全文获取类型
收费全文 | 1488篇 |
免费 | 115篇 |
国内免费 | 1篇 |
专业分类
1604篇 |
出版年
2024年 | 2篇 |
2023年 | 17篇 |
2022年 | 33篇 |
2021年 | 61篇 |
2020年 | 42篇 |
2019年 | 42篇 |
2018年 | 29篇 |
2017年 | 37篇 |
2016年 | 65篇 |
2015年 | 123篇 |
2014年 | 104篇 |
2013年 | 118篇 |
2012年 | 181篇 |
2011年 | 137篇 |
2010年 | 94篇 |
2009年 | 65篇 |
2008年 | 82篇 |
2007年 | 103篇 |
2006年 | 72篇 |
2005年 | 63篇 |
2004年 | 40篇 |
2003年 | 36篇 |
2002年 | 22篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1985年 | 1篇 |
1981年 | 2篇 |
1979年 | 3篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1967年 | 2篇 |
排序方式: 共有1604条查询结果,搜索用时 0 毫秒
41.
Thais R. Peclat Katie L. Thompson Gina M. Warner Claudia C.S. Chini Mariana
G. Tarrag Delaram Z. Mazdeh Chunlian Zhang Jose ZavalaSolorio Ganesh Kolumam Yao Liang Wong Robert L. Cohen Eduardo N. Chini 《Aging cell》2022,21(4)
Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age‐related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals. 相似文献
42.
Jingxin Chen Evan C. Ray Megan E. Yates Teresa M. Buck Jeffrey L. Brodsky Carol L. Kinlough Katie L. Winarski Rebecca P. Hughey Thomas R. Kleyman Shaohu Sheng 《The Journal of biological chemistry》2015,290(41):25140-25150
The extracellular regions of epithelial Na+ channel subunits are highly ordered structures composed of domains formed by α helices and β strands. Deletion of the peripheral knuckle domain of the α subunit in the αβγ trimer results in channel activation, reflecting an increase in channel open probability due to a loss of the inhibitory effect of external Na+ (Na+ self-inhibition). In contrast, deletion of either the β or γ subunit knuckle domain within the αβγ trimer dramatically reduces epithelial Na+ channel function and surface expression, and impairs subunit maturation. We systematically mutated individual α subunit knuckle domain residues and assessed functional properties of these mutants. Cysteine substitutions at 14 of 28 residues significantly suppressed Na+ self-inhibition. The side chains of a cluster of these residues are non-polar and are predicted to be directed toward the palm domain, whereas a group of polar residues are predicted to orient their side chains toward the space between the knuckle and finger domains. Among the mutants causing the greatest suppression of Na+ self-inhibition were αP521C, αI529C, and αS534C. The introduction of Cys residues at homologous sites within either the β or γ subunit knuckle domain resulted in little or no change in Na+ self-inhibition. Our results suggest that multiple residues in the α subunit knuckle domain contribute to the mechanism of Na+ self-inhibition by interacting with palm and finger domain residues via two separate and chemically distinct motifs. 相似文献
43.
Mochida GH Ganesh VS Felie JM Gleason D Hill RS Clapham KR Rakiec D Tan WH Akawi N Al-Saffar M Partlow JN Tinschert S Barkovich AJ Ali B Al-Gazali L Walsh CA 《American journal of human genetics》2010,87(6):882-889
The tight junction, or zonula occludens, is a specialized cell-cell junction that regulates epithelial and endothelial permeability, and it is an essential component of the blood-brain barrier in the cerebrovascular endothelium. In addition to functioning as a diffusion barrier, tight junctions are also involved in signal transduction. In this study, we identified a homozygous mutation in the tight-junction protein gene JAM3 in a large consanguineous family from the United Arab Emirates. Some members of this family had a rare autosomal-recessive syndrome characterized by severe hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Their clinical presentation overlaps with some reported cases of pseudo-TORCH syndrome as well as with cases involving mutations in occludin, another component of the tight-junction complex. However, massive intracranial hemorrhage distinguishes these patients from others. Homozygosity mapping identified the disease locus in this family on chromosome 11q25 with a maximum multipoint LOD score of 6.15. Sequence analysis of genes in the candidate interval uncovered a mutation in the canonical splice-donor site of intron 5 of JAM3. RT-PCR analysis of a patient lymphoblast cell line confirmed abnormal splicing, leading to a frameshift mutation with early termination. JAM3 is known to be present in vascular endothelium, although its roles in cerebral vasculature have not been implicated. Our results suggest that JAM3 is essential for maintaining the integrity of the cerebrovascular endothelium as well as for normal lens development in humans. 相似文献
44.
Richard B. Forward Jr Elizabeth Freeman Kristen Gall Katie Saba 《Marine and Freshwater Behaviour and Physiology》2013,45(5):305-319
The supratidal amphipod Talorchestia longicornis Say has a circadian rhythm in activity, in which it is active on the substrate surface at night and inactive in burrows during the day. The present study determined: (1) the circadian rhythms in individual versus groups of amphipods; (2) the range of temperature cycles that entrain the circadian rhythm; (3) entrainment by high-temperature cycles versus light?:?dark cycles, and (4) seasonal substrate temperature cycles. The circadian rhythm was determined by monitoring temporal changes in surface activity using a video system. Individual and groups of amphipods have similar circadian rhythms. Entrainment occurred only to temperature cycles that included temperatures below 20°C (10–20, 15–20, 17–19, 15–25°C) but not to temperatures above 20°C (20–25, 20–30°C), and required only a 2°C temperature cycle (17–19°C). Diel substrate temperatures were above 20°C in the summer and below 20°C during the winter. Upon simultaneous exposure to a diel high-temperature cycle (20–30°C) and a light?:?dark cycle phased differently, amphipods entrained to the light?:?dark cycle. Past studies found that a temperature cycle below 20°C overrode the light?:?dark cycle for entrainment. The functional significance of this change in entrainment cues may be that while buried during the winter, the activity rhythm remains in phase with the day?:?night cycle by the substrate temperature cycles. During the summer, T. longicornis switches to the light?:?dark cycle for entrainment, perhaps as a mechanism to phase activity precisely to the short summer nights. 相似文献
45.
Kandelaars KJ Fletcher A Dorrian J Baulk SD Dawson D 《Chronobiology international》2006,23(6):1265-1276
In recent years, there has been increasing interest in the use of bio-mathematical models to predict alertness, performance, and/or fatigue in operational settings. Current models use only biological factors to make their estimations, which can be limited in operational settings where social and geo-physical factors also dictate when sleep occurs. The interaction between social and biological factors that help determine the timing and duration of sleep during layover periods have been investigated in order to create and initially validate a mathematical model that may better predict sleep in the field. Participants were 32 male transmeridian airline pilots (17 captains, 10 first officers, and 5 second officers) flying the Sydney-Bangkok-London-Singapore-Sydney (SYD-LHR) pattern. Participants continued their regular schedule while wearing activity monitors and completing sleep and work diaries. The theoretical sleep timing model underpinning this analysis consists of separate formulations for short (<32 h) and long (>32 h) break periods. Longer break periods are split into three distinct phases-recovery (break start until first local night), personal (first local night until last local night), and preparation phases (last local night until break end)-in order to exploit potential differences specific to each. Furthermore, an iterative procedure combining prediction and retrodiction (i.e., using future duty timing information to predict current sleep timing) was developed to optimize predictive ability. Analysis found an interaction between the social and circadian sleep pressures that changed over the break period. Correlation analysis indicated a strong relationship between the actual sleep and new model's predictions (r = 0.7-0.9), a significant improvement when compared to existing models (r = 0.1-0.4). Social and circadian pressures play important roles in regulating sleep for international flight crews. An initial model has been developed in order to regulate sleep in these crews. The initial results have shown promise when applied to small sets of data; however, more rigorous validation must be carried out. 相似文献
46.
Slattery KM Wallace LK Murphy AJ Coutts AJ 《Journal of strength and conditioning research / National Strength & Conditioning Association》2006,20(1):47-52
The present investigation examined the physiological parameters that contribute to 3-km running performance. Following 2 familiarization sessions, 16 experienced male triathletes (Vo(2)max = 55.7 +/- 4.9 ml.kg(-1).min(-1), age = 31.3 +/- 11.7 years) performed a 3-km time trial (3kmTT) and were assessed for selected physiological and anthropometrical characteristics. Stepwise multiple regression and correlation analysis was used to determine the variables that significantly related to 3kmTT. The analysis revealed that 82.3% of the adjusted variance in 3kmTT performance could be explained by peak treadmill running velocity during a Vo(2)max test (Vmax) alone. The addition of the running velocity at lactate threshold (LT(vel)) and peak lactate concentration ([BLa(-)](peak)) to the prediction equation allowed for 93.6% of the adjusted variance in 3kmTT to be predicted (Y = -13.64 Vmax - 25.61 LT(vel) - 5.40 [BLa(-)](peak) + 1358.5). Correlation analysis revealed that Vmax (r = -0.91), LT(vel) (r = -0.90), and Vo(2)max (r = -0.80) were significantly related to running performance. These results show that Vmax was the single best predictor of 3-km running performance in experienced male triathletes and that both aerobic and anaerobic abilities are related to improved 3kmTT performance. Since the assessment of Vmax is relatively simple to implement, we suggest that determining Vmax may be a practical method for monitoring performance changes in short-term endurance running events. 相似文献
47.
Christian Frkjr‐Jensen Katie S. Kindt Rex A. Kerr Hiroshi Suzuki Katya Melnik‐Martinez Beate Gerstbreih Monica Driscol William R. Schafer 《Developmental neurobiology》2006,66(10):1125-1139
Voltage‐gated calcium channels (VGCCs) serve as a critical link between electrical signaling and diverse cellular processes in neurons. We have exploited recent advances in genetically encoded calcium sensors and in culture techniques to investigate how the VGCC α1 subunit EGL‐19 and α2/δ subunit UNC‐36 affect the functional properties of C. elegans mechanosensory neurons. Using the protein‐based optical indicator cameleon, we recorded calcium transients from cultured mechanosensory neurons in response to transient depolarization. We observed that in these cultured cells, calcium transients induced by extracellular potassium were significantly reduced by a reduction‐of‐function mutation in egl‐19 and significantly reduced by L‐type calcium channel inhibitors; thus, a main source of touch neuron calcium transients appeared to be influx of extracellular calcium through L‐type channels. Transients did not depend directly on intracellular calcium stores, although a store‐independent 2‐APB and gadolinium‐sensitive calcium flux was detected. The transients were also significantly reduced by mutations in unc‐36, which encodes the main neuronal α2/δ subunit in C. elegans. Interestingly, while egl‐19 mutations resulted in similar reductions in calcium influx at all stimulus strengths, unc‐36 mutations preferentially affected responses to smaller depolarizations. These experiments suggest a central role for EGL‐19 and UNC‐36 in excitability and functional activity of the mechanosensory neurons. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 相似文献
48.
Huang J Morehouse C Streicher K Higgs BW Gao J Czapiga M Boutrin A Zhu W Brohawn P Chang Y Viner J LaVallee T Richman L Jallal B Yao Y 《PloS one》2011,6(10):e26177
Purpose
Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies.Experimental Design
mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized.Results
The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes.Conclusions
The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic. 相似文献49.
Yue T Partyka K Maupin KA Hurley M Andrews P Kaul K Moser AJ Zeh H Brand RE Haab BB 《Proteomics》2011,11(18):3665-3674
The current best serum marker for pancreatic cancer, CA 19-9, detects a carbohydrate antigen on multiple protein carriers. Better knowledge of the protein carriers of the CA 19-9 antigen in various disease states may lead to improved diagnostic tests. To identify proteins that carry the CA 19-9 antigen, we immunoprecipitated the CA 19-9 antigen from pooled sera and identified the associated proteins using MS. Among the high-confidence identifications, we confirmed the presence of the CA 19-9 antigen on Apolipoprotein B-100 by antibody arrays and Western blot and on kininogen, ARVCF, and Apolipoprotein E by antibody arrays. We characterized the frequency and levels of the CA 19-9 antigen on the four proteins across various patient groups (pancreatic cancer, pancreatitis, and healthy controls) using antibody arrays. Nearly, 10-25% of the subjects showed elevations of the antigen on each protein, but the elevations were not associated with disease state or total CA 19-9 levels. These results contribute to our knowledge of the carrier proteins of an important functional glycan and the rate at which the glycan is displayed. This work also demonstrates a strategy for using the complementary methods of MS and antibody microarrays to identify protein carriers of glycans and assess the diagnostic value of measuring glycans on individual proteins. 相似文献
50.
Patterns of milk macronutrients and bioactive molecules across lactation in a western lowland gorilla (Gorilla gorilla) and a Sumatran orangutan (Pongo abelii) 下载免费PDF全文