全文获取类型
收费全文 | 185篇 |
免费 | 22篇 |
国内免费 | 1篇 |
专业分类
208篇 |
出版年
2022年 | 1篇 |
2021年 | 3篇 |
2020年 | 4篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 6篇 |
2015年 | 8篇 |
2014年 | 12篇 |
2013年 | 13篇 |
2012年 | 10篇 |
2011年 | 12篇 |
2010年 | 18篇 |
2009年 | 15篇 |
2008年 | 14篇 |
2007年 | 4篇 |
2006年 | 7篇 |
2005年 | 5篇 |
2004年 | 3篇 |
2003年 | 6篇 |
2002年 | 5篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1992年 | 3篇 |
1990年 | 2篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1975年 | 1篇 |
1974年 | 3篇 |
1971年 | 3篇 |
1970年 | 2篇 |
1964年 | 1篇 |
1955年 | 1篇 |
1951年 | 1篇 |
1948年 | 1篇 |
1947年 | 1篇 |
排序方式: 共有208条查询结果,搜索用时 14 毫秒
1.
The binding of 3H-corticosterone and 3H-11-dehydrocorticosterone to receptors in cytosol and nucleus was examined in fetal mouse brain and placenta using Sephadex gel filtration or charcoal to separate bound and unbound steroid. In the cytosol, competitive displacement of each steroid by the other was observed. The binding was unaffected by RNase, DNase, dithiothreitol or N-ethyl maleimide but was diminished by Pronase. Nuclei were isolated by hypotonic shock using dilute MgCl2 and the steroid receptor-complexes of both steroids were obtained from the nuclear sap. Receptor-complexes of both steroids were observed in brain and placental tissues. Competitive displacement of each steroid by the other was also observed in nuclear binding. Both 11-dehydrocorticosterone and 11-deoxycorticosterone bound to a chromatin fraction as did the hormone corticosterone. Identity of the steroids was established by using chromatography and co-crystallization techniques. This work raises the possibility that in the fetal mouse, 11-dehydrocorticosterone, previously considered biologically inactive and an abundant metabolite in fetal mouse tissues, may in fact play a more positive role in regulation. 相似文献
2.
D.?C.?DrakeEmail author B.?Maritz S.?M.?Jacobs C.?J.?Crous A.?Engelbrecht A.?Etale M.?J.?Fourie D.?G.?Furniss S.?L.?Scott S.?Parusnath D.?R.?Tye 《Hydrobiologia》2013,712(1):1-4
The biological and physico-chemical structure of near bottom habitats located under densely growing submerged vegetation, and their significance in the functioning of whole aquatic ecosystems, are very little known due to difficulties in sampling. Corer-type samplers, believed to be the best in littoral studies, do not work properly in such places, because their tube opening is easily clogged by plant shoots, acting as a stopper. In order to overcome this problem, an alteration to the shape of the tube ending is proposed. This can be done by its trimming at an accurate angle, or by fitting (permanently or interchangeably) a metal collar made of stainless steel to its end, so that the ending would resemble the shape of a needle. The modification can be applied to virtually all corer samplers. It was found to be efficient while sampling sediment cores for the purposes of both hydrobiological and paleolimnological studies on heavily overgrown macrophyte-dominated water ecosystems. 相似文献
3.
The OBF1 protein and its DNA-binding site are important for the function of an autonomously replicating sequence in Saccharomyces cerevisiae. 总被引:18,自引:5,他引:13
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The autonomously replicating sequence ARS121 was cloned as a 480-base-pair (bp) long DNA fragment that confers on plasmids autonomous replication in Saccharomyces cerevisiae. This fragment contains two OBF1-binding sites (sites I and II) of different affinities, as identified by a gel mobility shift assay and footprint analysis. Nucleotide substitutions (16 to 18 bp) within either of the two sites obliterated detectable in vitro OBF1 binding to the mutagenized site. Linker substitution (6 bp) mutations within the high-affinity site I showed effects similar to those of the complete substitution, whereas DNA mutagenized outside the binding site bound OBF1 normally. We also tested the mitotic stability of centromeric plasmids bearing wild-type and mutagenized copies of ARS121. Both deletion of the sites and the extensive base alterations within either of the two OBF1-binding sites reduced the percentage of plasmid-containing cells in the population from about 88% to 50 to 63% under selective growth and from about 46% to 15 to 20% after 10 to 12 generations of nonselective growth. Furthermore, linker (6 bp) substitutions within site I, the high-affinity binding site, showed similar deficiencies in plasmid stability. In contrast, plasmids containing linker substitutions in sequences contiguous to site I displayed wild-type stability. In addition, plasmid copy number analysis indicated that the instability probably resulted not from nondisjunction during mitosis but rather from inefficient plasmid replication. The results strongly support the notion that the OBF1-binding sites and the OBF1 protein are important for normal ARS function as an origin of replication. 相似文献
4.
The phenotype of the minichromosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication. 总被引:31,自引:8,他引:23
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
MCM3 is an essential gene involved in the maintenance of minichromosomes in yeast cells. It encodes a protein of 971 amino acids that shows striking homology to the Mcm2 protein. We have mapped the mcm3-1 mutation of the left arm of chromosome V approximately 3 kb centromere proximal of anp1. The mcm3-1 mutant was found to be thermosensitive for growth. Under permissive growth conditions, it was defective in minichromosome maintenance in an autonomously replicating sequence-specific manner and showed an increase in chromosome loss and recombination. Under nonpermissive conditions, mcm3-1 exhibited a cell cycle arrest phenotype, arresting at the large-bud stage with an undivided nucleus that had a DNA content of nearly 2n. These phenotypes are consistent with incomplete replication of the genome of the mcm3-1 mutant, possibly as a result of limited replication initiation at selective autonomously replicating sequences leading to cell cycle arrest before mitosis. The phenotype exhibited by the mcm3 mutant is very similar to that of mcm2, suggesting that the Mcm2 and Mcm3 protein may play interacting roles in DNA replication. 相似文献
5.
A family of Saccharomyces cerevisiae repetitive autonomously replicating sequences that have very similar genomic environments 总被引:20,自引:0,他引:20
We have characterized a family of moderately repetitive autonomously replicating sequences (ARSs) in Saccharomyces cerevisiae. Restriction mapping, deletion studies and hybridization studies suggest that these ARSs, which are probably less than 350 base-pairs in size, share one common feature: each is located close to, but not within, a repetitive sequence (131) of approximately 10(3) to approximately 1.5 X 10(3) base-pairs in length. These ARSs can be divided into two classes (X and Y) by their sequence homology and genomic environments. Each of the class X ARSs is embedded within a repetitive sequence (X) of variable length (approximately 0.3 X 10(3) to approximately 3.75 X 10(3) base-pairs); each of the class Y ARSs is embedded within a highly conserved repetitive sequence (Y) of approximately 5.2 X 10(3) base-pairs in length. Both of these sequences are located directly adjacent to the 131 sequence. 相似文献
6.
Isolation and characterization of the centromere from chromosome V (CEN5) of Saccharomyces cerevisiae. 总被引:22,自引:10,他引:12
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
We have cloned a functional centromeric DNA sequence from Saccharomyces cerevisiae. Using the 2 mu chromosome-loss mapping technique and meiotic tetrad analysis, we have identified this DNA sequence as the centromere of chromosome V (CEN5). The CEN5 sequence has been localized on an 1,100-base-pair BamHI-BglII restriction fragment. Plasmids containing CEN5 and an autonomously replicating sequence are mitotically stable in S. cerevisiae and segregate in a Mendelian fashion during meiosis. 相似文献
7.
8.
9.
10.
F Souza-Fonseca-Guimaraes Y Krasnova T Putoczki K Miles K P MacDonald L Town W Shi G C Gobe L McDade L A Mielke H Tye S L Masters G T Belz N D Huntington G Radford-Smith M J Smyth 《Cell death & disease》2016,7(7):e2302
Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn''s disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells; however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.Inflammatory bowel disease (IBD) is a gut-associated inflammatory disorder, which stems from a dysfunctional mucosal immune response to commensal bacteria.1 As a multifactorial disease, IBD is the consequence of a complex interplay between environmental triggers, genetic susceptibility, and immunoregulatory defects, resulting in a pathogenesis that is still poorly understood.2 These interactions result in the inability of an individual to control the normal inflammatory response to pathogens in the gut, leading to a chronic state of sustained and inappropriate inflammation. IBD underlies disease states such as ulcerative colitis (UC) and Crohn''s disease (CD), with symptoms including weight loss, abdominal pain, diarrhea, and rectal bleeding which often require intensive medical therapy and resective surgery.3 The pathogenesis of IBD, characterized by a defective mucosal immune response to microbial exposure in the gastrointestinal tract, is thought to be caused by a dysfunctional immune response to host microbiota, infection by specific pathogens, and/or a defective mucosal barrier to luminal pathogens.1, 2 IBD patients also have a high risk of developing colitis-associated colon cancer (CAC).4 Additionally, histological assessment of inflamed ileal and colonic segments from IBD patients typically shows increased infiltration of immune cells, particularly neutrophils, as well as crypt abscesses, mucin depletion, and ulcers—all correlating with the severity of small bowel and colonic tissue damage.5Cytotoxic pathways mediated by lymphocytes directly trigger cell death in target cells.6 These cytotoxic pathways are mediated by proteins such as perforin, which mediates pore formation in the target cell surface and allows granzyme (Grz)s to enter the intracellular compartment and induce cell death.7 To date, five different Grzs have been identified in humans (GrzA, GrzB, GrzH, GrzK, and GrzM), whereas mice express eleven Grzs (GrzA, GrzB, GrzC, GrzD, GrzE, GrzF, GrzG, GrzK, GrzL, GrzM, and GrzN).8, 9 Walch et al.10 recently demonstrated that Grzs (GrzA and GrzB) directly kill bacteria through granulysin-mediated delivery, suggesting that Grzs act as microbial modulating factors. Moreover, recently GrzA was shown to be increased in the colon biopsies of UC patients undergoing treatment with Etrolizumab, a monoclonal antibody targeting the β7 integrin subunit. Higher levels of GrzA could predict which patients were more likely to benefit from the therapy; however, the precise mechanism of action of GrzA in UC remains to be addressed.11 GrzM was initially described as being constitutively expressed by natural killer (NK) cells,12, 13 and specifically associated with inflammation.14 This enzyme has been shown to preferentially cleave methionine and leucine residues in target cells, mediating direct, non-specific cell death.15, 16 More recently, GrzM was also shown to be an important mediator for the release of MIP-1α from NK cells, inducing NK cell and neutrophil recruitment during early microbial infection.17 We now observe that GrzM expression is increased in inflamed colon tissue samples from UC, but not CD patients. Further, GrzM-deficient (GrzM−/−) mice are more sensitive to a mouse model of IBD and IBD-induced colorectal cancer (CRC). These findings demonstrate, for the first time, that GrzM has a critical role in mediating the early stages of the gut mucosal immune response. 相似文献