全文获取类型
收费全文 | 133篇 |
免费 | 11篇 |
出版年
2018年 | 2篇 |
2017年 | 2篇 |
2016年 | 1篇 |
2015年 | 12篇 |
2014年 | 10篇 |
2013年 | 11篇 |
2012年 | 6篇 |
2011年 | 9篇 |
2010年 | 11篇 |
2009年 | 9篇 |
2008年 | 11篇 |
2007年 | 8篇 |
2006年 | 5篇 |
2005年 | 6篇 |
2004年 | 7篇 |
2003年 | 1篇 |
2002年 | 2篇 |
2001年 | 1篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 7篇 |
1997年 | 1篇 |
1996年 | 4篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1977年 | 1篇 |
排序方式: 共有144条查询结果,搜索用时 968 毫秒
111.
Transposable elements induce spontaneous mutations, promote genome
rearrangements, regulate gene expression, and participate in the horizontal
spread of genes encoding traits such as antibiotic resistance among
bacterial genera too distantly related to undergo homologous recombination.
Here we review the bacterial transposon Tn5 and focus on those aspects of
its functional organization and transposition which provide insights into
how it and other elements may have arisen, proliferated, and evolved.
相似文献
112.
A mathematical approach was developed to model and optimize selection on multiple known quantitative trait loci (QTL) and polygenic estimated breeding values in order to maximize a weighted sum of responses to selection over multiple generations. The model allows for linkage between QTL with multiple alleles and arbitrary genetic effects, including dominance, epistasis, and gametic imprinting. Gametic phase disequilibrium between the QTL and between the QTL and polygenes is modeled but polygenic variance is assumed constant. Breeding programs with discrete generations, differential selection of males and females and random mating of selected parents are modeled. Polygenic EBV obtained from best linear unbiased prediction models can be accommodated. The problem was formulated as a multiple-stage optimal control problem and an iterative approach was developed for its solution. The method can be used to develop and evaluate optimal strategies for selection on multiple QTL for a wide range of situations and genetic models. 相似文献
113.
Eric A Gaucher Logan G Graddy Tang Li Rosalia CM Simmen Frank A Simmen David R Schreiber David A Liberles Christine M Janis Steven A Benner 《BMC biology》2004,2(1):19
Background
Joining a model for the molecular evolution of a protein family to the paleontological and geological records (geobiology), and then to the chemical structures of substrates, products, and protein folds, is emerging as a broad strategy for generating hypotheses concerning function in a post-genomic world. This strategy expands systems biology to a planetary context, necessary for a notion of fitness to underlie (as it must) any discussion of function within a biomolecular system. 相似文献114.
Sebastian A Baldauf Theo CM Bakker Fabian Herder Harald Kullmann Timo Thünken 《BMC evolutionary biology》2010,10(1):301
Background
Studies addressing the adaptive significance of female ornamentation have gained ground recently. However, the expression of female ornaments in relation to body size, known as trait allometry, still remains unexplored. Here, we investigated the allometry of a conspicuous female ornament in Pelvicachromis taeniatus, a biparental cichlid that shows mutual mate choice and ornamentation. Females feature an eye-catching pelvic fin greatly differing from that of males. 相似文献115.
Expression of the Dominant-Negative Tail of Myosin Va Enhances Exocytosis of Large Dense Core Vesicles in Neurons 总被引:1,自引:0,他引:1
Claudia Margarethe Bittins Tilo Wolf Eichler Hans-Hermann Gerdes 《Cellular and molecular neurobiology》2009,29(4):597-608
Regulated exocytosis of secretory vesicles is a fundamental process in neurotransmission and the release of hormones and growth
factors. The F-actin-binding motor protein myosin Va was recently shown to be involved in exocytosis of peptide-containing
large dense core vesicles of neuroendocrine cells. It has not previously been discussed whether it plays a similar role in
neurons. We performed live-cell imaging of cultured hippocampal neurons to measure the exocytosis of large dense core vesicles
containing fluorescently labelled neuropeptide Y. To address the role of myosin Va in this process, neurons were transfected
with the dominant-negative tail domain of myosin Va (myosinVa-tail). Under control conditions, about 0.75% of the labelled
large dense core vesicles underwent exocytosis during 5 min of stimulation. This value was doubled to 1.80% of the vesicles
when myosinVa-tail was expressed. Depolymerization of F-actin using latrunculin B resulted in a similar increase in exocytosis
in both control and myosinVa-tail expressing cells. Interestingly, the increase in exocytosis caused by myosinVa-tail expression
was completely abolished in the presence of KN-62, an inhibitor of calcium–calmodulin-dependent kinase II. We suggest that
myosinVa-tail causes the liberation of large dense core vesicles from the actin cytoskeleton, leading to an increase in exocytosis
in the cultured hippocampal neurons.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
116.
A mathematical approach to optimize selection on multiple quantitative trait loci (QTL) and an estimate of residual polygenic effects was applied to selection on two linked or unlinked additive QTL. Strategies to maximize total or cumulative discounted response over ten generations were compared to standard QTL selection on the sum of breeding values for the QTL and an estimated breeding value for polygenes, and to phenotypic selection. Optimal selection resulted in greater response to selection than standard QTL or phenotypic selection. Tight linkage between the QTL (recombination rate 0.05) resulted in a slightly lower response for standard QTL and phenotypic selection but in a greater response for optimal selection. Optimal selection capitalized on linkage by emphasizing selection on favorable haplotypes. When the objective was to maximize total response after ten generations and QTL were unlinked, optimal selection increased QTL frequencies to fixation in a near linear manner. When starting frequencies were equal for the two QTL, equal emphasis was given to each QTL, regardless of the difference in effects of the QTL and regardless of the linkage, but the emphasis given to each of the two QTL was not additive. These results demonstrate the ability of optimal selection to capitalize on information on the complex genetic basis of quantitative traits that is forthcoming. 相似文献
117.
Marije B Overdijk Sandra Verploegen Marijn B?gels Marjolein van Egmond Jeroen J Lammerts van Bueren Tuna Mutis Richard WJ Groen Esther Breij Anton CM Martens Wim K Bleeker Paul WHI Parren 《MABS-AUSTIN》2015,7(2):311-320
Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA''s mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt''s lymphoma cell lines. Phagocytosis contributed to DARA''s anti-tumor activity in vivo, in both a subcutaneous and an intravenous leukemic xenograft mouse model. Finally, DARA was shown to induce macrophage-mediated phagocytosis of MM cells isolated from 11 of 12 MM patients that showed variable levels of CD38 expression. In summary, we demonstrate that phagocytosis is a fast, potent and clinically relevant mechanism of action that may contribute to the therapeutic activity of DARA in multiple myeloma and potentially other hematological tumors. 相似文献
118.
Inès J Goossens-Beumer Jan Oosting Wim E Corver Marjolein JFW Janssen Bart Janssen Wilbert van Workum Eliane CM Zeestraten Cornelis JH van de Velde Hans Morreau Peter JK Kuppen Tom van Wezel 《BMC genomics》2015,16(1)
Background
In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data.Results
The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding.Conclusions
We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1550-0) contains supplementary material, which is available to authorized users. 相似文献119.
Kinetics of gene expression and bone remodelling in the clinical phase of collagen-induced arthritis
Katja CM Denninger Thomas Litman Troels Marstrand Kristian Moller Lars Svensson Tord Labuda ?sa Andersson 《Arthritis research & therapy》2015,17(1)
IntroductionPathological bone changes differ considerably between inflammatory arthritic diseases and most studies have focused on bone erosion. Collagen-induced arthritis (CIA) is a model for rheumatoid arthritis, which, in addition to bone erosion, demonstrates bone formation at the time of clinical manifestations. The objective of this study was to use this model to characterise the histological and molecular changes in bone remodelling, and relate these to the clinical disease development.MethodsA histological and gene expression profiling time-course study on bone remodelling in CIA was linked to onset of clinical symptoms. Global gene expression was studied with a gene chip array system.ResultsThe main histopathological changes in bone structure and inflammation occurred during the first two weeks following the onset of clinical symptoms in the joint. Hereafter, the inflammation declined and remodelling of formed bone dominated.Global gene expression profiling showed simultaneous upregulation of genes related to bone changes and inflammation in week 0 to 2 after onset of clinical disease. Furthermore, we observed time-dependent expression of genes involved in early and late osteoblast differentiation and function, which mirrored the histopathological bone changes. The differentially expressed genes belong to the bone morphogenetic pathway (BMP) and, in addition, include the osteoblast markers integrin-binding sialoprotein (Ibsp), bone gamma-carboxyglutamate protein (Bglap1), and secreted phosphoprotein 1 (Spp1). Pregnancy-associated protein A (Pappa) and periostin (Postn), differentially expressed in the early disease phase, are proposed to participate in bone formation, and we suggest that they play a role in early bone formation in the CIA model. Comparison to human genome-wide association studies (GWAS) revealed differential expression of several genes associated with human arthritis.ConclusionsIn the CIA model, bone formation in the joint starts shortly after onset of clinical symptoms, which results in bony fusion within one to two weeks. This makes it a candidate model for investigating the relationship between inflammation and bone formation in inflammatory arthritis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0531-7) contains supplementary material, which is available to authorized users. 相似文献120.
EG Ciolac SS Mantuani CM Neiva CEL Verardi DM Pess?a-Filho L Pimenta 《Biology of sport / Institute of Sport》2015,32(2):103-108
The aim of the present study was to analyse the usefulness of the 6-20 rating of perceived exertion (RPE) scale for prescribing and self-regulating high-intensity interval training (HIT) in young individuals. Eight healthy young subjects (age = 27.5±6.7 years) performed maximal graded exercise testing to determine their maximal and reserve heart rate (HR). Subjects then performed two HIT sessions (20 min on a treadmill) prescribed and regulated by their HR (HR: 1 min at 50% alternated with 1 min at 85% of reserve HR) or RPE (RPE: 1 minute at the 9-11 level [very light-fairly light] alternated with 1 minute at the 15-17 level [hard-very hard]) in random order. HR response and walking/running speed during the 20 min of exercise were compared between sessions. No significant difference between sessions was observed in HR during low- (HR: 135±15 bpm; RPE: 138±20 bpm) and high-intensity intervals (HR: 168±15 bpm; RPE: 170±18 bpm). Walking/running speed during low- (HR: 5.7±1.2 km · h−1; RPE: 5.7±1.3 km · h−1) and high-intensity intervals (HR: 7.8±1.9 km · h−1; RPE: 8.2±1.7 km · h−1) was also not different between sessions. No significant differences were observed in HR response and walking/running speed between HIT sessions prescribed and regulated by HR or RPE. This finding suggests that the 6-20 RPE scale may be a useful tool for prescribing and self-regulating HIT in young subjects. 相似文献