全文获取类型
收费全文 | 182篇 |
免费 | 23篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 6篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 3篇 |
2015年 | 10篇 |
2014年 | 8篇 |
2013年 | 14篇 |
2012年 | 17篇 |
2011年 | 17篇 |
2010年 | 3篇 |
2009年 | 5篇 |
2008年 | 13篇 |
2007年 | 12篇 |
2006年 | 7篇 |
2005年 | 6篇 |
2004年 | 8篇 |
2003年 | 2篇 |
2002年 | 6篇 |
2001年 | 2篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1995年 | 1篇 |
1994年 | 6篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 1篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1978年 | 3篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1952年 | 1篇 |
1948年 | 1篇 |
排序方式: 共有205条查询结果,搜索用时 15 毫秒
101.
Shenk D 《Culture, medicine and psychiatry》2012,36(3):535-556
The challenge of hiring and retaining well-trained caregivers for the growing numbers of elders in need of care is a global concern. This study was designed to understand the views of direct care workers and included 15 nurse aides and med techs working in an assisted living and special care assisted living community for people with dementia. Each participant was provided with a digital camera and asked to take photographs "to show what caregiving means to you." Analysis is based on group discussions about the full set of photographs created by the direct care workers and individual written and oral narratives about four photographs chosen by each participant. The categories generated from these data represent the direct care workers' perceptions of the approaches to quality caregiving and the relationships involved in doing their jobs well. By focusing on the essential relationships and interactions, rather than primarily on the required care, we can begin to imagine the caregiving experience in terms of a communal rather than an institutional experience. We can then productively turn our focus to the people involved rather than emphasize their roles as providers or recipients of care. 相似文献
102.
103.
Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Mochel F Knight MA Tong WH Hernandez D Ayyad K Taivassalo T Andersen PM Singleton A Rouault TA Fischbeck KH Haller RG 《American journal of human genetics》2008,82(3):652-660
A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis. 相似文献
104.
Hickey MJ Kwan RY Awad MM Kennedy CL Young LF Hall P Cordner LM Lyras D Emmins JJ Rood JI 《PLoS pathogens》2008,4(4):e1000045
Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens alpha-toxin has been shown capable of inducing these changes, but its potential synergy with perfringolysin O (theta-toxin) is less well understood. Similarly, Clostridium septicum is a highly virulent causative agent of spontaneous gas gangrene, but its effect on the microcirculation has not been examined. Therefore, the aim of this study was to use intravital microscopy to examine the effects of C. perfringens and C. septicum on the functional microcirculation, coupled with the use of isogenic toxin mutants to elucidate the role of particular toxins in the resultant microvascular perfusion deficits. This study represents the first time this integrated approach has been used in the analysis of the pathological response to clostridial toxins. Culture supernatants from wild-type C. perfringens induced extensive cell death within 30 min, as assessed by in vivo uptake of propidium iodide. Furthermore, significant reductions in capillary perfusion were observed within 60 min. Depletion of either platelets or neutrophils reduced the alteration in perfusion, consistent with a role for these blood-borne cells in obstructing perfusion. In addition, mutation of either the alpha-toxin or perfringolysin O structural genes attenuated the reduction in perfusion, a process that was reversed by genetic complementation. C. septicum also induced a marked reduction in perfusion, with the degree of microvascular compromise correlating with the level of the C. septicum alpha-toxin. Together, these data indicate that as a result of its ability to produce alpha-toxin and perfringolysin O, C. perfringens rapidly induces irreversible cellular injury and a marked reduction in microvascular perfusion. Since C. septicum induces a similar reduction in microvascular perfusion, it is postulated that this function is central to the pathogenesis of clostridial myonecrosis, irrespective of the causative bacterium. 相似文献
105.
Ciapponi L Cenci G Ducau J Flores C Johnson-Schlitz D Gorski MM Engels WR Gatti M 《Current biology : CB》2004,14(15):1360-1366
The MRN complex consists of the two evolutionarily conserved components Mre11 and Rad50 and the third less-conserved component Nbs1/Xrs2. This complex mediates telomere maintenance in addition to a variety of functions in response to DNA double-strand breaks, including homologous recombination, nonhomologous end joining (NHEJ), and activation of DNA damage checkpoints. Mutations in the Mre11 gene cause the human ataxia-telangiectasia-like disorder (ATDL). Here, we show that null mutations in the Drosophila mre11 and rad50 genes cause both telomeric fusion and chromosome breakage. Moreover, we demonstrate that these mutations are in the same epistasis group required for telomere capping and mitotic chromosome integrity. Using an antibody against Rad50, we show that this protein is uniformly distributed along mitotic chromosomes, and that Rad50 is unstable in the absence of its binding partner Mre11. To define the roles of rad50 and mre11 in telomere protection, mutant chromosome preparations were immunostained for both HP1 and HOAP, two proteins that protect Drosophila telomeres from fusion. Cytological analysis revealed that mutations in rad50 and mre11 drastically reduce accumulation of HOAP and HP1 at telomeres. This suggests that the MRN complex protects Drosophila telomeres by facilitating recruitment of HOAP and HP1 at chromosome ends. 相似文献
106.
Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis 总被引:25,自引:0,他引:25
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)
107.
108.
109.
Edward C. Couchman Hilary P. Browne Matt Dunn Trevor D. Lawley J. Glenn Songer Val Hall Liljana Petrovska Callum Vidor Milena Awad Dena Lyras Neil F. Fairweather 《BMC genomics》2015,16(1)
Background
Clostridium sordellii can cause severe infections in animals and humans, the latter associated with trauma, toxic shock and often-fatal gynaecological infections. Strains can produce two large clostridial cytotoxins (LCCs), TcsL and TcsH, related to those produced by Clostridium difficile, Clostridium novyi and Clostridium perfringens, but the genetic basis of toxin production remains uncharacterised.Results
Phylogenetic analysis of the genome sequences of 44 strains isolated from human and animal infections in the UK, US and Australia placed the species into four clades. Although all strains originated from animal or clinical disease, only 5 strains contained LCC genes: 4 strains contain tcsL alone and one strain contains tcsL and tcsH. Four toxin-positive strains were found within one clade. Where present, tcsL and tcsH were localised in a pathogenicity locus, similar to but distinct from that present in C. difficile. In contrast to C. difficile, where the LCCs are chromosomally localised, the C. sordellii tcsL and tcsH genes are localised on plasmids. Our data suggest gain and loss of entire toxigenic plasmids in addition to horizontal transfer of the pathogenicity locus. A high quality, annotated sequence of ATCC9714 reveals many putative virulence factors including neuraminidase, phospholipase C and the cholesterol-dependent cytolysin sordellilysin that are highly conserved between all strains studied.Conclusions
Genome analysis of C. sordellii reveals that the LCCs, the major virulence factors, are localised on plasmids. Many strains do not contain the LCC genes; it is probable that in several of these cases the plasmid has been lost upon laboratory subculture. Our data are consistent with LCCs being the primary virulence factors in the majority of infections, but LCC-negative strains may precipitate certain categories of infection. A high quality genome sequence reveals putative virulence factors whose role in virulence can be investigated.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1613-2) contains supplementary material, which is available to authorized users. 相似文献110.
Shu Wen Wen Raymond Shim Luke Ho Brooke J. Wanrooy Yogitha N. Srikhanta Kathryn Prame Kumar Alyce J. Nicholls SJ. Shen Tara Sepehrizadeh Michael de Veer Velandai K. Srikanth Henry Ma Thanh G. Phan Dena Lyras Connie H. Y. Wong 《Aging cell》2019,18(5)
Bacterial infection a leading cause of death among patients with stroke, with elderly patients often presenting with more debilitating outcomes. The findings from our retrospective study, supported by previous clinical reports, showed that increasing age is an early predictor for developing fatal infectious complications after stroke. However, exactly how and why older individuals are more susceptible to infection after stroke remains unclear. Using a mouse model of transient ischaemic stroke, we demonstrate that older mice (>12 months) present with greater spontaneous bacterial lung infections compared to their younger counterparts (7–10 weeks) after stroke. Importantly, we provide evidence that older poststroke mice exhibited elevated intestinal inflammation and disruption in gut barriers critical in maintaining colonic integrity following stroke, including reduced expression of mucin and tight junction proteins. In addition, our data support the notion that the localized pro‐inflammatory microenvironment driven by increased tumour necrosis factor‐α production in the colon of older mice facilitates the translocation and dissemination of orally inoculated bacteria to the lung following stroke onset. Therefore, findings of this study demonstrate that exacerbated dysfunction of the intestinal barrier in advanced age promotes translocation of gut‐derived bacteria and contributes to the increased risk to poststroke bacterial infection. 相似文献