全文获取类型
收费全文 | 450篇 |
免费 | 17篇 |
出版年
2022年 | 3篇 |
2021年 | 4篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2016年 | 10篇 |
2015年 | 16篇 |
2014年 | 22篇 |
2013年 | 22篇 |
2012年 | 20篇 |
2011年 | 20篇 |
2010年 | 12篇 |
2009年 | 16篇 |
2008年 | 18篇 |
2007年 | 22篇 |
2006年 | 28篇 |
2005年 | 15篇 |
2004年 | 11篇 |
2003年 | 17篇 |
2002年 | 11篇 |
2001年 | 6篇 |
2000年 | 18篇 |
1999年 | 14篇 |
1998年 | 9篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1993年 | 10篇 |
1992年 | 8篇 |
1991年 | 8篇 |
1990年 | 6篇 |
1989年 | 11篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1970年 | 3篇 |
排序方式: 共有467条查询结果,搜索用时 62 毫秒
91.
Mohamed Abou El Hassan Katherine Huang Manoja B. K. Eswara Zhaodong Xu Tao Yu Arthur Aubry Zuyao Ni Izzy Livne-bar Monika Sangwan Mohamad Ahmad Rod Bremner 《BMC molecular biology》2017,18(1):6
Background
STAT1 and IRF1 collaborate to induce interferon-γ (IFNγ) stimulated genes (ISGs), but the extent to which they act alone or together is unclear. The effect of single nucleotide polymorphisms (SNPs) on in vivo binding is also largely unknown.Results
We show that IRF1 binds at proximal or distant ISG sites twice as often as STAT1, increasing to sixfold at the MHC class I locus. STAT1 almost always bound with IRF1, while most IRF1 binding events were isolated. Dual binding sites at remote or proximal enhancers distinguished ISGs that were responsive to IFNγ versus cell-specific resistant ISGs, which showed fewer and mainly single binding events. Surprisingly, inducibility in one cell type predicted ISG-responsiveness in other cells. Several dbSNPs overlapped with STAT1 and IRF1 binding motifs, and we developed methodology to rapidly assess their effects. We show that in silico prediction of SNP effects accurately reflects altered binding both in vitro and in vivo.Conclusions
These data reveal broad cooperation between STAT1 and IRF1, explain cell type specific differences in ISG-responsiveness, and identify genetic variants that may participate in the pathogenesis of immune disorders.92.
Kowalczyk C Dunkel N Willen L Casal ML Mauldin EA Gaide O Tardivel A Badic G Etter AL Favre M Jefferson DM Headon DJ Demotz S Schneider P 《The Journal of biological chemistry》2011,286(35):30769-30779
The TNF family ligand ectodysplasin A (EDA) and its receptor EDAR are required for proper development of skin appendages such as hair, teeth, and eccrine sweat glands. Loss of function mutations in the Eda gene cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition that can be ameliorated in mice and dogs by timely administration of recombinant EDA. In this study, several agonist anti-EDAR monoclonal antibodies were generated that cross-react with the extracellular domains of human, dog, rat, mouse, and chicken EDAR. Their half-life in adult mice was about 11 days. They induced tail hair and sweat gland formation when administered to newborn EDA-deficient Tabby mice, with an EC(50) of 0.1 to 0.7 mg/kg. Divalency was necessary and sufficient for this therapeutic activity. Only some antibodies were also agonists in an in vitro surrogate activity assay based on the activation of the apoptotic Fas pathway. Activity in this assay correlated with small dissociation constants. When administered in utero in mice or at birth in dogs, agonist antibodies reverted several ectodermal dysplasia features, including tooth morphology. These antibodies are therefore predicted to efficiently trigger EDAR signaling in many vertebrate species and will be particularly suited for long term treatments. 相似文献
93.
Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons 总被引:2,自引:0,他引:2
94.
Mark J. Statham James Murdoch Jan Janecka Keith B. Aubry Ceiridwen J. Edwards Carl D. Soulsbury Oliver Berry Zhenghuan Wang David Harrison Malcolm Pearch Louise Tomsett Judith Chupasko Benjamin N. Sacks 《Molecular ecology》2014,23(19):4813-4830
Widely distributed taxa provide an opportunity to compare biogeographic responses to climatic fluctuations on multiple continents and to investigate speciation. We conducted the most geographically and genomically comprehensive study to date of the red fox (Vulpes vulpes), the world's most widely distributed wild terrestrial carnivore. Analyses of 697 bp of mitochondrial sequence in ~1000 individuals suggested an ancient Middle Eastern origin for all extant red foxes and a 400 kya (SD = 139 kya) origin of the primary North American (Nearctic) clade. Demographic analyses indicated a major expansion in Eurasia during the last glaciation (~50 kya), coinciding with a previously described secondary transfer of a single matriline (Holarctic) to North America. In contrast, North American matrilines (including the transferred portion of Holarctic clade) exhibited no signatures of expansion until the end of the Pleistocene (~12 kya). Analyses of 11 autosomal loci from a subset of foxes supported the colonization time frame suggested by mtDNA (and the fossil record) but, in contrast, reflected no detectable secondary transfer, resulting in the most fundamental genomic division of red foxes at the Bering Strait. Endemic continental Y‐chromosome clades further supported this pattern. Thus, intercontinental genomic exchange was overall very limited, consistent with long‐term reproductive isolation since the initial colonization of North America. Based on continental divergence times in other carnivoran species pairs, our findings support a model of peripatric speciation and are consistent with the previous classification of the North American red fox as a distinct species, V. fulva. 相似文献
95.
Andrew A. Sproul Samson Jacob Deborah Pre Soong Ho Kim Michael W. Nestor Miriam Navarro-Sobrino Ismael Santa-Maria Matthew Zimmer Soline Aubry John W. Steele David J. Kahler Alex Dranovsky Ottavio Arancio John F. Crary Sam Gandy Scott A. Noggle 《PloS one》2014,9(1)
Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer''s disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes. 相似文献
96.
E. Vennat J.-P. Attal D. Aubry M. Degrange 《Computer methods in biomechanics and biomedical engineering》2014,17(6):632-642
Dentine is the fundamental substrate of restorative dentistry, and its properties and characteristics are the key determinants of restorative processes. In contemporary restorative techniques, bonding to Dentine is created by the impregnation of the demineralised dentine by blends of resin monomers. In this paper, a numerical model of dentinal infiltration is proposed. The aim is to follow the resin front and to point out the optimal parameter set. The main tool is a level set technique to follow the evolving interface. It is coupled with the Navier–Stokes equation where capillary effect gives rise to the appearance of a new term in the variational approach than discretised by finite elements. Using an appropriate geometry representing demineralised dentine, the moving front is observed. First, a simulation of porosimetry test is achieved in order to validate the model. The two expected pore sizes are detected and the simulation also points out limitations of mercury intrusion porosimetry test in an educational way. Then a wetting fluid (representing the dental resin) is numerically infiltrated. In the dentinal porous network, capillarity is taken into account in our model by including a capillary term. A crucial conclusion is drawn from this study: resin application time by practitioners is sufficient if, in the infiltration process, the wetting phase is the resin. 相似文献
97.
Rachel Kanaziz Kathryn P. Huyvaert Caitlin P. Wells Dirk
H. Van
Vuren Lise M. Aubry 《Ecology and evolution》2022,12(5)
Maternal characteristics, social dynamics, and environmental factors can all influence reproduction and survival and shape trade‐offs that might arise between these components of fitness. Short‐lived mammals like the golden‐mantled ground squirrel (GMGS; Callospermophilus lateralis) tend to maximize effort toward current reproduction at the expense of survival but may be complicated by other aspects of the species’ life history and environment. Here, we use 25 years of data (1995–2020) collected from a population of GMGS at the Rocky Mountain Biological Research Laboratory in Gothic, Colorado, to test the effect of several maternal characteristics (e.g., age, experience, and timing of litter emergence), social context (e.g., litter sex ratio and kin density), and environmental context (e.g., date of bare ground and length of vegetative growing season) on survival of reproductive female GMGS using Cox proportional hazard models. Our results indicated that social dynamics (i.e., density) and environmental conditions (i.e., standardized first day of permanent snow cover and length of growing season) explained significant variation in annual maternal survival, while maternal characteristics did not. A higher density of related breeding females and the total number of females (both related and unrelated to the focal mother) were associated with an increase in the mortality hazard. A later standardized date of the first day of permanent snow cover and a shorter growing season both reduced the maternal mortality hazard. Together, our results suggest that factors extrinsic to the squirrels affect maternal survival and thus may also influence local population growth and dynamics in GMGS and other short‐lived, territorial mammal species. 相似文献
98.
99.
Mondésert-Deveraux Solenne Aubry Denis Allena Rachele 《Biomechanics and modeling in mechanobiology》2019,18(5):1281-1295
Biomechanics and Modeling in Mechanobiology - Considering the major role of confined cell migration in biological processes and diseases, such as embryogenesis or metastatic cancer, it has become... 相似文献
100.
É. N. Telina S. V. Kirshin R. S. Nizamov R. Kh. Akhmedzyanov Kh. S. Khamitov 《Neurophysiology》1989,21(6):514-518
Findings from radioligand research into smooth muscle in the cat nictitating membrane revealed the presence of specific [3H]prazosin binding sites corresponding to alpha-1 adrenoceptors. After smooth muscle sympathectomy, numbers of alpha-1 adrenoceptors rose without any significant change in their affinity. Incubating previously sympathectomized smooth muscle with noradrenaline led to a decline in the number of alpha-1 adrenoceptors — again without alteration in binding affinity. It was deduced that numbers of alpha-1 adrenoceptors are controlled by the sympathetic nervous system.S. V. Kurashov Medical Institute, Kazan'. Translated from Neirofiziologiya, Vol. 21, No. 6, pp. 735–741, November–December, 1989. 相似文献