全文获取类型
收费全文 | 1266篇 |
免费 | 105篇 |
国内免费 | 1篇 |
出版年
2023年 | 8篇 |
2022年 | 13篇 |
2021年 | 26篇 |
2020年 | 8篇 |
2019年 | 17篇 |
2018年 | 24篇 |
2017年 | 17篇 |
2016年 | 20篇 |
2015年 | 50篇 |
2014年 | 65篇 |
2013年 | 81篇 |
2012年 | 87篇 |
2011年 | 82篇 |
2010年 | 52篇 |
2009年 | 45篇 |
2008年 | 73篇 |
2007年 | 66篇 |
2006年 | 78篇 |
2005年 | 49篇 |
2004年 | 49篇 |
2003年 | 32篇 |
2002年 | 34篇 |
2001年 | 23篇 |
2000年 | 29篇 |
1999年 | 29篇 |
1998年 | 14篇 |
1997年 | 15篇 |
1996年 | 13篇 |
1995年 | 14篇 |
1994年 | 16篇 |
1993年 | 10篇 |
1992年 | 25篇 |
1991年 | 16篇 |
1990年 | 18篇 |
1989年 | 15篇 |
1988年 | 11篇 |
1985年 | 8篇 |
1983年 | 11篇 |
1979年 | 6篇 |
1977年 | 8篇 |
1976年 | 6篇 |
1975年 | 8篇 |
1974年 | 7篇 |
1973年 | 7篇 |
1972年 | 11篇 |
1971年 | 9篇 |
1970年 | 6篇 |
1969年 | 7篇 |
1967年 | 6篇 |
1966年 | 9篇 |
排序方式: 共有1372条查询结果,搜索用时 15 毫秒
151.
The RNA ligase RtcB is conserved in all domains of life and is essential for tRNA maturation in archaea and metazoa. Here we show that bacterial and archaeal RtcB catalyze the GTP-dependent ligation of RNA with 3'-phosphate and 5'-hydroxyl termini. Reactions with analogues of RNA and GTP suggest a mechanism in which RtcB heals the 3'-phosphate terminus by forming a 2',3'-cyclic phosphate before joining it to the 5'-hydroxyl group of a second RNA strand. Thus, RtcB can ligate RNA cleaved by RNA endonucleases, which generate 2',3'-cyclic phosphate and then 3'-phosphate termini on one strand, and a 5'-hydroxyl terminus on another strand. 相似文献
152.
Prashant V. Desai Thomas J. Raub Maria-Jesus Blanco 《Bioorganic & medicinal chemistry letters》2012,22(21):6540-6548
The requirement to cross a biological membrane can be a complex process especially if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramolecular H-bonds to increase membrane permeability and/or decrease P-gp efflux. 相似文献
153.
Castellanos María Eugenia Bardají Azucena Menegon Michela Mayor Alfredo Desai Meghna Severini Carlo Menéndez Clara Padilla Norma 《Malaria journal》2012,11(1):1-5
Background
To document the status of imported malaria infections and estimate the costs of treating of patients hospitalized with the diagnosis of imported malaria in the Slovak Republic during 2003 to 2008.Case study
Calculating and comparing the direct and indirect costs of treatment of patients diagnosed with imported malaria (ICD-10: B50 - B54) who used and not used chemoprophylaxis. The target sample included 19 patients diagnosed with imported malaria from 2003 to 2008, with 11 whose treatment did not include chemoprophylaxis and eight whose treatment did.Results
The mean direct cost of malaria treatment for patients without chemoprophylaxis was 1,776.0 EUR, and the mean indirect cost 524.2 EUR. In patients with chemoprophylaxis the mean direct cost was 405.6 EUR, and the mean indirect cost 257.4 EUR.Conclusions
The analysis confirmed statistically-significant differences between the direct and indirect costs of treatment with and without chemoprophylaxis for patients with imported malaria. 相似文献154.
Association of coagulation activation with clinical complications in sickle cell disease 总被引:1,自引:0,他引:1
Ataga KI Brittain JE Desai P May R Jones S Delaney J Strayhorn D Hinderliter A Key NS 《PloS one》2012,7(1):e29786
Background
The contribution of hypercoagulability to the pathophysiology of sickle cell disease (SCD) remains poorly defined. We sought to evaluate the association of markers of coagulation and platelet activation with specific clinical complications and laboratory variables in patients with SCD.Design and Methods
Plasma markers of coagulation activation (D-dimer and TAT), platelet activation (soluble CD40 ligand), microparticle-associated tissue factor (MPTF) procoagulant activity and other laboratory variables were obtained in a cohort of patients with SCD. Tricuspid regurgitant jet velocity was determined by Doppler echocardiography and the presence/history of clinical complications was ascertained at the time of evaluation, combined with a detailed review of the medical records.Results
No significant differences in the levels of D-dimer, TAT, soluble CD40 ligand, and MPTF procoagulant activity were observed between patients in the SS/SD/Sβ0 thalassemia and SC/Sβ+ thalassemia groups. Both TAT and D-dimer were significantly correlated with measures of hemolysis (lactate dehydrogenase, indirect bilirubin and hemoglobin) and soluble vascular cell adhesion molecule-1. In patients in the SS/SD/Sβ0 thalassemia group, D-dimer was associated with a history of stroke (p = 0.049), TAT was associated with a history of retinopathy (p = 0.0176), and CD40 ligand was associated with the frequency of pain episodes (p = 0.039). In multivariate analyses, D-dimer was associated with reticulocyte count, lactate dehydrogenase, NT-proBNP and history of stroke; soluble CD40 ligand was associated with WBC count and platelet count; and MPTF procoagulant activity was associated with hemoglobin and history of acute chest syndrome.Conclusions
This study supports the association of coagulation activation with hemolysis in SCD. The association of D-dimer with a history of stroke suggests that coagulation activation may contribute to the pathophysiology of stroke in clinically severe forms of SCD. More research is needed to evaluate the contribution of coagulation and platelet activation to clinical complications in SCD. 相似文献155.
Effects of biotic disturbances on forest carbon cycling in the United States and Canada 总被引:2,自引:0,他引:2
Jeffrey A. Hicke Craig D. Allen Ankur R. Desai Michael C. Dietze Ronald J. Hall Edward H. Hogg Daniel M. Kashian David Moore Kenneth F. Raffa Rona N. Sturrock James Vogelmann 《Global Change Biology》2012,18(1):7-34
Forest insects and pathogens are major disturbance agents that have affected millions of hectares in North America in recent decades, implying significant impacts to the carbon (C) cycle. Here, we review and synthesize published studies of the effects of biotic disturbances on forest C cycling in the United States and Canada. Primary productivity in stands was reduced, sometimes considerably, immediately following insect or pathogen attack. After repeated growth reductions caused by some insects or pathogens or a single infestation by some bark beetle species, tree mortality occurred, altering productivity and decomposition. In the years following disturbance, primary productivity in some cases increased rapidly as a result of enhanced growth by surviving vegetation, and in other cases increased slowly because of lower forest regrowth. In the decades following tree mortality, decomposition increased as a result of the large amount of dead organic matter. Net ecosystem productivity decreased immediately following attack, with some studies reporting a switch to a C source to the atmosphere, and increased afterward as the forest regrew and dead organic matter decomposed. Large variability in C cycle responses arose from several factors, including type of insect or pathogen, time since disturbance, number of trees affected, and capacity of remaining vegetation to increase growth rates following outbreak. We identified significant knowledge gaps, including limited understanding of carbon cycle impacts among different biotic disturbance types (particularly pathogens), their impacts at landscape and regional scales, and limited capacity to predict disturbance events and their consequences for carbon cycling. We conclude that biotic disturbances can have major impacts on forest C stocks and fluxes and can be large enough to affect regional C cycling. However, additional research is needed to reduce the uncertainties associated with quantifying biotic disturbance effects on the North American C budget. 相似文献
156.
Knight R Jansson J Field D Fierer N Desai N Fuhrman JA Hugenholtz P van der Lelie D Meyer F Stevens R Bailey MJ Gordon JI Kowalchuk GA Gilbert JA 《Nature biotechnology》2012,30(6):513-520
Metagenomics holds enormous promise for discovering novel enzymes and organisms that are biomarkers or drivers of processes relevant to disease, industry and the environment. In the past two years, we have seen a paradigm shift in metagenomics to the application of cross-sectional and longitudinal studies enabled by advances in DNA sequencing and high-performance computing. These technologies now make it possible to broadly assess microbial diversity and function, allowing systematic investigation of the largely unexplored frontier of microbial life. To achieve this aim, the global scientific community must collaborate and agree upon common objectives and data standards to enable comparative research across the Earth's microbiome. Improvements in comparability of data will facilitate the study of biotechnologically relevant processes, such as bioprospecting for new glycoside hydrolases or identifying novel energy sources. 相似文献
157.
Background
The antithrombin–heparin/heparan sulfate (H/HS) and thrombin–H/HS interactions are recognized as prototypic specific and non-specific glycosaminoglycan (GAG)–protein interactions, respectively. The fundamental structural basis for the origin of specificity, or lack thereof, in these interactions remains unclear. The availability of multiple co-crystal structures facilitates a structural analysis that challenges the long-held belief that the GAG binding sites in antithrombin and thrombin are essentially similar with high solvent exposure and shallow surface characteristics.Methodology
Analyses of solvent accessibility and exposed surface areas, gyrational mobility, symmetry, cavity shape/size, conserved water molecules and crystallographic parameters were performed for 12 X-ray structures, which include 12 thrombin and 16 antithrombin chains. Novel calculations are described for gyrational mobility and prediction of water loci and conservation.Results
The solvent accessibilities and gyrational mobilities of arginines and lysines in the binding sites of the two proteins reveal sharp contrasts. The distribution of positive charges shows considerable asymmetry in antithrombin, but substantial symmetry for thrombin. Cavity analyses suggest the presence of a reasonably sized bifurcated cavity in antithrombin that facilitates a firm ‘hand-shake’ with H/HS, but with thrombin, a weaker ‘high-five’. Tightly bound water molecules were predicted to be localized in the pentasaccharide binding pocket of antithrombin, but absent in thrombin. Together, these differences in the binding sites explain the major H/HS recognition characteristics of the two prototypic proteins, thus affording an explanation of the specificity of binding. This provides a foundation for understanding specificity of interaction at an atomic level, which will greatly aid the design of natural or synthetic H/HS sequences that target proteins in a specific manner. 相似文献158.
L Sun O Liu J Desai F Karbassi MA Sylvain A Shi Z Zhou CE Rocheleau BD Grant 《PLoS genetics》2012,8(7):e1002785
Rac1 is a founding member of the Rho-GTPase family and a key regulator of membrane remodeling. In the context of apoptotic cell corpse engulfment, CED-10/Rac1 acts with its bipartite guanine nucleotide exchange factor, CED-5/Dock180-CED-12/ELMO, in an evolutionarily conserved pathway to promote phagocytosis. Here we show that in the context of the Caenorhabditis elegans intestinal epithelium CED-10/Rac1, CED-5/Dock180, and CED-12/ELMO promote basolateral recycling. Furthermore, we show that CED-10 binds to the RAB-5 GTPase activating protein TBC-2, that CED-10 contributes to recruitment of TBC-2 to endosomes, and that recycling cargo is trapped in recycling endosomes in ced-12, ced-10, and tbc-2 mutants. Expression of GTPase defective RAB-5(Q78L) also traps recycling cargo. Our results indicate that down-regulation of early endosome regulator RAB-5/Rab5 by a CED-5, CED-12, CED-10, TBC-2 cascade is an important step in the transport of cargo through the basolateral recycling endosome for delivery to the plasma membrane. 相似文献
159.
McIntosh JR Grishchuk EL Morphew MK Efremov AK Zhudenkov K Volkov VA Cheeseman IM Desai A Mastronarde DN Ataullakhanov FI 《Cell》2008,135(2):322-333
Kinetochores of mitotic chromosomes are coupled to spindle microtubules in ways that allow the energy from tubulin dynamics to drive chromosome motion. Most kinetochore-associated microtubule ends display curving "protofilaments," strands of tubulin dimers that bend away from the microtubule axis. Both a kinetochore "plate" and an encircling, ring-shaped protein complex have been proposed to link protofilament bending to poleward chromosome motion. Here we show by electron tomography that slender fibrils connect curved protofilaments directly to the inner kinetochore. Fibril-protofilament associations correlate with a local straightening of the flared protofilaments. Theoretical analysis reveals that protofilament-fibril connections would be efficient couplers for chromosome motion, and experimental work on two very different kinetochore components suggests that filamentous proteins can couple shortening microtubules to cargo movements. These analyses define a ring-independent mechanism for harnessing microtubule dynamics directly to chromosome movement. 相似文献
160.
Mullen DG Desai AM Waddell JN Cheng XM Kelly CV McNerny DQ Majoros IJ Baker JR Sander LM Orr BG Banaszak Holl MM 《Bioconjugate chemistry》2008,19(9):1748-1752
Stochastic synthesis of a ligand coupled to a nanoparticle results in a distribution of populations with different numbers of ligands per nanoparticle. This distribution was resolved and quantified using HPLC and is in excellent agreement with the ligand/nanoparticle average measured by 1H NMR, gel permeation chromatography (GPC), and potentiometric titration, and yet significantly more disperse than commonly held perceptions of monodispersity. Two statistical models were employed to confirm that the observed heterogeneity is consistent with theoretical expectations. 相似文献