全文获取类型
收费全文 | 578篇 |
免费 | 78篇 |
国内免费 | 1篇 |
出版年
2021年 | 6篇 |
2020年 | 6篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 9篇 |
2015年 | 22篇 |
2014年 | 21篇 |
2013年 | 12篇 |
2012年 | 24篇 |
2011年 | 26篇 |
2010年 | 15篇 |
2009年 | 23篇 |
2008年 | 25篇 |
2007年 | 27篇 |
2006年 | 33篇 |
2005年 | 26篇 |
2004年 | 24篇 |
2003年 | 23篇 |
2002年 | 16篇 |
2001年 | 22篇 |
2000年 | 17篇 |
1999年 | 13篇 |
1998年 | 16篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 13篇 |
1994年 | 4篇 |
1993年 | 7篇 |
1992年 | 15篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 9篇 |
1988年 | 11篇 |
1987年 | 10篇 |
1986年 | 9篇 |
1985年 | 11篇 |
1984年 | 11篇 |
1983年 | 9篇 |
1982年 | 11篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 5篇 |
1977年 | 9篇 |
1976年 | 9篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1971年 | 6篇 |
1966年 | 3篇 |
1965年 | 3篇 |
排序方式: 共有657条查询结果,搜索用时 15 毫秒
61.
A Plonquet S Bastuji-Garin F Tahmasebi C Brisacier K Ledudal JP Farcet E Paillaud 《Immunity & ageing : I & A》2011,8(1):1-7
Background
Nosocomial infections are extremely common in the elderly and may be related to ageing of the immune system. The Immune Risk Phenotype (IRP), which predicts shorter survival in elderly patients, has not been evaluated as a possible risk factor for nosocomial infection. Our aim was to assess the prevalence of nosocomial infections in elderly in-patients and to investigate potential relationships between nosocomial infections and the immunophenotype, including IRP parameters.Results
We included 252 consecutive in-patients aged 70 years or over (mean age, 85 ± 6.2 years), between 2006 and 2008. Among them, 97 experienced nosocomial infections, yielding a prevalence rate of 38.5% (95% confidence interval, 32.5-44.5). The main infection sites were the respiratory tract (21%) and urinary tract (17.1%) When we compared immunological parameters including cell counts determined by flow cytometry in the groups with and without nosocomial infections, we found that the group with nosocomial infections had significantly lower values for the CD4/CD8 ratio and naive CD8 and CD4 T-cell counts and higher counts of memory CD8 T-cells with a significant increase in CD28-negative CD8-T cells. Neither cytomegalovirus status (positive in 193/246 patients) nor presence of the IRP was associated with nosocomial infections. However, nosocomial pneumonia was significantly more common among IRP-positive patients than IRP-negative patients (17/60 versus 28/180; p = 0.036).Conclusion
Immunological parameters that are easy to determine in everyday practice and known to be associated with immune system ageing and shorter survival in the elderly are also associated with an elevated risk of nosocomial pneumonia in the relatively short term. 相似文献62.
Funda E. Orkunoglu‐Suer Brennan T. Harmon Heather Gordish‐Dressman Priscilla M. Clarkson Paul D. Thompson Theodore J. Angelopoulos Paul M. Gordon Monica J. Hubal Niall M. Moyna Linda S. Pescatello Paul S. Visich Robert F. Zoeller Eric P. Hoffman Joseph M. Devaney 《Obesity (Silver Spring, Md.)》2011,19(3):662-666
Recently, a genome‐wide association study (GWAS) that identified eight single‐nucleotide polymorphisms (SNPs) associated with BMI highlighted a possible neuronal influence on the development of obesity. We hypothesized these SNPs would govern the response of BMI and subcutaneous fat to resistance training in young individuals (age = 24 years). We genotyped the eight GWAS‐identified SNPs in the article by Willer et al. in a cohort (n = 796) that undertook a 12‐week resistance‐training program. Females with a copy of the rare allele (C) for rs17782313 (MC4R) had significantly higher BMIs (CC/CT: n = 174; 24.70 ± 0.33 kg/m2, TT: n = 278; 23.41 ± 0.26 kg/m2, P = 0.002), and the SNP explained 1.9% of overall variation in BMI. Males with a copy of the rare allele (T) for rs6548238 (TMEM18) had lower amounts of subcutaneous fat pretraining (CT/TT: n = 65; 156,534 ± 7,415 mm3, CC: n = 136; 177,825 ± 5,139 mm3, P = 0.019) and males with a copy of the rare allele (A) for rs9939609 (FTO) lost a significant amount of subcutaneous fat with exercise (AT/AA: n = 83; ?798.35 ± 2,624.30 mm3, TT: n = 47; 9,435.23 ± 3,494.44 mm3, P = 0.021). Females with a copy of the G allele for a missense variant in the SH2B1 (rs7498665) was associated with less change of subcutaneous fat volume with exercise (AG/GG: n = 191; 9,813 ± 2,250 mm3 vs. AA: n = 126; 770 ± 2,772 mm3; P = 0.011). These data support the original finding that there is an association between measures of obesity and a variant near the MC4R gene and extends these results to a younger population and implicates FTO, TMEM18, and SH2B1 polymorphisms in subcutaneous fat regulation. 相似文献
63.
64.
Comparative studies have increased greatly in number in recent years due to advances in statistical and phylogenetic methodologies. For these studies, a trade-off often exists between the number of species that can be included in any given study and the number of individuals examined per species. Here, we describe a simple simulation study examining the effect of intraspecific sample size on statistical error in comparative studies. We find that ignoring measurement error has no effect on type I error of nonphylogenetic analyses, but can lead to increased type I error under some circumstances when using independent contrasts. We suggest using ANOVA to evaluate the relative amounts of within- and between-species variation when considering a phylogenetic comparative study. If within-species variance is particularly large and intraspecific sample sizes small, then either larger sample sizes or comparative methods that account for measurement error are necessary. 相似文献
65.
Kozak KH Larson A Bonett RM Harmon LJ 《Evolution; international journal of organic evolution》2005,59(9):2000-2016
An important dimension of adaptive radiation is the degree to which diversification rates fluctuate or remain constant through time. Focusing on plethodontid salamanders of the genus Desmognathus, we present a novel synthetic analysis of phylogeographic history, rates of ecomorphological evolution and species accumulation, and community assembly in an adaptive radiation. Dusky salamanders are highly variable in life history, body size, and ecology, with many endemic lineages in the southern Appalachian Highlands of eastern North America. Our results show that life-history evolution had important consequences for the buildup of plethodontid-salamander species richness and phenotypic disparity in eastern North America, a global hot spot of salamander biodiversity. The origin of Desmognathus species with aquatic larvae was followed by a high rate of lineage accumulation, which then gradually decreased toward the present time. The peak period of lineage accumulation in the group coincides with evolutionary partitioning of lineages with aquatic larvae into seepage, stream-edge, and stream microhabitats. Phylogenetic simulations demonstrate a strong correlation between morphology and microhabitat ecology independent of phylogenetic effects and suggest that ecomorphological changes are concentrated early in the radiation of Desmognathus. Deep phylogeographic fragmentation within many codistributed ecomorph clades suggests long-term persistence of ecomorphological features and stability of endemic lineages and communities through multiple climatic cycles. Phylogenetic analyses of community structure show that ecomorphological divergence promotes the coexistence of lineages and that repeated, independent evolution of microhabitat-associated ecomorphs has a limited role in the evolutionary assembly of Desmognathus communities. Comparing and contrasting our results to other adaptive radiations having different biogeographic histories, our results suggest that rates of diversification during adaptive radiation are intimately linked to the degree to which community structure persists over evolutionary time. 相似文献
66.
Margaret?O?Nwagwu Helen?Baines Jeffrey?B?Kerr Francis?JP?EblingEmail author 《Reproductive biology and endocrinology : RB&E》2005,3(1):48
Background
Testicular development is arrested in the hypogonadal (hpg) mouse due to a congenital deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) synthesis. Chronic treatment of male hpg mice with estradiol induces FSH synthesis and secretion, and causes testicular maturation and qualitatively normal spermatogenesis. As estradiol negative feedback normally inhibits FSH production in the male, this study tested whether this paradoxical response to estradiol in the male hpg mouse might be due to inadequate masculinisation or incomplete defeminization in the neonatal period. Previous studies have demonstrated that treatment of hpg mice with testosterone propionate in the immediate neonatal period is necessary to allow full reproductive behaviors to be expressed following suitable endocrine stimulation at adult ages. 相似文献67.
Collins XH Harmon SD Kaduce TL Berst KB Fang X Moore SA Raju TV Falck JR Weintraub NL Duester G Plapp BV Spector AA 《The Journal of biological chemistry》2005,280(39):33157-33164
20-Carboxyeicosatetraenoic acid (20-COOH-AA) is a bioactive metabolite of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid that produces vasoconstriction in the cerebral circulation. We found that smooth muscle (MSMC) and endothelial (MEC) cultures obtained from mouse brain microvessels convert [3H]20-HETE to 20-COOH-AA, indicating that the cerebral vasculature can produce this metabolite. The [3H]20-COOH-AA accumulated primarily in the culture medium, together with additional radiolabeled metabolites identified as the chain-shortened dicarboxylic acids 18-COOH-18:4, 18-COOH-18:3, and 16-COOH-16:3. N-Heptylformamide, a potent inhibitor of alcohol dehydrogenase (ADH), decreased the conversion of [3H]20-HETE to 20-COOH-AA by the MSMC and MEC and also by isolated mouse brain microvessels. Purified mouse and human ADH4, human ADH3, and horse liver ADH1 efficiently oxidized 20-HETE, and ADH4 and ADH3 were detected in MSMC and MEC by Western blotting. N-Heptylformamide inhibited the oxidation of 20-HETE by mouse and human ADH4 but not by ADH3. These results demonstrated that cerebral microvessels convert 20-HETE to 20-COOH-AA and that ADH catalyzes the reaction. Although ADH4 and ADH3 are expressed in MSMC and MEC, the inhibition produced by N-heptylformamide suggests that ADH4 is primarily responsible for 20-COOH-AA formation in the cerebral microvasculature. 相似文献
68.
69.
Goetz CA Harmon IR O'Neil JJ Burchill MA Farrar MA 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(8):4770-4778
Signals initiated by the IL7R are required for B cell development. However, the roles that distinct IL7R-induced signaling pathways play in this process remains unclear. To identify the function of the Raf and STAT5 pathways in IL7R-dependent B cell development, we used transgenic mice that express constitutively active forms of Raf (Raf-CAAX) or STAT5 (STAT5b-CA) throughout lymphocyte development. Both Raf-CAAX and STAT5b-CA mice exhibit large increases in pro-B cells. However, crossing the Raf-CAAX transgene onto the IL7R(-/-) background fails to rescue B cell development. In contrast, STAT5 activation selectively restores B cell expansion in IL7R(-/-) mice. Notably, the expansion of pro-B cells in STAT5b-CA mice correlated with an increase in cyclin D2, pim-1, and bcl-x(L) expression, suggesting that STAT5 directly affects pro-B cell proliferation and survival. In addition, STAT5 activation also restored B cell differentiation in IL7R(-/-) mice as determined by 1) the restoration of V(H) Ig gene rearrangement and 2) the appearance of immature and mature B cell subsets. These findings establish STAT5 as the key player entraining B cell development downstream of the IL7R. 相似文献
70.
Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus
下载免费PDF全文
![点击此处可从《PLoS biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Identification of signaling pathways that maintain and promote adult pancreatic islet functions will accelerate our understanding of organogenesis and improve strategies for treating diseases like diabetes mellitus. Previous work has implicated transforming growth factor-beta (TGF-beta) signaling as an important regulator of pancreatic islet development, but has not established whether this signaling pathway is required for essential islet functions in the adult pancreas. Here we describe a conditional system for expressing Smad7, a potent inhibitor of TGF-beta signaling, to identify distinct roles for this pathway in adult and embryonic beta cells. Smad7 expression in Pdx1+ embryonic pancreas cells resulted in striking embryonic beta cell hypoplasia and neonatal lethality. Conditional expression of Smad7 in adult Pdx1+ cells reduced detectable beta cell expression of MafA, menin, and other factors that regulate beta cell function. Reduced pancreatic insulin content and hypoinsulinemia produced overt diabetes that was fully reversed upon resumption of islet TGF-beta signaling. Thus, our studies reveal that TGF-beta signaling is crucial for establishing and maintaining defining features of mature pancreatic beta cells. 相似文献