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Hannah Priyadarshini Gideon JiaYao Phuah Amy J. Myers Bryan D. Bryson Mark A. Rodgers M. Teresa Coleman Pauline Maiello Tara Rutledge Simeone Marino Sarah M. Fortune Denise E. Kirschner Philana Ling Lin JoAnne L. Flynn 《PLoS pathogens》2015,11(1)
Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few “multi-functional” T cells were observed. However, granulomas were found to be “multi-functional” with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas. 相似文献
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During xenophagy, pathogens are selectively targeted by autophagy receptors to the autophagy machinery for their subsequent degradation. In infected cells, the autophagy receptor CALCOCO2/NDP52 targets Salmonella Typhimurium to the phagophore membrane by concomitantly interacting with LC3C and binding to ubiquitinated cytosolic bacteria or to LGALS8/GALECTIN 8 adsorbed on damaged vacuoles that contain bacteria. We recently reported that in addition, CALCOCO2 is also necessary for the maturation step of Salmonella Typhimurium-containing autophagosomes. Interestingly, the role of CALCOCO2 in maturation is independent of its role in targeting, as these functions rely on distinct binding domains and protein partners. Indeed, to mediate autophagosome maturation CALCOCO2 binds on the one hand to LC3A, LC3B, or GABARAPL2, and on the other hand to MYO6/MYOSIN VI, whereas the interaction with LC3C is dispensable. Therefore, the autophagy receptor CALCOCO2 plays a dual function during xenophagy first by targeting bacteria to nascent autophagosomes and then by promoting autophagosome maturation in order to destroy bacteria.Xenophagy is the process referring to the selective degradation of intracellular microorganisms by autophagy. Xenophagy is a very potent intrinsic cellular line of defense to fight pathogens and requires first the detection and targeting of microorganisms to growing phagophores prior to autophagosome maturation leading to microbial destruction. The targeting step can be achieved by cytosolic autophagy receptors, which bind on the one hand to the pathogen and on the other hand to LC3, a phagophore membrane-anchored protein. Once entrapped within an autophagosome, bacteria can survive or escape, unless they are rapidly destroyed. Therefore, autophagosome maturation allows the discharge of lysosomal enzymes in autolysosomes, allowing destruction of the bacteria. It is, however, not well known how autophagosomes mature, especially in the context of xenophagy. Recently, the endosomal membrane-bound protein TOM1 and the dynein motor MYO6 have been both shown to be implicated in the transport of endosomes into the vicinity of autophagosomes in order to ensure fusion of autophagosomes with vesicles of the endo/lysosomal pathway. Moreover, the concomitant absence of 3 autophagy receptors, CALCOCO2, TAX1BP1/T6BP, and OPTN/OPTINEURIN, impairs autophagosome biogenesis and maturation. As CALCOCO2 was already shown to have a MYO6 binding domain, we wondered whether CALCOCO2 could also be implicated in autophagosome maturation per se to promote bacterial degradation.We first observed that the binding site of CALCOCO2 to MYO6 was required for cells to control Salmonella Typhimurium intracellular growth. Nevertheless, when the binding of CALCOCO2 to MYO6 was abolished, bacteria were still efficiently targeted to autophagosomes, but yet still able to replicate to levels similar to the one observed in CALCOCO2-depleted cells. Strikingly, in noninfected cells the absence of CALCOCO2 perturbs the autophagy flux, resulting in a strong accumulation of autophagosomes, suggesting a positive role for CALCOCO2 in the autophagosome-lysosome fusion process. Surprisingly, we found that CALCOCO2 binding to LC3C, through its noncanonical LC3 interacting region (CLIR), is not involved in the maturation of autophagosomes. Instead, we identified another motif in the primary sequence of CALCOCO2, which mediates binding to at least LC3A, LC3B, and GABARAPL2 (but not LC3C). We referred to this motif as “LIR-like” as it differs from the canonical LIR motif by the absence of a hydrophobic residue in position X3. This LIR-like motif was necessary for autophagosome maturation, along with the domain of CALCOCO2 responsible for its binding to MYO6. Eventually, mutation of this LIR-like motif also resulted in an increased Salmonella Typhimurium intracellular proliferation, whereas bacteria were still efficiently targeted within nondegradative autophagosomes. Interestingly, the absence of the autophagy receptor OPTN also led to the accumulation of nondegradative autophagosomes, suggesting that other autophagy receptors could share CALCOCO2 dual functions in xenophagy.Having autophagy receptors ensuring both targeting and degradation of pathogens could be an important evolutionary advantage against infections. Indeed, this mechanism could help to reduce the delay necessary for maturation, thus avoiding adaptation of the pathogen to its new environment (as proposed for Coxiella burnetti, Listeria monocytogenes, and Legionella pneumophila) or its escape from the autophagosome. Conversely, pathogens could avoid autophagy entrapment or autophagic degradation by targeting CALCOCO2 or any other autophagy receptors, which could play similar roles. For instance Chikungunya virus was reported to target CALCOCO2 in human cells leading to increased virus replication. Nevertheless, redundancy among autophagy receptors could also ensure a selective immune advantage against pathogens targeting any one of these receptors.Our results and those from others suggest for now that CALCOCO2 serves as a docking platform for MYO6-bound endosomes, thus facilitating autophagosome maturation (Fig. 1). How this action is coordinated with CALCOCO2 directing pathogens to the phagophore membranes remains unclear. During xenophagy against Salmonella Typhimurium, CALCOCO2 interaction first with LC3C is necessary to further recruit other ATG8 orthologs and ensure the final degradation of bacteria. Since the LIR-like motifs bind several ATG8s, whereas the CLIR motif only mediates binding to LC3C, it is possible that binding of CALCOCO2 to LC3C induces conformational changes and uncovers the LIR-like motif that can be then engaged with other ATG8 orthologs to trigger autophagosome maturation. Moreover, it is still unclear whether the action of CALCOCO2 in autophagosome maturation is coordinated with other partners, such as STX17/SYNTAXIN 17, which is recruited on the external membrane of autophagosomes and regulate fusion with lysosomes.
Open in a separate windowFigure 1.Schematic model for the dual role of CALCOCO2 in xenophagy. CALCOCO2 targets bacteria to the phagophore through its LC3C binding site (CLIR motif), and, independently, regulates autophagosome maturation through its LC3A, LC3B, or GABARAPL2 binding site (LIR-like motif) and its MYO6 interacting region.Our findings reveal a new role for the autophagy receptor CALCOCO2 in autophagosome maturation, unravelling another function for CALCOCO2 in cell autonomous defense against pathogens: CALCOCO2 not only targets pathogens to phagophore membranes, but also regulates subsequent maturation of pathogen-containing autophagosomes, thus assuring efficient degradation of autophagy-targeted pathogens. 相似文献
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Marieke H. van der Linden Lidija Seslija Pauline Schneider Emma M. C. Driessen Patricia Garrido Castro Dominique J. P. M. Stumpel Eddy van Roon Jasper de Boer Owen Williams Rob Pieters Ronald W. Stam 《PloS one》2015,10(3)
Introduction
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions.Methods
For this, we performed gene expression profiling after siRNA-mediated repression of MLL-AF4, MLL-ENL, and AF4-MLL in MLL-rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples.Results
Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples.Conclusion
We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias. 相似文献117.
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Background
Patients with bipolar disorder experience cognitive and emotional impairment that may persist even during the euthymic state of the disease. These persistent symptoms in bipolar patients (BP) may be characterized by disturbances of emotion regulation and related fronto-limbic brain circuitry. The present study aims to investigate the modulation of fronto-limbic activity and connectivity in BP by the processing of emotional conflict.Methods
Fourteen euthymic BP and 13 matched healthy subjects (HS) underwent functional magnetic resonance imaging (fMRI) while performing a word-face emotional Stroop task designed to dissociate the monitoring/generation of emotional conflict from its resolution. Functional connectivity was determined by means of psychophysiological interaction (PPI) approach.Results
Relative to HS, BP were slower to process incongruent stimuli, reflecting higher amount of behavioral interference during emotional Stroop. Furthermore, BP showed decreased activation of the right dorsolateral prefrontal cortex (DLPFC) during the monitoring and a lack of bilateral amygdala deactivation during the resolution of the emotional conflict. In addition, during conflict monitoring, BP showed abnormal positive connectivity between the right DLPFC and several regions of the default mode network.Conclusions
Overall, our results highlighted dysfunctional processing of the emotion conflict in euthymic BP that may be subtended by abnormal activity and connectivity of the DLPFC during the conflict monitoring, which, in turn, leads to failure of amygdala deactivation during the resolution of the conflict. Emotional dysregulation in BP may be underpinned by a lack of top-down cognitive control and a difficulty to focus on the task due to persistent self-oriented attention. 相似文献120.
Pauline Rival Maximilian O. Press Jacob Bale Tanya Grancharova Soledad F. Undurraga Christine Queitsch 《Genetics》2014,198(2):747-754
It is widely appreciated that short tandem repeat (STR) variation underlies substantial phenotypic variation in organisms. Some propose that the high mutation rates of STRs in functional genomic regions facilitate evolutionary adaptation. Despite their high mutation rate, some STRs show little to no variation in populations. One such STR occurs in the Arabidopsis thaliana gene PFT1 (MED25), where it encodes an interrupted polyglutamine tract. Although the PFT1 STR is large (∼270 bp), and thus expected to be extremely variable, it shows only minuscule variation across A. thaliana strains. We hypothesized that the PFT1 STR is under selective constraint, due to previously undescribed roles in PFT1 function. We investigated this hypothesis using plants expressing transgenic PFT1 constructs with either an endogenous STR or synthetic STRs of varying length. Transgenic plants carrying the endogenous PFT1 STR generally performed best in complementing a pft1 null mutant across adult PFT1-dependent traits. In stark contrast, transgenic plants carrying a PFT1 transgene lacking the STR phenocopied a pft1 loss-of-function mutant for flowering time phenotypes and were generally hypomorphic for other traits, establishing the functional importance of this domain. Transgenic plants carrying various synthetic constructs occupied the phenotypic space between wild-type and pft1 loss-of-function mutants. By varying PFT1 STR length, we discovered that PFT1 can act as either an activator or repressor of flowering in a photoperiod-dependent manner. We conclude that the PFT1 STR is constrained to its approximate wild-type length by its various functional requirements. Our study implies that there is strong selection on STRs not only to generate allelic diversity, but also to maintain certain lengths pursuant to optimal molecular function. 相似文献