全文获取类型
收费全文 | 349篇 |
免费 | 24篇 |
专业分类
373篇 |
出版年
2022年 | 1篇 |
2021年 | 1篇 |
2019年 | 2篇 |
2018年 | 4篇 |
2017年 | 4篇 |
2016年 | 8篇 |
2015年 | 19篇 |
2014年 | 19篇 |
2013年 | 27篇 |
2012年 | 17篇 |
2011年 | 20篇 |
2010年 | 28篇 |
2009年 | 24篇 |
2008年 | 15篇 |
2007年 | 14篇 |
2006年 | 14篇 |
2005年 | 13篇 |
2004年 | 15篇 |
2003年 | 7篇 |
2002年 | 4篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 4篇 |
1995年 | 6篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1991年 | 3篇 |
1989年 | 2篇 |
1988年 | 7篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 16篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有373条查询结果,搜索用时 15 毫秒
91.
Jian Liu Alexander W Bell John JM Bergeron Corey M Yanofsky Brian Carrillo Christian EH Beaudrie Robert E Kearney 《Proteome science》2007,5(1):3-12
Background
Tandem mass spectrometry followed by database search is currently the predominant technology for peptide sequencing in shotgun proteomics experiments. Most methods compare experimentally observed spectra to the theoretical spectra predicted from the sequences in protein databases. There is a growing interest, however, in comparing unknown experimental spectra to a library of previously identified spectra. This approach has the advantage of taking into account instrument-dependent factors and peptide-specific differences in fragmentation probabilities. It is also computationally more efficient for high-throughput proteomics studies. 相似文献92.
JM Devaney S Wang P Furbert-Harris V Apprey M Ittmann B-D Wang J Olender NH Lee B Kwabi-Addo 《Epigenetics》2015,10(4):319-328
Increasing evidence suggests that aberrant DNA methylation changes may contribute to prostate cancer (PCa) ethnic disparity. To comprehensively identify DNA methylation alterations in PCa disparity, we used the Illumina 450K methylation platform to interrogate the methylation status of 485,577 CpG sites focusing on gene-associated regions of the human genome. Genomic DNA from African-American (AA; 7 normal and 3 cancers) and Caucasian (Cau; 8 normal and 3 cancers) was used in the analysis. Hierarchical clustering analysis identified probe-sets unique to AA and Cau samples, as well as common to both. We selected 25 promoter-associated novel CpG sites most differentially methylated by race (fold change > 1.5-fold; adjusted P < 0.05) and compared the β-value of these sites provided by the Illumina, Inc. array with quantitative methylation obtained by pyrosequencing in 7 prostate cell lines. We found very good concordance of the methylation levels between β-value and pyrosequencing. Gene expression analysis using qRT-PCR in a subset of 8 genes after treatment with 5-aza-2′-deoxycytidine and/or trichostatin showed up-regulation of gene expression in PCa cells. Quantitative analysis of 4 genes, SNRPN, SHANK2, MST1R, and ABCG5, in matched normal and PCa tissues derived from AA and Cau PCa patients demonstrated differential promoter methylation and concomitant differences in mRNA expression in prostate tissues from AA vs. Cau. Regression analysis in normal and PCa tissues as a function of race showed significantly higher methylation prevalence for SNRPN (P = 0.012), MST1R (P = 0.038), and ABCG5 (P < 0.0002) for AA vs. Cau samples. We selected the ABCG5 and SNRPN genes and verified their biological functions by Western blot analysis and siRNA gene knockout effects on cell proliferation and invasion in 4 PCa cell lines (2 AA and 2 Cau patients-derived lines). Knockdown of either ABCG5 or SNRPN resulted in a significant decrease in both invasion and proliferation in Cau PCa cell lines but we did not observe these remarkable loss-of-function effects in AA PCa cell lines. Our study demonstrates how differential genome-wide DNA methylation levels influence gene expression and biological functions in AA and Cau PCa. 相似文献
93.
Multi-category classification methods were used to detect SNP-mortality associations in broilers. The objective was to select a subset of whole genome SNPs associated with chick mortality. This was done by categorizing mortality rates and using a filter-wrapper feature selection procedure in each of the classification methods evaluated. Different numbers of categories (2, 3, 4, 5 and 10) and three classification algorithms (naïve Bayes classifiers, Bayesian networks and neural networks) were compared, using early and late chick mortality rates in low and high hygiene environments. Evaluation of SNPs selected by each classification method was done by predicted residual sum of squares and a significance test-related metric. A naïve Bayes classifier, coupled with discretization into two or three categories generated the SNP subset with greatest predictive ability. Further, an alternative categorization scheme, which used only two extreme portions of the empirical distribution of mortality rates, was considered. This scheme selected SNPs with greater predictive ability than those chosen by the methods described previously. Use of extreme samples seems to enhance the ability of feature selection procedures to select influential SNPs in genetic association studies. 相似文献
94.
95.
Davidson WS Koop BF Jones SJ Iturra P Vidal R Maass A Jonassen I Lien S Omholt SW 《Genome biology》2010,11(9):403
The International Collaboration to Sequence the Atlantic Salmon Genome (ICSASG) will produce a genome sequence that identifies
and physically maps all genes in the Atlantic salmon genome and acts as a reference sequence for other salmonids. 相似文献
96.
Steven JM Jones Janessa Laskin Yvonne Y Li Obi L Griffith Jianghong An Mikhail Bilenky Yaron S Butterfield Timothee Cezard Eric Chuah Richard Corbett Anthony P Fejes Malachi Griffith John Yee Montgomery Martin Michael Mayo Nataliya Melnyk Ryan D Morin Trevor J Pugh Tesa Severson Sohrab P Shah Margaret Sutcliffe Angela Tam Jefferson Terry Nina Thiessen Thomas Thomson Richard Varhol Thomas Zeng Yongjun Zhao Richard A Moore David G Huntsman Inanc Birol Martin Hirst Robert A Holt Marco A Marra 《Genome biology》2010,11(8):1-12
Background
Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.Results
In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.Conclusions
We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual. 相似文献97.
The evolutionary analysis of the Tnt1 retrotransposon in Nicotiana species reveals the high variability of its regulatory sequences 总被引:2,自引:0,他引:2
We studied the evolution of the tobacco Tnt1 retrotransposon by analyzing
Tnt1 partial sequences containing both coding domains and U3 regulatory
sequences obtained from a number of Nicotiana species. We detected three
different subfamilies of Tnt1 elements, Tnt1A, Tnt1B, and Tnt1C, that
differ completely in their U3 regions but share conserved flanking coding
and LTR regions. U3 divergence between the three subfamilies is found in
the region that contains the regulatory sequences that control the
expression of the well-characterized Tnt1-94 element. This suggests that
expression of the three Tnt1 subfamilies might be differently regulated.
The three Tnt1 subfamilies were present in the Nicotiana genome at the time
of species divergence, but have evolved independently since then in the
different genomes. Each Tnt1 subfamily seems to have conserved its ability
to transpose in a limited and different number of Nicotiana species. Our
results illustrate the high variability of Tnt1 regulatory sequences. We
propose that this high sequence variability could allow these elements to
evolve regulatory mechanisms in order to optimize their coexistence with
their host genome.
相似文献
98.
Mast cell activation by Mycobacterium tuberculosis: mediator release and role of CD48 总被引:3,自引:0,他引:3
Muñoz S Hernández-Pando R Abraham SN Enciso JA 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(11):5590-5596
Mast cells (MC) are abundant in the lung and other peripheral tissue, where they participate in inflammatory processes against bacterial infections. Like other effector cells of the innate immune system, MC interact directly with a wide variety of infectious agents. This interaction results in MC activation and inflammatory mediator release. We demonstrated that MC interact with Mycobacterium tuberculosis, triggering the release of several prestored reagents, such as histamine and beta-hexosaminidase, and de novo synthesized cytokines, such as TNF-alpha and IL-6. A number of M. tuberculosis Ags, ESAT-6, MTSA-10, and MPT-63, have been implicated in MC activation and mediator release. A MC plasmalemmal protein, CD48, was implicated in interactions with mycobacteria because CD48 appeared to aggregate in the MC membrane at sites of bacterial binding and because Abs to CD48 inhibited the MC histamine response to mycobacteria. Cumulatively, these findings suggest that MC, even in the absence of opsonins, can directly recognize M. tuberculosis and its Ags and have the potential to play an active role in mediating the host's innate response to M. tuberculosis infection. 相似文献
99.
100.
Cross-adaptation and molecular modeling study of receptor mechanisms common to four taste stimuli in humans 总被引:2,自引:2,他引:0
Psychophysical cross-adaptation experiments were performed with two
carbohydrates, sucrose (SUC) and fructose (FRU), and two sweeteners,
acesulfame-K (MOD) and dulcin (DUL). Seven subjects were asked to match
concentrations that elicited the same intensity as a sucrose reference (30
g/l). Cross-adaptation levels were calculated as the ratio of isointense
concentrations measured for a given stimulus before and under adaptation.
On average, cross-adaptation between SUC and FRU is low and apparently
reciprocal. By contrast, cross-adaptation between SUC and MOD is clearly
non-reciprocal: SUC adapts MOD significantly (24%, P < 0.005), but MOD
fails to adapt SUC (2%, P < 0.79). Significant and reciprocal
cross-enhancement is observed between DUL and MOD (approximately -20%, P
< 0.03), and also between SUC and DUL (approximately -15%, P < 0.08).
In parallel, molecular modeling of the four tastants was performed in order
to look for the 12 common binding motifs that were isolated on 14 other
tastants in a previous study. SUC and FRU each display 10 out of the 12
binding motifs, whereas DUL and MOD only display four and five distinct
motifs respectively and do not have any motif in common. Experimental
cross-adaptation levels seem to correlate well with the number of motifs
that molecules have in common. FRU and SUC share a majority of binding
motifs and correlatively show mutual cross-adaptation. Four motifs of MOD
are found among the 10 motifs of SUC, which may explain why SUC
cross-adapts MOD but not vice versa. By contrast, DUL and MOD do not share
any motif and do not cross- adapt. The various molecular mechanisms that
may be responsible for cross-adaptation and/or cross-enhancement are
discussed in light of our results.
相似文献