全文获取类型
收费全文 | 294篇 |
免费 | 46篇 |
出版年
2022年 | 2篇 |
2021年 | 5篇 |
2020年 | 7篇 |
2019年 | 4篇 |
2018年 | 7篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 8篇 |
2014年 | 3篇 |
2013年 | 17篇 |
2012年 | 25篇 |
2011年 | 17篇 |
2010年 | 13篇 |
2009年 | 16篇 |
2008年 | 14篇 |
2007年 | 15篇 |
2006年 | 18篇 |
2005年 | 26篇 |
2004年 | 17篇 |
2003年 | 21篇 |
2002年 | 10篇 |
2001年 | 5篇 |
2000年 | 5篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 2篇 |
1995年 | 4篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1990年 | 3篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1977年 | 2篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1970年 | 2篇 |
1969年 | 2篇 |
1965年 | 1篇 |
1963年 | 1篇 |
1959年 | 1篇 |
1953年 | 1篇 |
1948年 | 1篇 |
1933年 | 1篇 |
排序方式: 共有340条查询结果,搜索用时 15 毫秒
261.
Qualitative and quantitative changes in mitochondrial DNA (mtDNA) have been shown to be common causes of inherited neurodegenerative and muscular diseases, and have also been implicated in ageing. These diseases can be caused by primary mtDNA mutations, or by defects in nuclear‐encoded mtDNA maintenance proteins that cause secondary mtDNA mutagenesis or instability. Furthermore, it has been proposed that mtDNA copy number affects cellular tolerance to environmental stress. However, the mechanisms that regulate mtDNA copy number and the tissue‐specific consequences of mtDNA mutations are largely unknown. As post‐mitotic tissues differ greatly from proliferating cultured cells in their need for mtDNA maintenance, and as most mitochondrial diseases affect post‐mitotic cell types, the mouse is an important model in which to study mtDNA defects. Here, we review recently developed mouse models, and their contribution to our knowledge of mtDNA maintenance and its role in disease. 相似文献
262.
Saastamoinen M van der Sterren D Vastenhout N Zwaan BJ Brakefield PM 《The American naturalist》2010,176(6):686-698
The experience of environmental stress during development can substantially affect an organism's life history. These effects are often mainly negative, but a growing number of studies suggest that under certain environmental conditions early experience of such stress may yield individuals that are less sensitive to environmental stress later on in life. We used the butterfly Bicyclus anynana to study the effects of limited larval and adult food and forced flight on individual performance measured as reproduction and adult life span. Larvae exposed to food stress showed longer development and produced smaller adults. Thus, they were not able to fully compensate for the food deprivation during development. Females that experienced food stress during development did not increase tolerance for adult food limitation. However, females exposed to food stress during development coped better with forced flight compared with the control group. The apparent absence of costs of flight in poor-quality females may be a by-product of an altered body allocation, as females experiencing both food stress treatments had increased thorax ratios, compared with controls, and increased flight performances. The results reveal an important plasticity component to variation in flight performance and suggest that the cost of flight depends on an individual's internal condition. 相似文献
263.
Maternal antibodies in a wild altricial bird: effects on offspring immunity, growth and survival 总被引:2,自引:0,他引:2
1. In many animals immunity is not fully developed until adulthood but the young still need protection against various sets of pathogens. Thus, bird nestlings are highly dependent on antibodies received from their mother (in the eggs) during their rapid early growth period. The relationship between maternal immunity and the development of neonates' own immunity has been poorly studied. 2. It has been suggested that immune function plays an important part in mediating resource competition between different life-history traits, e.g. growth and reproduction. Maternal investment of antibodies has potentially permanent effects on offspring phenotype. Thus, the trade-offs between the immune function and other important life-history traits in the offspring will also affect the fitness of the mother. 3. Our supplemental feeding experiment in the magpie Pica pica indicates that the immunoglobulin levels of offspring at hatching are dependent on a mother's nutritional condition. In addition, the amount of maternal immunoglobulins transferred to offspring increases along the laying order within a nest. 4. We also found that at the age of 8-10 days the immunoglobulin production of the offspring has already begun. Furthermore, the maternal immunoglobulin levels of the offspring at hatching were positively related to their immunoglobulin levels on day 10. 5. Maternal immunoglobulins did not significantly affect offspring growth, but there was a negative relationship between self-produced immunoglobulins and growth over the first 10 days, indicating a trade-off between these traits. Nestlings' weight, however, had a positive relationship with immunoglobulin production suggesting that the observed trade-off between growth and immunoglobulin production is due to catch-up growth of nestlings with a low hatching weight. We found that within nests nestlings with higher maternal antibody levels had higher survival rate until day 20, but between nests there was an opposite relationship. 6. Evidently, there is a trade-off, in magpies, between maternal resources, immune function and growth, shaping the evolution of maternal investment in offspring immunity. 相似文献
264.
265.
266.
Götz A Tyynismaa H Euro L Ellonen P Hyötyläinen T Ojala T Hämäläinen RH Tommiska J Raivio T Oresic M Karikoski R Tammela O Simola KO Paetau A Tyni T Suomalainen A 《American journal of human genetics》2011,(5):66-642
Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure. 相似文献
267.
Ala-Poikela M Goytia E Haikonen T Rajamäki ML Valkonen JP 《Journal of virology》2011,85(13):6784-6794
The multifunctional helper component proteinase (HCpro) of potyviruses (genus Potyvirus; Potyviridae) shows self-interaction and interacts with other potyviral and host plant proteins. Host proteins that are pivotal to potyvirus infection include the eukaryotic translation initiation factor eIF4E and the isoform eIF(iso)4E, which interact with viral genome-linked protein (VPg). Here we show that HCpro of Potato virus A (PVA) interacts with both eIF4E and eIF(iso)4E, with interactions with eIF(iso)4E being stronger, as judged by the data of a yeast two-hybrid system assay. A bimolecular fluorescence complementation assay on leaves of Nicotiana benthamiana showed that HCpro from three potyviruses (PVA, Potato virus Y, and Tobacco etch virus) interacted with the eIF(iso)4E and eIF4E of tobacco (Nicotiana tabacum); interactions with eIF(iso)4E and eIF4E of potato (Solanum tuberosum) were weaker. In PVA-infected cells, interactions between HCpro and tobacco eIF(iso)4E were confined to round structures that colocalized with 6K2-induced vesicles. Point mutations introduced to a 4E binding motif identified in the C-terminal region of HCpro debilitated interactions of HCpro with translation initiation factors and were detrimental to the virulence of PVA in plants. The 4E binding motif conserved in HCpro of potyviruses and HCpro-initiation factor interactions suggest new roles for HCpro and/or translation factors in the potyvirus infection cycle. 相似文献
268.
Burckhardt CJ Suomalainen M Schoenenberger P Boucke K Hemmi S Greber UF 《Cell host & microbe》2011,10(2):105-117
Viral particle binding to plasma membrane receptors elicits virus motions, recruits signaling proteins, and triggers membrane bending and fission, finally resulting in endocytic virus uptake. Here we analyze how human adenovirus engages its receptor coxsackievirus adenovirus receptor (CAR) and coreceptor αv integrin to move on the plasma membrane. Virus binding to CAR through fiber knobs gave rise to diffusive motions and actomyosin-2-dependent drifts, while integrin-targeted viruses were spatially more confined. Diffusions, drifts, and confined motions were specifically observed with viral particles that were subsequently internalized. CAR-mediated drifts together with integrin binding supported fiber shedding from adenovirus particles, leading to?exposure of the membrane-lytic internal virion protein VI and enhanced viral escape from endosomes. Our results show that adenovirus uncoating is initiated at the plasma membrane by CAR drifting motion and binding to immobile integrins. 相似文献
269.
Oliver Robinson Marc Chadeau Hyam Ibrahim Karaman Rui Climaco Pinto Mika Ala-Korpela Evangelos Handakas Giovanni Fiorito He Gao Andy Heard Marjo‐Riitta Jarvelin Matthew Lewis Raha Pazoki Silvia Polidoro Ioanna Tzoulaki Matthias Wielscher Paul Elliott Paolo Vineis 《Aging cell》2020,19(6)
Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks. 相似文献
270.
Nadine Jetten Marjo M. P. C. Donners Allard Wagenaar Jack P. M. Cleutjens Nico van Rooijen Menno P. J. de Winther Mark J. Post 《PloS one》2013,8(7)