全文获取类型
收费全文 | 1659篇 |
免费 | 222篇 |
专业分类
1881篇 |
出版年
2022年 | 18篇 |
2021年 | 33篇 |
2020年 | 15篇 |
2019年 | 29篇 |
2018年 | 32篇 |
2017年 | 16篇 |
2016年 | 44篇 |
2015年 | 53篇 |
2014年 | 61篇 |
2013年 | 78篇 |
2012年 | 112篇 |
2011年 | 98篇 |
2010年 | 72篇 |
2009年 | 59篇 |
2008年 | 86篇 |
2007年 | 75篇 |
2006年 | 76篇 |
2005年 | 69篇 |
2004年 | 63篇 |
2003年 | 58篇 |
2002年 | 60篇 |
2001年 | 52篇 |
2000年 | 30篇 |
1999年 | 27篇 |
1998年 | 27篇 |
1997年 | 12篇 |
1996年 | 16篇 |
1995年 | 15篇 |
1994年 | 13篇 |
1993年 | 10篇 |
1992年 | 28篇 |
1991年 | 28篇 |
1990年 | 11篇 |
1989年 | 25篇 |
1988年 | 20篇 |
1987年 | 27篇 |
1986年 | 19篇 |
1985年 | 10篇 |
1983年 | 14篇 |
1982年 | 21篇 |
1981年 | 11篇 |
1980年 | 11篇 |
1979年 | 11篇 |
1978年 | 10篇 |
1977年 | 12篇 |
1975年 | 13篇 |
1973年 | 12篇 |
1945年 | 11篇 |
1939年 | 15篇 |
1938年 | 12篇 |
排序方式: 共有1881条查询结果,搜索用时 15 毫秒
61.
Olga Shomron Inbar Nevo-Yassaf Tamar Aviad Yakey Yaffe Eitan Erez Zahavi Anna Dukhovny Eran Perlson Ilya Brodsky Adva Yeheskel Metsada Pasmanik-Chor Anna Mironov Galina V. Beznoussenko Alexander A. Mironov Ella H. Sklan George H. Patterson Yoji Yonemura Mara Sannai Christoph Kaether Koret Hirschberg 《The Journal of cell biology》2021,220(6)
COPII and COPI mediate the formation of membrane vesicles translocating in opposite directions within the secretory pathway. Live-cell and electron microscopy revealed a novel mode of function for COPII during cargo export from the ER. COPII is recruited to membranes defining the boundary between the ER and ER exit sites, facilitating selective cargo concentration. Using direct observation of living cells, we monitored cargo selection processes, accumulation, and fission of COPII-free ERES membranes. CRISPR/Cas12a tagging, the RUSH system, and pharmaceutical and genetic perturbations of ER-Golgi transport demonstrated that the COPII coat remains bound to the ER–ERES boundary during protein export. Manipulation of the cargo-binding domain in COPII Sec24B prohibits cargo accumulation in ERES. These findings suggest a role for COPII in selecting and concentrating exported cargo rather than coating Golgi-bound carriers. These findings transform our understanding of coat proteins’ role in ER-to-Golgi transport. 相似文献
62.
63.
64.
Revaz Solomonia Nana Gogichaishvili Maia Nozadze Eka Lepsveridze David Dzneladze Tamar Kiguradze 《Cellular and molecular neurobiology》2013,33(1):119-127
Identification of compounds preventing the biochemical changes that underlie the epileptogenesis process is of great importance. We have previously shown that myo-Inositol (MI) daily treatment prevents certain biochemical changes that are triggered by kainic acid (KA)-induced status epilepticus (SE). The aim of the current work was to study the further influence of MI treatment on the biochemical changes of epileptogenesis and focus on changes in the hippocampus and neocortex of rats for the following GABA-A receptor subunits: α1, α4, γ2, and δ. After SE, one group of rats was treated with saline, while the second group was treated with MI. Control groups that were not treated by the convulsant received either saline or MI administration. 28–30 h after the experiment, a decrease in the amount of the α1 subunit was revealed in the hippocampus and MI had no significant influence on it. On the 28th day of the experiment, the amount of α1 was increased in both the KA? and KA + MI-treated groups. The α4 and γ2 subunits were strongly reduced in the hippocampus of KA-treated animals, but MI significantly halted this reduction. The effects of MI on α4 and γ2 subunit changes were significantly different between hippocampus and neocortex. On the twenty-eighth day after SE, a decrease in the amount of α1 was found in the neocortex, but MI treatment had no effect on it. The obtained results indicate that MI treatment interferes with some of the biochemical processes of epileptogenesis. 相似文献
65.
Tamar Burg-Golani Yair Pozniak Lev Rabinovich Nadejda Sigal Ran Nir Paz Anat A. Herskovits 《Journal of bacteriology》2013,195(23):5262-5272
Listeria monocytogenes is a Gram-positive human intracellular pathogen that infects diverse mammalian cells. Upon invasion, L. monocytogenes secretes multiple virulence factors that target host cellular processes and promote infection. It has been presumed, but was not empirically established, that the Sec translocation system is the primary mediator of this secretion. Here, we validate an important role for SecDF, a component of the Sec system, in the secretion of several critical L. monocytogenes virulence factors. A ΔsecDF mutant is demonstrated to exhibit impaired membrane translocation of listeriolysin O (LLO), PlcA, PlcB, and ActA, factors that mediate L. monocytogenes phagosomal escape and spread from cell to cell. This impaired translocation was monitored by accumulation of the factors on the bacterial membrane and by reduced activity upon secretion. This defect in secretion is shown to be associated with a severe intracellular growth defect of the ΔsecDF mutant in macrophages and a less virulent phenotype in mice, despite normal growth in laboratory medium. We further show that SecDF is upregulated when the bacteria reside in macrophage phagosomes and that it is necessary for efficient phagosomal escape. Taken together, these data support the premise that SecDF plays a role as a chaperone that facilitates the translocation of L. monocytogenes virulence factors during infection. 相似文献
66.
Phuti E. Makgotlho Gabriella Marincola Daniel Sch?fer Qian Liu Taeok Bae Tobias Geiger Elizabeth Wasserman Christiane Wolz Wilma Ziebuhr Bhanu Sinha 《PloS one》2013,8(8)
The Staphylococcus aureus regulatory saePQRS system controls the expression of numerous virulence factors, including extracellular adherence protein (Eap), which amongst others facilitates invasion of host cells. The saePQRS operon codes for 4 proteins: the histidine kinase SaeS, the response regulator SaeR, the lipoprotein SaeP and the transmembrane protein SaeQ. S. aureus strain Newman has a single amino acid substitution in the transmembrane domain of SaeS (L18P) which results in constitutive kinase activity. SDS was shown to be one of the signals interfering with SaeS activity leading to inhibition of the sae target gene eap in strains with SaeSL but causing activation in strains containing SaeSP. Here, we analyzed the possible involvement of the SaeP protein and saePQ region in SDS-mediated sae/eap expression. We found that SaePQ is not needed for SDS-mediated SaeS signaling. Furthermore, we could show that SaeS activity is closely linked to the expression of Eap and the capacity to invade host cells in a number of clinical isolates. This suggests that SaeS activity might be directly modulated by structurally non-complex environmental signals, as SDS, which possibly altering its kinase/phosphatase activity. 相似文献
67.
Rotem Kadir Tamar Harel Barak Markus Yonatan Perez Anna Bakhrat Idan Cohen Michael Volodarsky Miora Feintsein-Linial Elana Chervinski Joel Zlotogora Sara Sivan Ramon Y. Birnbaum Uri Abdu Stavit Shalev Ohad S. Birk 《PLoS genetics》2016,12(3)
Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size. 相似文献
68.
Mikolaj B. Ogrodnik Tamar Pirtskhalava Nassir M. Thalji Michael Hagler Diana Jurk Leslie A. Smith Grace Casaclang‐Verzosa Yi Zhu Marissa J. Schafer Tamara Tchkonia James L. Kirkland Jordan D. Miller 《Aging cell》2016,15(5):973-977
While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long‐term senolytic treatment is unknown. To determine whether long‐term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF+ cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK‐ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT–PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases. 相似文献
69.
Dario A. Breitel Louise Chappell-Maor Sagit Meir Irina Panizel Clara Pons Puig Yanwei Hao Tamar Yifhar Hagai Yasuor Mohamed Zouine Mondher Bouzayen Antonio Granell Richart Ilana Rogachev Asaph Aharoni 《PLoS genetics》2016,12(3)
The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process. 相似文献
70.