全文获取类型
收费全文 | 421篇 |
免费 | 41篇 |
国内免费 | 1篇 |
出版年
2023年 | 2篇 |
2022年 | 2篇 |
2021年 | 10篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2018年 | 9篇 |
2017年 | 6篇 |
2016年 | 12篇 |
2015年 | 29篇 |
2014年 | 30篇 |
2013年 | 32篇 |
2012年 | 42篇 |
2011年 | 31篇 |
2010年 | 19篇 |
2009年 | 15篇 |
2008年 | 18篇 |
2007年 | 28篇 |
2006年 | 15篇 |
2005年 | 20篇 |
2004年 | 12篇 |
2003年 | 25篇 |
2002年 | 18篇 |
2001年 | 12篇 |
2000年 | 10篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1997年 | 6篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1975年 | 4篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1956年 | 1篇 |
排序方式: 共有463条查询结果,搜索用时 31 毫秒
1.
Elizabeth S. Browne Johnny R. Porter Gonzalo Correa Jude Abadie Frank Svec 《The Journal of steroid biochemistry and molecular biology》1993,45(6):517-524
Dehydroepiandrosterone (DHEA) decreases the activity of hepatic tyrosine aminotransferase (TAT), a glucocorticoid-inducible enzyme, in the obese, hypercorticosteronemic Zucker rat. To investigate the mechanism of this antiglucocorticoid action, the effect of exogenous DHEA on hepatic glucocorticoid receptor (GC) number and affinity was quantitated. Food supplementation with DHEA (0.6% w/w) for 1 or 7 days had no effect on either receptor number or affinity in obese Zucker rats. After 28 days, however, DHEA treatment resulted in a nearly 40% decrease in cytosolic hepatic receptor content (Bmax; fmol/mg cytosolic protein) without any change in affinity (Kd) in both lean and obese rats. DHEA treatment for 28 days also resulted in an increased liver size and cytosolic protein content. When the hepatic GC receptor content was normalized based on the change in liver size and protein content, the apparent number of GC binding sites per liver was not affected by DHEA treatment. This observation suggests that DHEA's effect on GC receptor content may not be a specific action and that downregulation of the GC receptor is not the mechanism of DHEA action on GC induced TAT activity. This is supported by the effect of DHEA on obese rat TAT activity in the same experiment where the greatest inhibition occurred after only 1 day of treatment. From these experiments it is concluded that although long-term DHEA treatment may decrease the relative concentration of GC receptors in rat liver, this change is not the mechanism through which DHEA mediates its acute antiglucocorticoid action. 相似文献
2.
3.
4.
Thuvaraka Thavayogarajah Preetish Gangopadhyay Stefan Rahlfs Katja Becker Klaus Lingelbach Jude M. Przyborski Anthony A. Holder 《PloS one》2015,10(4)
Plasmodium falciparum invades human red blood cells, residing in a parasitophorous vacuole (PV), with a parasitophorous vacuole membrane (PVM) separating the PV from the host cell cytoplasm. Here we have investigated the role of N-myristoylation and two other N-terminal motifs, a cysteine potential S-palmitoylation site and a stretch of basic residues, as the driving force for protein targeting to the parasite plasma membrane (PPM) and subsequent translocation across this membrane. Plasmodium falciparum adenylate kinase 2 (Pf AK2) contains these three motifs, and was previously proposed to be targeted beyond the parasite to the PVM, despite the absence of a signal peptide for entry into the classical secretory pathway. Biochemical and microscopy analyses of PfAK2 variants tagged with green fluorescent protein (GFP) showed that these three motifs are involved in targeting the protein to the PPM and translocation across the PPM to the PV. It was shown that the N-terminal 37 amino acids of PfAK2 alone are sufficient to target and translocate GFP across the PPM. As a control we examined the N-myristoylated P. falciparum ADP-ribosylation factor 1 (PfARF1). PfARF1 was found to co-localise with a Golgi marker. To determine whether or not the putative palmitoylation and the cluster of lysine residues from the N-terminus of PfAK2 would modulate the subcellular localization of PfARF1, a chimeric fusion protein containing the N-terminus of PfARF1 and the two additional PfAK2 motifs was analysed. This chimeric protein was targeted to the PPM, but not translocated across the membrane into the PV, indicating that other features of the N-terminus of PfAK2 also play a role in the secretion process. 相似文献
5.
Emanuela Carlotti David Wrench Guglielmo Rosignoli Jacek Marzec Ajanthah Sangaralingam Lena Hazanov Miri Michaeli Simon Hallam Tracy Chaplin Sameena Iqbal Maria Calaminici Bryan Young Ramit Mehr Peter Campbell Jude Fitzgibbon John G. Gribben 《PloS one》2015,10(9)
Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10−2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease. 相似文献
6.
Rosette Megnekou Jean Claude Djontu Jude Daiga Bigoga Fabrice Mbah Medou Sandrine Tenou Abel Lissom 《PloS one》2015,10(8)
Background
Impact of the pathophysiology of Plasmodium falciparum placental malaria (PM) on the profile of some oxidative stress biomarkers and their relationship with poor pregnancy outcomes in women remain unknown.Methods
Between 2013 and 2014, peripheral blood and placenta tissue from 120 Cameroonian women at delivery were assessed for maternal haemoglobin and, parasitaemia respectively. Parasite accumulation in the placenta was investigated histologically. The levels of oxidative stress biomarkers Malondialdehyde (MDA), Nitric Oxide (NO), Superoxide dismutase (SOD), Catalase (CAT) and Gluthatione (GSH) in the supernatant of teased placenta tissues were determined by Colorimetric enzymatic assays.Results
Parasitaemia was inversely related to haemoglobin levels and birth weight (P <0.001 and 0.012, respectively). The level of lipid peroxide product (MDA) was significantly higher in the malaria infected (P = 0.0047) and anaemic (P = 0.024) women compared to their non-infected and non-anaemic counterparts, respectively. A similar trend was observed with SOD levels, though not significant. The levels of MDA also correlated positively with parasitaemia (P = 0.0024) but negatively with haemoglobin levels (P = 0.002). There was no association between parasitaemia, haemoglobin level and the other oxidative stress biomarkers. From histological studies, levels of MDA associated positively and significantly with placenta malaria infection and the presence of malaria pigments. The levels of SOD, NO and CAT increased with decreasing leukocyte accumulation in the intervillous space. Baby birth weight increased significantly with SOD and CAT levels, but decreased with levels of GSH.Conclusions
Placental P. falciparum infection may cause oxidative stress of the placenta tissue with MDA as a potential biomarker of PM, which alongside GSH could lead to poor pregnancy outcomes (anaemia and low birth weight). This finding contributes to the understanding of the pathophysiology of P. falciparum placental malaria in women. 相似文献7.
8.
Jude Bayham Nicolai V. Kuminoff Quentin Gunn Eli P. Fenichel 《Proceedings. Biological sciences / The Royal Society》2015,282(1818)
Managing infectious disease is among the foremost challenges for public health policy. Interpersonal contacts play a critical role in infectious disease transmission, and recent advances in epidemiological theory suggest a central role for adaptive human behaviour with respect to changing contact patterns. However, theoretical studies cannot answer the following question: are individual responses to disease of sufficient magnitude to shape epidemiological dynamics and infectious disease risk? We provide empirical evidence that Americans voluntarily reduced their time spent in public places during the 2009 A/H1N1 swine flu, and that these behavioural shifts were of a magnitude capable of reducing the total number of cases. We simulate 10 years of epidemics (2003–2012) based on mixing patterns derived from individual time-use data to show that the mixing patterns in 2009 yield the lowest number of total infections relative to if the epidemic had occurred in any of the other nine years. The World Health Organization and other public health bodies have emphasized an important role for ‘distancing’ or non-pharmaceutical interventions. Our empirical results suggest that neglect for voluntary avoidance behaviour in epidemic models may overestimate the public health benefits of public social distancing policies. 相似文献
9.
10.
Chukwunonso Onyilagha Ping Jia Nipun Jayachandran Sen Hou Ifeoma Okwor Shiby Kuriakose Aaron Marshall Jude E. Uzonna 《PLoS neglected tropical diseases》2015,9(4)