全文获取类型
| 收费全文 | 169篇 |
| 免费 | 12篇 |
专业分类
| 181篇 |
出版年
| 2023年 | 1篇 |
| 2022年 | 3篇 |
| 2021年 | 6篇 |
| 2019年 | 2篇 |
| 2018年 | 3篇 |
| 2017年 | 3篇 |
| 2016年 | 2篇 |
| 2015年 | 4篇 |
| 2014年 | 6篇 |
| 2013年 | 4篇 |
| 2012年 | 6篇 |
| 2011年 | 12篇 |
| 2010年 | 6篇 |
| 2009年 | 7篇 |
| 2008年 | 12篇 |
| 2007年 | 6篇 |
| 2006年 | 9篇 |
| 2005年 | 12篇 |
| 2004年 | 11篇 |
| 2003年 | 10篇 |
| 2002年 | 2篇 |
| 2001年 | 8篇 |
| 2000年 | 5篇 |
| 1999年 | 2篇 |
| 1998年 | 2篇 |
| 1996年 | 3篇 |
| 1992年 | 3篇 |
| 1991年 | 2篇 |
| 1990年 | 4篇 |
| 1989年 | 7篇 |
| 1988年 | 1篇 |
| 1987年 | 2篇 |
| 1986年 | 1篇 |
| 1985年 | 1篇 |
| 1984年 | 2篇 |
| 1983年 | 2篇 |
| 1979年 | 1篇 |
| 1978年 | 1篇 |
| 1975年 | 1篇 |
| 1972年 | 1篇 |
| 1971年 | 2篇 |
| 1968年 | 3篇 |
排序方式： 共有181条查询结果，搜索用时 15 毫秒
1.
Gudmundsson KS Wang Z Daluge SM Johnson LC Hazen R Condreay LD McGuigan C 《Nucleosides, nucleotides & nucleic acids》2004,23(12):1929-1937
Synthesis of phosphoramidate protides of carbocyclic D- and L-2',3'-dideoxy-2',3'-didehydro-7-deazaadenosine by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleosides against both HIV and HBV. 相似文献
2.
Kimmel CB Cresko WA Phillips PC Ullmann B Currey M von Hippel F Kristjánsson BK Gelmond O McGuigan K 《Evolution; international journal of organic evolution》2012,66(2):419-434
Evolution of similar phenotypes in independent populations is often taken as evidence of adaptation to the same fitness optimum. However, the genetic architecture of traits might cause evolution to proceed more often toward particular phenotypes, and less often toward others, independently of the adaptive value of the traits. Freshwater populations of Alaskan threespine stickleback have repeatedly evolved the same distinctive opercle shape after divergence from an oceanic ancestor. Here we demonstrate that this pattern of parallel evolution is widespread, distinguishing oceanic and freshwater populations across the Pacific Coast of North America and Iceland. We test whether this parallel evolution reflects genetic bias by estimating the additive genetic variance-covariance matrix (G) of opercle shape in an Alaskan oceanic (putative ancestral) population. We find significant additive genetic variance for opercle shape and that G has the potential to be biasing, because of the existence of regions of phenotypic space with low additive genetic variation. However, evolution did not occur along major eigenvectors of G, rather it occurred repeatedly in the same directions of high evolvability. We conclude that the parallel opercle evolution is most likely due to selection during adaptation to freshwater habitats, rather than due to biasing effects of opercle genetic architecture. 相似文献
3.
Evolutionary constraint results from the interaction between the distribution of available genetic variation and the position of selective optima. The availability of genetic variance in multitrait systems, as described by the additive genetic variance-covariance matrix (G), has been the subject of recent attempts to assess the prevalence of genetic constraints. However, evolutionary constraints have not yet been considered from the perspective of the phenotypes available to multivariate selection, and whether genetic variance is present in all phenotypes potentially under selection. Determining the rank of the phenotypic variance-covariance matrix (P) to characterize the phenotypes available to selection, and contrasting it with the rank of G, may provide a general approach to determining the prevalence of genetic constraints. In a study of a laboratory population of Drosophila bunnanda from northern Australia we applied factor-analytic modeling to repeated measures of individual wing phenotypes to determine the dimensionality of the phenotypic space described by P. The phenotypic space spanned by the 10 wing traits had 10 statistically supported dimensions. In contrast, factor-analytic modeling of G estimated for the same 10 traits from a paternal half-sibling breeding design suggested G had fewer dimensions than traits. Statistical support was found for only five and two genetic dimensions, describing a total of 99% and 72% of genetic variance in wing morphology in females and males, respectively. The observed mismatch in dimensionality between P and G suggests that although selection might act to shift the intragenerational population mean toward any trait combination, evolution may be restricted to fewer dimensions. 相似文献
4.
5.
Kelleher MR McGuigan C Andrei G Snoeck R De Clercq E Balzarini J 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):639-641
2'3'-Dideoxy furanopyrimidines were shown to display anti-HCMV activity via a non-nucleoside mechanism. Further studies into highly modified sugar derivatives led to the preparation of N-and O-alkylated C10 furanopyrimidine analogues, and this work is described herein. These compounds were tested against HCMV strains, and the first case of submicromolar activity was observed. 相似文献
6.
Crewther BT McGuigan MR Gill ND 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(7):1968-1975
This study compared the effectiveness of ratio and allometric scaling for normalizing speed, power, and strength in elite male rugby union players. Thirty rugby players (body mass [BM] 107.1 ± 10.1 kg, body height [BH] 187.8 ± 7.1 cm) were assessed for sprinting speed, peak power during countermovement jumps and squat jumps, and horizontal jumping distance. One-repetition maximum strength was assessed during a bench press, chin-up, and back squat. Performance was normalized using ratio and allometric scaling (Y/X), where Y is the performance, X, the body size variable (i.e., BM or BH), and b is the power exponent. An exponent of 1.0 was used during ratio scaling. Allometric scaling was applied using proposed exponents and derived exponents for each data set. The BM and BH variables were significantly related, or close to, performance during the speed, power and/or strength tests (p < 0.001-0.066). Ratio scaling and allometric scaling using proposed exponents were effective in normalizing performance (i.e., no significant correlations) for some of these tests. Allometric scaling with derived exponents normalized performance across all the tests undertaken, thereby removing the confounding effects of BM and BH. In terms of practical applications, allometric scaling with derived exponents may be used to normalize performance between larger rugby forwards and smaller rugby backs, and could provide additional information on rugby players of similar body size. Ratio scaling may provide the best predictive measure of performance (i.e., strongest correlations). 相似文献
7.
Katrina McGuigan Mark W. Blows 《Evolution; international journal of organic evolution》2010,64(7):1899-1911
Genetic covariation among multiple traits will bias the direction of evolution. Although a trait's phenotypic context is crucial for understanding evolutionary constraints, the evolutionary potential of one (focal) trait, rather than the whole phenotype, is often of interest. The extent to which a focal trait can evolve independently depends on how much of the genetic variance in that trait is unique. Here, we present a hypothesis‐testing framework for estimating the genetic variance in a focal trait that is independent of variance in other traits. We illustrate our analytical approach using two Drosophila bunnanda trait sets: a contact pheromone system comprised of cuticular hydrocarbons (CHCs), and wing shape, characterized by relative warps of vein position coordinates. Only 9% of the additive genetic variation in CHCs was trait specific, suggesting individual traits are unlikely to evolve independently. In contrast, most (72%) of the additive genetic variance in wing shape was trait specific, suggesting relative warp representations of wing shape could evolve independently. The identification of genetic variance in focal traits that is independent of other traits provides a way of studying the evolvability of individual traits within the broader context of the multivariate phenotype. 相似文献
8.
A promising route for understanding the origin and diversification of organismal form is through studies at the intersection
of evolution and development (evo-devo). While much has been learned over the last two decades concerning macroevolutionary
patterns of developmental change, a fundamental gap in the evo-devo synthesis is the integration of mathematical population
and quantitative genetics with studies of how genetic variation in natural populations affects developmental processes. This
micro-evo-devo synthesis requires model organisms with which to ask empirical questions. Threespine stickleback fish (Gasterosteus aculeatus), long a model for studying behavior, ecology and evolution, is emerging as a prominent model micro-evo-devo system. Research
on stickleback over the last decade has begun to address the genetic basis of morphological variation and sex determination,
and much of this work has important implications for understanding the genetics of speciation. In this paper we review recent
threespine stickleback micro-evo-devo results, and outline the resources that have been developed to make this synthesis possible.
The prospects for stickleback research to speed the micro-(and macro-) evo-devo syntheses are great, and this workhorse model
system is well situated to continue contributing to our understanding of the generation of diversity in organismal form for
many more decades. 相似文献
9.
Micropatterning is a process to precisely deposit molecules, typically proteins, onto a substrate of choice with micrometer resolution. Watson et al. (2021. J. Cell Biol. https://doi.org/10.1083/jcb.202009063) describe an innovative yet accessible strategy to enable the reproducible micropatterning of virtually any protein while maintaining its biological activity.Micropatterning involves depositing molecules, primarily proteins, in a precise pattern on a defined substrate. Since the first applications of micropatterning in biology in the 1970s (1), this technique has become increasingly adopted and led to a variety of important biological discoveries related to the impact and mechanisms of cellular architecture and subcellular cytoskeletal components on cell function (2, 3, 4). The basis of most micropatterning strategies has remained the same for decades: a substrate is coated with a specific, often micron scale, pattern of protein within a background of an anti-fouling agent. This can be achieved in two ways: the substrate is coated with the anti-fouling agent, which is then locally removed in a precisely defined pattern using light projection through a mask, and protein is then deposited in regions free of the anti-fouling agent. Alternatively, protein can be directly printed onto the substrate, for example using an elastomeric stamp, or by photochemical linking via patterned light, and then unpatterned substrate regions are backfilled with the anti-fouling agent. Protein patterns can then be used to control the architecture of whole cells or the organization of subcellular components.While micropatterning is potentially a very useful methodology for a number of applications, widespread adoption of this method was initially limited by the need for access to specialized photolithography equipment to generate either the stamps or to directly pattern the anti-fouling layers. Further, since the masks used to define the stamp or anti-fouling layer patterns are pattern specific, a new mask must be produced for every pattern alteration. Early micropatterning methods also were not ideal for creating patterns containing multiple proteins, as sequential protein stamping or sequential anti-fouling coating removal required tedious and time-consuming stamp or mask alignment to ensure accurate patterning. To overcome these two limitations, Strale and colleagues developed a micropatterning technique called LIMAP (light-induced molecular absorption), in which a UV laser within a microscope is used to photoexcise patterns in the anti-fouling layer without the need for a mask. Further the use of the microscope enables direct visualization of protein patterns and hence easy alignment during multiprotein patterning (5). Despite the increased accessibility achieved by this advance, a number of other challenges still limit the widespread application of LIMAP for micropatterning (Fig. 1). First, pattern robustness remains a challenge, as a proportion of protein attaches outside of the pattern in the anti-fouling region (patterns lacks specificity) and protein distribution on the pattern is not even (pattern lacks homogeneity). Second, maintaining the biological activity of the proteins printed can be a challenge, as LIMAP does not enable control over protein-substrate interactions and the orientation of the deposited protein on the substrate, which can result in inaccessibility of the protein’s biologically active domains. This second limitation in particular dramatically limits the types of protein that can be printed and hence cell types and biological questions that can be explored using the LIMAP technique.Open in a separate windowFigure 1.Overview of fibrinogen anchor micropatterning strategy and advantages over existing patterning techniques.In this issue, Watson and colleagues (6) present a new approach that overcomes these limitations by using fibrinogen anchors, functionalized to bind to any proteins of interest, to enable robust micropatterning of almost any combination of proteins. Specifically, as a first step, LIMAP was used to photopattern fibrinogen molecules conjugated to a specific binding target. In a second step, the protein of interest displaying the corresponding binding partner was then added, under appropriate buffer conditions to maintain protein activity, and bound preferentially to the fibrinogen anchors (Fig. 1). The authors describe generation of a number of conjugates, based on modification of fibrinogen-exposed amines, that enable application of the method to a number of proteins, including fibrinogen–Con A, a lectin that binds to insect cells, fibrinogen-NeutrAvidin to bind to biotinylated targets, fibrinogen-GBP to bind to GFP-tagged proteins (GBP stands for GFP-binding peptide, a nanobody against GFP), and fibrinogen-biotin to bind to streptavidin/NeutrAvidin fusions, as well as to biotinylated targets using a NeutrAvidin sandwich (fibrinogen-biotin::NeutrAvidin::biotinylated protein of interest). Of note, the simplicity of this conjugation process will enable greater adoption of this approach by the biology community.Fibrinogen was selected as the anchor molecule as its properties are such that homogeneous and specific patterning can be routinely achieved using LIMAP. By binding other proteins to the fibrinogen anchor, the authors demonstrate their method can produce micropatterns of the anchor bound with the same high specificity (proteins only pattern where they should) and high homogeneity (protein distribution within the pattern is less variable). Further, the authors take advantage of the library of different fibrinogen conjugates to generate patterns containing three different proteins that bind to three different sequentially patterned fibrinogen conjugates. While the improvements in selectivity and homogeneity achieved by Watson et al. are alone a significant step forward, the most exciting demonstrations in their study is that their method enables maintenance of the biological activity of printed proteins in a number of different contexts (6). For example, the authors pattern proteins to perform a microtubule gliding assay and show that printed kinesin motors maintain their ability to move microtubules with the expected gliding speed and dynamics. In another example, the authors exploit their ability to pattern multiple proteins at the subcellular scale and demonstrate that patterns of EGF can induce relocalization of the corresponding EGFR receptor only to regions of a cell attached to EGF-patterned regions on the substrate.The simplicity of the described approach and compatibility with different proteins make it attractive to explore a broad range of problems in the future. At the multicellular scale, this approach could be applied to understand localized cell–cell interactions during collective phenomena such as organoid patterning and models of early human development (7), cell competition dynamics (8), or collective cell migration (9). In particular, applying sequential patterning to create heterogeneous signaling within a cellular island would be interesting to explore developmental patterning circuits. At the single-cell scale, this approach could be useful for understanding heterogeneity in cell populations, although the patterning throughput achievable using microscope “writing” could limit the number cells that can be assessed for such applications. Integration of this anchoring approach with higher throughput mask-based micropatterning methods could address this, however. Perhaps most excitingly, this approach offers a powerful strategy to broadly control subcellular features in a cell. For example, this opens the possibility to probe which downstream networks are activated upon receptor engagement and to control the spatial locations of signaling components within a cell (10). This clever addition to the micropatterning tool kit significantly expands the types of problems that micropatterning can be used to explore while maintaining the accessibility of the technique to the biological community. 相似文献
10.
Howard Gamper Yujia Mao Isao Masuda Henri McGuigan Gregor Blaha Yuhong Wang Shoujun Xu Ya-Ming Hou 《Nucleic acids research》2021,49(17):10046
Inducing tRNA +1 frameshifting to read a quadruplet codon has the potential to incorporate a non-natural amino acid into the polypeptide chain. While this strategy is being considered for genome expansion in biotechnology and bioengineering endeavors, a major limitation is a lack of understanding of where the shift occurs in an elongation cycle of protein synthesis. Here, we use the high-efficiency +1-frameshifting SufB2 tRNA, containing an extra nucleotide in the anticodon loop, to address this question. Physical and kinetic measurements of the ribosome reading frame of SufB2 identify twice exploration of +1 frameshifting in one elongation cycle, with the major fraction making the shift during translocation from the aminoacyl-tRNA binding (A) site to the peptidyl-tRNA binding (P) site and the remaining fraction making the shift within the P site upon occupancy of the A site in the +1-frame. We demonstrate that the twice exploration of +1 frameshifting occurs during active protein synthesis and that each exploration is consistent with ribosomal conformational dynamics that permits changes of the reading frame. This work indicates that the ribosome itself is a determinant of changes of the reading frame and reveals a mechanistic parallel of +1 frameshifting with –1 frameshifting. 相似文献