全文获取类型
收费全文 | 3693篇 |
免费 | 252篇 |
专业分类
3945篇 |
出版年
2024年 | 1篇 |
2023年 | 19篇 |
2022年 | 49篇 |
2021年 | 86篇 |
2020年 | 56篇 |
2019年 | 68篇 |
2018年 | 100篇 |
2017年 | 70篇 |
2016年 | 128篇 |
2015年 | 189篇 |
2014年 | 205篇 |
2013年 | 289篇 |
2012年 | 329篇 |
2011年 | 294篇 |
2010年 | 187篇 |
2009年 | 167篇 |
2008年 | 280篇 |
2007年 | 235篇 |
2006年 | 231篇 |
2005年 | 219篇 |
2004年 | 169篇 |
2003年 | 176篇 |
2002年 | 140篇 |
2001年 | 34篇 |
2000年 | 22篇 |
1999年 | 24篇 |
1998年 | 30篇 |
1997年 | 24篇 |
1996年 | 23篇 |
1995年 | 17篇 |
1994年 | 14篇 |
1993年 | 11篇 |
1992年 | 11篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1978年 | 1篇 |
1973年 | 3篇 |
1972年 | 3篇 |
排序方式: 共有3945条查询结果,搜索用时 0 毫秒
81.
Irene Faravelli Megi Meneri Domenica Saccomanno Daniele Velardo Elena Abati Delia Gagliardi Valeria Parente Lucia Petrozzi Dario Ronchi Nino Stocchetti Edoardo Calderini Grazia D’Angelo Giovanna Chidini Edi Prandi Giulia Ricci Gabriele Siciliano Nereo Bresolin Giacomo Pietro Comi Stefania Corti Francesca Magri Alessandra Govoni 《Journal of cellular and molecular medicine》2020,24(5):3034-3039
The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response. 相似文献
82.
Maria Stio Alessandra Celli Cristina Treves 《The Journal of steroid biochemistry and molecular biology》2001,77(4-5):213-222
This study examines the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], two vitamin D analogues (KH 1060 and EB 1089, which are 20-epi-22-oxa and 22,24-diene-analogues, respectively), 9-cis retinoic acid and all-trans retinoic acid on proliferation of SH-SY5Y human neuroblastoma cells, after treatment for 7 days. Cell number did not change when the cells were incubated with 1, 10 or 100 nM 1,25(OH)2D3 or its derivatives, but significantly decreased in the presence of the two retinoids (0.001–10 μM final concentration). A synergistic inhibition was observed, when SH-SY5Y cells were treated combining 0.1 μM 9-cis retinoic acid and 10 nM 1,25(OH)2D3 or 10 nM KH 1060, and 1 μM 9-cis retinoic acid and 10 nM 1,25(OH)2D3 or 10 nM EB 1089. Acetylcholinesterase activity showed a significant increase, in comparison with controls, after treatment of the cells for 7 days with 0.1 or 1 μM 9-cis retinoic acid, alone or combined with 10 nM 1,25(OH)2D3 or 10 nM KH 1060 or 10 nM EB 1089. This increase was synergistic, combining 1 μM 9-cis retinoic acid and 10 nM 1,25(OH)2D3 or EB 1089. The levels of the c-myc encoded protein remarkably decreased after treatment of SH-SY5Y cells for 1, 3, 7 days with 0.1 and 1 μM 9-cis retinoic acid, alone or combined with 10 nM 1,25(OH)2D3 or 10 nM KH 1060 or 10 nM EB 1089. In particular, the association of 1 μM 9-cis retinoic acid and 10 nM 1,25(OH)2D3 or 10 nM EB 1089 resulted in a synergistic c-myc inhibition, in comparison with that obtained in the presence of the retinoid alone. These findings may have therapeutic implications in human neuroblastoma. 相似文献
83.
84.
85.
86.
In vitro import assays have shown that the thylakoid twin-arginine translocase (Tat) system transports folded proteins in a unidirectional manner. Here, we expressed a natural substrate, pre-23K, and a 23K presequence-green fluorescent protein (GFP) chimera in vivo in tobacco protoplasts. Both are imported into chloroplasts, targeted to the thylakoids, and processed to the mature size by the lumen-facing processing peptidase. However, the vast majority of mature GFP and about half of the 23K are then returned to the stroma. Mutations in the twin-arginine motif block thylakoid targeting and maturation, confirming an involvement of the Tat apparatus. Mutation of the processing site yields membrane-associated intermediate-size protein in vivo, indicating a delayed reversal of translocation to the stroma and suggesting a longer lived interaction with the Tat machinery. We conclude that, in vivo, the Tat system can reject substrates at a late stage in translocation and on a very large scale, indicating the influence of factors that are absent in reconstitution assays. 相似文献
87.
Francesca Ripamonti Luisa Albano Anna Rossini Serena Borrelli Sonia Fabris Roberto Mantovani Antonino Neri Andrea Balsari Alessandra Magnifico Elda Tagliabue 《Journal of cellular physiology》2013,228(4):871-878
Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR–ΔNp63α axis in proliferation of SCC tumor‐initiating cells (TICs). SCC cell lines A‐431, Cal‐27, and SCC‐25 treated with EGF showed a time‐dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non‐differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non‐differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR–ΔNp63α axis is crucial for proliferation of TICs present in SCCs. J. Cell. Physiol. 228: 871–878, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
88.
Blanda Di Luccia Nicola Manzo Loredana Baccigalupi Viola Calabrò Elvira Crescenzi Ezio Ricca Alessandra Pollice 《PloS one》2013,8(7)
It is now commonly accepted that the intestinal microbiota plays a crucial role in the gut physiology and homeostasis, and that both qualitative and quantitative alterations in the compositions of the gut flora exert profound effects on the host’s intestinal cells. In spite of this, the details of the interaction between commensal bacteria and intestinal cells are still largely unknown and only in few cases the molecular mechanisms have been elucidated. Here we analyze the effects of molecules produced and secreted by Lactobacillus gasseri SF1183 on human intestinal HCT116 cells. L. gasseri is a well known species of lactic acid bacteria, commonly associated to the human intestine and SF1183 is a human strain previously isolated from an ileal biopsy of an healthy volunteer. SF1183 produces and secretes, in a growth phase-dependent way, molecule(s) able to drastically interfere with HCT116 cell proliferation. Although several attempts to purify and identify the bioactive molecule(s) have been so far unsuccessful, a partial characterization has indicated that it is smaller than 3 kDa, thermostable and of proteinaceous nature. L. gasseri molecule(s) stimulate a G1-phase arrest of the cell cycle by up-regulation of p21WAF1 rendering cells protected from intrinsic and extrinsic apoptosis. A L. gasseri-mediated reduction of apoptosis and of cell proliferation could be relevant in protecting epithelial barrier integrity and helping in reconstituting tissutal homeostasis. 相似文献
89.
Capone S Zampaglione I Vitelli A Pezzanera M Kierstead L Burns J Ruggeri L Arcuri M Cappelletti M Meola A Ercole BB Tafi R Santini C Luzzago A Fu TM Colloca S Ciliberto G Cortese R Nicosia A Fattori E Folgori A 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(10):7462-7471
Induction of multispecific, functional CD4+ and CD8+ T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4+ and CD8+ cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN-gamma ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4+ T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-gamma+CD8+ and CD4+ T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV. 相似文献
90.
Giuseppe Puddu Luigi Maiorano Alessandra Falcucci Fabio Corsi Luigi Boitani 《Biodiversity and Conservation》2009,18(8):2001-2016
The Corsican red deer, a sub-species of the European red deer endemic to Sardinia and Corsica, was abundant on both islands
at the beginning of 1900. It went extinct in Corsica and reached a minimum of 100 individuals in Sardinia by 1970. Numbers
have recovered in Sardinia with more than 1,000 rutting males now present; in the 1980s the deer was reintroduced to Corsica,
but the Sardinian population remains fragmented. We developed a potential distribution model in Sardinia using Ecological
Niche Factor Analysis. To assess the deer’s protection status we compared the model with the existing and proposed conservation
areas and investigated different conservation scenarios in relation to the expansion of its current range and resilience to
future changes in land use and predicted trends of desertification. According to our results over 70% of Sardinia is unsuitable
to the deer, nevertheless high suitability areas (Mediterranean forests away from main roads) are available throughout the
island, particularly in the south and in the central-eastern part. Existing protected areas do not provide for the conservation
of the deer but public owned forests, where hunting is prohibited, extend some level of protection, and the protected areas
proposed by the Regional administration, if implemented, will be increasing this protection. Three main areas have emerged
as conservation priorities to guarantee adequate conservation potential in the future. Our approach provides valuable data
to inform conservation policy, and could be easily replicated in other parts of the Mediterranean. 相似文献