全文获取类型
收费全文 | 529篇 |
免费 | 30篇 |
出版年
2022年 | 3篇 |
2021年 | 7篇 |
2020年 | 4篇 |
2019年 | 3篇 |
2018年 | 4篇 |
2017年 | 5篇 |
2016年 | 11篇 |
2015年 | 20篇 |
2014年 | 20篇 |
2013年 | 32篇 |
2012年 | 28篇 |
2011年 | 36篇 |
2010年 | 24篇 |
2009年 | 28篇 |
2008年 | 28篇 |
2007年 | 24篇 |
2006年 | 25篇 |
2005年 | 30篇 |
2004年 | 26篇 |
2003年 | 30篇 |
2002年 | 27篇 |
2001年 | 7篇 |
2000年 | 5篇 |
1999年 | 8篇 |
1998年 | 5篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1991年 | 8篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 2篇 |
1983年 | 4篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 7篇 |
1976年 | 4篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1970年 | 3篇 |
1969年 | 2篇 |
1967年 | 3篇 |
1966年 | 3篇 |
1962年 | 2篇 |
排序方式: 共有559条查询结果,搜索用时 15 毫秒
91.
Anders West Poul Jennum Sofie Amalie Simonsen Birgit Sander Milena Pavlova Helle K. Iversen 《Chronobiology international》2017,34(6):687-697
Introduction and rationale: Stroke is a major cause of acquired cerebral disability among adults, frequently accompanied by depression, anxiety, cognitive impairment, disrupted sleep and fatigue. New ways of intervention to prevent these complications are therefore needed. The major circadian regulator, the suprachiasmatic nucleus, is mainly controlled by natural daylight, and the blue spectrum is considered the most powerful. During stroke rehabilitation, patients typically are mostly indoors and therefore not exposed to the natural daytime variation in light intensity. Furthermore, several rehabilitation hospitals may be exposed to powerful light in the blue spectrum, but at a time that is adversely related to their endogenous circadian phase, for example in the late evening instead of the daytime. Hypothesis: Naturalistic light that mimics the natural daytime spectrum variation will have a positive impact on the health of poststroke patients admitted to rehabilitation. We test specifically for improved sleep and less fatigue (questionnaires, polysomnography, Actiwatch), improved well-being (questionnaires), lessen anxiety and depression (questionnaires), improved cognition (tests), stabilizing of the autonomous nervous system (ECG/HR, blood pressure, temperature) and stabilizing of the diurnal biochemistry (blood markers). Study design: The study is a prospective parallel longitudinal randomized controlled study (quasi randomization). Stroke patients in need of rehabilitation will be included at the acute stroke unit and randomized to either the intervention unit (naturalistic lighting) or the control unit (CU) (standard lighting). The naturalistic light is installed in the entire IU (Cromaviso, Denmark). Conclusion: This study aims to elucidate the influence of naturalistic light on patients during long-term hospitalization in a real hospital setting. The hypotheses are based on preclinical research, as studies using naturalistic light have never been performed before. Investigating the effects of naturalistic light in a clinical setting is therefore much needed. 相似文献
92.
Transient protein interactions are paramount to life where fast and efficient transfer of information and cargo are often integral to pathways and networks. However, complexes formed by transient protein interactions are often times resistant to direct structural characterization due to their inherent, dynamic nature, so our knowledge to date typically derives from biochemical, biophysical and computational methods. In this issue, Shimada and co‐authors present the crystal structure of the mammalian cytochrome c oxidase in complex with its electron donor cytochrome c, identifying a new class of protein–protein interaction termed “soft and specific”. 相似文献
93.
The “cost‐benefit” hypothesis states that avian body organs show mass changes consistent with the trade‐off between their functional importance and maintenance cost, which may vary throughout the annual cycle. Flightless moulting common scoter Melanitta nigra in Danish marine waters select rich undisturbed offshore feeding areas lacking predators, suggesting active feeding during moult. We tested four predictions relating to organ size during flightlessness in moulting male common scoter under this hypothesis. Namely that (i) pectoral muscles would show atrophy followed by hypertrophy, but that there would be no change in (ii) leg muscles and heart (the locomotory architecture required to sustain diving for food), (iii) digestive organs and liver (required to process food), or (iv) fat deposits (because birds could fulfil daily energy requirements from locally abundant food resources). Dissection of scoters collected at different stages during wing moult south of the Danish island of Læsø provided data on organ size that were consistent with these predictions. Pectoral muscle mass showed a c.23% atrophy during the middle of the flightless period relative to that at the end of moult. There was no significant loss in leg muscle, heart, digestive organs (except gizzard mass), liver, fat reserves or body mass with remigial growth. These findings are consistent with the hypothesis that common scoter moult in a rich feeding area, and rely on their diet to meet the nutritional requirements of remigial moult. These results differ in detail from those of a similar study of terrestrial feeding moulting greylag geese Anser anser, but because of the widely differing ecology of the species concerned, both sets of findings provide strong support for the hypothesis that variations in phenotypic plasticity in size of fat stores, locomotor and digestive organs can be interpreted as evolutionary adaptations to meet the conflicting needs (feather growth, nutritional challenges and predator avoidance) of the flightless moult period in different Anatidae species. 相似文献
94.
Anne Jørgensen John E Nielsen Jane E Morthorst Poul Bjerregaard Henrik Leffers 《Reproductive biology and endocrinology : RB&E》2009,7(1):1-7
Background
Until recently, the limit of spatial resolution of ultrasound systems has prevented characterization of structures <1 mm. Hence, the study of ovarian follicular development in rodents has been based on one-time histological examination of excised tissues; i.e., longitudinal study of day-to-day ovarian changes has not been possible in mice and rats. The objective was to establish an ultrasonographic approach to study follicular and luteal dynamics in mice and rats.Methods
Experiment 1 was a pilot study to develop methods of immobilization (physical restraint vs. general anesthesia) and determine technical factors affecting ovarian images using ultrasound bio-microscopy in rats vs. mice. The hair coat was removed over the thoraco-lumber area using depilation cream, and a highly viscous acoustic gel was applied while the animals were maintained in sternal recumbency. In Experiment 2, changes in ovarian structures during the estrous cycle were monitored by twice daily ultrasonography in 10 mice for 2 estrous cycles.Results
Ovarian images were not distinct in rats due to attenuation of ultrasound waves. Physical restraint, without general anesthesia, was insufficient for immobilization in mice. By placing the transducer face over the dorsal flank, the kidney was visualized initially as a point of reference. A routine of moving the transducer a few millimetres caudo-laterally from the kidney was established to quickly and consistently localize the ovaries; the total time to scan both ovaries in a mouse was about 10 minutes. By comparing vaginal cytology with non-anesthetized controls, repeated exposure to anesthesia did not affect the estrous cycle. Temporal changes in the number of follicles in 3 different size categories support the hypothesis that follicles ≥ 20 microns develop in a wave-like fashion.Conclusion
The mouse is a suitable model for the study of ovarian dynamics using transcutaneous ultrasound bio-microscopy. Repeated general anesthesia for examination had no apparent effect on the estrous cycle, and preliminary results revealed a wave-like pattern of ovarian follicle development in mice. 相似文献95.
96.
Jørgensen JP Lauridsen AM Kristensen P Dissing K Johnsen AH Hendil KB Hartmann-Petersen R 《Journal of molecular biology》2006,360(5):1043-1052
We have identified Adrm1 as a novel component of the regulatory ATPase complex of the 26 S proteasome: Adrm1 was precipitated with an antibody to proteasomes and vice versa. Adrm1 co-migrated with proteasomes on gel-filtration chromatography and non-denaturing polyacrylamide gel electrophoresis. Adrm1 has been described as an interferon-gamma-inducible, heavily glycosylated membrane protein of 110 kDa. However, we found Adrm1 in mouse tissues only as a 42 kDa peptide, corresponding to the mass of the non-glycosylated peptide chain, and it could not be induced in HeLa cells with interferon. Adrm1 was present almost exclusively in soluble 26 S proteasomes, albeit a small fraction was membrane-associated, like proteasomes. Adrm1 was found in cells in amounts equimolar with S6a, a 26 S proteasome subunit. HeLa cells contain no pool of free Adrm1 but recombinant Adrm1 could bind to pre-existing 26 S proteasomes in cell extracts. Adrm1 may be distantly related to the yeast proteasome subunit Rpn13, mutants of which are reported to display no obvious phenotype. Accordingly, knock-down of Adrm1 in HeLa cells had no effect on the amount of proteasomes, or on degradation of bulk cell protein, or accumulation of polyubiquitinylated proteins. This indicates that Adrm1 has a specialised role in proteasome function. 相似文献
97.
P25alpha/tubulin polymerization promoting protein (TPPP) is a brain specific phosphoprotein that displays microtubule bundling activity. In the mature brain, p25alpha/TPPP distributes to oligodendrocytes and choroid plexus epithelium. We mapped the spatial and temporal distribution of p25alpha/TPPP in the developing rat brain. Having localized its expression to neuronal tissue by Western blot analyses, the distribution of p25alpha/TPPP to developing oligodendrocytes was confirmed using a specific antibody. In the pre-natal and post-natal brain, p25alpha/TPPP was localized to the perinuclear cytoplasm of myelinating oligodendrocytes from embryonic (E) day E20 as verified from cellular co-localization with 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Oligodendrocyte progenitor cells and pre-myelinating oligodendrocytes identified by the expression of NG2 proteoglycan and CD9, respectively, both failed to contain p25alpha/TPPP. In contrast, P25alpha/TPPP co-localized with beta(IV)-tubulin from post-natal (p) day P10 suggesting that p25alpha/TPPP plays an important role for tubulin-related transport in developing, myelinating oligodendrocytes. 相似文献
98.
Dueholm MS Nielsen SB Hein KL Nissen P Chapman M Christiansen G Nielsen PH Otzen DE 《Biochemistry》2011,50(39):8281-8290
The amyloid fold is usually considered a result of protein misfolding. However, a number of studies have recently shown that the amyloid structure is also used in nature for functional purposes. CsgA is the major subunit of Escherichia coli curli, one of the most well-characterized functional amyloids. Here we show, using a highly efficient approach to prepare monomeric CsgA, that in vitro fibrillation of CsgA occurs under a wide variety of environmental conditions and that the resulting fibrils exhibit similar structural features. This highlights how fibrillation is "hardwired" into amyloid that has evolved for structural purposes in a fluctuating extracellular environment and represents a clear contrast to disease-related amyloid formation. Furthermore, we show that CsgA polymerization in vitro is preceded by the formation of thin needlelike protofibrils followed by aggregation of the amyloid fibrils. 相似文献
99.
Nguyen HD Trinh BT Tran QN Nguyen HD Pham HD Hansen PE Duus F Connolly JD Nguyen LH 《Phytochemistry》2011,72(2-3):290-295
Friedolanostanes, (22Z,24E)-3β-acetoxy-9α-hydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid, (22Z,24E)-3β,9α-dihydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid, (22Z,24E)-9α-hydroxy-3-oxo-17,14-friedolanosta-14,22,24-trien-26-oic acid, a friedocycloartane, (22Z,24E)-3α-hydroxy-17,13-friedocycloarta-12,22,24-trien-26-oic acid, and a benzophenone, benthaphenone, together with known compounds (22Z,24E)-3α,9α-dihydroxy-17,13-friedolanosta-12,22,24-trien-26-oic acid, methyl (24E)-3α,23-dihydroxy-17,14-friedolanosta-8,14,24-trien-26-oate, glutinol, lupeol, and stigmasterol, were isolated from leaves and bark of Garcinia benthami. Their structures were elucidated using spectroscopic techniques, mainly 1-D and 2-D NMR spectroscopy, and chemical correlations. 相似文献
100.
Gaborit N Larbouret C Vallaghe J Peyrusson F Bascoul-Mollevi C Crapez E Azria D Chardès T Poul MA Mathis G Bazin H Pèlegrin A 《The Journal of biological chemistry》2011,286(13):11337-11345
In oncology, simultaneous inhibition of epidermal growth factor receptor (EGFR) and HER2 by monoclonal antibodies (mAbs) is an efficient therapeutic strategy but the underlying mechanisms are not fully understood. Here, we describe a time-resolved fluorescence resonance energy transfer (TR-FRET) method to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies. First, we tested this antibody-based TR-FRET assay in NIH/3T3 cell lines that express EGFR and/or HER2 and in various tumor cell lines. Then, we used the antibody-based TR-FRET assay to evaluate in vitro the effect of different targeted therapies on EGFR/HER2 heterodimers in the ovarian carcinoma cell line SKOV-3. A simultaneous incubation with Cetuximab (anti-EGFR) and Trastuzumab (anti-HER2) disturbed EGFR/HER2 heterodimers resulting in a 72% reduction. Cetuximab, Trastuzumab or Pertuzumab (anti-HER2) alone induced a 48, 44, or 24% reduction, respectively. In contrast, the tyrosine kinase inhibitors Erlotinib and Lapatinib had very little effect on EGFR/HER2 dimers concentration. In vivo, the combination of Cetuximab and Trastuzumab showed a better therapeutic effect (median survival and percentage of tumor-free mice) than the single mAbs. These results suggest a correlation between the extent of the mAb-induced EGFR/HER2 heterodimer reduction and the efficacy of such mAbs in targeted therapies. In conclusion, quantifying EGFR/HER2 heterodimers using our antibody-based TR-FRET assay may represent a useful method to predict the efficacy and explain the mechanisms of action of therapeutic mAbs, in addition to other commonly used techniques that focus on antibody-dependent cellular cytotoxicity, phosphorylation, and cell proliferation. 相似文献