全文获取类型
收费全文 | 582篇 |
免费 | 53篇 |
出版年
2023年 | 3篇 |
2022年 | 5篇 |
2021年 | 10篇 |
2020年 | 5篇 |
2018年 | 7篇 |
2017年 | 7篇 |
2016年 | 14篇 |
2015年 | 23篇 |
2014年 | 26篇 |
2013年 | 35篇 |
2012年 | 59篇 |
2011年 | 37篇 |
2010年 | 26篇 |
2009年 | 17篇 |
2008年 | 29篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 34篇 |
2004年 | 27篇 |
2003年 | 39篇 |
2002年 | 46篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 8篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 5篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1977年 | 6篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1973年 | 3篇 |
1960年 | 1篇 |
排序方式: 共有635条查询结果,搜索用时 46 毫秒
51.
Mpindi JP Sara H Haapa-Paananen S Kilpinen S Pisto T Bucher E Ojala K Iljin K Vainio P Björkman M Gupta S Kohonen P Nees M Kallioniemi O 《PloS one》2011,6(2):e17259
Background
Meta-analysis of gene expression microarray datasets presents significant challenges for statistical analysis. We developed and validated a new bioinformatic method for the identification of genes upregulated in subsets of samples of a given tumour type (‘outlier genes’), a hallmark of potential oncogenes.Methodology
A new statistical method (the gene tissue index, GTI) was developed by modifying and adapting algorithms originally developed for statistical problems in economics. We compared the potential of the GTI to detect outlier genes in meta-datasets with four previously defined statistical methods, COPA, the OS statistic, the t-test and ORT, using simulated data. We demonstrated that the GTI performed equally well to existing methods in a single study simulation. Next, we evaluated the performance of the GTI in the analysis of combined Affymetrix gene expression data from several published studies covering 392 normal samples of tissue from the central nervous system, 74 astrocytomas, and 353 glioblastomas. According to the results, the GTI was better able than most of the previous methods to identify known oncogenic outlier genes. In addition, the GTI identified 29 novel outlier genes in glioblastomas, including TYMS and CDKN2A. The over-expression of these genes was validated in vivo by immunohistochemical staining data from clinical glioblastoma samples. Immunohistochemical data were available for 65% (19 of 29) of these genes, and 17 of these 19 genes (90%) showed a typical outlier staining pattern. Furthermore, raltitrexed, a specific inhibitor of TYMS used in the therapy of tumour types other than glioblastoma, also effectively blocked cell proliferation in glioblastoma cell lines, thus highlighting this outlier gene candidate as a potential therapeutic target.Conclusions/Significance
Taken together, these results support the GTI as a novel approach to identify potential oncogene outliers and drug targets. The algorithm is implemented in an R package (Text S1). 相似文献52.
Enerly E Steinfeld I Kleivi K Leivonen SK Aure MR Russnes HG Rønneberg JA Johnsen H Navon R Rødland E Mäkelä R Naume B Perälä M Kallioniemi O Kristensen VN Yakhini Z Børresen-Dale AL 《PloS one》2011,6(2):e16915
Introduction
Few studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information.Methods
We investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods.Results
We identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process.Conclusion
This study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer. 相似文献53.
Traditionally, people have inhabited places with ready access to fresh water.
Today, over 50% of the global population lives in urban areas, and water
can be directed via tens of kilometres of pipelines. Still, however, a large
part of the world''s population is directly dependent on access to natural
freshwater sources. So how are inhabited places related to the location of
freshwater bodies today? We present a high-resolution global analysis of how
close present-day populations live to surface freshwater. We aim to increase the
understanding of the relationship between inhabited places, distance to surface
freshwater bodies, and climatic characteristics in different climate zones and
administrative regions. Our results show that over 50% of the
world''s population lives closer than 3 km to a surface freshwater body, and
only 10% of the population lives further than 10 km away. There are,
however, remarkable differences between administrative regions and climatic
zones. Populations in Australia, Asia, and Europe live closest to water.
Although populations in arid zones live furthest away from freshwater bodies in
absolute terms, relatively speaking they live closest to water considering the
limited number of freshwater bodies in those areas. Population distributions in
arid zones show statistically significant relationships with a combination of
climatic factors and distance to water, whilst in other zones there is no
statistically significant relationship with distance to water. Global studies on
development and climate adaptation can benefit from an improved understanding of
these relationships between human populations and the distance to fresh
water. 相似文献
54.
55.
Siltanen S Wahlfors T Schindler M Saramäki OR Mpindi JP Latonen L Vessella RL Tammela TL Kallioniemi O Visakorpi T Schleutker J 《PloS one》2011,6(10):e26595
ARLTS1 is a recently characterized tumor suppressor gene at 13q14.3, a region frequently deleted in both sporadic and hereditary prostate cancer (PCa). ARLTS1 variants, especially Cys148Arg (T442C), increase susceptibility to different cancers, including PCa. In this study the role of Cys148Arg substitution was investigated as a risk factor for PCa using both genetic and functional analysis. Cys148Arg genotypes and expression of the ARLTS1 were explored in a large set of familial and unselected PCa cases, clinical tumor samples, xenografts, prostate cancer cell lines and benign prostatic hyperplasia (BPH) samples. The frequency of the variant genotype CC was significantly higher in familial (OR = 1.67, 95% CI = 1.08–2.56, P = 0.019) and unselected patients (OR = 1.52, 95% CI = 1.18–1.97, P = 0.001) and the overall risk was increased (OR = 1.54, 95% CI = 1.20–1.98, P = 0.0007). Additional analysis with clinicopathological data revealed an association with an aggressive disease (OR = 1.28, 95% CI = 1.05-∞, P = 0.02). The CC genotype of the Cys148Arg variant was also contributing to the lowered ARLTS1 expression status in lymphoblastoid cells from familial patients. In addition significantly lowered ARLTS1 expression was observed in clinical tumor samples compared to BPH samples (P = 0.01). The ARLTS1 co-expression signature based on previously published microarray data was generated from 1587 cancer samples confirming the low expression of ARLTS1 in PCa and showed that ARLTS1 expression was strongly associated with immune processes. This study provides strong confirmation of the important role of ARLTS1 Cys148Arg variant as a contributor in PCa predisposition and a potential marker for aggressive disease outcome. 相似文献
56.
Greggio E Bergantino E Carter D Ahmad R Costin GE Hearing VJ Clarimon J Singleton A Eerola J Hellström O Tienari PJ Miller DW Beilina A Bubacco L Cookson MR 《Journal of neurochemistry》2005,93(1):246-256
Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely. 相似文献
57.
Background
Progestins as respiratory stimulants in chronic obstructive pulmonary disease (COPD) have been investigated in males and during wakefulness. However, sleep and gender may influence therapeutic responses. We investigated the effects of a 2-week medroxyprogesterone acetate (MPA) therapy on sleep and nocturnal breathing in postmenopausal women.Methods
A single-blind placebo-controlled trial was performed in 15 postmenopausal women with moderate to severe COPD. A 12-week trial included 2-week treatment periods with placebo and MPA (60 mg/d/14 days). All patients underwent a polysomnography with monitoring of SaO2 and transcutaneous PCO2 (tcCO2) at baseline, with placebo, with medroxyprogesterone acetate (MPA 60 mg/d/14 days), and three and six weeks after cessation of MPA.Results
Thirteen patients completed the trial. At baseline, the average ± SD of SaO2 mean was 90.6 ± 3.2 % and the median of SaO2 nadir 84.8 % (interquartile range, IQR 6.1). MPA improved them by 1.7 ± 1.6 %-units (95 % confidence interval (CI) 0.56, 2.8) and by 3.9 %-units (IQR 4.9; 95% CI 0.24, 10.2), respectively. The average of tcCO2 median was 6.0 ± 0.9 kPa and decreased with MPA by 0.9 ± 0.5 kPa (95% CI -1.3, -0.54). MPA improved SaO2 nadir and tcCO2 median also during REM sleep. Three weeks after cessation of MPA, the SaO2 mean remained 1.4 ± 1.8 %-units higher than at baseline, the difference being not significant (95% CI -0.03, 2.8). SaO2 nadir was 2.7 %-units (IQR 4.9; 95% CI 0.06, 18.7) higher than at baseline. Increases in SaO2 mean and SaO2 nadir during sleep with MPA were inversely associated with baseline SaO2 mean (r = -0.70, p = 0.032) and baseline SaO2 nadir (r = -0.77, p = 0.008), respectively. Treatment response in SaO2 mean, SaO2 nadir and tcCO2 levels did not associate with pack-years smoked, age, BMI, spirometric results or sleep variables.Conclusion
MPA-induced respiratory improvement in postmenopausal women seems to be consistent and prolonged. The improvement was greater in patients with lower baseline SaO2 values. Long-term studies in females are warranted. 相似文献58.
Rzhepishevska OI Lindström EB Tuovinen OH Dopson M 《Biotechnology and bioengineering》2005,92(5):559-567
This study presents a design for a novel bioreactor that uses alternating vacuum and positive pressure cycles to transfer acidic leach solution in and out of contact with finely ground sulfidic mine tailings. These tailings constitute an environmental problem that needs experimental data to support the development of management and control strategies. A conventional stirred tank bioreactor was used as a reference system. Both bioreactors were inoculated with mixed cultures of acidophilic iron and sulfur oxidizers. The rate of the bioleaching of tailings was 0.50 +/- 0.14 g Fe/L . day in the stirred tank bioreactor and 0.17 +/- 0.05 g Fe/L . day in the novel bioreactor. Microbial populations were identified in the two-bioreactor systems by analysis of 16S rRNA genes involving amplification, denaturing gradient gel electrophoresis (DGGE), cloning, and sequencing. The inoculum contained sulfur-oxidizing Acidithiobacillus caldus and Acidithiobacillus thiooxidans, iron oxidizers from the genera Leptospirillum and Ferroplasma, and a chemoorganotrophic Alicyclobacillus sp. During bioleaching of the tailings, the microbial populations in both bioreactors were similar to the inoculum culture, except that At. thiooxidans outgrew At. caldus. Sequences consistent with a Sulfobacillus sp. were amplified from both bioreactor samples although this bacterium was initially below the level of detection in the inoculum. After prolonged operation, Ferroplasma acidiphilum and an uncultured bacterium related to the CFB group were also detected in the novel bioreactor, whereas Sulfobacillus sp. was no longer detected. The novel bioreactor has potential uses in other areas of environmental biotechnology that involves periodic contact of liquids with solid substrates. 相似文献
59.
Santa H Kammonen J Lehtonen O Karimäki J Pastinen O Leisola M Turunen O 《Biochimica et biophysica acta》2005,1749(1):65-73
We used molecular dynamics simulations to study how a non-natural substrate, L-ribose, interacts with the active site of Actinoplanes missouriensis xylose isomerase. The simulations showed that L-ribose does not stay liganded in the active site in the same way as D-xylose, in which the oxygens O2 and O4 are liganded to the metal M1. The oxygen O4 of L-ribose moved away from the metal M1 to an upside down position. Furthermore, the distances of the carbons C1 and C2 of L-ribose to the catalytic metal M2 were higher than in the case of D-xylose. These findings explain the extremely low reaction rate of xylose isomerase with L-ribose. The mutation V135N close to the C5-OH of the substrate increased the reaction efficiency 2- to 4-fold with L-ribose. V135N did not affect the reaction with D-xylose and L-arabinose, whereas the reaction with D-glucose was impaired, probably due to a hydrogen bond between Asn-135 and the substrate. When L-ribose was the substrate, Asn-135 formed a hydrogen bond to Glu-181. As a consequence, O4 of L-ribose stayed liganded to the metal M1 in the V135N mutant in molecular dynamics simulations. This explains the decreased K(m) of the V135N mutant with L-ribose. 相似文献
60.
Nymalm Y Puranen JS Nyholm TK Käpylä J Kidron H Pentikäinen OT Airenne TT Heino J Slotte JP Johnson MS Salminen TA 《The Journal of biological chemistry》2004,279(9):7962-7970
Integrin alpha(1)beta(1) is one of four collagen-binding integrins in humans. Collagens bind to the alphaI domain and in the case of alpha(2)I collagen binding is competitively inhibited by peptides containing the RKKH sequence and derived from the metalloproteinase jararhagin of snake venom from Bothrops jararaca. In alpha(2)I, these peptides bind near the metal ion-dependent adhesion site (MIDAS), where a collagen (I)-like peptide is known to bind; magnesium is required for binding. Published structures of the ligand-bound "open" conformation of alpha(2)I differs significantly from the "closed" conformation seen in the structure of apo-alpha(2)I near MIDAS. Here we show that two peptides, CTRKKHDC and CARKKHDC, derived from jararhagin also bind to alpha(1)I and competitively inhibit collagen I binding. Furthermore, calorimetric and fluorimetric measurements show that the structure of the complex of alpha(1)I with Mg(2+) and CTRKKHDC differs from structure in the absence of peptide. A comparison of the x-ray structure of apo-alpha(1)I ("closed" conformation) and a model structure of the alpha(1)I ("open" conformation) based on the closely related structure of alpha(2)I reveals that the binding site is partially blocked to ligands by Glu(255) and Tyr(285) in the "closed" structure, whereas in the "open" structure helix C is unwound and these residues are shifted, and the "RKKH" peptides fit well when docked. The "open" conformation of alpha(2)I resulting from binding a collagen (I)-like peptide leads to exposure of hydrophobic surface, also seen in the model of alpha(1)I and shown experimentally for alpha(1)I using a fluorescent hydrophobic probe. 相似文献