
92.
Functional interactions between Prp8, Prp18, Slu7, and U5 snRNA during the second step of pre-mRNA splicing
下载免费PDF全文
![点击此处可从《RNA (New York, N.Y.)》网站下载免费的PDF全文](/ch/ext_images/free.gif)
After the second transesterification step of pre-mRNA splicing, the Prp22 helicase catalyzes release of spliced mRNA by disrupting contacts in the spliceosome that likely involve Prp8. Mutations at Arg1753 in Prp8, which suppress helicase-defective prp22 mutants, elicit temperature-sensitive growth phenotypes, indicating that interactions in the spliceosome involving Prp8-R1753 might be broken prematurely at 37 degrees C. Here we report that mutations in loop I of the U5 snRNA or in Prp18 can suppress the temperature-sensitive prp8-R1753 mutants. The same gain-of-function PRP18 alleles can also alleviate the growth phenotypes of multiple slu7-ts mutants, indicating a functional link between Prp8 and the second step splicing factors Prp18 and Slu7. These findings, together with the demonstration that changes at Arg1753 in Prp8 impair step 2 of pre-mRNA splicing in vitro, are consistent with a model in which (1) Arg1753 plays a role in stabilizing U5/exon interactions prior to exon joining and (2) these contacts persist until they are broken by the helicase Prp22. 相似文献
93.
Nicholas C. Grassly Gagandeep Kang Beate Kampmann 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2015,370(1671)
The reason for holding a meeting to discuss biological challenges to vaccines is simple: not all vaccines work equally well in all settings. This special issue reviews the performance of vaccines in challenging environments, summarizes current thinking on the reasons why vaccines underperform and considers what approaches are necessary to understand the heterogeneity in responses and to improve vaccine immunogenicity and efficacy. 相似文献
94.
Agata Jacewicz Lidia Chico Paul Smith Beate Schwer Stewart Shuman 《RNA (New York, N.Y.)》2015,21(3):401-414
Saccharomyces cerevisiae Msl5 orchestrates spliceosome assembly by binding the intron branchpoint sequence 5′-UACUAAC and, with its heterodimer partner protein Mud2, establishing cross intron-bridging interactions with the U1 snRNP at the 5′ splice site. Here we define the central Msl5 KH-QUA2 domain as sufficient for branchpoint RNA recognition. The 1.8 Å crystal structure of Msl5-(KH-QUA2) bound to the branchpoint highlights an extensive network of direct and water-mediated protein–RNA and intra-RNA atomic contacts at the interface that illuminate how Msl5 recognizes each nucleobase of the UACUAAC element. The Msl5 structure rationalizes a large body of mutational data and inspires new functional studies herein, which reveal how perturbations of the Msl5·RNA interface impede the splicing of specific yeast pre-mRNAs. We also identify interfacial mutations in Msl5 that bypass the essentiality of Sub2, a DExD-box ATPase implicated in displacing Msl5 from the branchpoint in exchange for the U2 snRNP. These studies establish an atomic resolution framework for understanding splice site selection and early spliceosome dynamics. 相似文献
95.
Yhc1 and U1-C are essential subunits of the yeast and human U1 snRNP, respectively, that stabilize the duplex formed by U1 snRNA at the pre-mRNA 5′ splice site (5′SS). Mutational analysis of Yhc1, guided by the human U1 snRNP crystal structure, highlighted the importance of Val20 and Ser19 at the RNA interface. Though benign on its own, V20A was lethal in the absence of branchpoint-binding complex subunit Mud2 and caused a severe growth defect in the absence of U1 subunit Nam8. S19A caused a severe defect with mud2▵. Essential DEAD-box ATPase Prp28 was bypassed by mutations of Yhc1 Val20 and Ser19, consistent with destabilization of U1•5′SS interaction. We extended the genetic analysis to SmD3, which interacts with U1-C/Yhc1 in U1 snRNP, and to SmB, its neighbor in the Sm ring. Whereas mutations of the interface of SmD3, SmB, and U1-C/Yhc1 with U1-70K/Snp1, or deletion of the interacting Snp1 N-terminal peptide, had no growth effect, they elicited synthetic defects in the absence of U1 subunit Mud1. Mutagenesis of the RNA-binding triad of SmD3 (Ser-Asn-Arg) and SmB (His-Asn-Arg) provided insights to built-in redundancies of the Sm ring, whereby no individual side-chain was essential, but simultaneous mutations of Asn or Arg residues in SmD3 and SmB were lethal. Asn-to-Ala mutations SmB and SmD3 caused synthetic defects in the absence of Mud1 or Mud2. All three RNA site mutations of SmD3 were lethal in cells lacking the U2 snRNP subunit Lea1. Benign C-terminal truncations of SmD3 were dead in the absence of Mud2 or Lea1 and barely viable in the absence of Nam8 or Mud1. In contrast, SMD3-E35A uniquely suppressed the temperature-sensitivity of lea1▵. 相似文献
96.
97.
Age‐dependent decline in fin regenerative capacity in the short‐lived fish Nothobranchius furzeri
下载免费PDF全文
![点击此处可从《Aging cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The potential to regenerate declines with age in a wide range of organisms. A popular model system to study the mechanisms of regeneration is the fin of teleost fish, which has the ability to fully regrow upon amputation. Here, we used the short‐lived killifish Nothobranchius furzeri to analyse the impact of aging on fin regeneration in more detail. We observed that young fish were able to nearly completely (98%) regenerate their amputated caudal fins within 4 weeks, whereas middle‐aged fish reached 78%, old fish 57% and very old fish 46% of their original fin size. The difference in growth rate between young and old fish was already significant at 3 days post amputation (dpa) and increased with time. We therefore hypothesized that early events are crucial for the age‐related differences in regenerative capacity. Indeed, we could observe a higher percentage of proliferating cells in early regenerating fin tissue of young fish compared with aged fish and larger fractions of apoptotic cells in aged fish. Furthermore, young fish showed peak upregulation of several genes involved in fgf and wnt/β‐catenin signalling at an earlier time point than old fish. Our findings suggest that regenerative processes are initiated earlier and that regeneration overall is more efficient in younger fish. 相似文献
98.
Proust H Hoffmann B Xie X Yoneyama K Schaefer DG Yoneyama K Nogué F Rameau C 《Development (Cambridge, England)》2011,138(8):1531-1539
Strigolactones are a novel class of plant hormones controlling shoot branching in seed plants. They also signal host root proximity during symbiotic and parasitic interactions. To gain a better understanding of the origin of strigolactone functions, we characterised a moss mutant strongly affected in strigolactone biosynthesis following deletion of the CAROTENOID CLEAVAGE DIOXYGENASE 8 (CCD8) gene. Here, we show that wild-type Physcomitrella patens produces and releases strigolactones into the medium where they control branching of protonemal filaments and colony extension. We further show that Ppccd8 mutant colonies fail to sense the proximity of neighbouring colonies, which in wild-type plants causes the arrest of colony extension. The mutant phenotype is rescued when grown in the proximity of wild-type colonies, by exogenous supply of synthetic strigolactones or by ectopic expression of seed plant CCD8. Thus, our data demonstrate for the first time that Bryophytes (P. patens) produce strigolactones that act as signalling factors controlling developmental and potentially ecophysiological processes. We propose that in P. patens, strigolactones are reminiscent of quorum-sensing molecules used by bacteria to communicate with one another. 相似文献
99.
Apfelbeck B Goymann W 《Proceedings. Biological sciences / The Royal Society》2011,278(1722):3233-3242
Competition elevates plasma testosterone in a wide variety of vertebrates, including humans. The ‘challenge hypothesis’ proposes that seasonal peaks in testosterone during breeding are caused by social challenges from other males. However, during experimentally induced male–male conflicts, testosterone increases only in a minority of songbird species tested so far. Why is this so? Comparative evidence suggests that species with a short breeding season may not elevate testosterone levels during territory defence. These species may even be limited in their physiological capability to increase testosterone levels, which can be tested by injecting birds with gonadotropin-releasing hormone (GnRH). We studied two populations of black redstarts that differ in breeding altitude, morphology and the length of their breeding season. Unexpectedly, males of neither population increased testosterone in response to a simulated territorial intrusion, but injections with GnRH resulted in a major elevation of testosterone. Thus, black redstarts would have been capable of mounting a testosterone response during the male–male challenge. Our data show, for the first time, that the absence of an androgen response to male–male challenges is not owing to physiological limitations to increase testosterone. Furthermore, in contrast to comparative evidence between species, populations of black redstarts with a long breeding season do not show the expected elevation in testosterone during male–male challenges. 相似文献
100.
Hamza TH Chen H Hill-Burns EM Rhodes SL Montimurro J Kay DM Tenesa A Kusel VI Sheehan P Eaaswarkhanth M Yearout D Samii A Roberts JW Agarwal P Bordelon Y Park Y Wang L Gao J Vance JM Kendler KS Bacanu SA Scott WK Ritz B Nutt J Factor SA Zabetian CP Payami H 《PLoS genetics》2011,7(8):e1002237
Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson''s disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP''s main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients. 相似文献