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991.
992.
Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence, at face value, seems incompatible with a mother''s need to maintain a functional immune system during pregnancy. A particular conundrum is evident if we consider that maternal antigen presenting cells, activated in order to prime T cells to pathogen-derived antigens, would also have the capacity to prime T cells to co-ingested placental antigens. Here, we address this paradox using a transgenic system in which placental membranes are tagged with a strong surrogate antigen (ovalbumin). We find that although a remarkably large quantity of acellular ovalbumin-containing placental material is released into maternal blood, splenic CD8 T cells in pregnant mice bearing unmanipulated T cell repertoires are not primed to ovalbumin even if the mice are intravenously injected with adjuvants. This failure was largely independent of regulatory T cells, and instead was linked to the intrinsic characteristics of the released material that rendered it selectively non-immunogenic, potentially by sequestering it from CD8α+ dendritic cells. The release of ovalbumin-containing placental material into maternal blood thus had no discernable impact on CD8 T cell priming to soluble ovalbumin injected intravenously during pregnancy, nor did it induce long-term tolerance to ovalbumin. Together, these results outline a major pathway governing the maternal immune response to the placenta, and suggest how tolerance to placental antigens can be maintained systemically without being detrimental to host defense. 相似文献
993.
Lars L. E. Sj?gren Noriaki Tanabe Panagiotis Lymperopoulos Nadir Z. Khan Steven R. Rodermel Henrik Aronsson Adrian K. Clarke 《The Journal of biological chemistry》2014,289(16):11318-11330
The molecular chaperone ClpC/Hsp93 is essential for chloroplast function in vascular plants. ClpC has long been held to act both independently and as the regulatory partner for the ATP-dependent Clp protease, and yet this and many other important characteristics remain unclear. In this study, we reveal that of the two near-identical ClpC paralogs (ClpC1 and ClpC2) in Arabidopsis chloroplasts, along with the closely related ClpD, it is ClpC1 that is the most abundant throughout leaf maturation. An unexpectedly large proportion of both chloroplast ClpC proteins (30% of total ClpC content) associates to envelope membranes in addition to their stromal localization. The Clp proteolytic core is also bound to envelope membranes, the amount of which is sufficient to bind to all the similarly localized ClpC. The role of such an envelope membrane Clp protease remains unclear although it appears uninvolved in preprotein processing or Tic subunit protein turnover. Within the stroma, the amount of oligomeric ClpC protein is less than that of the Clp proteolytic core, suggesting most if not all stromal ClpC functions as part of the Clp protease; a proposal supported by the near abolition of Clp degradation activity in the clpC1 knock-out mutant. Overall, ClpC appears to function primarily within the Clp protease, as the principle stromal protease responsible for maintaining homeostasis, and also on the envelope membrane where it possibly confers a novel protein quality control mechanism for chloroplast preprotein import. 相似文献
994.
Adrian E. Morelli Adriana T. Larregina 《Apoptosis : an international journal on programmed cell death》2010,15(9):1083-1097
One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance
to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens.
Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen
(Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based
therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach
to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate
the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic
cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host
disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could
have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies
in transplantation. 相似文献
995.
Kholoud Arafat Rabah Iratni Takashi Takahashi Khatija Parekh Yusra Al Dhaheri Thomas E. Adrian Samir Attoub 《PloS one》2013,8(6)
A major challenge for oncologists and pharmacologists is to develop more potent and less toxic drugs that will decrease the tumor growth and improve the survival of lung cancer patients. Salinomycin is a polyether antibiotic used to kill gram-positive bacteria including mycobacteria, protozoans such as plasmodium falciparum, and the parasites responsible for the poultry disease coccidiosis. This old agent is now a serious anti-cancer drug candidate that selectively inhibits the growth of cancer stem cells. We investigated the impact of salinomycin on survival, colony growth, migration and invasion of the differentiated human non-small cell lung cancer lines LNM35 and A549. Salinomycin caused concentration- and time-dependent reduction in viability of LNM35 and A549 cells through a caspase 3/7-associated cell death pathway. Similarly, salinomycin (2.5–5 µM for 7 days) significantly decreased the growth of LNM35 and A549 colonies in soft agar. Metastasis is the main cause of death related to lung cancer. In this context, salinomycin induced a time- and concentration-dependent inhibition of cell migration and invasion. We also demonstrated for the first time that salinomycin induced a marked increase in the expression of the pro-apoptotic protein NAG-1 leading to the inhibition of lung cancer cell invasion but not cell survival. These findings identify salinomycin as a promising novel therapeutic agent for lung cancer. 相似文献
996.
Ecological restoration of forest ecosystems is increasingly being implemented in many parts of the world, as a response to widespread forest loss and degradation. In common with other conservation management interventions, restoration efforts should be directed towards areas where the maximum benefits are likely to be achieved. Such prioritisation requires the development of appropriate criteria and indicators (C&I), an issue poorly addressed by previous research. In particular, there is need for C&I that are operational, suitable for spatial analysis and mapping and applicable to a broad range of contexts. This investigation aimed to verify whether this might be achieved through the elicitation of experts’ opinion, when considering biodiversity conservation as the main objective of restoration. A Delphi process was performed, aimed at defining the key ecological criteria and a broad set of indicators. 389 criteria and 669 related indicators were provided in total and grouped into clusters relating to individual criteria. A total of 20 criteria referred to the need for restoration and 18 to its feasibility. In the second round of the Delphi process, 8 definitive criteria were identified along with some 90 related indicators. Finally, a face-to-face meeting was conducted to show how ready-to-use C&I can be obtained for application to a specific context starting from the Delphi's results. The study highlights the potential value of combining the Delphi process and face-to-face meetings for identifying practically applicable C&I for planning ecological restoration. However, the diversity of views identified within a single group of stakeholders suggests that the development of a generally applicable set of C&I for forest restoration will be difficult to achieve in practice. 相似文献
997.
Francesca Munari Szabolcs Soeroes Hans Michael Zenn Adrian Schomburg Nils Kost Sabrina Schr?der Rebecca Klingberg Nasrollah Rezaei-Ghaleh Alexandra Stützer Kathy Ann Gelato Peter Jomo Walla Stefan Becker Dirk Schwarzer Bastian Zimmermann Wolfgang Fischle Markus Zweckstetter 《The Journal of biological chemistry》2012,287(40):33756-33765
Binding of heterochromatin protein 1 (HP1) to the histone H3 lysine 9 trimethylation (H3K9me3) mark is a hallmark of establishment and maintenance of heterochromatin. Although genetic and cell biological aspects have been elucidated, the molecular details of HP1 binding to H3K9me3 nucleosomes are unknown. Using a combination of NMR spectroscopy and biophysical measurements on fully defined recombinant experimental systems, we demonstrate that H3K9me3 works as an on/off switch regulating distinct binding modes of hHP1β to the nucleosome. The methyl-mark determines a highly flexible and very dynamic interaction of the chromodomain of hHP1β with the H3-tail. There are no other constraints of interaction or additional multimerization interfaces. In contrast, in the absence of methylation, the hinge region and the N-terminal tail form weak nucleosome contacts mainly with DNA. In agreement with the high flexibility within the hHP1β-H3K9me3 nucleosome complex, the chromoshadow domain does not provide a direct binding interface. Our results report the first detailed structural analysis of a dynamic protein-nucleosome complex directed by a histone modification and provide a conceptual framework for understanding similar interactions in the context of chromatin. 相似文献
998.
Kornelia Jumel Fiona J. J. Fogg David A. Hutton J. P. Pearson Adrian Allen S. E. Harding 《European biophysics journal : EBJ》1997,25(5-6):477-480
The distribution of molecular weights for polymeric colonic mucus glycoprotein or ``mucin' isolated and solubilised in the
presence of protease inhibitors from pig colons is shown to be considerably greater than its ``subunit' (thiol reduction
product) and papain digested forms using the technique of size-exclusion chromatography coupled to multi-angle laser light
scattering, and confirmed by sedimentation equilibrium measurements. The conformation of this mucin is probed by examining
the molecular weight – intrinsic viscosity relationship in terms of the Mark-Houwink-Kuhn-Sakurada analysis for its polymeric
(or ``whole'), reduced and papain-digested forms: an exponent ``a' of (1.1±0.1) is obtained indicating a linear random coil conformation consistent with other mucins. Size-exclusion chromatography
coupled to multi-angle laser light scattering is shown to provide a relatively simple complementary technique to sedimentation
equilibrium for the molecular weight distribution analysis of polydisperse materials.
Received: 29 November 1996 / Accepted: 2 December 1996 相似文献
999.
Inherited retinal disorders (IRDs) result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER) causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR) complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention. 相似文献
1000.