全文获取类型
收费全文 | 700篇 |
免费 | 90篇 |
出版年
2021年 | 14篇 |
2020年 | 16篇 |
2019年 | 5篇 |
2018年 | 13篇 |
2017年 | 8篇 |
2016年 | 18篇 |
2015年 | 32篇 |
2014年 | 32篇 |
2013年 | 41篇 |
2012年 | 54篇 |
2011年 | 33篇 |
2010年 | 31篇 |
2009年 | 18篇 |
2008年 | 35篇 |
2007年 | 25篇 |
2006年 | 24篇 |
2005年 | 27篇 |
2004年 | 30篇 |
2003年 | 30篇 |
2002年 | 28篇 |
2001年 | 17篇 |
2000年 | 16篇 |
1999年 | 17篇 |
1998年 | 7篇 |
1997年 | 5篇 |
1996年 | 11篇 |
1995年 | 7篇 |
1994年 | 5篇 |
1993年 | 7篇 |
1992年 | 10篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 6篇 |
1987年 | 11篇 |
1986年 | 11篇 |
1984年 | 9篇 |
1983年 | 6篇 |
1982年 | 11篇 |
1981年 | 7篇 |
1979年 | 7篇 |
1978年 | 9篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1975年 | 5篇 |
1974年 | 9篇 |
1973年 | 6篇 |
1972年 | 7篇 |
1971年 | 5篇 |
1969年 | 7篇 |
1937年 | 4篇 |
排序方式: 共有790条查询结果,搜索用时 702 毫秒
61.
Multiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 imprinting control region 下载免费PDF全文
Kanduri M Kanduri C Mariano P Vostrov AA Quitschke W Lobanenkov V Ohlsson R 《Molecular and cellular biology》2002,22(10):3339-3344
The 5' region of the H19 gene harbors a methylation-sensitive chromatin insulator within an imprinting control region (ICR). Insertional mutagenesis in combination with episomal assays identified nucleosome positioning sequences (NPSs) that set the stage for the remarkably precise distribution of the four target sites for the chromatin insulator protein CTCF to nucleosome linker sequences in the H19 ICR. Changing positions of the NPSs resulted in loss of both CTCF target site occupancy and insulator function, suggesting that the NPSs optimize the fidelity of the insulator function. We propose that the NPSs ensure the fidelity of the repressed status of the maternal Igf2 allele during development by constitutively maintaining availability of the CTCF target sites. 相似文献
62.
Otsuki M Gao H Dahlman-Wright K Ohlsson C Eguchi N Urade Y Gustafsson JA 《Molecular endocrinology (Baltimore, Md.)》2003,17(9):1844-1855
Estrogens have important physiological roles in the cardiovascular system. We use DNA microarray technology to study the molecular mechanism of estrogen action in the heart and to identify novel estrogen-regulated genes. In this investigation we identify genes that are regulated by chronic estrogen treatment of mouse heart. We present our detailed characterization of one of these genes, lipocalin-type prostaglandin D synthase (L-PGDS). Northern and Western blot analysis revealed that L-PGDS was induced both by acute and chronic estrogen treatment. Northern blot analysis, using estrogen receptor (ER)-disrupted mice, suggests that L-PGDS is specifically induced by ERbeta in vivo. In further support of ERbeta-selective regulation, we identify a functional estrogen-responsive element in the L-PGDS promoter, the activity of which is up-regulated by ERbeta, but not by ERalpha. We demonstrate that a one-nucleotide change (A to C) in the L-PGDS estrogen-responsive element affects receptor selectivity. 相似文献
63.
D'Elia HF Mattsson LA Ohlsson C Nordborg E Carlsten H 《Arthritis research & therapy》2003,5(4):R202-R209
Hormone replacement therapy (HRT) modulates the imbalance in bone remodeling, thereby decreasing bone loss. Sex hormones are known to influence rheumatic diseases. The aim of this study was to investigate the effects of HRT on the serum levels of hormones and cytokines regulating bone turnover in 88 postmenopausal women with active rheumatoid arthritis (RA) randomly allocated to receive HRT plus calcium and vitamin D3 or calcium and vitamin D3 alone for 2 years. An increase in estradiol (E2) correlated strongly with improvement of bone mineral density in the hip (P < 0.001) and lumbar spine (P < 0.001). Both baseline levels and changes during the study of IL-6 and erythrocyte sedimentation rate were correlated positively (P < 0.001). HRT for 2 years resulted in an increase of the bone anabolic factor, insulin-like growth factor 1 (IGF-1) (P < 0.05) and a decrease of serum levels of soluble IL-6 receptor (sIL-6R) (P < 0.05), which is known to enhance the biological activity of IL-6, an osteoclast-stimulating and proinflammatory cytokine. Baseline levels of IL-6 and IGF-1 were inversely associated (P < 0.05), and elevation of IGF-1 was connected with decrease in erythrocyte sedimentation rate (P < 0.05) after 2 years. Interestingly, increase in serum levels of E2 was associated with reduction of sIL-6R (P < 0.05) and reduction of sIL-6R was correlated with improved bone mineral density in the lumbar spine (P < 0.05). The latter association was however not significant after adjusting for the effect of E2 (P = 0.075). The influences of IGF-1 and the IL-6/sIL-6R pathways suggest possible mechanisms whereby HRT may exert beneficial effects in RA. However, to confirm this hypothesis future and larger studies are needed. 相似文献
64.
Liang L Kanduri C Pilartz M Svensson K Song JH Wentzel P Eriksson U Ohlsson R 《The International journal of developmental biology》2000,44(7):785-790
Gametic marks are stably propagated in order to manifest parent of origin-specific expression patterns of imprinted genes in the developing conceptus. Although the character of the imprint has not yet been fully elucidated, there is compelling evidence that it involves a methylation mark. This is exemplified by a region upstream of the H19 gene, which is not only methylated in a parent of origin-specific manner, but also regulates the silencing of the maternal Igf2 and paternal H19 alleles, respectively. We show here that the parental-specific methylation patterns within the differentially methylated domain (DMD) are perturbed in the soma during in vitro organogenesis. Under these conditions, the paternal DMD allele becomes partially demethylated, whereas the maternal DMD allele gains methylation. Despite these effects, there were no changes in allelic Igf2 or H19 expression patterns in the embryo. Finally, we show that although TSA derepresses the paternal H19 allele in ectoplacental cone when in vitro developed, there is no discernible effect on the methylation status of the paternally inherited 5'-flank in comparison to control samples. Collectively, this data demonstrates that the parental mark is sensitive to a subset of environmental cues and that a certain degree of plasticity of the gametic mark is tolerated without affecting the manifestation of the imprinted state. 相似文献
65.
Kanduri C Holmgren C Pilartz M Franklin G Kanduri M Liu L Ginjala V Ullerås E Mattsson R Ohlsson R 《Current biology : CB》2000,10(8):449-457
BACKGROUND: During mouse prenatal development, the neighbouring insulin-like growth factor II (Igf2) and H19 loci are expressed monoallelically from the paternal and maternal alleles, respectively. Identical spatiotemporal expression patterns and enhancer deletion experiments show that the Igf2 and H19 genes share a common set of enhancers. Deletion of a differentially methylated region in the 5' flank of the H19 gene partially relieves the repression of the maternal Igf2 and paternal H19 alleles in the soma. The mechanisms underlying the function of the 5' flank of the H19 gene are, however, unknown. RESULTS: Chromatin analysis showed that the 5' flank of the mouse H19 gene contains maternal-specific, multiple nuclease hypersensitive sites that map to linker regions between positioned nucleosomes. These features could be recapitulated in an episomal-based H19 minigene, which was propagated in human somatic cells. Although the 5' flank of the H19 promoter has no intrinsic silencer activity under these conditions, it unidirectionally extinguished promoter-enhancer communications in a position-dependent manner, without directly affecting the enhancer function. CONCLUSIONS: The unmethylated 5' flank of the H19 gene adopts an unusual and maternal-specific chromatin conformation in somatic cells and regulates enhancer-promoter communications, thereby providing an explanation for its role in manifesting the repressed state of the maternally inherited Igf2 allele. 相似文献
66.
Peter Smittenaar Robb B. Rutledge Peter Zeidman Rick A. Adams Harriet Brown Glyn Lewis Raymond J. Dolan 《PloS one》2015,10(10)
One expression of executive control involves proactive preparation for future events, and this contrasts with stimulus driven reactive control exerted in response to events. Here we describe findings from a response inhibition task, delivered using a smartphone-based platform, that allowed us to index proactive and reactive inhibitory self-control in a large community sample (n = 12,496). Change in stop-signal reaction time (SSRT) when participants are provided with advance information about an upcoming trial, compared to when they are not, provides a measure of proactive control while SSRT in the absence of advance information provides a measure of reactive control. Both forms of control rely on overlapping frontostriatal pathways known to deteriorate in healthy aging, an age-related decline that occurs at an accelerated rate in men compared to women. Here we ask whether these patterns of age-related decline are reflected in similar changes in proactive and reactive inhibitory control across the lifespan. As predicted, we observed a decline in reactive control with natural aging, with a greater rate of decline in men compared to women (~10 ms versus ~8 ms per decade of adult life). Surprisingly, the benefit of preparation, i.e. proactive control, did not change over the lifespan and women showed superior proactive control at all ages compared to men. Our results suggest that reactive and proactive inhibitory control partially rely on distinct neural substrates that are differentially sensitive to age-related change. 相似文献
67.
FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure
68.
Michele Carbone Erin G. Flores Mitsuru Emi Todd A. Johnson Tatsuhiko Tsunoda Dusty Behner Harriet Hoffman Mary Hesdorffer Masaki Nasu Andrea Napolitano Amy Powers Michael Minaai Francine Baumann Peter Bryant-Greenwood Olivia Lauk Michaela B. Kirschner Walter Weder Isabelle Opitz Harvey I. Pass Giovanni Gaudino Sandra Pastorino Haining Yang 《PLoS genetics》2015,11(12)
We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies). 相似文献
69.
Benjamin E. Bodnar Cassidy W. Claassen Julie Solomon Harriet Mayanja-Kizza Asghar Rastegar 《PloS one》2015,10(3)
Purpose
The MUYU Collaboration is a partnership between Mulago Hospital-Makerere University College of Health Sciences (M-MakCHS), in Kampala, Uganda, and the Yale University School of Medicine. The program allows Ugandan junior faculty to receive up to 1 year of subspecialty training within the Yale hospital system. The authors performed a qualitative study to assess the effects of this program on participants, as well as on M-MakCHS as an institution.Methods
Data was collected via semi-structured interviews with exchange participants. Eight participants (67% of those eligible as of 4/2012) completed interviews. Study authors performed data analysis using standard qualitative data analysis techniques.Results
Analysis revealed themes addressing the benefits, difficulties, and opportunities for improvement of the program. Interviewees described the main benefit of the program as its effect on their fund of knowledge. Participants also described positive effects on their clinical practice and on medical education at M-MakCHS. Most respondents cited financial issues as the primary difficulty of participation. Post-participation difficulties included resource limitations and confronting longstanding institutional and cultural habits. Suggestions for programmatic improvement included expansion of the program, ensuring appropriate management of pre-departure expectations, and refinement of program mentoring structures. Participants also voiced interest in expanding post-exchange programming to ensure both the use of and the maintenance of new capacity.Conclusions
The MUYU Collaboration has benefitted both program participants and M-MakCHS, though these benefits remain difficult to quantify. This study supports the assertion that resource-poor to resource-rich exchanges have the potential to provide significant benefits to the resource-poor partner. 相似文献70.
Vincent Kayina Samuel Kyobe Fred A. Katabazi Edgar Kigozi Moses Okee Beatrice Odongkara Harriet M. Babikako Christopher C. Whalen Moses L. Joloba Philippa M. Musoke Ezekiel Mupere 《PloS one》2015,10(4)