全文获取类型
收费全文 | 46846篇 |
免费 | 3774篇 |
国内免费 | 229篇 |
专业分类
50849篇 |
出版年
2023年 | 320篇 |
2022年 | 320篇 |
2021年 | 702篇 |
2020年 | 591篇 |
2019年 | 580篇 |
2018年 | 988篇 |
2017年 | 883篇 |
2016年 | 1518篇 |
2015年 | 2423篇 |
2014年 | 2363篇 |
2013年 | 3133篇 |
2012年 | 4047篇 |
2011年 | 3516篇 |
2010年 | 2020篇 |
2009年 | 1656篇 |
2008年 | 2848篇 |
2007年 | 2705篇 |
2006年 | 2681篇 |
2005年 | 2342篇 |
2004年 | 2369篇 |
2003年 | 2140篇 |
2002年 | 2025篇 |
2001年 | 1080篇 |
2000年 | 1125篇 |
1999年 | 727篇 |
1998年 | 374篇 |
1997年 | 224篇 |
1996年 | 248篇 |
1995年 | 300篇 |
1994年 | 226篇 |
1993年 | 213篇 |
1992年 | 323篇 |
1991年 | 327篇 |
1990年 | 251篇 |
1989年 | 262篇 |
1988年 | 222篇 |
1987年 | 187篇 |
1986年 | 174篇 |
1985年 | 228篇 |
1984年 | 216篇 |
1983年 | 167篇 |
1982年 | 146篇 |
1981年 | 122篇 |
1980年 | 125篇 |
1979年 | 125篇 |
1978年 | 121篇 |
1977年 | 111篇 |
1976年 | 115篇 |
1975年 | 109篇 |
1974年 | 96篇 |
排序方式: 共有10000条查询结果,搜索用时 12 毫秒
991.
Wang Shih-Wei Chung Chih-Ling Yu-Chen Kao René Martin Hans-Joachim Knölker Meng-Shin Shiao 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):920-935
Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-β (TGF-β) activity. PBrP inhibits TGF-β-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-β-induced epithelial–mesenchymal transition in epithelial cells. PBrP inhibits TGF-β signalling by reducing the cell-surface expression of type II TGF-β receptor (TβRII) and promotes receptor degradation. Gene silencing approaches suggest that MyoVa plays a crucial role in PBrP-induced TβRII turnover and the subsequent reduction of TGF-β signalling. Because, TGF-β signalling is crucial in the regulation of diverse pathophysiological processes such as tissue fibrosis and cancer development, PBrP should be further explored for its therapeutic role in treating fibrotic diseases and cancer. 相似文献
992.
Catfish detect and identify invisible prey by sensing their ultra-weak electric fields with electroreceptors. Any neuron that deals with small-amplitude input has to overcome sensitivity limitations arising from inherent threshold non-linearities in spike-generation mechanisms. Many sensory cells solve this issue with stochastic resonance, in which a moderate amount of intrinsic noise causes irregular spontaneous spiking activity with a probability that is modulated by the input signal. Here we show that catfish electroreceptors have adopted a fundamentally different strategy. Using a reverse correlation technique in which we take spike interval durations into account, we show that the electroreceptors generate a supra-threshold bias current that results in quasi-periodically produced spikes. In this regime stimuli modulate the interval between successive spikes rather than the instantaneous probability for a spike. This alternative for stochastic resonance combines threshold-free sensitivity for weak stimuli with similar sensitivity for excitations and inhibitions based on single interspike intervals. 相似文献
993.
Cantrup R Dixit R Palmesino E Bonfield S Shaker T Tachibana N Zinyk D Dalesman S Yamakawa K Stell WK Wong RO Reese BE Kania A Sauvé Y Schuurmans C 《PloS one》2012,7(3):e32795
Background
The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture.Methodology/Principal Findings
In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam.Conclusions/Significance
We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina. 相似文献994.
Campos-Junior PH Costa GM Lacerda SM Rezende-Neto JV de Paula AM Hofmann MC de França LR 《Biology of reproduction》2012,86(5):155, 1-155,10
In the seminiferous epithelium, spermatogonial stem cells (SSCs) are located in a particular environment called the "niche" that is controlled by the basement membrane, key testis somatic cells, and factors originating from the vascular network. However, the role of Leydig cells (LCs) as a niche component is not yet clearly elucidated. Recent studies showed that peccaries (Tayassu tajacu) present a peculiar LC cytoarchitecture in which these cells are located around the seminiferous tubule lobes, making the peccary a unique model for investigating the SSC niche. This peculiarity allowed us to subdivide the seminiferous tubule cross-sections in three different testis parenchyma regions (tubule-tubule, tubule-interstitium, and tubule-LC contact). Our aims were to characterize the different spermatogonial cell types and to determine the location and/or distribution of the SSCs along the seminiferous tubules. Compared to differentiating spermatogonia, undifferentiated spermatogonia (A(und)) presented a noticeably higher nuclear volume (P < 0.05), allowing an accurate evaluation of their distribution. Immunostaining analysis demonstrated that approximately 93% of A(und) were GDNF receptor alpha 1 positive (GFRA1(+)), and these cells were preferentially located adjacent to the interstitial compartment without LCs (P < 0.05). The expression of colony-stimulating factor 1 was observed in LCs and peritubular myoid cells (PMCs), whereas its receptor was present in LCs and in GFRA1(+) A(und). Taken together, our findings strongly suggest that LCs, different from PMCs, might play a minor role in the SSC niche and physiology and that these steroidogenic cells are probably involved in the differentiation of A(und) toward type A(1) spermatogonia. 相似文献
995.
Durand JD Shen KN Chen WJ Jamandre BW Blel H Diop K Nirchio M Garcia de León FJ Whitfield AK Chang CW Borsa P 《Molecular phylogenetics and evolution》2012,64(1):73-92
The family Mugilidae comprises mainly coastal marine species that are widely distributed in all tropical, subtropical and temperate seas. Mugilid species are generally considered to be ecologically important and they are a major food resource for human populations in certain parts of the world. The taxonomy and systematics of the Mugilidae are still much debated and based primarily on morphological characters. In this study, we provide the first comprehensive molecular systematic account of the Mugilidae using phylogenetic analyses of nucleotide sequence variation at three mitochondrial loci (16S rRNA, cytochrome oxidase I, and cytochrome b) for 257 individuals from 55 currently recognized species. The study covers all 20 mugilid genera currently recognized as being valid. The family comprises seven major lineages that radiated early on from the ancestor to all current forms. All genera that were represented by two species or more, except Cestraeus, turned out to be paraphyletic or polyphyletic. Thus, the present phylogenetic results generally disagree with the current taxonomy at the genus level and imply that the anatomical characters used for the systematics of the Mugilidae may be poorly informative phylogenetically. The present results should provide a sound basis for a taxonomic revision of the mugilid genera. A proportion of the species with large distribution ranges (including Moolgarda seheli, Mugil cephalus and M. curema) appear to consist of cryptic species, thus warranting further taxonomic and genetic work at the infra-generic level. 相似文献
996.
Moussaïd M Guillot EG Moreau M Fehrenbach J Chabiron O Lemercier S Pettré J Appert-Rolland C Degond P Theraulaz G 《PLoS computational biology》2012,8(3):e1002442
In human crowds as well as in many animal societies, local interactions among individuals often give rise to self-organized collective organizations that offer functional benefits to the group. For instance, flows of pedestrians moving in opposite directions spontaneously segregate into lanes of uniform walking directions. This phenomenon is often referred to as a smart collective pattern, as it increases the traffic efficiency with no need of external control. However, the functional benefits of this emergent organization have never been experimentally measured, and the underlying behavioral mechanisms are poorly understood. In this work, we have studied this phenomenon under controlled laboratory conditions. We found that the traffic segregation exhibits structural instabilities characterized by the alternation of organized and disorganized states, where the lifetime of well-organized clusters of pedestrians follow a stretched exponential relaxation process. Further analysis show that the inter-pedestrian variability of comfortable walking speeds is a key variable at the origin of the observed traffic perturbations. We show that the collective benefit of the emerging pattern is maximized when all pedestrians walk at the average speed of the group. In practice, however, local interactions between slow- and fast-walking pedestrians trigger global breakdowns of organization, which reduce the collective and the individual payoff provided by the traffic segregation. This work is a step ahead toward the understanding of traffic self-organization in crowds, which turns out to be modulated by complex behavioral mechanisms that do not always maximize the group's benefits. The quantitative understanding of crowd behaviors opens the way for designing bottom-up management strategies bound to promote the emergence of efficient collective behaviors in crowds. 相似文献
997.
998.
Gergely Losonczy Attila Vajas Lili Takács Erika Dzsudzsák ágnes Fekete éva Márhoffer László Kardos éva Ajzner Bego?a Hurtado Pablo Garcia de Frutos András Berta István Balogh 《PloS one》2012,7(11)
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD. 相似文献
999.
N Le Trant S R Meshnick K Kitchener J W Eaton A Cerami 《The Journal of biological chemistry》1983,258(1):125-130
Leishmania tropica, Trypanosoma brucei, Trypanosoma cruzi, and Crithidia fasciculata have superoxide dismutases which are insensitive to cyanide and sensitive to peroxide and azide, properties characteristic of iron-containing superoxide dismutase. Studies on the superoxide dismutase of C. fasciculata have revealed that: 1) the enzyme is located in the cytosol; 2) isozymes exist; 3) the major superoxide dismutase isozyme (superoxide dismutase 2) has Mr approximately equal to 43,000 and consists of two equal-sized subunits, each of which contains 1.4 atoms of iron. Comparisons of the amino acid content of this crithidial superoxide dismutase with those of superoxide dismutases from other sources suggests that the crithidial enzyme is closely related to bacterial Fe-containing superoxide dismutases, and only distantly related to human Mn- and Cu,Zn-containing superoxide dismutases and to Euglena Fe-containing superoxide dismutase. Attempts are now underway to develop specific inhibitors of the trypanosomatid superoxide dismutase which may be of use in the treatment of leishmaniasis or trypanosomiasis. 相似文献
1000.
Recombinant YIp5 plasmids with the DNA from Triticum aestivum are capable of autonomous replication in Saccharomyces cerevisiae. The URA transformants are unstable without selection pressure, and transformation of yeast cells with these plasmids occurs at high frequency. The cloned sequences were characterized and analyzed to state their belonging to Triticum tribe. 相似文献