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排序方式: 共有236条查询结果,搜索用时 234 毫秒
41.
Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Singh M Chien M Tan C Hongo JA de Sauvage F Plowman G Yan M 《Nature》2006,444(7122):1083-1087
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours. 相似文献
42.
The separation of the effects of environmental variability from the impacts of fishing has been elusive, but is essential for sound fisheries management. We distinguish environmental effects from fishing effects by comparing the temporal variability of exploited versus unexploited fish stocks living in the same environments. Using the unique suite of 50-year-long larval fish surveys from the California Cooperative Oceanic Fisheries Investigations we analyse fishing as a treatment effect in a long-term ecological experiment. Here we present evidence from the marine environment that exploited species exhibit higher temporal variability in abundance than unexploited species. This remains true after accounting for life-history effects, abundance, ecological traits and phylogeny. The increased variability of exploited populations is probably caused by fishery-induced truncation of the age structure, which reduces the capacity of populations to buffer environmental events. Therefore, to avoid collapse, fisheries must be managed not only to sustain the total viable biomass but also to prevent the significant truncation of age structure. The double jeopardy of fishing to potentially deplete stock sizes and, more immediately, to amplify the peaks and valleys of population variability, calls for a precautionary management approach. 相似文献
43.
Wai-Leong Chooi Ming-Huat Lim 《黑龙江大学自然科学学报》2004,21(4):46-49
设IF是域,V是或者域IF上所有m×n矩阵的空间或者是特征不为2及3的域IF上所有n×n对称矩阵的空间.对于每个被固定的正整数s≥2,Qs定义V×V中满足rank(A+B)=rank(A)+rank(B)≤s的所有矩阵对(A,B)的集合.刻划了V上满足ψ(Qs)(∈)Qs的加法映射ψ.当charIF≠2时,也描述了IF上从n×n矩阵空间到p×q矩阵空间保秩加性的线性算子的结构. 相似文献
44.
Lim J Crespo-Barreto J Jafar-Nejad P Bowman AB Richman R Hill DE Orr HT Zoghbi HY 《Nature》2008,452(7188):713-718
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases. 相似文献
45.
The pathogen protein EspF(U) hijacks actin polymerization using mimicry and multivalency 总被引:1,自引:0,他引:1
Sallee NA Rivera GM Dueber JE Vasilescu D Mullins RD Mayer BJ Lim WA 《Nature》2008,454(7207):1005-1008
Enterohaemorrhagic Escherichia coli attaches to the intestine through actin pedestals that are formed when the bacterium injects its protein EspF(U) (also known as TccP) into host cells. EspF(U) potently activates the host WASP (Wiskott-Aldrich syndrome protein) family of actin-nucleating factors, which are normally activated by the GTPase CDC42, among other signalling molecules. Apart from its amino-terminal type III secretion signal, EspF(U) consists of five-and-a-half 47-amino-acid repeats. Here we show that a 17-residue motif within this EspF(U) repeat is sufficient for interaction with N-WASP (also known as WASL). Unlike most pathogen proteins that interface with the cytoskeletal machinery, this motif does not mimic natural upstream activators: instead of mimicking an activated state of CDC42, EspF(U) mimics an autoinhibitory element found within N-WASP. Thus, EspF(U) activates N-WASP by competitively disrupting the autoinhibited state. By mimicking an internal regulatory element and not the natural activator, EspF(U) selectively activates only a precise subset of CDC42-activated processes. Although one repeat is able to stimulate actin polymerization, we show that multiple-repeat fragments have notably increased potency. The activities of these EspF(U) fragments correlate with their ability to coordinate activation of at least two N-WASP proteins. Thus, this pathogen has used a simple autoinhibitory fragment as a component to build a highly effective actin polymerization machine. 相似文献
46.
47.
Why fishing magnifies fluctuations in fish abundance 总被引:1,自引:0,他引:1
Anderson CN Hsieh CH Sandin SA Hewitt R Hollowed A Beddington J May RM Sugihara G 《Nature》2008,452(7189):835-839
It is now clear that fished populations can fluctuate more than unharvested stocks. However, it is not clear why. Here we distinguish among three major competing mechanisms for this phenomenon, by using the 50-year California Cooperative Oceanic Fisheries Investigations (CalCOFI) larval fish record. First, variable fishing pressure directly increases variability in exploited populations. Second, commercial fishing can decrease the average body size and age of a stock, causing the truncated population to track environmental fluctuations directly. Third, age-truncated or juvenescent populations have increasingly unstable population dynamics because of changing demographic parameters such as intrinsic growth rates. We find no evidence for the first hypothesis, limited evidence for the second and strong evidence for the third. Therefore, in California Current fisheries, increased temporal variability in the population does not arise from variable exploitation, nor does it reflect direct environmental tracking. More fundamentally, it arises from increased instability in dynamics. This finding has implications for resource management as an empirical example of how selective harvesting can alter the basic dynamics of exploited populations, and lead to unstable booms and busts that can precede systematic declines in stock levels. 相似文献
48.
Risheg H Graham JM Clark RD Rogers RC Opitz JM Moeschler JB Peiffer AP May M Joseph SM Jones JR Stevenson RE Schwartz CE Friez MJ 《Nature genetics》2007,39(4):451-453
Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex. 相似文献
49.
A microRNA component of the p53 tumour suppressor network 总被引:5,自引:0,他引:5
50.
Hyuneui Lim Dae-Hwan Jung Jung-Hyun Noh Gyeong-Rin Choi Wan-Doo Kim 《科学通报(英文版)》2009,54(19):3613-3616
This paper describes a simple fabrication method for creating superhydrophobic and transparent glass surfaces that mimic natural surfaces such as lotus leaves, moth eyes or cicada wings. Nanostructured glass surfaces were created by a combination of colloidal lithography and plasma etching. A colloidal mask was formed simply by the spin coating of the polystyrene beads and with modification of the interparticle distance between the beads. The etching of the glasses was conducted by CF4 plasma. Tower-shaped nanostructures at an aspect ratio of 1:4 were treated using fluoroalkylsilane selfassembled monolayers (SAMs) to obtain the hydrophobic surfaces. The treated glass surfaces showed superhydrophobicity with a water contact angle of around 150° and a hexadecane contact angle of around 110° Furthermore, the nanostructured glass was transparent to visible light. 相似文献