全文获取类型
收费全文 | 1326篇 |
免费 | 102篇 |
出版年
2023年 | 7篇 |
2022年 | 14篇 |
2021年 | 37篇 |
2020年 | 20篇 |
2019年 | 26篇 |
2018年 | 18篇 |
2017年 | 31篇 |
2016年 | 54篇 |
2015年 | 68篇 |
2014年 | 92篇 |
2013年 | 91篇 |
2012年 | 108篇 |
2011年 | 104篇 |
2010年 | 60篇 |
2009年 | 51篇 |
2008年 | 65篇 |
2007年 | 65篇 |
2006年 | 62篇 |
2005年 | 53篇 |
2004年 | 55篇 |
2003年 | 51篇 |
2002年 | 50篇 |
2001年 | 13篇 |
2000年 | 10篇 |
1999年 | 15篇 |
1998年 | 16篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 10篇 |
1994年 | 11篇 |
1993年 | 7篇 |
1992年 | 5篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 7篇 |
1983年 | 9篇 |
1982年 | 8篇 |
1981年 | 4篇 |
1980年 | 5篇 |
1979年 | 11篇 |
1978年 | 6篇 |
1977年 | 5篇 |
1975年 | 5篇 |
1974年 | 3篇 |
1964年 | 4篇 |
1956年 | 5篇 |
排序方式: 共有1428条查询结果,搜索用时 15 毫秒
31.
Mahban Irandoust Julian Alvarez Zarate Isabelle Hubeek Ellen M. van Beek Karin Schornagel Aart J. F. Broekhuizen Mercan Akyuz Arjan A. van de Loosdrecht Ruud Delwel Peter J. Valk Edwin Sonneveld Pamela Kearns Ursula Creutzig Dirk Reinhardt Eveline S. J. M. de Bont Eva A. Coenen Marry M. van den Heuvel-Eibrink C. Michel Zwaan Gertjan J. L. Kaspers Jacqueline Cloos Timo K. van den Berg 《PloS one》2013,8(1)
Background
Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRPα) on macrophages. Although AML cells express SIRPα, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRPα in acute myeloid leukemia.Design and Methods
We analyzed the expression of SIRPα, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRPα on two low SIRPα expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRPα expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs.Results
By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRPα is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0–M3. Interestingly, AML patients with high SIRPα expression had a poor prognosis. Our results also showed that SIRPα is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRPα with an agonistic antibody in the cells stably expressing chimeric SIRPα, led to inhibition of growth and induction of programmed cell death. Finally, the SIRPα-derived signaling synergized with the activity of established antileukemic drugs.Conclusions
Our data indicate that triggering of SIRPα has antileukemic effect and may function as a potential therapeutic target in AML. 相似文献32.
Ru Wang Markku Alen Zhusheng Yu Petri Wiklund Shu Mei Cheng Timo T?rm?kangas Peijie Chen Sulin Cheng 《PloS one》2013,8(12)
Vitamin D is well known for its regulatory role in calcium and phosphate homeostasis, but its role in muscle mass and strength during growth remains inconclusive. We explored the association of serum 25-hydroxyvitamin D (25(OH)D) with muscle development in girls from 11 to 18-years old. Whole body lean tissue mass (LMWB), appendicular lean mass (aLM), muscle cross-sectional area at the lower leg (mCSA), maximal voluntary contraction of elbow flexors (MVCelbow) and knee extensors (MVCknee) were assessed in 217 girls aged 10–13 years (at baseline), 215 in 2-year and 226 in 7.5-year follow-up. Serum concentration of 25(OH)D and intact parathyroid hormone (PTH) were analyzed retrospectively and girls were categorized according to their 25(OH)D levels (consistently insufficient 25(OH)D GLL <50 nmol/l and consistently sufficient GHH >50 nmol/l from baseline to 7-year follow-up). We found that 25(OH)D level declined until menarche (p<0.05) while LMWB, aLM, mCSA, MVCelbow and MVCknee continued to increase (p<0.001 for all) post menarche. At pre-menarche, the GLL (n = 34) had higher LMWB and aLM than the GHH (n = 21, p<0.05), while post-menarche the GHH (n = 15) had a greater catch-up gain in LMWB (p = 0.004), aLM (p = 0.001) and mCSA (p = 0.027) compared to the GLL (n = 65) over the first 2-year period. At the age of 18, no differences in muscle mass/strength between the low (n = 151) and high (n = 77) levels of 25(OH)D groups were found. This finding was independent of vitamin D receptor genotype and other confounders. In conclusion, our results showed that levels of 25(OH)D have no significant negative influence on the development of muscle mass and strength during pubertal growth both with longitudinal and cross-sectional comparison. On the contrary, our results suggest that the temporary negative association between 25(OH)D and muscle mass arises as a consequence of fast growth prior to menarche, and this negative association is diminished through catch-up growth after menarche. 相似文献
33.
The measurement of glomerular filtration rate (GFR) is the gold standard in kidney function assessment. Currently, investigators determine GFR by measuring the level of the endogenous biomarker creatinine or exogenously applied radioactive labeled inulin (3H or 14C). Creatinine has the substantial drawback that proximal tubular secretion accounts for ~50% of total renal creatinine excretion and therefore creatinine is not a reliable GFR marker. Depending on the experiment performed, inulin clearance can be determined by an intravenous single bolus injection or continuous infusion (intravenous or osmotic minipump). Both approaches require the collection of plasma or plasma and urine, respectively. Other drawbacks of radioactive labeled inulin include usage of isotopes, time consuming surgical preparation of the animals, and the requirement of a terminal experiment. Here we describe a method which uses a single bolus injection of fluorescein isothiocyanate-(FITC) labeled inulin and the measurement of its fluorescence in 1-2 μl of diluted plasma. By applying a two-compartment model, with 8 blood collections per mouse, it is possible to measure GFR in up to 24 mice per day using a special work-flow protocol. This method only requires brief isoflurane anesthesia with all the blood samples being collected in a non-restrained and awake mouse. Another advantage is that it is possible to follow mice over a period of several months and treatments (i.e. doing paired experiments with dietary changes or drug applications). We hope that this technique of measuring GFR is useful to other investigators studying mouse kidney function and will replace less accurate methods of estimating kidney function, such as plasma creatinine and blood urea nitrogen. 相似文献
34.
35.
36.
Sascha Venturelli Alexander Berger Alexander B?cker Christian Busch Timo Weiland Seema Noor Christian Leischner Sabine Schleicher Mascha Mayer Thomas S. Weiss Stephan C. Bischoff Ulrich M. Lauer Michael Bitzer 《PloS one》2013,8(8)
The polyphenolic alcohol resveratrol has demonstrated promising activities for the prevention and treatment of cancer. Different modes of action have been described for resveratrol including the activation of sirtuins, which represent the class III histone deacetylases (HDACs). However, little is known about the activity of resveratrol on the classical HDACs of class I, II and IV, although these classes are involved in cancer development or progression and inhibitors of HDACs (HDACi) are currently under investigation as promising novel anticancer drugs. We could show by in silico docking studies that resveratrol has the chemical structure to inhibit the activity of different human HDAC enzymes. In vitro analyses of overall HDAC inhibition and a detailed HDAC profiling showed that resveratrol inhibited all eleven human HDACs of class I, II and IV in a dose-dependent manner. Transferring this molecular mechanism into cancer therapy strategies, resveratrol treatment was analyzed on solid tumor cell lines. Despite the fact that hepatocellular carcinoma (HCC) is known to be particularly resistant against conventional chemotherapeutics, treatment of HCC with established HDACi already has shown promising results. Testing of resveratrol on hepatoma cell lines HepG2, Hep3B and HuH7 revealed a dose-dependent antiproliferative effect on all cell lines. Interestingly, only for HepG2 cells a specific inhibition of HDACs and in turn a histone hyperacetylation caused by resveratrol was detected. Additional testing of human blood samples demonstrated a HDACi activity by resveratrol ex vivo. Concluding toxicity studies showed that primary human hepatocytes tolerated resveratrol, whereas in vivo chicken embryotoxicity assays demonstrated severe toxicity at high concentrations. Taken together, this novel pan-HDACi activity opens up a new perspective of resveratrol for cancer therapy alone or in combination with other chemotherapeutics. Moreover, resveratrol may serve as a lead structure for chemical optimization of bioavailability, pharmacology or HDAC inhibition. 相似文献
37.
de Araujo Junior Raimundo Fernandes Eich Christina Jorquera Carla Schomann Timo Baldazzi Fabio Chan Alan B. Cruz Luis J. 《Molecular and cellular biochemistry》2020,468(1-2):153-168
Molecular and Cellular Biochemistry - Accumulating evidence indicates that ceramide (Cer) and palmitic acid (PA) possess the ability to modulate switching of macrophage phenotypes and possess... 相似文献
38.
Hydrobiologia - Forestry-related land use can cause increasing instream sedimentation, burying and eradicating stream bryophytes, with severe ecological consequences. However, there is limited... 相似文献
39.
Grey mullets are remarkably characterized by their overall uniform external morphology. Identifying species as well as positioning the Mugiliformes in a phylogenetic context is rather difficult. Most recently they were placed in the newly erected Ovalentaria, but more detailed relationships to potential sister taxa were not resolved. Studying the internal morphology, especially the osteology, might provide new insights into the evolution of the Mugiliformes as well as help clarify their phylogenetic position within the Ovalentaria. A detailed osteology of the golden grey mullet Liza aurata is presented. The use of cleared and stained specimens allowed for a complete examination of bony and cartilaginous structures, and a 3D reconstruction from a μCT data set provided additional information on the positional relationships of the bones. Following this, the data obtained were compared with different mugilid species, particularly with the flathead grey mullet Mugil cephalus. Several differences between these species could be identified, such as the position of the basisphenoid, the shape of the hyomandibular and the composition of the branchial arches. These characters might help in understanding the evolutionary changes happening within the mugiliforms and will provide the basis to study this taxon in detail, finally allowing the reconstruction of the body plan of grey mullets. 相似文献
40.