全文获取类型
收费全文 | 2243篇 |
免费 | 143篇 |
专业分类
2386篇 |
出版年
2023年 | 7篇 |
2022年 | 23篇 |
2021年 | 45篇 |
2020年 | 28篇 |
2019年 | 37篇 |
2018年 | 55篇 |
2017年 | 27篇 |
2016年 | 70篇 |
2015年 | 101篇 |
2014年 | 101篇 |
2013年 | 168篇 |
2012年 | 189篇 |
2011年 | 172篇 |
2010年 | 96篇 |
2009年 | 93篇 |
2008年 | 144篇 |
2007年 | 133篇 |
2006年 | 130篇 |
2005年 | 104篇 |
2004年 | 111篇 |
2003年 | 98篇 |
2002年 | 88篇 |
2001年 | 24篇 |
2000年 | 12篇 |
1999年 | 16篇 |
1998年 | 31篇 |
1997年 | 17篇 |
1996年 | 21篇 |
1995年 | 14篇 |
1994年 | 20篇 |
1993年 | 25篇 |
1992年 | 16篇 |
1991年 | 13篇 |
1990年 | 22篇 |
1989年 | 7篇 |
1988年 | 10篇 |
1987年 | 8篇 |
1986年 | 4篇 |
1985年 | 18篇 |
1984年 | 9篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1981年 | 15篇 |
1980年 | 9篇 |
1979年 | 10篇 |
1978年 | 7篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1968年 | 2篇 |
排序方式: 共有2386条查询结果,搜索用时 0 毫秒
131.
Adriana Simionescu-Bankston Giovanna Leoni Yanru Wang Peter P. Pham Arivudainambi Ramalingam James B. DuHadaway Victor Faundez Asma Nusrat George C. Prendergast Grace K. Pavlath 《Developmental biology》2013
Actin dynamics are necessary at multiple steps in the formation of multinucleated muscle cells. BAR domain proteins can regulate actin dynamics in several cell types, but have been little studied in skeletal muscle. Here, we identify novel functions for the N-BAR domain protein, Bridging integrator 3 (Bin3), during myogenesis in mice. Bin3 plays an important role in regulating myofiber size in vitro and in vivo. During early myogenesis, Bin3 promotes migration of differentiated muscle cells, where it colocalizes with F-actin in lamellipodia. In addition, Bin3 forms a complex with Rac1 and Cdc42, Rho GTPases involved in actin polymerization, which are known to be essential for myotube formation. Importantly, a Bin3-dependent pathway is a major regulator of Rac1 and Cdc42 activity in differentiated muscle cells. Overall, these data classify N-BAR domain proteins as novel regulators of actin-dependent processes in myogenesis, and further implicate BAR domain proteins in muscle growth and repair. 相似文献
132.
Matteo Nadai Giovanna Sattin Giorgio Palù Manlio Palumbo Sara N. Richter 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
G-quadruplexes are polymorphic non-canonical nucleic acid conformations involved both in physiological and pathological processes. Given the high degree of folding heterogeneity and comparable conformational stabilities, different G-quadruplex forms can occur simultaneously, hence rendering the use of basic instrumental methods for structure determination, like X-ray diffraction or NMR, hardly useful. Footprinting techniques represent valuable and relatively rapid alternative to characterize DNA folding. The natural diterpenoid clerocidin is an alkylating agent that specifically reacts at single-stranded DNA regions, with different mechanisms depending on the exposed nucleotide.Methods
Clerocidin was used to footprint G-quadruplex structures formed by telomeric and oncogene promoter sequences (c-myc, bcl-2, c-kit2), and by the thrombin binding aptamer.Results
The easy modulability of CL reactivity towards DNA bases permitted to discriminate fully and partially protected sites, highlights stretched portions of the G-quadruplex conformation, and discriminate among topologies adopted by one sequence in different environmental conditions. Importantly, CL displayed the unique property to allow detection of G-quadruplex folding within a duplex context.Conclusions
CL is a finely performing new tool to unveil G-quadruplex arrangements in DNA sequences under genomically relevant conditions.General significance
Nucleic acid G-quadruplex structures are an emerging research field because of the recent indication of their involvement in a series of key biological functions, in particular in regulation of proliferation-associated gene expression. The use of clerocidin as footprinting agent to identify G-quadruplex structures under genomically relevant conditions may allow detection of new G-quadruplex-based regulatory regions. 相似文献133.
Maria Eugenia Carlotti Elena Ugazio Simona Sapino Ivana Fenoglio Giovanna Greco Bice Fubini 《Free radical research》2013,47(3):312-322
TiO2 nanoparticles hazard is associated to their photocatalytic activity causing release of DNA damaging ROS (Reactive Oxygen Species), lipid peroxidation and skin damage. Various coatings have been proposed to minimize photocatalysis, while keeping the potential to block UV radiations. Uncoated and variously coated commercial nano-titania have been classified on the basis of UVB-induced lipoperoxidation of linoleic acid. A selection of the most and the least protective specimens was then examined by ESR (Electron Spin Resonance) to evidence the presence of surface paramagnetic centres and the release of ROS in aqueous suspensions (spin trapping). Paramagnetic centres and ROS were correlated with the extent of lipid peroxidation. When tested on porcine skin (mimicking the human one), titania acted as on linoleic acid. The combined use of lipid peroxidation of simple fatty acids with ESR analysis is here proposed as a possible screening tool for the evaluation of the potential toxicity of nano-titania in sunscreen preparations. 相似文献
134.
Abstract The genus Allium L. in Italy. IV. A DNA cytophotometric study on the pollen grain of Allium chamaemoly L. — A cytophotometric analysis of DNA contents in pollen generative and vegetative nuclei of Allium chamaemoly L. was carried out. DNA synthesis in both nuclei was confirmed and a lightly higher DNA amount than 2C in the vegetative nucleus was pointed out. An analysis of the Fast-green stainable histones in the generative and vegetative nuclei was also accomplished. While the generative nucleus had a very high content of Fast-green stainable histone, the vegetative one have nearly no stainable histone. The occurrence of DNA synthesis and the very low histone content suggest the vegetative nucleus is functional and biochemically activ. The higher than 2C DNA content supports the possibility of a DNA amplification process including probably the amplification of ribosomal cistrons in the pollen vegetative nucleus. 相似文献
135.
Rappocciolo G Jenkins FJ Hensler HR Piazza P Jais M Borowski L Watkins SC Rinaldo CR 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(3):1741-1749
Human herpesvirus 8 (HHV-8) causes Kaposi's sarcoma and pleural effusion lymphoma. In this study, we show that dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN; CD209) is a receptor for HHV-8 infection of myeloid DCs and macrophages. DC-SIGN was required for virus attachment to these cells and DC-SIGN-expressing cell lines. HHV-8 binding and infection were blocked by anti-DC-SIGN mAb and soluble DC-SIGN, and mannan, a natural ligand for DC-SIGN. Infection of DCs and macrophages with HHV-8 led to production of viral proteins, with little production of viral DNA, similar to HHV-8 infection of vascular endothelial cells. Infection of DCs resulted in down-regulation of DC-SIGN, a decrease in endocytic activity, and an inhibition of Ag stimulation of CD8+ T cells. We propose that DC-SIGN serves as a portal for immune dysfunction and oncogenesis caused by HHV-8 infection. 相似文献
136.
137.
Delgado S Castillo Neyra R Quispe Machaca VR Ancca Juárez J Chou Chu L Verastegui MR Moscoso Apaza GM Bocángel CD Tustin AW Sterling CR Comrie AC Náquira C Cornejo del Carpio JG Gilman RH Bern C Levy MZ 《PLoS neglected tropical diseases》2011,5(2):e970
Background
The history of Chagas disease control in Peru and many other nations is marked by scattered and poorly documented vector control campaigns. The complexities of human migration and sporadic control campaigns complicate evaluation of the burden of Chagas disease and dynamics of Trypanosoma cruzi transmission.Methodology/Principal Findings
We conducted a cross-sectional serological and entomological study to evaluate temporal and spatial patterns of T. cruzi transmission in a peri-rural region of La Joya, Peru. We use a multivariate catalytic model and Bayesian methods to estimate incidence of infection over time and thereby elucidate the complex history of transmission in the area. Of 1,333 study participants, 101 (7.6%; 95% CI: 6.2–9.0%) were confirmed T. cruzi seropositive. Spatial clustering of parasitic infection was found in vector insects, but not in human cases. Expanded catalytic models suggest that transmission was interrupted in the study area in 1996 (95% credible interval: 1991–2000), with a resultant decline in the average annual incidence of infection from 0.9% (95% credible interval: 0.6–1.3%) to 0.1% (95% credible interval: 0.005–0.3%). Through a search of archival newspaper reports, we uncovered documentation of a 1995 vector control campaign, and thereby independently validated the model estimates.Conclusions/Significance
High levels of T. cruzi transmission had been ongoing in peri-rural La Joya prior to interruption of parasite transmission through a little-documented vector control campaign in 1995. Despite the efficacy of the 1995 control campaign, T. cruzi was rapidly reemerging in vector populations in La Joya, emphasizing the need for continuing surveillance and control at the rural-urban interface. 相似文献138.
Santamaria R Fiorito F Irace C De Martino L Maffettone C Granato GE Di Pascale A Iovane V Pagnini U Colonna A 《Biochimica et biophysica acta》2011,1813(5):704-712
Cellular iron metabolism is essentially controlled by the binding of cytosolic iron regulatory proteins (IRP1 or IRP2) to iron-responsive elements (IREs) located on mRNAs coding for proteins involved in iron acquisition, utilization and storage. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent toxins of current interest that occurs as poisonous chemical in the environment. TCDD exposure has been reported to induce a broad spectrum of toxic and biological responses, including significant changes in gene expression for heme and iron metabolism associated with liver injury. Here, we have investigated the molecular effects of TCDD on the iron metabolism providing the first evidence that administration of the toxin TCDD to mammalian cells affects the maintenance of iron homeostasis. We found that exposure of Madin-Darby Bovine Kidney cell to TCDD caused a divergent modulation of IRP1 and IRP2 RNA-binding capacity. Interestingly, we observed a concomitant IRP1 down-regulation and IRP2 up-regulation thus determining a marked enhancement of transferrin receptor 1 (TfR-1) expression and a biphasic response in ferritin content. The changed ferritin content coupled to TfR-1 induction after TCDD exposure impairs the cellular iron homeostasis, ultimately leading to significant changes in the labile iron pool (LIP) extent. Since important iron requirement changes occur during the regulation of cell growth, it is not surprising that the dioxin-dependent iron metabolism dysregulation herein described may be linked to cell-fate decision, supporting the hypothesis of a central connection among exposure to dioxins and the regulation of critical cellular processes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. 相似文献
139.
Guerrini G Ciciani G Cambi G Bruni F Selleri S Melani F Montali M Martini C Ghelardini C Norcini M Costanzo A 《Bioorganic & medicinal chemistry》2008,16(8):4471-4489
The synthesis and binding studies of a series of 3-acylpyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides 8-substituted are reported. High-affinity ligands at benzodiazepine site on GABA(A) receptor complex (GABA(A)/BzR complex) were obtained when the 3-aroyl substituent is represented by a five-member heteroaroyl ring (furoyl-, thenoyl-, and pyrroyl-). Moreover the type of heteroaroyl ring at position 3 influences the feature of the substituent at position 8 to obtain high-affinity ligands: a 'hydrogen-bond acceptor ring' at position 3 is synergic with an electron donor substituent at position 8, while a 'hydrogen-bond donor ring' is synergic with a withdrawing substituent. Compounds 8a, 9b, and 11 were deeply studied in vivo for their pharmacological effects considering six potential benzodiazepine actions: motor coordination, anticonvulsant action, spontaneous motor activity and explorative activity, anxiolytic-like effects, mouse learning and memory modulation, and ethanol-potentiating action. To rationalize and qualitatively interpret the GABA(A)/Bz binding affinities of compounds 8a and 11, a dynamic molecular modeling study has been performed, with the aim of assessing the preferred geometry of protein-ligand complex. 相似文献
140.
Samanta Pino Raffaele Saladino Giorgia Botta Giovanna Costanzo 《Journal of biomolecular structure & dynamics》2013,31(1):6-7
Our laboratories analyze the synthetic reactions leading from formamide, NH2COH to prebiotically relevant compounds in the presence of catalysts. We have described the formation of all the biological nucleic bases of carboxylic acids of two aminoacids, and of condensing agents in the presence of catalysts of terrestrial origin (Saladino et al., 2012) and of one meteorite. Heat-dependent synthetic reactions from NH2COH lead to the synthesis of acyclonucleosides, not (yet?) to that of nucleosides [hurdle # 1]. Nucleosides are phosphorylated in the presence of NH2COH and a phosphate source yielding cyclic nucleotides as well. (Costanzo et al., 2007). 3′,5′-cyclic GMP nonenzymatically polymerizes up to at least 25mers, as shown by PAGE, MALDI ToF, 31P-NMR, specific RNAse and inhibitors analyses (Costanzo et al., 2012).The reaction is stimulated by 1,8-diazabicycloundec-7-ene and dimethylformamide. 3′,5′-cUMP does not polymerize spontaneously [hurdle # 2], 3′,5′-cAMP polymerizes very poorly [hurdle # 3]. We will discuss data on the polymerization of 3′,5′-cCMP and on a ribozyme activity exerted by oligomers neosynthesized from cyclic nucleotides. This approach finds its larger perspective in the evolutionary scenario depicted by Trifonov (2009). 相似文献