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91.
Daniela Rossi Mariangela Urbano Alice Pedrali Massimo Serra Daniele Zampieri Maria Grazia Mamolo Christian Laggner Caterina Zanette Chiara Florio Dirk Schepmann Bernard Wuensch Ornella Azzolina Simona Collina 《Bioorganic & medicinal chemistry》2010,18(3):1204-1212
In order to investigate the molecular features involved in sigma receptors (σ-Rs) binding, new compounds based on arylalkylaminoalcoholic, arylalkenyl- and arylalkylaminic scaffolds were synthesized and their affinity towards σ1- and σ2-Rs subtypes was evaluated. The most promising compounds were also screened for their affinity at μ-opioid, δ-opioid and κ-opioid receptors. Biological results are herein presented and discussed. 相似文献
92.
da Silva LM Galbiatti AL Ruiz MT Raposo LS Maniglia JV Pavarino EC Goloni-Bertollo EM 《Molecular biology reports》2012,39(2):887-893
Alterations in folate metabolism may contribute to the process of carcinogenesis by influencing DNA methylation and genomic
stability. Polymorphisms in genes encoding enzymes involved in this pathway may alter enzyme activity and consequently interfere
in concentrations of homocysteine and S-adenosylmethionine that are important for DNA synthesis and cellular methylation reactions.
The objectives were to investigate MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms involved in folate metabolism on head and neck cancer risk and the association between these polymorphisms
with risk factors. Polymorphisms were investigated in 762 individuals (272 patients and 490 controls) by polymerase chain
reaction–restriction fragment length polymorphism (PCR–RFLP) and Real Time-PCR. Chi-square and Multiple logistic regression
were used for the statistical analysis. Multiple logistic regression showed that tobacco and male gender were predictors for
the disease (P < 0.05). Hardy–Weinberg equilibrium showed that the genotypic distributions were in equilibrium for both groups in all polymorphisms
studied. The BHMT 742GA or AA genotypes associated with tobacco consumption (P = 0.016) increase the risk for head and neck squamous cell carcinoma (HNSCC). The present study suggests that BHMT 742GA polymorphism associated to tobacco modulate HNSCC risk. However, further investigation of gene–gene interactions in
folate metabolism and studies in different populations are needed to investigate polymorphisms and HNSCC risk. 相似文献
93.
Cláudio de Oliveira Cunha Luiz Fernando Goda Zuleta Luiz Gonzaga Paula de Almeida Luciane Prioli Ciapina Wardsson Lustrino Borges Rosa Maria Pitard José Ivo Baldani Rosangela Straliotto Sérgio Miana de Faria Mariangela Hungria Benildo Sousa Cavada Fábio Martins Mercante Ana Tereza Ribeiro de Vasconcelos 《Journal of bacteriology》2012,194(23):6675-6676
The genus Burkholderia represents a challenge to the fields of taxonomy and phylogeny and, especially, to the understanding of the contrasting roles as either opportunistic pathogens or bacteria with biotechnological potential. Few genomes of nonpathogenic strains, especially of diazotrophic symbiotic bacteria, have been sequenced to improve understanding of the genus. Here, we contribute with the complete genome sequence of Burkholderia phenoliruptrix strain BR3459a (CLA1), an effective diazotrophic symbiont of the leguminous tree Mimosa flocculosa Burkart, which is endemic to South America. 相似文献
94.
Mariangela Urbano Miguel Guerrero Jian Zhao Subash Velaparthi S. Adrian Saldanha Peter Chase Zhiwei Wang Olivier Civelli Peter Hodder Marie-Therese Schaeffer Steven Brown Hugh Rosen Edward Roberts 《Bioorganic & medicinal chemistry letters》2012,22(23):7135-7141
Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure–activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders. 相似文献
95.
Crescioli C Sottili M Bonini P Cosmi L Chiarugi P Romagnani P Vannelli GB Colletti M Isidori AM Serio M Lenzi A Di Luigi L 《European journal of cell biology》2012,91(2):139-149
Inflammatory myopathies (IMs) are systemic diseases characterized by a T helper (Th) 1 type inflammatory response and cell infiltrates within skeletal muscles. The mainstay of treatment is drugs aimed at suppressing the immune system - corticosteroids and immunosuppressants. About 25% of patients are non-responders. Skeletal muscle cells seem actively involved in the immune-inflammatory response and not only a target; understanding the molecular bases of IMs might help drug development strategies. Within muscles the interaction between the chemokine interferon (IFN)γ inducible 10 kDa protein, CXCL10 or IP-10, and its specific receptor CXCR3, present on Th1 type infiltrating cells, likely plays a pivotal role, potentially offering the opportunity for therapeutic intervention. We aimed to clarify the involvement of human skeletal muscle cells in inflammatory processes in terms of CXCL10 secretion, to elucidate the engaged molecular mechanism(s) and, finally, to evaluate muscular cell responses, if any, to some immunosuppressants routinely used in IM treatment, such as methylprednisolone, methotrexate, cyclosporin A and Infliximab. We first isolated and characterized human fetal skeletal muscle cells (Hfsmc), which expressed the specific lineage markers and showed the competence to react in the context of an in vitro alloresponse. CXCL10 protein secretion by Hfsmc was similarly induced by the inflammatory cytokines interferon (IFN)γ and tumor necrosis factor (TNF)α, above undetectable control levels, through the activation of Stat1 and NF-kB pathways, respectively; CXCL10 secretion was significantly magnified by cytokine combination, and this synergy was associated to a significant up-regulation of TNFαRII; cytokine-induced CXCL10 secretion was considerably affected only by Infliximab. Our data suggested that human skeletal muscle cells might actively self-promote muscular inflammation by eliciting CXCL10 secretion, which is known to amplify Th1 cell tissue infiltration in vivo. In conclusion, we sustain that pharmacological targeting of CXCL10 within muscular cells might contribute to keep in control pro-Th1 polarization of the immune/inflammatory response. 相似文献
96.
97.
98.
Natalicchio A De Stefano F Perrini S Laviola L Cignarelli A Caccioppoli C Quagliara A Melchiorre M Leonardini A Conserva A Giorgino F 《American journal of physiology. Endocrinology and metabolism》2009,296(2):E228-E237
The p66(Shc) protein isoform regulates MAP kinase activity and the actin cytoskeleton turnover, which are both required for normal glucose transport responses. To investigate the role of p66(Shc) in glucose transport regulation in skeletal muscle cells, L6 myoblasts with antisense-mediated reduction (L6/p66(Shc)as) or adenovirus-mediated overexpression (L6/p66(Shc)adv) of the p66(Shc) protein were examined. L6/(Shc)as myoblasts showed constitutive activation of ERK-1/2 and disruption of the actin network, associated with an 11-fold increase in basal glucose transport. GLUT1 and GLUT3 transporter proteins were sevenfold and fourfold more abundant, respectively, and were localized throughout the cytoplasm. Conversely, in L6 myoblasts overexpressing p66(Shc), basal glucose uptake rates were reduced by 30% in parallel with a approximately 50% reduction in total GLUT1 and GLUT3 transporter levels. Inhibition of the increased ERK-1/2 activity with PD98059 in L6/(Shc)as cells had a minimal effect on increased GLUT1 and GLUT3 protein levels, but restored the actin cytoskeleton, and reduced the abnormally high basal glucose uptake by 70%. In conclusion, p66(Shc) appears to regulate the glucose transport system in skeletal muscle myoblasts by controlling, via MAP kinase, the integrity of the actin cytoskeleton and by modulating cellular expression of GLUT1 and GLUT3 transporter proteins via ERK-independent pathways. 相似文献
99.
100.
We examined the role of G proteins in modulating the response of living cells to receptor activation. The response of an effector, phospholipase C-β to M3 muscarinic receptor activation was measured using sensors that detect the generation of inositol triphosphate or diacylglycerol. The recently discovered translocation of Gβγ from plasma membrane to endomembranes on receptor activation attenuated this response. A FRET based G protein sensor suggested that in contrast to translocating Gβγ, non-translocating Gβγ subunits do not dissociate from the αq subunit on receptor activation leading to prolonged retention of the heterotrimer state and an accentuated response. M3 receptors with tethered αq induced differential responses to receptor activation in cells with or without an endogenous translocation capable γ subunit. G protein heterotrimer dissociation and βγ translocation are thus unanticipated modulators of the intensity of a cell''s response to an extracellular signal. 相似文献