全文获取类型
收费全文 | 521篇 |
免费 | 91篇 |
专业分类
612篇 |
出版年
2021年 | 4篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 8篇 |
2017年 | 9篇 |
2016年 | 6篇 |
2015年 | 15篇 |
2014年 | 13篇 |
2013年 | 18篇 |
2012年 | 23篇 |
2011年 | 21篇 |
2010年 | 14篇 |
2009年 | 15篇 |
2008年 | 31篇 |
2007年 | 20篇 |
2006年 | 20篇 |
2005年 | 19篇 |
2004年 | 26篇 |
2003年 | 23篇 |
2002年 | 19篇 |
2001年 | 20篇 |
2000年 | 30篇 |
1999年 | 16篇 |
1998年 | 17篇 |
1997年 | 9篇 |
1996年 | 9篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1993年 | 4篇 |
1992年 | 8篇 |
1991年 | 10篇 |
1990年 | 15篇 |
1989年 | 10篇 |
1988年 | 15篇 |
1987年 | 4篇 |
1986年 | 14篇 |
1985年 | 22篇 |
1984年 | 15篇 |
1983年 | 8篇 |
1981年 | 3篇 |
1980年 | 6篇 |
1979年 | 7篇 |
1978年 | 3篇 |
1977年 | 6篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1973年 | 3篇 |
1969年 | 4篇 |
1964年 | 3篇 |
排序方式: 共有612条查询结果,搜索用时 15 毫秒
551.
Erika Tetetla-Rangel Juan Manuel Dupuy José Luis Hernández-Stefanoni Paul H. Hoekstra 《Biodiversity and Conservation》2017,26(7):1705-1721
Determining which factors affect species richness is important for conservation theory and practice. However, richness of common and rare species may be affected by different factors. We use an extensive inventory of woody plants from a tropical dry forest landscape in Yucatan, Mexico to assess the unique effects of environmental variables, spatial dependence of sampling sites, forest stand age and the combined effect of all groups of variables on species richness of woody plants with different levels of rarity (common, intermediate, rare, very rare)—according to their abundance, habitat specificity and spatial distribution range in the landscape. Analyzing separately common species and those with different levels of rarity uncovered contrasting patterns and correlates of species richness that were not apparent when focusing on all woody plants. In particular, richness of common and intermediate species was influenced mainly by environmental factors, whereas richness of very rare species was affected mostly by the unique effect of spatial dependence of sampling sites, suggesting a main role of environmental filtering and dispersal limitation, respectively. However, common and very rare species also responded inversely to some landscape metrics, revealing contrasting environmental preferences of these groups of species. These contrasting results suggest different underlying mechanisms and the need for very different conservation strategies. Therefore, basic and applied research on tropical forest biodiversity should consider separately species with different levels of rarity, focusing on which factors control variation in each level, and paying special attention to very rare species, generally the most specious and vulnerable to local extinction. 相似文献
552.
Christopher M. Yates Edward P. Garvey Sammy R. Shaver Robert J. Schotzinger William J. Hoekstra 《Bioorganic & medicinal chemistry letters》2017,27(15):3243-3248
While the orally-active azoles such as fluconazole and posaconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver, and reproductive toxicities). Recently we described the rationally-designed, antifungal agent VT-1161 that is more selective for fungal CYP51 than related human CYP enzymes such as CYP3A4. Herein, we describe the use of a homology model of Aspergillus fumigatus to design and optimize a novel series of highly selective, broad spectrum fungal CYP51 inhibitors. This series includes the oral antifungal VT-1598 that exhibits excellent potency against yeast, dermatophyte, and mold fungal pathogens. 相似文献
553.
554.
Berber Kapitein Joost A. Aalberse Mark R. Klein Wilco de Jager Maarten O. Hoekstra Edward F. Knol Berent J. Prakken 《Cell stress & chaperones》2013,18(1):87-95
Heat shock protein 60 (hsp60) is a highly conserved stress protein and target of self-reactive T cells in various inflammatory diseases. Not much is known about a possible role in atopic disease. As atopic diseases are considered to be the result of a disturbance in the balance between T helper cells type 2 and regulatory T cells, it is of interest to know whether hsp60 acts as a bystander antigen in atopic disease. Our aim was to investigate whether hsp60 is involved in the chronicity of inflammation of atopic dermatitis (AD). We studied the expression of hsp60 in skin tissue of adults with AD by immunohistochemistry. Peripheral blood mononuclear cells (PBMC) of children with AD were cultured with hsp60 and proliferative responses, cytokine secretion, surface markers, and functional assays were compared to responses of PBMC of healthy controls (HC). Hsp60 was detected more in lesional skin of AD patients compared to nonlesional skin. Furthermore, PBMC of children with AD proliferated more strongly in response to hsp60 compared to HC. hsp60-reactive T cells of atopic children produced high levels of IFNγ and low levels of IL-10. In vitro activation with hsp60 leads to the induction of CD4+CD25bright T cells expressing FOXP3 in both HC as well as in atopic children. However, despite their regulatory phenotype, hsp60-induced CD4+CD25brightCD127−FOXP3+ T cells of AD patients were incapable of suppressing effector T cells in vitro. hsp60 is recognized by proinflammatory (IFNγ high, IL-10 low) T cells in atopic patients and is more present in lesional AD skin. This suggests that hsp60-specific T cell responses contribute to local inflammation in AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-012-0361-3) contains supplementary material, which is available to authorized users. 相似文献555.
Sarah D Kocher Cai Li Wei Yang Hao Tan Soojin V Yi Xingyu Yang Hopi E Hoekstra Guojie Zhang Naomi E Pierce Douglas W Yu 《Genome biology》2013,14(12):R142
Background
Taxa that harbor natural phenotypic variation are ideal for ecological genomic approaches aimed at understanding how the interplay between genetic and environmental factors can lead to the evolution of complex traits. Lasioglossum albipes is a polymorphic halictid bee that expresses variation in social behavior among populations, and common-garden experiments have suggested that this variation is likely to have a genetic component.Results
We present the L. albipes genome assembly to characterize the genetic and ecological factors associated with the evolution of social behavior. The de novo assembly is comparable to other published social insect genomes, with an N50 scaffold length of 602 kb. Gene families unique to L. albipes are associated with integrin-mediated signaling and DNA-binding domains, and several appear to be expanded in this species, including the glutathione-s-transferases and the inositol monophosphatases. L. albipes has an intact DNA methylation system, and in silico analyses suggest that methylation occurs primarily in exons. Comparisons to other insect genomes indicate that genes associated with metabolism and nucleotide binding undergo accelerated evolution in the halictid lineage. Whole-genome resequencing data from one solitary and one social L. albipes female identify six genes that appear to be rapidly diverging between social forms, including a putative odorant receptor and a cuticular protein.Conclusions
L. albipes represents a novel genetic model system for understanding the evolution of social behavior. It represents the first published genome sequence of a primitively social insect, thereby facilitating comparative genomic studies across the Hymenoptera as a whole. 相似文献556.
Recent rapid developments in genomics will likely lead to a rapid expansion in identifying defective genes causing a variety of diseases, implying a vast increase in the number of therapeutic targets. Treatment of such diseases may include strategies ranging from gene delivery and replacement to antisense approaches. For successful development of gene therapies, a minimal requirement involves the engineering of appropriate gene- or oligonucleotide-carrier systems, which are necessary for protective purposes (against nucleases) and transport (to target tissue and cells in vivo). Further, they should also display the propensity to efficiently translocate the oligonucleotides and gene constructs into cells, via passage across several membrane barriers. The emphasis in this review will be on the use of cationic lipids for that purpose. Crucial to successful application of this sophisticated technology in vivo will be a need for a better understanding of fundamental and structural parameters that govern transfection efficiency, including the issues of cationic lipid/DNA complex assembly (with or without helper lipid), stability towards biological fluids, complex-target membrane interaction and translocation, and gene-integration into the nucleus. Biophysical and biochemical characterization of so called lipoplexes, and their interaction with cells in vitro, are considered instrumental in reaching such insight. Here, most recent advances in cationic lipid-mediated gene delivery are discussed from such a perspective. 相似文献
557.
Treatment of stenosed coronary arteries by balloon angioplasty and stenting results in arterial injury including severe damage to the endothelium at the site of treatment and initiates a complex cascade of inflammatory processes that may lead to the development of in-stent restenosis (ISR). Many clinical and biological factors involved in the progression of restenotic lesions have been studied in detail over the past few years but the mystery behind the pathophysiological mechanisms of this disease is still unresolved. In the present work, the effects of re-endothelialization and nitric oxide release on neointimal growth are investigated in-silico using a two dimensional multi-scale model of ISR. The effect of stent deployment depths on the development of ISR is studied as a function of time after stenting. Two dimensional domains were prepared by deploying bare metal stent struts at three different deployment depths into the tissue. Shear stress distribution on endothelial cells, obtained by blood flow simulations, was translated into nitric oxide production that keeps the smooth muscle cells in quiescent state. The cellular growth trends were plotted as a function of time and the data indicate a positive correlation between the neointimal growths and strut deployment depths in the presence of a functional endothelium, in qualitative agreement with in-vivo data. Additionally, no ISR is observed if a functional endothelium appears much earlier. 相似文献
558.
John A. Painter Edward A. Graviss Hoang Hoa Hai Duong Thi Cam Nhung Tran Thi Thanh Nga Ngan P. Ha Kirsten Wall Le Thien Huong Loan Matt Parker Lilia Manangan Rick O’Brien Susan A. Maloney R. M. Hoekstra Randall Reves 《PloS one》2013,8(12)
Rationale
Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth.Objectives
1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR.Methods
We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR.Results
The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants.Conclusions
During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population. 相似文献559.
Zelda de Lange Dingeman C. Rijken Tiny Hoekstra Karin R. Conradie Johann C. Jerling Marlien Pieters 《PloS one》2013,8(12)
Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT. 相似文献
560.
Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression 总被引:2,自引:0,他引:2
van der Hoogt CC de Haan W Westerterp M Hoekstra M Dallinga-Thie GM Romijn JA Princen HM Jukema JW Havekes LM Rensen PC 《Journal of lipid research》2007,48(8):1763-1771
In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (-59% and -60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (-72%; P < 0.01) as well as the CE transfer activity in plasma (-73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool. 相似文献