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101.
V Granatiero V Giorgio T Calì M Patron M Brini P Bernardi V Tiranti M Zeviani G Pallafacchina D De Stefani R Rizzuto 《Cell death and differentiation》2016,23(2):231-241
Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear- and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A>G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A>G cells. This is due to a specific downregulation of mitochondrial Ca2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient.Mitochondrial disorders include a wide range of pathological conditions characterized by defects in organelle homoeostasis and energy metabolism, in particular in the electron transport chain (ETC) complexes. They are mostly caused by mutations in nuclear- or mtDNA-encoded genes of the respiratory chain complexes leading to a variety of clinical manifestations, ranging from lesions in specific tissues, such as in Leber''s hereditary optic neuropathy, to complex multisystem syndromes, such as myoclonic epilepsy with ragged-red fibers, Leigh syndrome or the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS).1, 2 Despite the detailed knowledge of the molecular defects in these diseases, their pathogenesis remains poorly understood. The heterogeneity of signs and symptoms depends on the diversity of the genetic background and on patient-specific compensatory mechanisms. Several studies investigated the consequences of nuclear DNA mutations on intracellular organelle physiology and Ca2+ homeostasis.3, 4 Here we analyzed a cohort of patients with mutations in the mtDNA-encoded ND5 subunit of NADH dehydrogenase in order to correlate the clinical phenotype with relevant intracellular parameters involved in mitochondrial physiology, such as the rate of autophagy and mitophagy fluxes, mitochondrial Ca2+ dynamics, mitochondrial membrane potential and their functional relationship.Mitochondrial Ca2+ is a key regulator of organelle physiology, and impairment of cation homeostasis is a general feature of many pathological conditions, including mitochondrial diseases.5 In addition, Ca2+ uptake in this organelle has recently been demonstrated to be a fundamental regulator of autophagy.6, 7 Autophagy is involved in physiological organelle turnover and in the removal of damaged or non-functional mitochondria by autophagy (called ‘mitophagy'')8, 9, 10, 11 and is critical for organelle quality control. Given the pivotal role of mitochondrial Ca2+ in the adaptation of adenosine triphosphate (ATP) production to cellular energy demand, the recent identification of the channel responsible for Ca2+ entry into the organelle, the mitochondrial Ca2+ uniporter (MCU), is instrumental for the understanding of the regulation of mitochondrial Ca2+ transport in both physiological and pathological conditions. MCU was identified in 2011,12, 13 and in the following years, molecular insight on its complex regulatory mechanism was obtained. The pore region is composed of MCU, its isoform MCUb14 and essential MCU regulator (EMRE).15 The channel is gated by the Ca2+-sensitive proteins mitochondrial Ca2+ uptake 1 (MICU1) and MICU216, 17, 18, 19 and further regulated by the SLC25A23 protein.20 As to its cellular function, mitochondrial Ca2+ has been shown to stimulate ATP production by positive regulation of three key dehydrogenases of the tricarboxylic acid cycle21 and of the ETC.22 In parallel, unregulated and sustained organelle Ca2+ overload can also lead to the opening of the mitochondrial permeability transition pore,23, 24 with consequent dissipation of mitochondrial membrane potential (ΔΨmt), release of caspase cofactors and activation of the apoptotic cascade.5 Despite the significant molecular understanding of all these cellular processes, their role in the pathogenesis of mitochondrial diseases is still poorly understood. Here we investigated the interplay of these pathways and the possibility of their contribution to determine the severity of the pathology in a cellular model consisting of fibroblasts from patients carrying mutations in the mitochondrial ND5 gene. 相似文献
102.
Elaborate cognitive skills arose independently in different taxonomic groups. Self-recognition is conventionally identified by the understanding that one’s own mirror reflection does not represent another individual but oneself, which has never been proven in any elasmobranch species to date. Manta rays have a high encephalization quotient, similar to those species that have passed the mirror self-recognition test, and possess the largest brain of all fish species. In this study, mirror exposure experiments were conducted on two captive giant manta rays to document their response to their mirror image. The manta rays did not show signs of social interaction with their mirror image. However, frequent unusual and repetitive movements in front of the mirror suggested contingency checking; in addition, unusual self-directed behaviors could be identified when the manta rays were exposed to the mirror. The present study shows evidence for behavioral responses to a mirror that are prerequisite of self-awareness and which has been used to confirm self-recognition in apes. 相似文献
103.
Mark Agostino Ricardo L. Mancera Paul A. Ramsland Juan Fernández‐Recio 《Journal of molecular recognition : JMR》2016,29(11):555-568
The antibody crystallizable fragment (Fc) is recognized by effector proteins as part of the immune system. Pathogens produce proteins that bind Fc in order to subvert or evade the immune response. The structural characterization of the determinants of Fc–protein association is essential to improve our understanding of the immune system at the molecular level and to develop new therapeutic agents. Furthermore, Fc‐binding peptides and proteins are frequently used to purify therapeutic antibodies. Although several structures of Fc–protein complexes are available, numerous others have not yet been determined. Protein–protein docking could be used to investigate Fc–protein complexes; however, improved approaches are necessary to efficiently model such cases. In this study, a docking‐based structural bioinformatics approach is developed for predicting the structures of Fc–protein complexes. Based on the available set of X‐ray structures of Fc–protein complexes, three regions of the Fc, loosely corresponding to three turns within the structure, were defined as containing the essential features for protein recognition and used as restraints to filter the initial docking search. Rescoring the filtered poses with an optimal scoring strategy provided a success rate of approximately 80% of the test cases examined within the top ranked 20 poses, compared to approximately 20% by the initial unrestrained docking. The developed docking protocol provides a significant improvement over the initial unrestrained docking and will be valuable for predicting the structures of currently undetermined Fc–protein complexes, as well as in the design of peptides and proteins that target Fc. 相似文献
104.
105.
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance 总被引:16,自引:0,他引:16
McCubrey JA Steelman LS Chappell WH Abrams SL Wong EW Chang F Lehmann B Terrian DM Milella M Tafuri A Stivala F Libra M Basecke J Evangelisti C Martelli AM Franklin RA 《Biochimica et biophysica acta》2007,1773(8):1263-1284
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors. 相似文献
106.
107.
M Bucciantini P Chiarugi P Cirri L Taddei M Stefani G Raugei P Nordlund G Ramponi 《FEBS letters》1999,456(1):73-78
The low molecular weight phosphotyrosine protein phosphatase (LMW-PTP) is phosphorylated by Src and Src-related kinases both in vitro and in vivo; in Jurkat cells, and in NIH-3T3 cells, it becomes tyrosine-phosphorylated upon stimulation by PDGF. In this study we show that pp60Src phosphorylates in vitro the enzyme at two tyrosine residues, Tyr131 and Tyr132, previously indicated as the main phosphorylation sites of the enzyme, whereas phosphorylation by the PDGF-R kinase is much less effective and not specific. The effects of LMW-PTP phosphorylation at each tyrosine residue were investigated by using Tyr131 and Tyr132 mutants. We found that the phosphorylation at either residue has differing effects on the enzyme behaviour: Tyr131 phosphorylation is followed by a strong (about 25-fold) increase of the enzyme specific activity, whereas phosphorylation at Tyr132 leads to Grb2 recruitment. These differing effects are discussed on the light of the enzyme structure. 相似文献
108.
Angela Privitera Giancarlo Rappazzo Paola Sangari Viviana Gianninò Lidia Licciardello Stefania Stefani 《FEMS microbiology letters》1998,164(2):289-294
A 16S/23S ribosomal spacer from a Haemophilus parainfluenzae rrn locus was cloned and sequenced. Analysis of PCR-amplified genomic fragments showed that this region is strongly conserved among unrelated isolates; computer analysis of database homologies showed that the spacer consists of sequence blocks, arranged in a mosaic-like structure, with strong homologies with analogous blocks present in the spacer regions of Haemophilus influenzae, Haemophilus ducreyi and Actinobacillus spp. It also contains a tRNAGlu gene, which is highly homologous to tRNAGlu genes found in spacers of other species. These data strongly support the hypothesis that recombination events are involved in the organisation of the sequence of the spacer, as a result of horizontal gene transfer. 相似文献
109.
110.
Andrea Sacconi Claudia De Vitis Luisa de Latouliere Simona di Martino Francesca De Nicola Frauke Goeman Carla Mottini Francesca Paolini Michela DAscanio Alberto Ricci Agostino Tafuri Paolo Marchetti Arianna Di Napoli Luciano De Biase Andrea Negro Christian Napoli Paolo Anibaldi Valentina Salvati Darragh Duffy Benjamin Terrier Maurizio Fanciulli Carlo Capalbo Salvatore Sciacchitano Giovanni Blandino Giulia Piaggio Rita Mancini Gennaro Ciliberto 《Cell death & disease》2021,12(11)