全文获取类型
收费全文 | 396篇 |
免费 | 29篇 |
国内免费 | 3篇 |
出版年
2021年 | 9篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 2篇 |
2017年 | 7篇 |
2016年 | 10篇 |
2015年 | 12篇 |
2014年 | 13篇 |
2013年 | 18篇 |
2012年 | 13篇 |
2011年 | 22篇 |
2010年 | 14篇 |
2009年 | 16篇 |
2008年 | 17篇 |
2007年 | 24篇 |
2006年 | 11篇 |
2005年 | 16篇 |
2004年 | 15篇 |
2003年 | 7篇 |
2002年 | 8篇 |
2001年 | 13篇 |
2000年 | 13篇 |
1999年 | 11篇 |
1998年 | 7篇 |
1997年 | 14篇 |
1996年 | 6篇 |
1995年 | 5篇 |
1993年 | 5篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 3篇 |
1988年 | 7篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 7篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1974年 | 7篇 |
1973年 | 6篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1970年 | 4篇 |
1954年 | 2篇 |
1949年 | 2篇 |
排序方式: 共有428条查询结果,搜索用时 15 毫秒
1.
Emily Olfson Catherine E. Cottrell Nicholas O. Davidson Christina A. Gurnett Jonathan W. Heusel Nathan O. Stitziel Li-Shiun Chen Sarah Hartz Rakesh Nagarajan Nancy L. Saccone Laura J. Bierut 《PloS one》2015,10(9)
The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations. 相似文献
2.
3.
T P McDonald M B Cottrell R E Clift C W Jackson 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1992,199(3):287-290
In an effort to explain the different platelet production capabilities of both normal and hypoxic male and female C3H and BALB/c mice, megakaryocyte size and number were determined utilizing bone marrow from both normal and hypoxic mice. The results indicate that normal BALB/c female mice have increased numbers of megakaryocytes, but of smaller size compared with either BALB/c male mice or to both sexes of C3H mice. An inverse relationship between the size and number of megakaryocytes was found in both normal and hypoxic mice; therefore, to evaluate total megakaryocyte characteristics, we calculated total megakaryocyte masses (TMM). With hypoxia, megakaryocyte number decreased, whereas megakaryocyte size increased. Despite the increase in megakaryocyte size, hypoxia caused a significant decrease in TMM (P less than 0.005) in all mice, but female C3H mice had higher TMM (P less than 0.05) than did female BALB/c mice. These data show that hypoxia decreases TMM in mice, and that the effect is greater in C3H mice than in BALB/c mice. 相似文献
4.
Recently there has been an explosive growth in the use of helicopters and fixed wing aircraft for the transportation of patients who are ill and injured. Although using such methods of transport may result in faster access to health care centres, their ultimate role for the civilian population is unclear. Unfortunately, there are many problems associated with aeromedical transport, particularly with rotary wing aircraft, which have shown an alarming tendency to crash. The use of lighter than air vehicles (blimps, hot air balloons) might offer most of the advantages of conventional aieromedical transport, with an appreciable improvement in safety. 相似文献
5.
K A Green A Cadogan G A Cottrell 《Comparative biochemistry and physiology. A, Comparative physiology》1989,93(1):47-51
1. The platelet aggregation response to several known platelet agonists was evaluated in four Asian elephants. The platelets were highly responsive to stimulation with platelet-activating factor (PAF) and collagen, less responsive to adenosine diphosphate (ADP) and non-responsive to arachidonic acid, serotonin and epinephrine. 2. Arachidonic acid (1 x 10(-4) M), while inducing no aggregation, caused the release of 1248 +/- 1147 pg/ul (mean +/- SD) of thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 from stimulated platelet. The addition of 1 x 10(-4) M ADP to platelets caused suboptimal aggregation and the release of only 25 +/- 10 pg TXB2/microliters. 3. The calcium channel blocker, verapamil, produced a dose-dependent inhibition of PAF-induced but not collagen-induced aggregation. The cyclooxygenase inhibitor, acetylsalicylic acid, produced no inhibition of either collagen- or PAF-induced aggregation. 相似文献
6.
G. Trevor Cottrell 《生物化学与生物物理学报:生物膜》2005,1711(2):126-141
The capacity of multiple connexins to hetero-oligomerize into functional heterogeneous gap junction channels has been demonstrated in vivo1, in vitro2, and in nonmammalian expression systems. These heterogeneous channels display gating activity, channel conductances, selectivity and regulatory behaviors that are sometimes not predicted by the behaviors of the corresponding homogeneous channels. Such observations suggest that heteromerization of gap junction proteins offers an efficient cellular strategy for finely regulating cell-to-cell communication. The available evidence strongly indicates that heterogeneous gap junction assembly is important to normal growth and differentiation, and may influence the appearance of several disease states. Definitive evidence that heterogeneous gap junction channels differentially regulate electrical conduction in excitable cells is absent. This review examines the prevalence, regulation, and implications of gap junction channel hetero-oligomerization. 相似文献
7.
While long-term fixation and storage of specimens is common and useful for many research projects, it is particularly important for space flight investigations where samples may not be returned to Earth for several months (International Space Station) or years (manned mission to Mars). We examined two critical challenges of space flight experimentation: the effect of long-term fixation on the quality of mouse bone preservation and the preservation of antigens and enzymes for both histochemical and immunohistochemical analyses, and how the animal/sample processing affects the preservation. We show that long-term fixation minimally affects standard histological staining, but that enzyme histochemistry and immunolabeling are greatly compromised. Further, we demonstrate that whole animal preservation is not as suitable as whole leg or stripped leg preservation for long-term fixation and all histological analyses. Overall, we recommend whole leg processing for long-term storage of bone specimens in fixative prior to embedding in plastic for histological examination. 相似文献
8.
Dane D. Jensen Cody B. Godfrey Christian Niklas Meritxell Canals Martina Kocan Daniel P. Poole Jane E. Murphy Farzad Alemi Graeme S. Cottrell Christoph Korbmacher Nevin A. Lambert Nigel W. Bunnett Carlos U. Corvera 《The Journal of biological chemistry》2013,288(32):22942-22960
TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists. 相似文献
9.
Objectives To explore whether the angiotensin T -converting enzyme (ACE) I/D (insertion/ deletion) polymorphism is associated with the susceptibility to high altitude pulmonary edema (HAPE) in the Han Chinese. Methods One hundred and forty-seven HAPE-p (HAPE patients) and 193 HAPE-r (HAPE resistants) were enrolled from the Yushu earthquake reconstruction workers in Qinghai province where the altitude is over 3 500 m above sea level. Blood samples were collected from each of the HAPE-p and HAPE-r groups. Information about physiological phenotypes was obtained via fieldwork investigation. The ACE-I/D polymorphism in HAPE-p and HAPE-r was detected by polymerase chain reaction (PCR). Results The SaO2 was significantly lower while HR was significantly higher in HAPE-p group than those in HAPE-r group. The genotype frequencies of ACE-I/D for II, ID, DD in HAPE-r and HAPE-p groups were 0.430, 0.446, 0.124 and 0.435, 0.469, 0.095, respectively, the allelic frequencies of I and D were 0.650, 0.350 and 0.670, 0.330, respectively. The OR of ID, DD and D alleles relative to II for HAPE was 0.961 (0.610-1.514), 1.322 (0.634-2.758) and 1.080 (0.783-1.489). There was no significant difference of the genotypic and the allelic frequencies in ACE-I/D polymorphism between HAPE-p and HAPE-r groups. Conclusions There is no relation between ACE-I/D polymorphism and HAPE in the Han Chinese. 相似文献
10.
LISE COMTE LAËTITIA BUISSON MARTIN DAUFRESNE GAËL GRENOUILLET 《Freshwater Biology》2013,58(4):625-639
1. Climate change could be one of the main threats faced by aquatic ecosystems and freshwater biodiversity. Improved understanding, monitoring and forecasting of its effects are thus crucial for researchers, policy makers and biodiversity managers. 2. Here, we provide a review and some meta‐analyses of the literature reporting both observed and predicted climate‐induced effects on the distribution of freshwater fish. After reviewing three decades of research, we summarise how methods in assessing the effects of climate change have evolved, and whether current knowledge is geographically or taxonomically biased. We conducted multispecies qualitative and quantitative analyses to find out whether the observed responses of freshwater fish to recent changes in climate are consistent with those predicted under future climate scenarios. 3. We highlight the fact that, in recent years, freshwater fish distributions have already been affected by contemporary climate change in ways consistent with anticipated responses under future climate change scenarios: the range of most cold‐water species could be reduced or shift to higher altitude or latitude, whereas that of cool‐ and warm‐water species could expand or contract. 4. Most evidence about the effects of climate change is underpinned by the large number of studies devoted to cold‐water fish species (mainly salmonids). Our knowledge is still incomplete, however, particularly due to taxonomic and geographic biases. 5. Observed and expected responses are well correlated among families, suggesting that model predictions are supported by empirical evidence. The observed effects are of greater magnitude and show higher variability than the predicted effects, however, indicating that other drivers of changes may be interacting with climate and seriously affecting freshwater fish. 6. Finally, we suggest avenues of research required to address current gaps in what we know about the climate‐induced effects on freshwater fish distribution, including (i) the need for more long‐term data analyses, (ii) the assessment of climate‐induced effects at higher levels of organisation (e.g. assemblages), (iii) methodological improvements (e.g. accounting for uncertainty among projections and species’ dispersal abilities, combining both distributional and empirical approaches and including multiple non‐climatic stressors) and (iv) systematic confrontation of observed versus predicted effects across multi‐species assemblages and at several levels of biological organisation (i.e. populations and assemblages). 相似文献