全文获取类型
收费全文 | 1292篇 |
免费 | 145篇 |
出版年
2023年 | 6篇 |
2022年 | 8篇 |
2021年 | 14篇 |
2019年 | 6篇 |
2018年 | 12篇 |
2017年 | 11篇 |
2016年 | 27篇 |
2015年 | 39篇 |
2014年 | 67篇 |
2013年 | 65篇 |
2012年 | 93篇 |
2011年 | 125篇 |
2010年 | 112篇 |
2009年 | 66篇 |
2008年 | 63篇 |
2007年 | 66篇 |
2006年 | 76篇 |
2005年 | 65篇 |
2004年 | 50篇 |
2003年 | 48篇 |
2002年 | 51篇 |
2001年 | 16篇 |
2000年 | 20篇 |
1999年 | 25篇 |
1998年 | 23篇 |
1997年 | 15篇 |
1996年 | 17篇 |
1995年 | 20篇 |
1994年 | 18篇 |
1993年 | 12篇 |
1992年 | 14篇 |
1991年 | 12篇 |
1990年 | 10篇 |
1989年 | 9篇 |
1988年 | 13篇 |
1987年 | 5篇 |
1986年 | 11篇 |
1985年 | 14篇 |
1984年 | 15篇 |
1983年 | 9篇 |
1982年 | 12篇 |
1981年 | 11篇 |
1980年 | 5篇 |
1979年 | 6篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1974年 | 5篇 |
1972年 | 6篇 |
1969年 | 5篇 |
1967年 | 6篇 |
排序方式: 共有1437条查询结果,搜索用时 15 毫秒
151.
Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4) 总被引:7,自引:0,他引:7
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Donaudy F Snoeckx R Pfister M Zenner HP Blin N Di Stazio M Ferrara A Lanzara C Ficarella R Declau F Pusch CM Nürnberg P Melchionda S Zelante L Ballana E Estivill X Van Camp G Gasparini P Savoia A 《American journal of human genetics》2004,74(4):770-776
Myosins have been implicated in various motile processes, including organelle translocation, ion-channel gating, and cytoskeleton reorganization. Different members of the myosin superfamily are responsible for syndromic and nonsyndromic hearing impairment in both humans and mice. MYH14 encodes one of the heavy chains of the class II nonmuscle myosins, and it is localized within the autosomal dominant hearing impairment (DFNA4) critical region. After demonstrating that MYH14 is highly expressed in mouse cochlea, we performed a mutational screening in a large series of 300 hearing-impaired patients from Italy, Spain, and Belgium and in a German kindred linked to DFNA4. This study allowed us to identify a nonsense and two missense mutations in large pedigrees, linked to DFNA4, as well as a de novo allele in a sporadic case. Absence of these mutations in healthy individuals was tested in 200 control individuals. These findings clearly demonstrate the role of MYH14 in causing autosomal dominant hearing loss and further confirm the crucial role of the myosin superfamily in auditive functions. 相似文献
152.
We previously discovered that BapA, a bacterial beta-peptidyl aminopeptidase, is able to hydrolyze two otherwise metabolically inert beta-peptides [Geueke B, Namoto K, Seebach D and Kohler H-PE (2005) J Bacteriol 187, 5910-5917]. Here, we describe the purification and characterization of two distinct bacterial beta-peptidyl aminopeptidases that originated from different environmental isolates. Both bapA genes encode a preprotein with a signal sequence and were flanked by ORFs that code for enzymes with similar predicted functions. To form the active enzymes, which had an (alphabeta)(4) quaternary structure, the preproteins needed to be cleaved into two subunits. The two beta-peptidyl aminopeptidases had 86% amino acid sequence identity, hydrolyzed a variety of beta-peptides and mixed beta/alpha-peptides, and exhibited unique substrate specificities. The prerequisite for peptides being accepted as substrates was the presence of a beta-amino acid at the N-terminus; peptide substrates with an N-terminal alpha-amino acid were not hydrolyzed at all. Both enzymes cleaved the peptide bond between the N-terminal beta-amino acid and the amino acid at the second position of tripeptidic substrates of the general structure H-betahXaa-Ile-betahTyr-OH according to the following preferences with regard to the side chain of the N-terminal beta-amino acid: aliphatic and aromatic > OH-containing > hydrogen, basic and polar. Experiments with the tripeptides H-d-betahVal-Ile-betahTyr-OH and H-betahVal-Ile-betahTyr-OH demonstrated that the two BapA enzymes preferred the peptide with the l-configuration of the N-terminal beta-homovaline residue as a substrate. 相似文献
153.
154.
Hesso Farhan Markus W. Wendeler Sandra Mitrovic Eugenio Fava Yael Silberberg Roded Sharan Marino Zerial Hans-Peter Hauri 《The Journal of cell biology》2010,189(6):997-1011
To what extent the secretory pathway is regulated by cellular signaling is unknown. In this study, we used RNA interference to explore the function of human kinases and phosphatases in controlling the organization of and trafficking within the secretory pathway. We identified 122 kinases/phosphatases that affect endoplasmic reticulum (ER) export, ER exit sites (ERESs), and/or the Golgi apparatus. Numerous kinases/phosphatases regulate the number of ERESs and ER to Golgi protein trafficking. Among the pathways identified, the Raf–MEK (MAPK/ERK [extracellular signal-regulated kinase] kinase)–ERK cascade, including its regulatory proteins CNK1 (connector enhancer of the kinase suppressor of Ras-1) and neurofibromin, controls the number of ERESs via ERK2, which targets Sec16, a key regulator of ERESs and COPII (coat protein II) vesicle biogenesis. Our analysis reveals an unanticipated complexity of kinase/phosphatase-mediated regulation of the secretory pathway, uncovering a link between growth factor signaling and ER export. 相似文献
155.
The parasite-host cell interface is a key compartment of vacuolated intracellular pathogens but little is known about its molecular composition and architecture. We used in vivo cross-linking to analyse the parasite-host cell interface of asexual stages of the most virulent human malaria parasite Plasmodium falciparum. We show that the integral membrane protein members of the early transcribed membrane protein (ETRAMP) family and exported protein 1 (EXP-1), which are components of the parasite-host cell interface, form complexes of oligomeric arrays in this compartment. The most notable feature is that each ETRAMP member and EXP-1 define separate arrays, demonstrating that the protein distribution in this membrane is non-random. Each of three recombinant ETRAMPs readily oligomerized in bacterial membranes, confirming that these arrays can form independently of other Plasmodium proteins. We propose that the malaria parasite-host cell interface contains patches of integral membrane proteins forming a mosaic of different microdomains in this membrane. 相似文献
156.
Borgwardt KM Gretton A Rasch MJ Kriegel HP Schölkopf B Smola AJ 《Bioinformatics (Oxford, England)》2006,22(14):e49-e57
MOTIVATION: Many problems in data integration in bioinformatics can be posed as one common question: Are two sets of observations generated by the same distribution? We propose a kernel-based statistical test for this problem, based on the fact that two distributions are different if and only if there exists at least one function having different expectation on the two distributions. Consequently we use the maximum discrepancy between function means as the basis of a test statistic. The Maximum Mean Discrepancy (MMD) can take advantage of the kernel trick, which allows us to apply it not only to vectors, but strings, sequences, graphs, and other common structured data types arising in molecular biology. RESULTS: We study the practical feasibility of an MMD-based test on three central data integration tasks: Testing cross-platform comparability of microarray data, cancer diagnosis, and data-content based schema matching for two different protein function classification schemas. In all of these experiments, including high-dimensional ones, MMD is very accurate in finding samples that were generated from the same distribution, and outperforms its best competitors. Conclusions: We have defined a novel statistical test of whether two samples are from the same distribution, compatible with both multivariate and structured data, that is fast, easy to implement, and works well, as confirmed by our experiments. AVAILABILITY: http://www.dbs.ifi.lmu.de/~borgward/MMD. 相似文献
157.
Nyfeler B Zhang B Ginsburg D Kaufman RJ Hauri HP 《Traffic (Copenhagen, Denmark)》2006,7(11):1473-1481
Exit of soluble secretory proteins from the endoplasmic reticulum (ER) can occur by receptor-mediated export as exemplified by blood coagulation factors V and VIII. Their efficient secretion requires the membrane lectin ER Golgi intermediate compartment protein-53 (ERGIC-53) and its soluble luminal interaction partner multiple coagulation factor deficiency protein 2 (MCFD2), which form a cargo receptor complex in the early secretory pathway. ERGIC-53 also interacts with the two lysosomal glycoproteins cathepsin Z and cathepsin C. Here, we tested the subunit interdependence and cargo selectivity of ERGIC-53 and MCFD2 by short interference RNA-based knockdown. In the absence of ERGIC-53, MCFD2 was secreted, whereas knocking down MCFD2 had no effect on the localization of ERGIC-53. Cargo binding properties of the ERGIC-53/MCFD2 complex were analyzed in vivo using yellow fluorescent protein fragment complementation. We found that MCFD2 is dispensable for the binding of cathepsin Z and cathepsin C to ERGIC-53. The results indicate that ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and suggest that MCFD2 is a recruitment factor for blood coagulation factors V and VIII. 相似文献
158.
The endoplasmic reticulum (ER) of higher eukaryotic cells is a dynamic network of interconnected membrane tubules that pervades almost the entire cytoplasm. On the basis of the morphological changes induced by the disruption of the cytoskeleton or molecular motor proteins, the commonly accepted model has emerged that microtubules and conventional kinesin (kinesin-1) are essential determinants in establishing and maintaining the structure of the ER by active membrane expansion. Surprisingly, very similar ER phenotypes have now been observed when the cytoskeleton-linking ER membrane protein of 63 kDa (CLIMP-63) is mutated, revealing stable attachment of ER membranes to the microtubular cytoskeleton as a novel requirement for ER maintenance. Additional recent findings suggest that ER maintenance also requires ongoing homotypic membrane fusion, possibly controlled by the p97/p47/VICP135 protein complex. Work on other proteins proposed to regulate ER structure, including huntingtin, the EF-hand Ca(2+)-binding protein p22, the vesicle-associated membrane protein-associated protein B and kinectin isoforms further contribute to the new emerging concept that ER shape is not only determined by motor driven processes but by a variety of different mechanisms. 相似文献
159.
Gangliosides are not essential for influenza virus infection 总被引:1,自引:0,他引:1
Matrosovich M Suzuki T Hirabayashi Y Garten W Webster RG Klenk HD 《Glycoconjugate journal》2006,23(1-2):107-113
Sialic acid is known to be an essential part of influenza virus receptors, but the specific identity of the receptor molecules
on target cells is still not defined. In particular, the relative roles played by cellular sialylglycoproteins and gangliosides
in virus entry into target cells remain unclear. To test whether gangliosides are essential for virus infection, we used the
GM-95 mutant cell line of mouse B16 melanoma which lacks synthesis of major glycosphingolipids including gangliosides. We
found that GM-95 cells grown in serum-containing medium harboured substantial amounts of ganglioside receptors for influenza
virus due to incorporation of serum gangliosides. To obtain ganglioside-free cells, we adapted GM-95 cells to growth in defined
serum-free (sf) medium. Ganglioside-free GM-95-sf cells could be infected by avian and human influenza A viruses and produced
infectious virus progeny demonstrating that gangliosides were neither absolutely necessary for the early nor for the late
stages of the infection. However, sensitivity of the GM-95-sf cells to the viruses was 2–4 times lower than that of the ganglioside-containing
parent cell line. Further studies are needed to specify whether this effect was due to the lack of gangliosides, neutral glycosphingolipids,
or other effects. 相似文献
160.
The hydrodistillates and solvent extracts of the fruit bodies of Ganoderma lucidum (Fr.) P. Karst. and Spongiporus leucomallellus (Murril) A. David were investigated. The constituents in both oils comprised hydrocarbons, monoterpenes, sesquiterpenes, and fatty acids. Major volatiles of G. lucidum were trans-anethol, R-(-)-linalool, S-(+)-carvone and alpha-bisabolol, while the essential oil of S. leucomallellus contained relatively large amounts of R-(-)-1-octene-3-ol, R-(-)-linalool, 1-hepten-3-one and (Z)-nerolidol. From the n-hexane extract of G. lucidum, the steroid ester ergosta-7,22-diene-3beta-yl pentadecanoate could be identified. From S. leucomallellus two constituents showing structures of 3,4-seco-lanostane type triterpene acids were identified as (+)-23-oxo-3,4-seco-lanosta-4(28),7(8),9(11),24(31)-tetraene-3,26-dicarboxylic acid and (+)-20-hydroxy-23-oxo-3,4-seco-lanosta-4(28),7(8),9(11),24(31)-tetraene3,26-dicarboxylic acid, respectively. Cytotoxicity and antimicrobial activity of selected compounds were investigated using standard tests. 相似文献