全文获取类型
收费全文 | 921篇 |
免费 | 61篇 |
出版年
2023年 | 1篇 |
2022年 | 7篇 |
2021年 | 18篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 25篇 |
2017年 | 17篇 |
2016年 | 31篇 |
2015年 | 48篇 |
2014年 | 53篇 |
2013年 | 85篇 |
2012年 | 70篇 |
2011年 | 81篇 |
2010年 | 62篇 |
2009年 | 48篇 |
2008年 | 54篇 |
2007年 | 60篇 |
2006年 | 57篇 |
2005年 | 50篇 |
2004年 | 32篇 |
2003年 | 46篇 |
2002年 | 45篇 |
2001年 | 9篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 3篇 |
1997年 | 5篇 |
1996年 | 2篇 |
1995年 | 8篇 |
1994年 | 7篇 |
1993年 | 6篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1982年 | 2篇 |
1981年 | 1篇 |
排序方式: 共有982条查询结果,搜索用时 15 毫秒
171.
Francesca Megiorni Giovanni Luca Gravina Simona Camero Simona Ceccarelli Andrea Del Fattore Vincenzo Desiderio Federica Papaccio Heather P. McDowell Rajeev Shukla Antonio Pizzuti Filip Beirinckx Philippe Pujuguet Laurent Saniere Ellen Van der Aar Roberto Maggio Francesca De Felice Cinzia Marchese Carlo Dominici Vincenzo Tombolini Claudio Festuccia Francesco Marampon 《Journal of hematology & oncology》2017,10(1):161
Background
EPH (erythropoietin-producing hepatocellular) receptors are clinically relevant targets in several malignancies. This report describes the effects of GLPG1790, a new potent pan-EPH inhibitor, in human embryonal rhabdomyosarcoma (ERMS) cell lines.Methods
EPH-A2 and Ephrin-A1 mRNA expression was quantified by real-time PCR in 14 ERMS tumour samples and in normal skeletal muscle (NSM). GLPG1790 effects were tested in RD and TE671 cell lines, two in vitro models of ERMS, by performing flow cytometry analysis, Western blotting and immunofluorescence experiments. RNA interfering experiments were performed to assess the role of specific EPH receptors. Radiations were delivered using an x-6 MV photon linear accelerator. GLPG1790 (30 mg/kg) in vivo activity alone or in combination with irradiation (2 Gy) was determined in murine xenografts.Results
Our study showed, for the first time, a significant upregulation of EPH-A2 receptor and Ephrin-A1 ligand in ERMS primary biopsies in comparison to NSM. GLPG1790 in vitro induced G1-growth arrest as demonstrated by Rb, Cyclin A and Cyclin B1 decrease, as well as by p21 and p27 increment. GLPG1790 reduced migratory capacity and clonogenic potential of ERMS cells, prevented rhabdosphere formation and downregulated CD133, CXCR4 and Nanog stem cell markers. Drug treatment committed ERMS cells towards skeletal muscle differentiation by inducing a myogenic-like phenotype and increasing MYOD1, Myogenin and MyHC levels. Furthermore, GLPG1790 significantly radiosensitized ERMS cells by impairing the DNA double-strand break repair pathway. Silencing of both EPH-A2 and EPH-B2, two receptors preferentially targeted by GLPG1790, closely matched the effects of the EPH pharmacological inhibition. GLPG1790 and radiation combined treatments reduced tumour mass by 83% in mouse TE671 xenografts.Conclusions
Taken together, our data suggest that altered EPH signalling plays a key role in ERMS development and that its pharmacological inhibition might represent a potential therapeutic strategy to impair stemness and to rescue myogenic program in ERMS cells.172.
Crugnola Cristina Riva; Maggiolini Alfio; Caprin Claudia; Martini Cinzia De; Giudici Federica 《Dreaming》2008,18(3):201
This study examines the content of dreams of 10 to 11-year-old boys (n = 80) and girls (n = 102) gathered using the Most Recent Dream Method (Hartmann, Elkin, & Garg, 1991) and analyzed through the Hall and Van de Castle Method (1966; Domhoff, 1996). The study compares the dreams of the Italian sample with those of a normative adult sample and other research on the dreams of preadolescents of various countries (United States, Spain, and Switzerland). In the main it confirms the results of such preadolescent dream analysis research (Avila-White, Schneider, & Domhoff, 1999; Oberst, Charles, & Chamarro, 2005; Saline, 1999; Strauch & Lederbogen, 1999), highlighting in particular the importance of aggressive physical interaction in the participants under study. The data that emerge from dream analysis may be compared with the results of research into problems of aggression and transgression in boys and girls at this age (Achenbach & Rescorla, 2007). Dream analysis may represent a significant contribution to the study of preadolescence, allowing the characteristics and prevailing themes of preadolescents to be compared with those of participants from other age ranges. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
173.
Meschini S Condello M Calcabrini A Marra M Formisano G Lista P De Milito A Federici E Arancia G 《Autophagy》2008,4(8):1020-1033
In our previous studies, the bisindolic alkaloid voacamine (VOA), isolated from the plant Peschiera fuchsiaefolia, proved to exert a chemosensitizing effect on cultured multidrug resistant (MDR) osteosarcoma cells exposed to doxorubicin (DOX). In particular, VOA was capable of inhibiting P-glycoprotein action in a competitive way, thus explaining the enhancement of the cytotoxic effect induced by DOX on MDR cells. Afterwards, preliminary observations suggested that such an enhancement did not involve the apoptotic process but was due instead to the induction of autophagic cell death. The results of the present investigation demonstrate that the plant alkaloid VOA is an autophagy inducer able to exert apoptosis-independent cytotoxic effect on both wild-type and MDR tumor cells. In fact, under treatment condition causing about 50 percent of cell death, no evidence of apoptosis could be revealed by microscopical observations, Annexin V-FITC labeling and analysis of PARP cleavage, whereas the same cells underwent apoptosis when treated with apoptosis inducers, such as doxorubicin and staurosporine. Conversely, VOA-induced autophagy was clearly evidentiated by electron microscopy observations, monodansylcadaverine staining, LC3 expression, and conversion. These results were confirmed by the analysis of the modulating effects of the pretreatment with autophagy inhibitors prior to VOA administration. In addition, transfection of osteosarcoma cells with siRNA against ATG genes reduced VOA cytotoxicity. In conclusion, considering the very debated dual role of autophagy in cancer cells (protective or lethal, pro- or anti- apoptotic) our findings seem to demonstrate, at least in vitro, that a natural product able to induce autophagy can be effective against drug resistant tumors, either used alone or in association with conventional chemotherapeutics. 相似文献
174.
Exponential decline of deep-sea ecosystem functioning linked to benthic biodiversity loss 总被引:7,自引:0,他引:7
Danovaro R Gambi C Dell'Anno A Corinaldesi C Fraschetti S Vanreusel A Vincx M Gooday AJ 《Current biology : CB》2008,18(1):1-8
BACKGROUND: Recent investigations suggest that biodiversity loss might impair the functioning and sustainability of ecosystems. Although deep-sea ecosystems are the most extensive on Earth, represent the largest reservoir of biomass, and host a large proportion of undiscovered biodiversity, the data needed to evaluate the consequences of biodiversity loss on the ocean floor are completely lacking. RESULTS: Here, we present a global-scale study based on 116 deep-sea sites that relates benthic biodiversity to several independent indicators of ecosystem functioning and efficiency. We show that deep-sea ecosystem functioning is exponentially related to deep-sea biodiversity and that ecosystem efficiency is also exponentially linked to functional biodiversity. These results suggest that a higher biodiversity supports higher rates of ecosystem processes and an increased efficiency with which these processes are performed. The exponential relationships presented here, being consistent across a wide range of deep-sea ecosystems, suggest that mutually positive functional interactions (ecological facilitation) can be common in the largest biome of our biosphere. CONCLUSIONS: Our results suggest that a biodiversity loss in deep-sea ecosystems might be associated with exponential reductions of their functions. Because the deep sea plays a key role in ecological and biogeochemical processes at a global scale, this study provides scientific evidence that the conservation of deep-sea biodiversity is a priority for a sustainable functioning of the worlds' oceans. 相似文献
175.
Ferrari S Galletti R Pontiggia D Manfredini C Lionetti V Bellincampi D Cervone F De Lorenzo G 《Plant physiology》2008,146(2):669-681
Polygalacturonases (PGs), enzymes that hydrolyze the homogalacturonan of the plant cell wall, are virulence factors of several phytopathogenic fungi and bacteria. On the other hand, PGs may activate defense responses by releasing oligogalacturonides (OGs) perceived by the plant cell as host-associated molecular patterns. Tobacco (Nicotiana tabacum) and Arabidopsis (Arabidopsis thaliana) plants expressing a fungal PG (PG plants) have a reduced content of homogalacturonan. Here, we show that PG plants are more resistant to microbial pathogens and have constitutively activated defense responses. Interestingly, either in tobacco PG or wild-type plants treated with OGs, resistance to fungal infection is suppressed by exogenous auxin, whereas sensitivity to auxin of PG plants is reduced in different bioassays. The altered plant defense responses and auxin sensitivity in PG plants may reflect an increased accumulation of OGs and subsequent antagonism of auxin action. Alternatively, it may be a consequence of perturbations of cellular physiology and elevated defense status as a result of altered cell wall architecture. 相似文献
176.
Cinzia Finazzo Jeffrey Harmer Bernhard Jaun Evert C. Duin Felix Mahlert Rudolf K. Thauer Sabine Van Doorslaer Arthur Schweiger 《Journal of biological inorganic chemistry》2003,8(5):586-593
Methyl-coenzyme M reductase (MCR), which catalyses the reduction of methyl-coenzyme M (CH(3)-S-CoM) with coenzyme B (H-S-CoB) to CH(4) and CoM-S-S-CoB, contains the nickel porphinoid F430 as prosthetic group. The active enzyme exhibits the Ni(I)-derived axial EPR signal MCR(red1) both in the absence and presence of the substrates. When the enzyme is competitively inhibited by coenzyme M (HS-CoM) the MCR(red1) signal is partially converted into the rhombic EPR signal MCR(red2). To obtain deeper insight into the geometric and electronic structure of the red2 form, pulse EPR and ENDOR spectroscopy at X- and Q-band microwave frequencies was used. Hyperfine interactions of the four pyrrole nitrogens were determined from ENDOR and HYSCORE data, which revealed two sets of nitrogens with hyperfine couplings differing by about a factor of two. In addition, ENDOR data enabled observation of two nearly isotropic (1)H hyperfine interactions. Both the nitrogen and proton data indicate that the substrate analogue coenzyme M is axially coordinated to Ni(I) in the MCR(red2) state. 相似文献
177.
Gabriella Lania Zhen Zhang Cinzia Caprio Anne M. Moon Antonio Baldini 《Developmental biology》2009,328(1):109-394
The thyroid develops within the pharyngeal apparatus from endodermally-derived cells. The many derivatives of the pharyngeal apparatus develop at similar times and sometimes from common cell types, explaining why many syndromic disorders express multiple birth defects affecting different structures that share a common pharyngeal origin. Thus, different derivatives may share common genetic networks during their development. Tbx1, the major gene associated with DiGeorge syndrome, is a key player in the global development of the pharyngeal apparatus, being required for virtually all its derivatives, including the thyroid. Here we show that Tbx1 regulates the size of the early thyroid primordium through its expression in the adjacent mesoderm. Because Tbx1 regulates the expression of Fgf8 in the mesoderm, we postulated that Fgf8 mediates critical Tbx1-dependent interactions between mesodermal cells and endodermal thyrocyte progenitors. Indeed, conditional ablation of Fgf8 in Tbx1-expressing cells caused an early thyroid phenotype similar to that of Tbx1 mutant mice. In addition, expression of an Fgf8 cDNA in the Tbx1 domain rescued the early size defect of the thyroid primordium in Tbx1 mutants. Thus, we have established that a Tbx1->Fgf8 pathway in the pharyngeal mesoderm is a key size regulator of mammalian thyroid. 相似文献
178.
Most of the ambient dissolved organic carbon (DOC) is refractory to microbial degradation; bacteria can consume a minor but variable part of the DOC pool over periods of hours and days. It is important to increase our knowledge of the dynamics of the biodegradable fraction of DOC (BDOC) to understand the global carbon budget.Several methods for determining BDOC have been developed; however, the problem of most of them is the time (days/weeks) required for the colonization and/or determination.In this paper, we describe the application to seawater of a plug-flow bioreactor to measure BDOC within 3–4 h. The bioreactor was built following Søndergaard and Worm [Søndergaard, M., Worm, J., 2001. Measurement of biodegradable dissolved organic carbon (BDOC) in lake water with a bioreactor. Water Res. 35, 2505-2513.] protocols for the measurement of BDOC in lake water. We analyzed BDOC on samples collected in the Gulf of Trieste during autumn–winter and summer 2003–2004. BDOC concentrations varied from 8 to 24 μM and represented from 10.3% to 25.5% of the total DOC. To evaluate the effectiveness of this method, we compared bioreactor BDOC measurement with data obtained from batch cultures. The results indicate that BDOC in coastal seawater can be measured rapidly and reliably with this bioreactor. 相似文献
179.
The 1-deoxy-d-xylulose 5-phosphate synthase gene co-localizes with a major QTL affecting monoterpene content in grapevine 总被引:2,自引:0,他引:2
Juri Battilana Laura Costantini Francesco Emanuelli Federica Sevini Cinzia Segala Sergio Moser Riccardo Velasco Giuseppe Versini M. Stella Grando 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2009,118(4):653-669
Muscat flavor is a relevant trait both in winemaking and in fresh grape consumption. From a chemical point of view, it is
strongly related to the accumulation of monoterpenes in berries. However, knowledge of the genetic mechanisms underlying its
regulation is still limited. The objective of this study was to dissect the genetic determinism of aroma in grapevine by applying
the analysis of quantitative trait loci (QTL) and the candidate gene (CG) approach. Two F1 segregating progenies were evaluated through high-resolution gas chromatography–mass spectrometry (HRGC–MS) for the amounts
of individual monoterpenes over 3 and 2 years. In the Italia × Big Perlon cross 34 CGs, chosen according to gene ontology
(GO) terms, were placed on a complete map and tested for linkage with QTLs for linalool, nerol and geraniol levels. Two CGs
mapped within a QTL for linalool content on LG 10. A third one co-localized with a major QTL for the level of the three monoterpenes
on LG 5; this gene encodes 1-deoxy-d-xylulose 5-phosphate synthase (DXS), which is the first enzyme in the plastidial pathway of terpene biosynthesis. Depending
on these findings, we report the first in silico analysis of grapevine DXS genes based on the whole genome sequence. Further research on the functional significance of these associations might help
to understand the genetic control of Muscat flavor.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
J. Battilana and L. Costantini equally contributed to the work. 相似文献
180.
Fabrizio Lombardo Raffaele Ronca Cinzia Rizzo Montserrat Mestres-Simòn Alessandra Lanfrancotti Chiara Currà Gabriella Fiorentino Catherine Bourgouin Josè M.C. Ribeiro Vincenzo Petrarca Marta Ponzi Mario Coluzzi Bruno Arcà 《Insect biochemistry and molecular biology》2009,39(7):457-466
The Anopheles gambiae salivary gland protein 6 (gSG6) is a small protein specifically found in the salivary glands of adult female mosquitoes. We report here the expression of a recombinant form of the protein and we show that in vivo gSG6 is expressed in distal-lateral lobes and is secreted with the saliva while the female mosquito probes for feeding. Injection of gSG6 dsRNA into adult A. gambiae females results in decreased gSG6 protein levels, increased probing time and reduced blood feeding ability. gSG6 orthologs have been found so far only in the salivary glands of Anopheles stephensi and Anopheles funestus, both members of the Cellia subgenus. We report here the gSG6 sequence from five additional anophelines, four species of the A. gambiae complex and Anopheles freeborni, a member of the subgenus Anopheles. We conclude that gSG6 plays some essential blood feeding role and was recruited in the anopheline subfamily most probably after the separation of the lineage which gave origin to Cellia and Anopheles subgenera. 相似文献