全文获取类型
收费全文 | 3828篇 |
免费 | 339篇 |
国内免费 | 2篇 |
出版年
2022年 | 24篇 |
2021年 | 53篇 |
2020年 | 52篇 |
2019年 | 51篇 |
2018年 | 45篇 |
2017年 | 53篇 |
2016年 | 99篇 |
2015年 | 149篇 |
2014年 | 179篇 |
2013年 | 229篇 |
2012年 | 296篇 |
2011年 | 293篇 |
2010年 | 185篇 |
2009年 | 168篇 |
2008年 | 229篇 |
2007年 | 237篇 |
2006年 | 225篇 |
2005年 | 234篇 |
2004年 | 240篇 |
2003年 | 199篇 |
2002年 | 205篇 |
2001年 | 32篇 |
2000年 | 22篇 |
1999年 | 45篇 |
1998年 | 52篇 |
1997年 | 46篇 |
1996年 | 33篇 |
1995年 | 28篇 |
1994年 | 26篇 |
1993年 | 41篇 |
1992年 | 31篇 |
1991年 | 23篇 |
1990年 | 27篇 |
1989年 | 30篇 |
1988年 | 23篇 |
1987年 | 19篇 |
1986年 | 21篇 |
1985年 | 16篇 |
1984年 | 18篇 |
1983年 | 21篇 |
1982年 | 17篇 |
1981年 | 19篇 |
1980年 | 9篇 |
1979年 | 16篇 |
1978年 | 12篇 |
1977年 | 13篇 |
1976年 | 10篇 |
1974年 | 11篇 |
1968年 | 6篇 |
1967年 | 6篇 |
排序方式: 共有4169条查询结果,搜索用时 31 毫秒
991.
Bertrand Lell Selidji Agnandji Isabelle von Glasenapp Sonja Haertle Sunny Oyakhiromen Saadou Issifou Johan Vekemans Amanda Leach Marc Lievens Marie-Claude Dubois Marie-Ange Demoitie Terrell Carter Tonya Villafana W. Ripley Ballou Joe Cohen Peter G. Kremsner 《PloS one》2009,4(10)
Background
The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion – based formulation (AS02) and a formulation based on liposomes (AS01).Methods & Principal Findings
In this Phase II, double-blind study (), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01E or RTS,S/AS02D, on a 0–1–2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02D/AS01E) of 0.88 (95% CI: 0.68–1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated. NCT00307021Conclusions
RTS,S/AS01E proved similarly as well tolerated and immunogenic as RTS,S/AS02D, completing an essential step in the age de-escalation process within the RTS,S clinical development plan.Trial Registration
ClinicalTrials.gov. NCT00307021相似文献992.
Jun Peng Jingzhen Ding Chibing Tan Bruce Baggenstoss Zhi Zhang Suzanne M. Lapolla Jialing Lin 《Apoptosis : an international journal on programmed cell death》2009,14(10):1145-1153
Both pro-apoptotic Bax and anti-apoptotic Bcl-2 are structurally homologous to the pore-forming domain of bacterial toxins.
Bax proteins oligomerize in the mitochondrial outer membranes forming pores that release cytochrome c from the mitochondrial
intermembrane space. Bcl-2 proteins also form pores that, however, are much smaller than the Bax pore. It is unknown whether
Bcl-2 forms monomeric or oligomeric pores. Here, we characterized the Bcl-2 pore formation in liposomes using biophysical
and biochemical techniques. The results show that the Bcl-2 pore enlarges as the concentration of Bcl-2 increases, suggesting
that the pore is formed by Bcl-2 oligomers. As expected from oligomerization-mediated pore-formation, the small pores are
formed earlier than the large ones. Bcl-2 oligomers form pores faster than the monomer, indicating that the oligomerization
constitutes an intermediate step of the pore formation. A Bcl-2 mutant with higher affinity for oligomerization forms pores
faster than wild type Bcl-2. Bcl-2 oligomers were detected in the liposomal membranes under conditions that Bcl-2 forms pores,
and the extent of oligomerization was positively correlated with the pore-forming activity. Therefore, Bcl-2 oligomerizes
in membranes forming pores, but the extent of oligomerization and the size of the resulting pores are much smaller than that
of Bax, supporting the model that Bcl-2 is a defective Bax. 相似文献
993.
The drastic increase in the cost for discovering and developing a new drug along with the high attrition rate of development candidates led to shifting drug‐discovery strategy to parallel assessment of comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking into consideration the interplay among profiling parameters. In particular, this article will review recent advances in accurate assessment of solubility and other physicochemical parameters. The proper interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational optimization of drug candidates in drug discovery. The impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented. 相似文献
994.
Kebing Yu Anthony Sabelli Lisa DeKeukelaere Richard Park Suzanne Sindi Constantine A. Gatsonis Arthur Salomon 《Proteomics》2009,9(11):3115-3125
As proteomic data sets increase in size and complexity, the necessity for database‐centric software systems able to organize, compare, and visualize all the proteomic experiments in a lab grows. We recently developed an integrated platform called high‐throughput autonomous proteomic pipeline (HTAPP) for the automated acquisition and processing of quantitative proteomic data, and integration of proteomic results with existing external protein information resources within a lab‐based relational database called PeptideDepot. Here, we introduce the peptide validation software component of this system, which combines relational database‐integrated electronic manual spectral annotation in Java with a new software tool in the R programming language for the generation of logistic regression spectral models from user‐supplied validated data sets and flexible application of these user‐generated models in automated proteomic workflows. This logistic regression spectral model uses both variables computed directly from SEQUEST output in addition to deterministic variables based on expert manual validation criteria of spectral quality. In the case of linear quadrupole ion trap (LTQ) or LTQ‐FTICR LC/MS data, our logistic spectral model outperformed both XCorr (242% more peptides identified on average) and the X!Tandem E‐value (87% more peptides identified on average) at a 1% false discovery rate estimated by decoy database approach. 相似文献
995.
Question. Can strategic burning, targeting differing ecological characteristics of native and exotic species, facilitate restoration of native understorey in weed‐invaded temperate grassy eucalypt woodlands? Location. Gippsland Plains, eastern Victoria, Australia. Methods. In a replicated, 5‐year experimental trial, the effects of repeated spring or autumn burning were evaluated for native and exotic plants in a representative, degraded Eucalyptus tereticornis grassy woodland. Treatments aimed to reduce seed banks and modify establishment conditions of exotic annual grasses, and to exhaust vegetative reserves of exotic perennial grasses. Treatments were applied to three grassland patch types, dominated by the native grass Austrodanthonia caespitosa, ubiquitous exotic annuals, or the common exotic perennial grass Paspalum dilatatum. Results. The dominant native grass Austrodanthonia caespitosa and native forbs were resilient to repeated fires, and target exotic annuals and perennials were suppressed differentially by autumn and spring fires. Exotic annuals were also suppressed by drought, reducing the overall treatment effects but indicating important opportunities for restoration. The initially sparse exotic geophyte Romulea rosea increased in cover with fire and the impact of this species on native forbs requires further investigation. There was minimal increase in diversity of subsidiary natives with fire, probably owing to lack of propagules. Conclusions. While fire is often considered to increase ecosystem invasibility, our study showed that strategic use of fire, informed by the relative responses of available native and exotic taxa, is potentially an effective step towards restoration of weed‐invaded temperate eucalypt woodlands. 相似文献
996.
997.
Lisa F. Barcellos Suzanne L. May Patricia P. Ramsay Hong L. Quach Julie A. Lane Joanne Nititham Janelle A. Noble Kimberly E. Taylor Diana L. Quach Sharon A. Chung Jennifer A. Kelly Kathy L. Moser Timothy W. Behrens Michael F. Seldin Glenys Thomson John B. Harley Patrick M. Gaffney Lindsey A. Criswell 《PLoS genetics》2009,5(10)
A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10−13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation. 相似文献
998.
The growing trend of employing multiproduct manufacturing facilities along with the randomness inherent in the biopharmaceutical manufacturing environment is creating significant scheduling and planning challenges for the biopharmaceutical industry. This work focuses on capturing the effect of uncertainty in fermentation titers when optimizing the planning of biopharmaceutical manufacturing campaigns. A mixed integer linear programming (MILP) model based on previous work is derived via chance constrained programming (CCP). The methodology is applied to two illustrative examples, and the results are compared with those from the deterministic model and a multiscenario model accompanied by an iterative construction algorithm. The computational results indicate that the proposed methodology offers significant improvements in solution quality over the compared approaches and presents an opportunity for biopharmaceutical manufacturers to make better medium term planning decisions, particularly under uncertain manufacturing conditions. 相似文献
999.
Prokaryotic type II and type III pantothenate kinases: The same monomer fold creates dimers with distinct catalytic properties 总被引:3,自引:0,他引:3
Hong BS Yun MK Zhang YM Chohnan S Rock CO White SW Jackowski S Park HW Leonardi R 《Structure (London, England : 1993)》2006,14(8):1251-1261
Three distinct isoforms of pantothenate kinase (CoaA) in bacteria catalyze the first step in coenzyme A biosynthesis. The structures of the type II (Staphylococcus aureus, SaCoaA) and type III (Pseudomonas aeruginosa, PaCoaA) enzymes reveal that they assemble nearly identical subunits with actin-like folds into dimers that exhibit distinct biochemical properties. PaCoaA has a fully enclosed pantothenate binding pocket and requires a monovalent cation to weakly bind ATP in an open cavity that does not interact with the adenine nucleotide. Pantothenate binds to an open pocket in SaCoaA that strongly binds ATP by using a classical P loop architecture coupled with specific interactions with the adenine moiety. The PaCoaA*Pan binary complex explains the resistance of bacteria possessing this isoform to the pantothenamide antibiotics, and the similarity between SaCoaA and human pantothenate kinase 2 explains the molecular basis for the development of the neurodegenerative phenotype in three mutations in the human protein. 相似文献
1000.
Penélope González-Sampériz Suzanne A.G. Leroy Santiago Fernández María José Gil-García Blas Valero-Garcés 《Review of Palaeobotany and Palynology》2010,162(3):427-37
A palaeobotanical analysis of the Pleistocene floras and vegetation in the Iberian Peninsula shows the existence of patched landscapes with Pinus woodlands, deciduous and mixed forests, parklands (savannah-like), shrublands, steppes and grasslands. Extinctions of Arctotertiary woody taxa are recorded during the Early and Middle Pleistocene, but glacial refugia facilitated the survival of a number of temperate, Mediterranean and Ibero-North African woody angiosperms. The responses of Iberian vegetation to climatic changes during the Pleistocene have been spatially and temporarily complex, including rapid changes of vegetation in parallel to orbital and suborbital variability, and situations of multi-centennial resilience or accommodation to climatic changes. Regional characteristics emerged as soon as for the Middle Pleistocene, if not earlier: Ericaceae in the Atlantic coast indicating wetter climate, thermo-mediterranean elements in the south as currently, and broad-leaf trees in the northeastern. Overall, steppe landscapes and open Pinus woodlands prevailed over many continental regions during the cold spells of the Late Pleistocene. The maintenance of a high phytodiversity during the glacials was linked to several refuge zones in the coastal shelves of the Mediterranean and intramountainous valleys. Northern Iberia, especially on coastal areas, was also patched with populations of tree species, and this is not only documented by palaeobotanical data (pollen and charcoal) but also postulated by phylogeographical models. 相似文献