全文获取类型
收费全文 | 333篇 |
免费 | 40篇 |
国内免费 | 2篇 |
出版年
2022年 | 2篇 |
2021年 | 2篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 8篇 |
2014年 | 14篇 |
2013年 | 12篇 |
2012年 | 24篇 |
2011年 | 18篇 |
2010年 | 14篇 |
2009年 | 14篇 |
2008年 | 13篇 |
2007年 | 19篇 |
2006年 | 15篇 |
2005年 | 17篇 |
2004年 | 15篇 |
2003年 | 10篇 |
2002年 | 9篇 |
2001年 | 12篇 |
2000年 | 14篇 |
1999年 | 13篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1995年 | 8篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1992年 | 16篇 |
1991年 | 10篇 |
1990年 | 11篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 8篇 |
1985年 | 1篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1972年 | 1篇 |
1966年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有375条查询结果,搜索用时 15 毫秒
21.
Lipoproteins produced by ApoE-/- astrocytes infected with adenovirus expressing human ApoE 总被引:1,自引:0,他引:1
We have developed an astrocyte cell culture system that is attractive for the study of apoE structure and its impact on astrocyte lipoproteins and neuronal function. Primary astrocytes from apoE-/- mice were infected with adenovirus expressing apoE3 or apoE4 and the nascent lipoproteins secreted were characterized. The nascent apoE-containing astrocyte particles were predominantly the size of plasma high density lipoprotein (HDL). ApoE4, in contrast to apoE3, appeared to be distributed in two distinct lipoprotein peaks and the apoE4-containing lipoproteins contained significantly more radiolabeled triglyceride. On electron micrographs the astrocyte particles were both discoidal and spherical in shape with a prevalence of stacked discs in apoE3 particles, but single discs and larger spheres in apoE4 particles. The apoE4 discs were significantly wider than apoE3 discs. These properties of the astrocyte lipoproteins are similar to those obtained from apoE isoform transgenic mice. Astrocyte lipoproteins containing apoE3, but not apoE4, stimulated neurite outgrowth in Neuro-2a cells. These studies suggest that the isoform-specific effects of apoE lipoproteins may involve differences in particle size and composition. Finally we demonstrate the usefulness of this system by expressing a truncated apoE3 (delta202-299) mutant and show preliminary data indicating that a liver X receptor agonist promotes HDL output by the astrocytes without an increase in apoE in the media. This cell culture system is more flexible and allows for more rapid expression of apoE mutants. 相似文献
22.
It is commonly believed that colonization of early-season cotton, Gossypium hirsutum L., by overwintered boll weevils, Anthonomus grandis grandis Boheman, is concentrated on field margins. However, supporting experimental evidence is not available. In 1999 and 2000, we examined colonization patterns of overwintered boll weevils in Central Texas cotton on the bases of adult collections by a pneumatic sampler and hand collections of abscised infested squares. Samples were taken from sites arranged in a grid that extended inward >70 m from the field margin. Adults were collected from shortly after seedling emergence until the flowering stage, and infested squares were collected during the one-third grown square stage. Despite numerical trends, the numbers of adult weevils collected were not significantly different between years or sexes, or among plant phenological stages. Field-to-field variation among collections was considerable and likely prevented detection of differences among these factors. Spatial patterns represented by adult weevil and infested square collections were examined by logistic regressions fitted to the respective probabilities of weevil detection at each designated sample site. Although we observed trends for slightly decreased probability of weevil detection with increased distance from the field margin, these trends were too weak to be demonstrated statistically. Our results indicate the boll weevil does not consistently exhibit a strong edge-oriented colonization pattern, and that management tactics that are predicated on these patterns, such as border sprays, should be used with caution. 相似文献
23.
CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
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)
Astuto LM Bork JM Weston MD Askew JW Fields RR Orten DJ Ohliger SJ Riazuddin S Morell RJ Khan S Riazuddin S Kremer H van Hauwe P Moller CG Cremers CW Ayuso C Heckenlively JR Rohrschneider K Spandau U Greenberg J Ramesar R Reardon W Bitoun P Millan J Legge R Friedman TB Kimberling WJ 《American journal of human genetics》2002,71(2):262-275
Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. 相似文献
24.
Erica J Reschly Mary G Sorci-Thomas W Sean Davidson Stephen C Meredith Catherine A Reardon Godfrey S Getz 《The Journal of biological chemistry》2002,277(12):9645-9654
Mice have a monodisperse high density lipoprotein (HDL) profile, whereas humans have two major subfractions designated HDL(2) and HDL(3). Human apoA-I transgenic mice exhibit a human-like HDL profile, indicating that the amino acid sequence of apoA-I is a determinant of the HDL profile. Comparison of the primary sequence of mouse and human apoA-I and the previously designated "hinge" domain of apoA-I led us to hypothesize that alpha-helices 7 and 8 (7/8) are determinants of HDL subclass distribution. The following proteins were expressed in Escherichia coli: human apoA-I, T7-hAI; mouse apoA-I, T7-mAI; chimeric human apoA-I containing murine helices 7/8 in place of human helices 7/8, T7-hAI(m7/8); and the reciprocal chimera, T7-mAI(h7/8). The recombinant proteins were examined for their association with human plasma HDL subclasses. The results demonstrated that T7-hAI bound HDL(2) and HDL(3) equally well, whereas T7-mAI bound to HDL(2) preferentially. T7-hAI(m7/8) behaved like T7-mAI, and T7-mAI(h7/8) behaved like T7-hAI. Thus, alpha-helices 7/8 are strong contributors to the pattern of HDL subclass association. Self-association, alpha-helicity, cholesterol efflux, and lecithin-cholesterol acyltransferase activity of the recombinant proteins were also assessed. Human apoA-I self-associates more and activates human lecithin-cholesterol acyltransferase better than mouse apoA-I. These differential characteristics of human and mouse apoA-I are not dependent on helices 7/8. 相似文献
25.
Through metabolic engineering, new enzymatic pathways can be introduced into cells to enable or enhance production or biotransformation of chemicals. However, these changes have physiological consequences that can be important but are not well understood. Here we describe the use of two-dimensional gel electrophoresis (2-DE) to detect changes in the proteome of Escherichia coli cells that have been engineered to transform the pollutant trichloroethene (TCE) with the enzyme toluene o-monooxygenase (TOM). Comparison of 2-DE gels (isoelectric point range 4-7) for E. coli cells with and without the ability to synthesize TOM revealed 31 new proteins in TOM-containing cells as well as nine proteins not detected in those cells but present in the plasmid control strain. Exposure of TOM-containing cells to TCE led to the synthesis of four new proteins and the loss of only one protein. Thus, this example of metabolic engineering has a substantial and complex impact on the physiology of these cells that was clearly revealed using a proteomic approach. 相似文献
26.
Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene 总被引:5,自引:0,他引:5
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)
Hagan DM Ross AJ Strachan T Lynch SA Ruiz-Perez V Wang YM Scambler P Custard E Reardon W Hassan S Nixon P Papapetrou C Winter RM Edwards Y Morrison K Barrow M Cordier-Alex MP Correia P Galvin-Parton PA Gaskill S Gaskin KJ Garcia-Minaur S Gereige R Hayward R Homfray T 《American journal of human genetics》2000,66(5):1504-1515
The HLXB9 homeobox gene was recently identified as a locus for autosomal dominant Currarino syndrome, also known as hereditary sacral agenesis (HSA). This gene specifies a 403-amino acid protein containing a homeodomain preceded by a very highly conserved 82-amino acid domain of unknown function; the remainder of the protein is not well conserved. Here we report an extensive mutation survey that has identified mutations in the HLXB9 gene in 20 of 21 patients tested with familial Currarino syndrome. Mutations were also detected in two of seven sporadic Currarino syndrome patients; the remainder could be explained by undetected mosaicism for an HLXB9 mutation or by genetic heterogeneity in the sporadic patients. Of the mutations identified in the 22 index patients, 19 were intragenic and included 11 mutations that could lead to the introduction of a premature termination codon. The other eight mutations were missense mutations that were significantly clustered in the homeodomain, resulting, in each patient, in nonconservative substitution of a highly conserved amino acid. All of the intragenic mutations were associated with comparable phenotypes. The only genotype-phenotype correlation appeared to be the occurrence of developmental delay in the case of three patients with microdeletions. HLXB9 expression was analyzed during early human development in a period spanning Carnegie stages 12-21. Signal was detected in the basal plate of the spinal cord and hindbrain and in the pharynx, esophagus, stomach, and pancreas. Significant spatial and temporal expression differences were evident when compared with expression of the mouse Hlxb9 gene, which may partly explain the significant human-mouse differences in mutant phenotype. 相似文献
27.
Cady CT Lahn M Vollmer M Tsuji M Seo SJ Reardon CL O'Brien RL Born WK 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(4):1790-1798
Random heterocopolymers of glutamic acid and tyrosine (pEY) evoke strong, genetically controlled immune responses in certain mouse strains. We found that pE50Y50 also stimulated polyclonal proliferation of normal gamma delta, but not alpha beta, T cells. Proliferation of gamma delta T cells did not require prior immunization with this Ag nor the presence of alpha beta T cells, but was enhanced by IL-2. The gamma delta T cell response proceeded in the absence of accessory cells, MHC class II, beta 2-microglobulin, or TAP-1, suggesting that Ag presentation by MHC class I/II molecules and peptide processing are not required. Among normal splenocytes, as with gamma delta T cell hybridomas, the response was strongest with V gamma 1+ gamma delta T cells, and in comparison with related polypeptides, pE50Y50 provided the strongest stimulus for these cells. TCR gene transfer into a TCR-deficient alpha beta T cell showed that besides the TCR, no other components unique to gamma delta T cells are needed. Furthermore, interactions between only the T cells and pE50Y50 were sufficient to bring about the response. Thus, pE50Y50 elicited a response distinct from those of T cells to processed/presented peptides or superantigens, consistent with a mechanism of Ig-like ligand recognition of gamma delta T cells. Direct stimulation by ligands resembling pE50Y50 may thus selectively evoke contributions of gamma delta T cells to the host response. 相似文献
28.
F Goodman M L Giovannucci-Uzielli C Hall W Reardon R Winter P Scambler 《American journal of human genetics》1998,63(4):992-1000
Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation consisting of 3/4 syndactyly in the hands and 4/5 syndactyly in the feet, with digit duplication in the syndactylous web. The condition recently has been found to result from different-sized expansions of an amino-terminal polyalanine tract in HOXD13. We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype. In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. This phenotype has not been reported in any mice with genetic modifications of the HoxD gene cluster. The two different deletions affect the first exon and the homeobox, respectively, in each case producing frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the affected genes may encode proteins that exert a dominant negative or novel effect, they are most likely to act as null alleles. Either possibility has interesting implications for the role of HOXD13 in human autopod development. 相似文献
29.