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561.
Enkvist E Raidaru G Vaasa A Pehk T Lavogina D Uri A 《Bioorganic & medicinal chemistry letters》2007,17(19):5336-5339
Carbocyclic analogs of 3'-deoxyadenosine were synthesized as racemates and the resulting stereoisomers were separated by chromatography on a chiral column. The conjugation of obtained compounds with hexa-(D-arginine) via 6-aminohexanoic acid linker led to a highly potent inhibitor of several basophilic protein kinases with some selectivity towards cAMP-dependent protein kinase. 相似文献
562.
Despite extensive theoretical and empirical research into offspring food solicitation behaviour as a model for parent-offspring conflict and communication, the adaptive value of parental responsiveness to begging has never been tested experimentally. Game theory models, as well as empirical studies, suggest that begging conveys information on offspring state, which implies that parental investment can be better translated to fitness by responding to begging when allocating resources rather than by ignoring it. However, this assumption and its underlying mechanisms have received little or no attention. Here we show by experiments with hand-raised house sparrow (Passer domesticus) nestlings that a 'responsive parent' will do better than a hypothetical 'non-responsive' mutant (that provides similar food amounts, but irrespective of begging). This is neither because food-deprived nestlings convert food to mass more efficiently, however, nor because responsiveness reduces costly begging. Rather, responsiveness to begging is adaptive because it reduces two opposing risks: one is wasting time when returning too soon to feed already satiated nestlings and the other is repeatedly overlooking some nestlings as a result of the stochastic nature of a random, non-responsive strategy. This study provides the first experimental evidence for the adaptive value of parental responsiveness to offspring begging. 相似文献
563.
Sigal A Danon T Cohen A Milo R Geva-Zatorsky N Lustig G Liron Y Alon U Perzov N 《Nature protocols》2007,2(6):1515-1527
We present a protocol to tag proteins expressed from their endogenous chromosomal locations in individual mammalian cells using central dogma tagging. The protocol can be used to build libraries of cell clones, each expressing one endogenous protein tagged with a fluorophore such as the yellow fluorescent protein. Each round of library generation produces 100-200 cell clones and takes about 1 month. The protocol integrates procedures for high-throughput single-cell cloning using flow cytometry, high-throughput cDNA generation and 3' rapid amplification of cDNA ends, semi-automatic protein localization screening using fluorescent microscopy and freezing cells in 96-well format. 相似文献
564.
Nassir Molhm Arad Uri Lee Sang-Yong Journo Shani Mirza Salahuddin Renn Christian Zimmermann Herbert Pelletier Julie Sévigny Jean Müller Christa E. Fischer Bilha 《Purinergic signalling》2019,15(2):247-263
Purinergic Signalling - Overproduction of extracellular diphosphate due to hydrolysis of ATP by NPP1 leads to pathological calcium diphosphate (pyrophosphate) dihydrate deposition (CPPD)... 相似文献
565.
Nava Saati Amiram Ravid Uri A. Liberman Ruth Koren 《In vitro cellular & developmental biology. Animal》1997,33(4):310-314
Summary Agents that increase intracellular cAMP (cAMP elevating agents) and 1,25(OH)2D3 inhibit the proliferation of many cell types. We investigated the combined effect of 1,25(OH)2D3 and cAMP elevating agents on exponentially growing mouse 3T3 fibroblasts. The following cAMP elevating agents were used:
theophylline and pentoxyfilline, which inhibit cAMP-dependent phosphodiesterase; prostaglandin E2 which activates adenylate cyclase by a receptor-mediated mechanism; forskolin, which directly stimulates adenylate cyclase;
and the cell permeable cAMP analogs 8-bromo cAMP and N6 benzoyl cAMP. 1,25(OH)2D3 and cAMP elevating agents were added to exponentially growing fibroblasts cultured in 96-well microtiter plates and cell
number was monitored 3–7 d later. 1,25(OH)2D3 and the cAMP elevating agents as single agents inhibited the growth of the 3T3 cells. The combined treatment of the fibroblasts
with 1,25(OH)2D3 and the cAMP elevating agents resulted in an antiproliferative effect that was more than additive. The synergistic interaction
depended on the dose of 1,25(OH)2D3 and was apparent already at 10−8
M of the hormone. The specificity of the effect of 1,25(OH)2D3 was demonstrated by the finding that 24,25-dihydroxyvitamin D3, a vitamin D metabolite with low affinity for the vitamin D receptor, did not affect the antiproliferative effect of cAMP
elevating agents. From the synergistic interaction between 1,25(OH)2D3 and the cell permeable cAMP analogs, we infer that the site of interaction between the two signaling pathways is distal to
the cAMP generating and degrading machinery. 相似文献
566.
Charcoal assemblages from five Terminal Pleistocene sites in the Central Negev Highlands, Israel, have been analyzed. Eleven taxa have been identified, two of which, juniper andPaliurus, no longer grow in this district, and one,Pinus (of which only a single occurrence was encountered), is considered intrusive, and the rest are taxa which still characterize the region today. Among these latter,Pistacia atlantica (which is the dominant tree in this area today) was the most common. Association of juniper andPaliurus is found today only in the northern Near East. It can not be ascertained that such an association characterized the Central Negev Highlands throughout the entire period spanned by the charcoal assemblages, since it is possible thatPistacia atlantica may have become temporarily extinct. In any case the former occurrence of juniper and particularlyPaliurus in the Central Negev Highlands clearly point to higher humidity in this region during the final stages of the Pleistocene. This conclusion is corroborated by a variety of proxy climatic indicators throughout the southern Levant. 相似文献
567.
Biological systems often display modularity, in the sense that they can be decomposed into nearly independent subsystems. Recent studies have suggested that modular structure can spontaneously emerge if goals (environments) change over time, such that each new goal shares the same set of sub-problems with previous goals. Such modularly varying goals can also dramatically speed up evolution, relative to evolution under a constant goal. These studies were based on simulations of model systems, such as logic circuits and RNA structure, which are generally not easy to treat analytically. We present, here, a simple model for evolution under modularly varying goals that can be solved analytically. This model helps to understand some of the fundamental mechanisms that lead to rapid emergence of modular structure under modularly varying goals. In particular, the model suggests a mechanism for the dramatic speedup in evolution observed under such temporally varying goals. 相似文献
568.
Fatma Daoud Aurora Candelario-Martínez Jean-Marie Billard Avi Avital Malik Khelfaoui Yael Rozenvald Maryvonne Guegan Dominique Mornet Danielle Jaillard Uri Nudel Jamel Chelly Dalila Martínez-Rojas Serge Laroche David Yaffe Cyrille Vaillend 《PloS one》2009,4(8)
Background
Duchenne muscular dystrophy (DMD) is caused by deficient expression of the cytoskeletal protein, dystrophin. One third of DMD patients also have mental retardation (MR), likely due to mutations preventing expression of dystrophin and other brain products of the DMD gene expressed from distinct internal promoters. Loss of Dp71, the major DMD-gene product in brain, is thought to contribute to the severity of MR; however, the specific function of Dp71 is poorly understood.Methodology/Principal Findings
Complementary approaches were used to explore the role of Dp71 in neuronal function and identify mechanisms by which Dp71 loss may impair neuronal and cognitive functions. Besides the normal expression of Dp71 in a subpopulation of astrocytes, we found that a pool of Dp71 colocalizes with synaptic proteins in cultured neurons and is expressed in synaptic subcellular fractions in adult brains. We report that Dp71-associated protein complexes interact with specialized modular scaffolds of proteins that cluster glutamate receptors and organize signaling in postsynaptic densities. We then undertook the first functional examination of the brain and cognitive alterations in the Dp71-null mice. We found that these mice display abnormal synapse organization and maturation in vitro, altered synapse density in the adult brain, enhanced glutamatergic transmission and reduced synaptic plasticity in CA1 hippocampus. Dp71-null mice show selective behavioral disturbances characterized by reduced exploratory and novelty-seeking behavior, mild retention deficits in inhibitory avoidance, and impairments in spatial learning and memory.Conclusions/Significance
Results suggest that Dp71 expression in neurons play a regulatory role in glutamatergic synapse organization and function, which provides a new mechanism by which inactivation of Dp71 in association with that of other DMD-gene products may lead to increased severity of MR. 相似文献569.
Anna Aronovich Dalit Tchorsh Elias Shezen Chava Rosen Yael Klionsky Sivan Cohen Orna Tal Uri Martinowitz Helena Katchman Smadar Eventov-Friedman Ninette Amariglio Jasmine Jacob-Hirsch Gideon Rechavi Yair Reisner 《PloS one》2009,4(12)
Very little is known about the mechanisms that contribute to organ size differences between species. In the present study, we used a mouse model of embryonic pig tissue implantation to define the role of host Factor VIII in controlling the final size attained by the implant. We show here that pig embryonic spleen, pancreas, and liver all grow to an increased size in mice that are deficient in the Factor VIII clotting cascade. Similar results were obtained using the transplantation model after treatment with the low molecular weight heparin derivative Clexane which markedly enhanced transplant size. Likewise, enhanced size was found upon treatment with the direct thrombin inhibitor Dabigatran, suggesting that organ size regulation might be mediated by thrombin, downstream of Factor VIII. Considering that thrombin was shown to mediate various functions unrelated to blood clotting, either directly by cleavage of protease-activated receptors (PARs) or indirectly by cleaving osteopontin (OPN) on stroma cells, the role of PAR1 and PAR4 antagonists as well as treatment with cleaved form of OPN (tcOPN) were tested. While the former was not found to have an impact on overgrowth of embryonic pig spleen implants, marked reduction of size was noted upon treatment with the (tcOPN). Collectively, our surprising set of observations suggests that factors of the coagulation cascade have a novel role in organ size control. 相似文献
570.
Ussama M. Abdel-Motal Kim Wigglesworth Uri Galili 《Cancer immunology, immunotherapy : CII》2009,58(10):1545-1556
α-Gal glycolipids capable of converting tumors into endogenous vaccines, have α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) and
are extracted from rabbit RBC membranes. α-Gal epitopes bind anti-Gal, the most abundant natural antibody in humans constituting
1% of immunoglobulins. α-Gal glycolipids insert into tumor cell membranes, bind anti-Gal and activate complement. The complement
cleavage peptides C5a and C3a recruit inflammatory cells and APC into the treated lesion. Anti-Gal further opsonizes the tumor
cells and targets them for effective uptake by recruited APC, via Fcγ receptors. These APC transport internalized tumor cells
to draining lymph nodes, and present immunogenic tumor antigen peptides for activation of tumor specific T cells. The present
study demonstrates the ability of α-gal glycolipids treatment to prevent development of metastases at distant sites and to
protect against tumor challenge in the treated mice. Adoptive transfer studies indicate that this protective immune response
is mediated by CD8+ T cells, activated by tumor lesions turned vaccine. This T cell activation is potent enough to overcome
the suppressive activity of Treg cells present in tumor bearing mice, however it does not elicit an autoimmune response against
antigens on normal cells. Insertion of α-gal glycolipids and subsequent binding of anti-Gal are further demonstrated with
human melanoma cells, suggesting that intratumoral injection of α-gal glycolipids is likely to elicit a protective immune
response against micrometastases also in cancer patients. 相似文献