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101.
102.
Purpose
siRNA may be delivered as electrostatic complexes with cationic lipids (lipoplexes) or polycations (polyplexes). The purpose of this project was to determine the effect of cellular internalization mechanism(s) on siRNA-mediated gene silencing efficiency.Methods
Lipoplexes were formed comprising siRNA and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol and dioleoyl phosphatidylethanolamine (DOPE), and polyplexes comprised siRNA with polyethylenimine (PEI). During transfections, specific uptake mechanisms were inhibited by pharmacological agents and RNAi-mediated knockdown of proteins involved in various endocytosis pathways. Confocal fluorescence microscopy further elucidated the predominant endocytic pathways of siRNA delivery via colocalization of vectors with endocytic vesicle markers.Results
Inhibition of macropinocytosis (MP), caveolin-mediated endocytosis (CvME), flotillin-mediated endocytosis (FME) and knockdown of ARF6 significantly decreased PEI/siRNA-mediated gene silencing. Inhibition of endocytosis pathways, however, had negligible effect on lipoplex uptake and gene silencing mediated by lipoplexes. Rather, internalization of lipoplexes and subsequent siRNA-mediated gene silencing occurred via an energy-independent process.Conclusions
MP, CvME and FME, but not the acidified clathrin-mediated pathway, lead to effective gene silencing by PEI/siRNA polyplexes. Lipoplexes, in contrast, deliver siRNA primarily by direct fusion of the liposomal and cellular membranes. These results provide a new understanding of the mechanisms of siRNA delivery materials in HeLa cells and may aid in design of more effective RNAi strategies.103.
104.
Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene 总被引:3,自引:0,他引:3
Yamaguchi K Cochran EJ Murrell JR Polymeropoulos MH Shannon KM Crowther RA Goedert M Ghetti B 《Acta neuropathologica》2005,110(3):298-305
We report here a case of diffuse Lewy body disease with the A53T mutation in the -synuclein gene. The proband presented at the age of 41 years with parkinsonism that was poorly responsive to levodopa. She subsequently developed cognitive impairment and moderate dementia, and died at the age of 50. Her father, paternal grandfather and uncle were all reported to have suffered from Parkinsons disease. Staining of tissue sections from the probands brain with hematoxylin-eosin and -synuclein antibodies showed small numbers of Lewy bodies in a few brain regions. This contrasted with large numbers of Lewy neurites and neuroaxonal spheroids in many brain regions. By electron microscopy, Lewy neurites consisted of abnormal filaments and dense granular material. Isolated filaments resembled those previously described in idiopathic Parkinsons disease and dementia with Lewy bodies. They were decorated by antibodies specific for the N and C termini of -synuclein, indicating the presence of the full-length protein. Nucleus accumbens and the lower layers in limbic areas of the cerebral cortex showed prominent vacuolation, with frequent clustering of microvacuoles around Lewy neurites. Nerve cell loss was most extensive in dorsal motor nucleus of the vagus nerve, substantia nigra and nucleus basalis of Meynert. Neurofibrillary tangles and senile plaques were not observed. However, in several brain regions, a few widely scattered tau-positive nerve cell bodies and neurites were present. By electron microscopy, Alzheimer-type paired helical and straight filaments were seen. 相似文献
105.
106.
W. Michael McCormack Jr. Joseph J. Shen Stacey M. Curry Sue Ann Berend Catherine Kashork Halit Pinar Lorraine Potocki Bassem A. Bejjani 《American journal of medical genetics. Part A》2002,112(4):384-389
Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21‐q34) and del(13)(13q22‐q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy‐Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage‐sensitive gene in 13q22‐q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22‐q33 may cause this anomaly. These findings suggest that microdeletions in 13q22‐q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high‐resolution cytogenetic analysis (550 band level or greater) of 13q22‐q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM. © 2002 Wiley‐Liss, Inc. 相似文献
107.
Frequent translocations occur between low copy repeats on chromosome 22q11.2 (LCR22s) and telomeric bands of partner chromosomes 总被引:2,自引:0,他引:2
Spiteri E Babcock M Kashork CD Wakui K Gogineni S Lewis DA Williams KM Minoshima S Sasaki T Shimizu N Potocki L Pulijaal V Shanske A Shaffer LG Morrow BE 《Human molecular genetics》2003,12(15):1823-1837
The chromosome 22q11.2 region is susceptible to rearrangements, mediated by low copy repeats (LCR22s). Deletions and duplications are mediated by homologous recombination events between LCR22s. The recurrent balanced constitutional translocation t(11;22)(q23;q11) breakpoint occurs in an LCR22 and is mediated by double strand breaks in AT-rich palindromes on both chromosomes 11 and 22. Recently, two cases of a t(17;22)(q11;q11) were reported, mediated by a similar mechanism (21). Except for these constitutional translocations, the molecular basis for non-recurrent, reciprocal 22q11.2 translocations is not known. To determine whether there are specific mechanisms that could mediate translocations, we analyzed cell lines derived from 14 different individuals by genotyping and FISH mapping. Somatic cell hybrid analysis was carried out for four cell lines. In five cell lines, the translocation breakpoints occurred in the same LCR22 as for the t(11;22) translocation, suggesting that similar molecular mechanisms are responsible. An additional three occurred in other LCR22s, and six were in non-LCR22 regions, mostly in the proximal half of the 22q11.2 region. The translocation breakpoints on the partner chromosomes were all located in the telomeric bands, proximal to the most telomeric unique sequence probe, in eight cell lines and distal to those loci in six. Therefore, several of the breakpoints were found to occur in the vicinity of highly dynamic regions of the genome, 22q11.2 and telomeric bands. We hypothesize that these regions are more susceptible to breakage and repair, resulting in translocations. 相似文献
108.
A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster 总被引:4,自引:0,他引:4
We performed a systematic analysis of 929 human disease gene entries associated with at least one mutant allele in the Online Mendelian Inheritance in Man (OMIM) database against the recently completed genome sequence of Drosophila melanogaster. The results of this search have been formatted as an updateable and searchable on-line database called Homophila. Our analysis identified 714 distinct human disease genes (77% of disease genes searched) matching 548 unique Drosophila sequences, which we have summarized by disease category. This breakdown into disease classes creates a picture of disease genes that are amenable to study using Drosophila as the model organism. Of the 548 Drosophila genes related to human disease genes, 153 are associated with known mutant alleles and 56 more are tagged by P-element insertions in or near the gene. Examples of how to use the database to identify Drosophila genes related to human disease genes are presented. We anticipate that cross-genomic analysis of human disease genes using the power of Drosophila second-site modifier screens will promote interaction between human and Drosophila research groups, accelerating the understanding of the pathogenesis of human genetic disease. The Homophila database is available at http://homophila.sdsc.edu. 相似文献
109.
Heiko Uthoff Christoph Thalhammer Mihael Potocki Tobias Reichlin Markus Noveanu Markus Aschwanden Daniel Staub Nisha Arenja Thenral Socrates Raphael Twerenbold Sarah Mutschmann‐Sanchez Corinna Heinisch Kurt A. Jaeger Alexandre Mebazaa Christian Mueller 《European journal of heart failure》2010,12(5):469-476
110.
Mihael Potocki Tobias Breidthardt Tobias Reichlin Nils G Morgenthaler Andreas Bergmann Markus Noveanu Nora Schaub Heiko Uthoff Heike Freidank Lorenz Buser Roland Bingisser Michael Christ Alexandre Mebazaa Christian Mueller 《Critical care (London, England)》2009,13(4):R122