全文获取类型
收费全文 | 661篇 |
免费 | 57篇 |
出版年
2023年 | 5篇 |
2022年 | 13篇 |
2021年 | 19篇 |
2020年 | 8篇 |
2019年 | 9篇 |
2018年 | 10篇 |
2017年 | 12篇 |
2016年 | 16篇 |
2015年 | 34篇 |
2014年 | 38篇 |
2013年 | 35篇 |
2012年 | 57篇 |
2011年 | 49篇 |
2010年 | 32篇 |
2009年 | 27篇 |
2008年 | 36篇 |
2007年 | 31篇 |
2006年 | 36篇 |
2005年 | 24篇 |
2004年 | 28篇 |
2003年 | 36篇 |
2002年 | 32篇 |
2001年 | 16篇 |
2000年 | 9篇 |
1999年 | 10篇 |
1998年 | 5篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1991年 | 5篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1981年 | 2篇 |
1980年 | 6篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1977年 | 11篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 3篇 |
1972年 | 7篇 |
1971年 | 2篇 |
1969年 | 2篇 |
排序方式: 共有718条查询结果,搜索用时 15 毫秒
131.
The binding to isolated hepatocyte plasma membranes of radioactively labelled inhibitors of microfilamentous and microtubular protein function ([3H]cytochalasin B and [3H]colchicine, respectively) was studied as one means of assessing the degree of association of these proteins with cell surface membranes. [3H]Cytochalasin B which behaved identically to the unlabelled compound with respect to binding to these membranes was prepared by reduction of cytochalasin A with NaB3H4. The binding was rapid, readily reversible, proportional to the amount of membrane and relatively insentive to changes of pH or ionic strength. At 10?6 M [3H]cytochalasin B, glucose or p-chloromercuribenzoate, an inhibitor of glucose transport inhibited binding by about 20%; treatment of membranes with 0.6 M KI which depolymerizes F actin to G actin caused about 60% inhibition of binding. These two types of inhibition were additive indicating two separate classes of binding sites, one associated with sugar transport and one with microfilaments. Filamentous structures with the diameter of microfilaments (50 Å) were seen in electron micrographs of thin sections of the membranes. At concentrations greater than 10?5 M [3H]cytochalasin B, binding was proportional to drug concentration, characteristic of non-specific adsorption or partitioning. Intracellular membranes of the hepatocyte also bound [3H]cytochalasin B, those of the smooth endoplasmic reticulum to a greater extent than plasma membranes.[3H]Colchicine bound to plasma membranes in proportion to the amount of membrane and at a rate compatible with binding to tubulin. However, other properties of the binding including effects of temperature, drug concentration and antisera against tubulin were different from those of binding to tubulin. Hence, no evidence was obtained for association of microtubular elements with these membranes. Despite this there appeared to be an interdependence between microtubule and microfilament inhibitors: vinblastine sulfate stimulated [3H]cytochalasin B binding and cytochalasin B stimulated 3H colchicine binding. [3H]Colchicine also bound to intracellular membranes, especially smooth microsomes. 相似文献
132.
133.
Sheina Lew-Levy Rachel Reckin Noa Lavi Jurgi Cristóbal-Azkarate Kate Ellis-Davies 《Human nature (Hawthorne, N.Y.)》2017,28(4):367-394
Hunting and gathering is, evolutionarily, the defining subsistence strategy of our species. Studying how children learn foraging skills can, therefore, provide us with key data to test theories about the evolution of human life history, cognition, and social behavior. Modern foragers, with their vast cultural and environmental diversity, have mostly been studied individually. However, cross-cultural studies allow us to extrapolate forager-wide trends in how, when, and from whom hunter-gatherer children learn their subsistence skills. We perform a meta-ethnography, which allows us to systematically extract, summarize, and compare both quantitative and qualitative literature. We found 58 publications focusing on learning subsistence skills. Learning begins early in infancy, when parents take children on foraging expeditions and give them toy versions of tools. In early and middle childhood, children transition into the multi-age playgroup, where they learn skills through play, observation, and participation. By the end of middle childhood, most children are proficient food collectors. However, it is not until adolescence that adults (not necessarily parents) begin directly teaching children complex skills such as hunting and complex tool manufacture. Adolescents seek to learn innovations from adults, but they themselves do not innovate. These findings support predictive models that find social learning should occur before individual learning. Furthermore, these results show that teaching does indeed exist in hunter-gatherer societies. And, finally, though children are competent foragers by late childhood, learning to extract more complex resources, such as hunting large game, takes a lifetime. 相似文献
134.
135.
Argentine ants (Linepithema humile) live in groups of nests connected by trails to each other and to stable food sources. In a field study, we investigated whether some ants recruit directly from established, persistent trails to food sources, thus accelerating food collection. Our results indicate that Argentine ants recruit nestmates to food directly from persistent trails, and that the exponential increase in the arrival rate of ants at baits is faster than would be possible if recruited ants traveled from distant nests. Once ants find a new food source, they walk back and forth between the bait and sometimes share food by trophallaxis with nestmates on the trail. Recruiting ants from nearby persistent trails creates a dynamic circuit, like those found in other distributed systems, which facilitates a quick response to changes in available resources. 相似文献
136.
Lucy N. Mekies Danielle Regev Binyamin Eisen Jonatan Fernandez-Gracia Polina Baskin Ronen Ben Jehuda Rita Shulman Irina Reiter Raz Palty Michael Arad Eyal Gottlieb Ofer Binah 《Journal of cellular and molecular medicine》2021,25(8):3922-3934
Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is an X-linked disease affecting male and rarely adult heterozygous females, resulting in death by the late 20s to early 30s. Previous studies reported depressed left ventricular function in DMD patients which may result from deranged intracellular Ca2+-handling. To decipher the mechanism(s) underlying the depressed LV function, we tested the hypothesis that iPSC-CMs generated from DMD patients feature blunted positive inotropic response to β-adrenergic stimulation. To test the hypothesis, [Ca2+]i transients and contractions were recorded from healthy and DMD-CMs. While in healthy CMs (HC) isoproterenol caused a prominent positive inotropic effect, DMD-CMs displayed a blunted inotropic response. Next, we tested the functionality of the sarcoplasmic reticulum (SR) by measuring caffeine-induced Ca2+ release. In contrast to HC, DMD-CMs exhibited reduced caffeine-induced Ca2+ signal amplitude and recovery time. In support of the depleted SR Ca2+ stores hypothesis, in DMD-CMs the negative inotropic effects of ryanodine and cyclopiazonic acid were smaller than in HC. RNA-seq analyses demonstrated that in DMD CMs the RNA-expression levels of specific subunits of the L-type calcium channel, the β1-adrenergic receptor (ADRβ1) and adenylate cyclase were down-regulated by 3.5-, 2.8- and 3-fold, respectively, which collectively contribute to the depressed β-adrenergic responsiveness. 相似文献
137.
Antifolates have a crucial role in the treatment of various cancers by inhibiting key enzymes in purine and thymidylate biosynthesis. However, the frequent emergence of inherent and acquired antifolate resistance in solid tumors calls for the development of novel therapeutic strategies to overcome this chemoresistance. The core of solid tumors is highly hypoxic due to poor blood circulation, and this hypoxia is considered to be a major contributor to drug resistance. However, the cytotoxic activity of antifolates under hypoxia is poorly characterized. Here we show that under severe hypoxia, gene expression of ubiquitously expressed key enzymes and transporters in folate metabolism and nucleoside homeostasis is downregulated. We further demonstrate that carcinoma cells become completely refractory, even at sub-millimolar concentrations, to all hydrophilic and lipophilic antifolates tested. Moreover, tumor cells retained sensitivity to the proteasome inhibitor bortezomib and the topoisomerase II inhibitor doxorubicin, which are independent of cell cycle. We provide evidence that this antifolate resistance, associated with repression of folate metabolism, is a result of the inability of antifolates to induce DNA damage under hypoxia, and is attributable to a hypoxia-induced cell cycle arrest, rather than a general anti-apoptotic mechanism. Our findings suggest that solid tumors harboring a hypoxic core of cell cycle-arrested cells may display antifolate resistance while retaining sensitivity to the chemotherapeutics bortezomib and doxorubicin. This study bears important implications for the molecular basis underlying antifolate resistance under hypoxia and its rational overcoming in solid tumors. 相似文献
138.
The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes 总被引:40,自引:0,他引:40
J Y Fu J L Masferrer K Seibert A Raz P Needleman 《The Journal of biological chemistry》1990,265(28):16737-16740
We report here that the bacterial lipopolysaccharide endotoxin induces human blood monocytes in a time- and dose-dependent manner to release prodigious amounts of prostaglandins with thromboxane A2, the major metabolite formed. Cells responded to as little as 1 ng/ml lipopolysaccharide to release prostaglandin E2 and thromboxane A2 with maximal stimulation at 10 micrograms/ml. Lipopolysaccharide was found to induce increased activity of cyclooxygenase enzyme without affecting the activities of phospholipase and thromboxane synthase or the formation of 5-lipoxygenase products (e.g. leukotriene B4). The glucocorticoid dexamethasone completely blocked the lipopolysaccharide-induced prostanoid release by inhibiting the activity of monocyte cyclooxygenase. Dexamethasone did not affect phospholipase and thromboxane synthase activities or leukotriene formation. Immunoprecipitation of [35S]methionine-labeled cyclooxygenase confirmed that the effect of lipopolysaccharide and dexamethasone on the monocyte prostanoid production could be attributed to an increase or decrease, respectively, in cellular cyclooxygenase de novo synthesis. 相似文献
139.
Treatment with the mitochondrial‐targeted antioxidant peptide SS‐31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice 下载免费PDF全文
Stefano Tarantini Noa M. Valcarcel‐Ares Andriy Yabluchanskiy Gabor A. Fulop Peter Hertelendy Tripti Gautam Eszter Farkas Aleksandra Perz Peter S. Rabinovitch William E. Sonntag Anna Csiszar Zoltan Ungvari 《Aging cell》2018,17(2)
Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age‐related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age‐related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24‐month‐old C57BL/6 mice were treated with a cell‐permeable, mitochondria‐targeted antioxidant peptide (SS‐31; 10 mg kg?1 day?1, i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS–31 significantly improved neurovascular coupling responses by increasing NO‐mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS–31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age‐related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria‐targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age‐related vascular cognitive impairment (VCI). 相似文献
140.
René Uebe Noa Keren‐Khadmy Natalie Zeytuni Emanuel Katzmann Yotam Navon Geula Davidov Ronit Bitton Jürgen M. Plitzko Dirk Schüler Raz Zarivach 《Molecular microbiology》2018,107(4):542-557
Magnetospirillum gryphiswaldense MSR‐1 synthesizes membrane‐enclosed magnetite (Fe3O4) nanoparticles, magnetosomes, for magnetotaxis. Formation of these organelles involves a complex process comprising key steps which are governed by specific magnetosome‐associated proteins. MamB, a cation diffusion facilitator (CDF) family member has been implicated in magnetosome‐directed iron transport. However, deletion mutagenesis studies revealed that MamB is essential for the formation of magnetosome membrane vesicles, but its precise role remains elusive. In this study, we employed a multi‐disciplinary approach to define the role of MamB during magnetosome formation. Using site‐directed mutagenesis complemented by structural analyses, fluorescence microscopy and cryo‐electron tomography, we show that MamB is most likely an active magnetosome‐directed transporter serving two distinct, yet essential functions. First, MamB initiates magnetosome vesicle formation in a transport‐independent process, probably by serving as a landmark protein. Second, MamB transport activity is required for magnetite nucleation. Furthermore, by determining the crystal structure of the MamB cytosolic C‐terminal domain, we also provide mechanistic insight into transport regulation. Additionally, we present evidence that magnetosome vesicle growth and chain formation are independent of magnetite nucleation and magnetic interactions respectively. Together, our data provide novel insight into the role of the key bifunctional magnetosome protein MamB, and the early steps of magnetosome formation. 相似文献