全文获取类型
收费全文 | 8370篇 |
免费 | 723篇 |
国内免费 | 1篇 |
出版年
2023年 | 47篇 |
2022年 | 111篇 |
2021年 | 215篇 |
2020年 | 137篇 |
2019年 | 152篇 |
2018年 | 183篇 |
2017年 | 151篇 |
2016年 | 241篇 |
2015年 | 439篇 |
2014年 | 468篇 |
2013年 | 569篇 |
2012年 | 716篇 |
2011年 | 643篇 |
2010年 | 435篇 |
2009年 | 409篇 |
2008年 | 525篇 |
2007年 | 482篇 |
2006年 | 431篇 |
2005年 | 367篇 |
2004年 | 320篇 |
2003年 | 345篇 |
2002年 | 303篇 |
2001年 | 100篇 |
2000年 | 78篇 |
1999年 | 113篇 |
1998年 | 68篇 |
1997年 | 75篇 |
1996年 | 49篇 |
1995年 | 61篇 |
1994年 | 52篇 |
1993年 | 51篇 |
1992年 | 59篇 |
1991年 | 52篇 |
1990年 | 41篇 |
1989年 | 40篇 |
1988年 | 46篇 |
1987年 | 27篇 |
1986年 | 28篇 |
1985年 | 35篇 |
1984年 | 31篇 |
1983年 | 28篇 |
1982年 | 27篇 |
1981年 | 23篇 |
1980年 | 21篇 |
1979年 | 34篇 |
1978年 | 21篇 |
1977年 | 22篇 |
1974年 | 36篇 |
1973年 | 19篇 |
1969年 | 19篇 |
排序方式: 共有9094条查询结果,搜索用时 156 毫秒
991.
Lines MA Huang L Schwartzentruber J Douglas SL Lynch DC Beaulieu C Guion-Almeida ML Zechi-Ceide RM Gener B Gillessen-Kaesbach G Nava C Baujat G Horn D Kini U Caliebe A Alanay Y Utine GE Lev D Kohlhase J Grix AW Lohmann DR Hehr U Böhm D;FORGE Canada Consortium Majewski J Bulman DE Wieczorek D Boycott KM 《American journal of human genetics》2012,90(2):369-377
Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. 相似文献
992.
Apirat Chaikuad Ivan Alfano Georgina Kerr Caroline E. Sanvitale Jan H. Boergermann James T. Triffitt Frank von Delft Stefan Knapp Petra Knaus Alex N. Bullock 《The Journal of biological chemistry》2012,287(44):36990-36998
Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling. 相似文献
993.
Tennstaedt A Pöpsel S Truebestein L Hauske P Brockmann A Schmidt N Irle I Sacca B Niemeyer CM Brandt R Ksiezak-Reding H Tirniceriu AL Egensperger R Baldi A Dehmelt L Kaiser M Huber R Clausen T Ehrmann M 《The Journal of biological chemistry》2012,287(25):20931-20941
Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed. 相似文献
994.
V Pierre G Martinez C Coutton J Delaroche S Yassine C Novella K Pernet-Gallay S Hennebicq PF Ray C Arnoult 《Development (Cambridge, England)》2012,139(16):2955-2965
Sperm-head elongation and acrosome formation, which take place during the last stages of spermatogenesis, are essential to produce competent spermatozoa that are able to cross the oocyte zona pellucida and to achieve fertilization. During acrosome biogenesis, acrosome attachment and spreading over the nucleus are still poorly understood and to date no proteins have been described to link the acrosome to the nucleus. We recently demonstrated that a deletion of DPY19L2, a gene coding for an uncharacterized protein, was responsible for a majority of cases of type I globozoospermia, a rare cause of male infertility that is characterized by the exclusive production of round-headed acrosomeless spermatozoa. Here, using Dpy19l2 knockout mice, we describe the cellular function of the Dpy19l2 protein. We demonstrate that the protein is expressed predominantly in spermatids with a very specific localization restricted to the inner nuclear membrane facing the acrosomal vesicle. We show that the absence of Dpy19l2 leads to the destabilization of both the nuclear dense lamina (NDL) and the junction between the acroplaxome and the nuclear envelope. Consequently, the acrosome and the manchette fail to be linked to the nucleus leading to the disruption of vesicular trafficking, failure of sperm nuclear shaping and eventually to the elimination of the unbound acrosomal vesicle. Finally, we show for the first time that Dpy19l3 proteins are also located in the inner nuclear envelope, therefore implying that the Dpy19 proteins constitute a new family of structural transmembrane proteins of the nuclear envelope. 相似文献
995.
Lee DK Van Norman JM Murphy C Adhikari E Reed JW Sieburth LE 《Development (Cambridge, England)》2012,139(4):805-815
Development is often coordinated by biologically active mobile compounds that move between cells or organs. Arabidopsis mutants with defects in the BYPASS1 (BPS1) gene overproduce an active mobile compound that moves from the root to the shoot and inhibits growth. Here, we describe two related Arabidopsis genes, BPS2 and BPS3. Analyses of single, double and triple mutants revealed that all three genes regulate production of the same mobile compound, the bps signal, with BPS1 having the largest role. The triple mutant had a severe embryo defect, including the failure to properly establish provascular tissue, the shoot meristem and the root meristem. Aberrant expression of PINFORMED1, DR5, PLETHORA1, PLETHORA2 and WUSCHEL-LIKE HOMEOBOX5 were found in heart-stage bps triple-mutant embryos. However, auxin-induced gene expression, and localization of the PIN1 auxin efflux transporter, were intact in bps1 mutants, suggesting that the primary target of the bps signal is independent of auxin response. Thus, the bps signal identifies a novel signaling pathway that regulates patterning and growth in parallel with auxin signaling, in multiple tissues and at multiple developmental stages. 相似文献
996.
997.
Leslie Jacquemin Pierre-Yves Pontalier Caroline Sablayrolles 《The International Journal of Life Cycle Assessment》2012,17(8):1028-1041
Purpose
Life cycle assessment (LCA) methodology is a well-established analytical method to quantify environmental impacts, which has been mainly applied to products. However, recent literature would suggest that it has also the potential as an analysis and design tool for processes, and stresses that one of the biggest challenges of this decade in the field of process systems engineering (PSE) is the development of tools for environmental considerations.Method
This article attempts to give an overview of the integration of LCA methodology in the context of industrial ecology, and focuses on the use of this methodology for environmental considerations concerning process design and optimization.Results
The review identifies that LCA is often used as a multi-objective optimization of processes: practitioners use LCA to obtain the inventory and inject the results into the optimization model. It also shows that most of the LCA studies undertaken on process analysis consider the unit processes as black boxes and build the inventory analysis on fixed operating conditions.Conclusions
The article highlights the interest to better assimilate PSE tools with LCA methodology, in order to produce a more detailed analysis. This will allow optimizing the influence of process operating conditions on environmental impacts and including detailed environmental results into process industry. 相似文献998.
999.
Malolactic fermentation (MLF) is an integral step in red winemaking, which in addition to deacidifying wine can also influence
the composition of volatile fermentation-derived compounds with concomitant affects on wine sensory properties. Long-established
winemaking protocols for MLF induction generally involve inoculation of bacteria starter cultures post alcoholic fermentation,
however, more recently there has been a trend to introduce bacteria earlier in the fermentation process. For the first time,
this study shows the impact of bacterial inoculation on wine quality parameters that define red wine, including wine colour
and phenolics, and volatile fermentation-derived compounds. This study investigates the effects of inoculating Shiraz grape
must with malolactic bacteria at various stages of alcoholic fermentation [beginning of alcoholic fermentation (co-inoculation,
with yeast), mid-alcoholic fermentation, at pressing and post alcoholic fermentation] on the kinetics of MLF and wine chemical
composition. Co-inoculation greatly reduced the overall fermentation time by up to 6 weeks, the rate of alcoholic fermentation
was not affected by the presence of bacteria and the fermentation-derived wine volatiles profile was distinct from wines produced
where bacteria were inoculated late or post alcoholic fermentation. An overall slight decrease in wine colour density observed
following MLF was not influenced by the MLF inoculation regime. However, there were differences in anthocyanin and pigmented
polymer composition, with co-inoculation exhibiting the most distinct profile. Differences in yeast and bacteria metabolism
at various stages in fermentation are proposed as the drivers for differences in volatile chemical composition. This study
demonstrates, with an in-depth analysis, that co-inoculation of yeast and bacteria in wine fermentation results in shorter
total vinification time and produces sound wines, thus providing the opportunity to stabilise wines more rapidly than traditional
inoculation regimes permit and thereby reducing potential for microbial spoilage. 相似文献
1000.
Morley AD King S Roberts B Lever S Teobald B Fisher A Cook T Parker B Wenlock M Phillips C Grime K 《Bioorganic & medicinal chemistry letters》2012,22(1):532-536
Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles. 相似文献